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As we wait for a vaccine, heres a snapshot of potential COVID-19 treatments – Science News

By daniellenierenberg

Aggressive public health measures tostem the tidal wave of coronavirus infections have left people isolated,unemployed and wondering when it will all end. Life probably wont gocompletely back to normal until vaccines against the virus are available,experts warn.

Researchers are working hard on thatfront. At least six vaccines are currently being tested in people, says EstherKrofah, chief executive of the FasterCures center at the Milken Institute in Washington,D.C. We expect about two dozen more toenter clinical trials by this summer and early fall. That is a huge number,Krofah said at an April 17 briefing. Dozens more are in earlier stages oftesting.

In unpublished, preliminary results of a test of one vaccine, inoculated people made as many antibodies against the coronavirus as people who have recovered from COVID-19 (SN: 5/18/20). The mRNA-based vaccine induces human cells to make one of the viruss proteins, which the immune system then builds antibodies to attack. That study was small, only eight people, but a second phase of safety testing has begun.

But vaccinestake time to test thoroughly (SN: 2/21/20). Even with acceleratedtimelines and talk of emergency use of promising vaccines for health care workersand others at high risk of catching the virus, the general public will likelywait a year or more to be vaccinated.

In the meantime, new treatments may helpsave lives or lessen the severity of disease in people who become ill.Researchers around the world are experimenting with more than 130 drugs to findout if any can help COVID-19 patients, according to atracker maintained by the Milken Institute.

Some of those drugs are aimed atstopping the virus, while others may help calm overactive immune responses thatdamage lungs and other organs. Although researchers are testing a battery ofrepurposed drugs and devising new ones, there is still a great deal ofuncertainty over whether the drugs help, or maybe even hurt.

The wait is frustrating, but theres still much doctors and scientists dont know about how this new coronavirus affects the body. Getting answers will take time, and finding measures to counter the virus that are both safe and effective will take even more. Early results suggest that the antiviral drug remdesivir can modestly speed recovery from COVID-19 (SN: 5/13/20). It is not a cure, but the drug may become the new standard of care as researchers continue to test other therapies.

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Antiviral drugs interfere with a viruss ability to replicate itself, though such drugs are difficult to create. Remdesivir is being tested in half a dozen clinical trials worldwide. The drug mimics a building block of RNA, the genetic material of the coronavirus (SN: 3/10/20). When the virus copies its RNA, remdesivir replaces some of the building blocks, preventing new virus copies from being produced, laboratory studies have shown.

Early results in COVID-19 patients given the drug outside of a clinical trial showed that 68 percent needed less oxygen support after treatment, as reported online April 10 in the New England Journal of Medicine (SN: 4/29/20). The drug went to very sick patients, including those who needed oxygen from a ventilator or through tubes in the nose. Other researchers have disputed those results, questioning the study methods and statistical analyses, which may have given an exaggerated impression of good outcomes. The studys authors say they have reanalyzed the data and still conclude that remdesivir has benefits.

Soon after, the U.S. National Instituteof Allergy and Infectious Diseases announced that hospitalized patients withCOVID-19 who got intravenous remdesivir recoveredmore quickly than those on a placebo: in 11 days versus 15. Those findingshad not been reviewed by other scientists at the time of the announcement. Thedug provides researchers with a baseline for comparing other treatments. Wethink its really opening the door to the fact that we now have the capabilityof treating, Anthony Fauci, director of the NIAID said April 29 in a newsbriefing at the White House.

Antiviral medications used against HIV are also being tested against COVID-19. The combination of lopinavir and ritonavir stops an HIV enzyme called the M protease from cutting viral proteins so that the virus can replicate itself. The SARS-CoV-2 virus produces a similar enzyme. But early results from a small study in China showed that the combination didnt stop viral replication or improve symptoms (SN: 3/19/20), and there were side effects.

For now, the Society of Critical CareMedicine recommendsagainst using the drugs, and the Infectious Diseases Society of Americasays patients should get the drugs onlyas part of a clinical trial. Several large trials may report results soon.

The HIV drugs may not work well against SARS-CoV-2, even though the viruses have similar M proteases: The coronaviruss enzyme lacks a pocket where the drugs fit in the HIV version of the enzyme.

This illustrates why antiviral drugs areso difficult to develop. Designing a drug requires knowing the 3-D structure ofthe viruss proteins, which can take months to years. But researchers arealready getting some close-up views of the new coronavirus. A team in Chinaexamined the structure of the coronaviruss M protease and designed smallmolecules that could block a part of the protein necessary to do its job. Theteam describedtwo such molecules, dubbed 11a and 11b, April 22 in Science.

In test tubes, both molecules stopped the virus from replicating in monkey cells. In mice, 11a stuck around longer in the blood than 11b, so the researchers tested 11a further and found it seemed safe in rats and beagles. More animal tests will probably be needed to show whether it stops the virus, then multiple stages of human tests will have to follow. The drug development and testing process often takes on average 10 years or more, and can fail at any point along the way.

Meanwhile, hundreds of thousands of people worldwide have already recovered from COVID-19, and many are donating blood that might contain virus-fighting antibodies. Clinical trials are under way to test whether antibodies from recovered patients blood plasma can help people fight off the virus (SN: 4/25/20, p. 6). More such trials are planned.

Stopping the virus is only half the problem. In some people seriously ill with COVID-19, their immune system becomes the enemy, unleashing storms of immune chemicals called cytokines. Those cytokines trigger immune cells to join the fight against the virus, but sometimes the cells go too far, causing damaging inflammation.

Some of the drugs used to calm cytokines in cancer patients (SN: 6/27/18, p. 22) may also help people with COVID-19 ride out the storm, says cancer researcher Lee Greenberger, chief scientific officer of Leukemia and Lymphoma Society. Several of those drugs are being tested against the coronavirus now.

Hydroxychloroquine, a drug approved totreat autoimmune disorders such as lupus and rheumatoid arthritis, became ahousehold word after President Trump touted it as a possible COVID-19treatment.

The drug is being tested in numerouslarge clinical trials around the world to see if it might help calm cytokinestorms in COVID-19 patients as well. But so far, there is no solid evidence thatit works either to prevent infection in people or to treat people who alreadyhave the disease.

And in some studies the drug has caused serious side effects, including causing irregular heartbeats, says Raymond Woosley, a pharmacologist at the University of Arizona College of Medicine in Phoenix. People with heart problems, low potassium or low oxygen levels in their blood are at higher risk of these side effects, he says. And those are exactly the kinds of patients who are most vulnerable to COVID-19. So, the very sickest COVID patients are those at most risk for these life-threatening arrhythmias and cardiac effects.

Results of some rigorous clinical trialsof hydroxychloroquine are expected this summer. Meanwhile, the U.S. Food andDrug Administration allows the drug to be used when no other treatment isavailable and patients cant join a clinical trial.

Todays enthusiasm for any drug thatseems promising feels familiar, says Woosley. He remembers the excitement overAZT, the first drug used to fight HIV in the 1980s. It wasnt the best drug tocombat the AIDS epidemic, and better ones came later. Likewise, the firsttreatments for COVID-19 might be better than nothing, but not the best we willultimately get.

Meanwhile, we wait.

With hundreds of clinical trials going on around the world, some answers may come soon. But for now, keeping the coronavirus contained will probably require aggressive testing, tracing and isolating contacts of people who have the virus and continued social distancing.

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Harvard and the Brigham call for 31 retractions of cardiac …

By daniellenierenberg

Harvard Medical School and Brigham and Womens Hospital have recommended that 31 papers from a former lab director be retracted from medical journals.

The papers from the lab of Dr. Piero Anversa, who studied cardiac stem cells, included falsified and/or fabricated data, according to a statement to Retraction Watch and STAT from the two institutions.

Last year, the hospital agreed to a $10 million settlement with the U.S. government over allegations Anversa and two colleagues work had been used to fraudulently obtain federal funding. Anversa and Dr. Annarosa Leri who have had at least one paper already retracted, and one subject to an expression of concern had at one point sued Harvard and the Brigham unsuccessfully for alerting journals to problems in their work back in 2014. Anversas lab closed in 2015; Anversa, Leri, and their colleagueDr. Jan Kajstura no longer work at the hospital.

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While the Brighamsettled with the U.S. Department of Justice, the U.S. Office of Research Integrity, which oversees research misconduct investigations involving National Institutes of Health funding, has not made a finding in the case. The university and the hospital have not said which journals the 31 papers appeared in, but the journal Circulation retracted a paper by Anversa and colleagues in 2014, and The Lancet issued an expression of concern about another in the same year.

It is not clear how, or whether, the call for retractions by Harvard and the Brigham is related to the Brighams settlement with the government.

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Following a review of research conducted in the former lab of Piero Anversa, we determined that 31 publications included falsified and/or fabricated data, and we have notified all relevant journals, Harvard and the Brigham told STAT and Retraction Watch.

Anversa has previously corrected eight of his papers, many for failures to disclose conflicts of interest. He practically invented the field of cardiac stem cell therapy when he first reported that cardiac cells were capable of regeneration, Cardiobrief and MedPage Today wrote about him last year.

Anversas work was based on the idea that the heart contains stem cells that could regenerate cardiac muscle. He and his colleagues claimed that they had identified such cells, known as c-kit cells. When various research teams tried to reproduce the results, however, they failed. Still, some scientists have tried to inject c-kit cells into damaged hearts, with mixed results at best.

For 10 years, he ran everything, said Jeffery Molkentin, a researcher at Cincinnati Childrens whose lab was among the first to question the basis of Anversas results in a 2014 paper in Nature. It really is a relief that this has been corrected. I think this is good for everybody.

For the most part, the field has already worked this in, Molkentin told STAT and Retraction Watch. Its like when Wall Street has worked in the next two interest rate hikes.

There are no stem cells in the heart. Quit trying to publish those results.

Jeffery Molkentin, Cincinnati Children's

Still, he said, a small number of researchers continue to publish findings that agree with Anversas. Maybe these 31 retractions will keep pushing the pendulum a little further to the right and these people will slowly start to back off even more, he said.

Its just discouraging when you see these papers keep popping up, Molkentin said. There are no stem cells in the heart. Quit trying to publish those results.

Anversa published at least 55 papers that listed Harvard as an affiliation. In 2014, a former research fellow described an atmosphere of fear and information control in his lab.

Anversa, who according to publications was most recently affiliated with the Cardiocentro Ticino and University of Zurich, could not be reached for comment. An email to his address at Cardiocentro Ticino bounced back. A number of Anversas co-authors either did not immediately respond to a request for comment, or declined.

We are committed to upholding the highest ethical standards and to rigorously maintaining the integrity of our research, Harvard and the Brigham said. Any concerns brought to our attention are reviewed in accordance with institutional policies and applicable regulations.

Anversa was born in Parma, Italy, in 1940 and received his medical degree from the University of Parma in 1965. He gained prominence as a stem-cell researcher at New York Medical College in Valhalla, N.Y., where he worked before moving to Harvard Medical School and the Brigham in 2007. Anversa became a full professor in 2010.

Throughout his career, Anversa has received several commendations, including a research achievement award from the American Heart Association, which in 2004 also named him a distinguished scientist.

Although journals often act on retraction recommendations by universities, they do not always do so, and it sometimes takes a while. Journals retract roughly 1,400 scholarly papers each year, out of some 3 million total publications.Anversas total would put him in the top 20 list of scientists with the most retractions in the world. The 10 scientists worldwide with the most retracted papers have at least 39, and in one case Japanese anesthesiologist Yoshitaka Fujii 183 such articles.

So what do the calls for retraction mean for cardiology?

What seems obvious to me is a need for transparency, Yale cardiologist Dr. Harlan Krumholz told STAT and Retraction Watch. The scientific community needs to know what was found, why papers were retracted, and what is recommended with regard to his work going forward. Also, what has happened to work that was based on his work. Without this knowledge it is hard to know what it means.

Some of Anversas work has already been retracted or corrected.

Suzanne Grant, a spokeswoman for the American Heart Association/American Stroke Association, said that one 2012 paper published in the journal Circulation and co-authored by Anversa was retracted in 2014. The AHA has corrected a number of other Anversa papers, mostly by adding additional disclosures.

Grant said the AHA was evaluating Harvards findings and would again take appropriate action if needed.

Harvard also flagged two Anversa papers one from 2001 and the other from 2011 to the New England Journal of Medicine, and the publication is separately investigating images published in a 2002 paper, spokeswoman Jennifer Zeis said.

Seil Collins, a spokesman for the Lancet journals, said the publication group was investigating the 2011 paper that had already been tagged with an expression of concern after receiving new information from Harvard.

This story is a collaboration between STAT andRetraction Watch. It has been updated with information from some journals. Reporter Andrew Joseph contributed.

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cardiac disease and stem cells | Stem Cell Treatment in …

By daniellenierenberg

Despite many breakthroughs in cardiovascular treatment, heart attacks and heart failure still pose a very large threat to the American population. The largest challenge in patients who have had a cardiac complication is the restoration of function to the damaged heart. Since damaged heart tissue is very difficult for the body to replace, physicians are continually looking for new methods of treating the heart.

Regenerative treatment through the use of stem cells is showing a large amount of potential at not only helping reverse the resulting damage of a cardiac attack, but in actually re-growing the damaged tissue in order to restore function.

To understand what stem cells can potentially do for the heart, it is important to first understand the different heart cells that can be damaged in a cardiac event. Destruction of the heart muscle cells, called cardiomyocytes, is the primary cause behind loss of function in a damaged heart. These cells are the muscle behind heart contraction, which sends blood to the rest of the body.

Secondly, vascular endothelial cells (inner lining of blood vessels) and smooth muscle cells (outer lining of blood vessels) each play an important role in the formation of new arteries. These serve to draw nutrients and oxygen to the remaining cardiomyocytes following heart damage, directly influencing the capabilities of a damaged heart.

Numerous studies are being conducted into the purposing of stem cells this manner, with one study providing evidence that bone marrow stem cells were able to develop into the required myocardial cells in mice. The ability to develop human hematopoietic stem cells for heart muscle is already documented technique, with the method of application into humans and the results of implantation still under study.

The research currently being performed on stem cells for cardiac treatment is focused on developing known stem cell traits into a working cure for cardiac complications. The current hurdles researchers face include how to best expand stem cells injected into the heart, how to best deliver the cells, and how to discover new niches (groupings) of stem cells in the body.

Delivery: Current methods of delivery include generic IV injection, which is minimally invasive with varying degrees of success. The most dependable method is to have direct injection into the heart, which requires surgery for visualization. Complications may include potentially clogging the arteries with the introduced stem cells and the invasiveness of the surgery.

Expanding Stem Cells: The majority of transplanted stem cells fail to reach the area of damage. It is crucial for a physician to be able to accurately deliver a large amount of stem cells to offer the patient the best treatment. Methods of better stem cell isolation, identification, and expansion into tissue are currently being developed.

Physician First Choice offers stem cell therapy for cardiac disease. The clinic has multiple stem cell doctors with extensive experience in stem cell therapy for numerous conditions. The stem cell clinic sees patients from all over California and the country, providing both IV stem cell therapy and injections into arthritic joints and areas with tendonitis and ligament injury.

Call (888) 988-0515 for more information and scheduling today!

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Progenitor Cell Product Market 2020| Worldwide Industry Share, Size, Gross Margin, Trend, Future Demand, Analysis by Top Leading Player and Forecast…

By daniellenierenberg

The report on the global Progenitor Cell Product market is comprehensively prepared with main focus on the competitive landscape, geographical growth, segmentation, and market dynamics, including drivers, restraints, and opportunities. It sheds light on key production, revenue, and consumption trends so that players could improve their sales and growth in the GlobalProgenitor Cell Product Market.It brings to light key factors affecting the growth of different segments and regions in the global Progenitor Cell Product market. It also offers SWOT, Porters Five Forces, and PESTLE analysis to thoroughly examine the global Progenitor Cell Product market.It offers a detailed analysis of the competition and leading companies of the global Progenitor Cell Product market. Here, it concentrates on the recent developments, sales, market value, production, gross margin, and other important factors of the business of top players operating in the global Progenitor Cell Product market.

Key companies operating in the global Progenitor Cell Product market include:NeuroNova AB, StemCells, ReNeuron Limited, Asterias Biotherapeutics, Thermo Fisher Scientific, STEMCELL Technologies, Axol Bio, R&D Systems, Lonza, ATCC, Irvine Scientific, CDI

Get PDF Sample Copy of the Report to understand the structure of the complete report: (Including Full TOC, List of Tables & Figures, Chart) :

https://www.qyresearch.com/sample-form/form/1412432/global-progenitor-cell-product-market

With deep quantitative and qualitative analysis, the report provides encyclopedic and accurate research study on important aspects of the global Progenitor Cell Product market. It gives a detailed study on manufacturing cost, upstream and downstream buyers, distributors, marketing strategy, and marketing channel development trends of the global Progenitor Cell Product market. Furthermore, it provides strategic bits of advice and recommendations for players to ensure success in the global Progenitor Cell Product market.

Segmental Analysis

The report has classified the global Progenitor Cell Product industry into segments including product type and application. Every segment is evaluated based on growth rate and share. Besides, the analysts have studied the potential regions that may prove rewarding for the Progenitor Cell Product manufcaturers in the coming years. The regional analysis includes reliable predictions on value and volume, thereby helping market players to gain deep insights into the overall Progenitor Cell Product industry.

Global Progenitor Cell Product Market Segment By Type:

, Pancreatic progenitor cells, Cardiac Progenitor Cells, Intermediate progenitor cells, Neural progenitor cells (NPCs), Endothelial progenitor cells (EPC), Others

Global Progenitor Cell Product Market Segment By Application:

Progenitor Cell Product

Competitive Landscape

It is important for every market participant to be familiar with the competitive scenario in the global Progenitor Cell Product industry. In order to fulfil the requirements, the industry analysts have evaluated the strategic activities of the competitors to help the key players strengthen their foothold in the market and increase their competitiveness.

Key companies operating in the global Progenitor Cell Product market includeNeuroNova AB, StemCells, ReNeuron Limited, Asterias Biotherapeutics, Thermo Fisher Scientific, STEMCELL Technologies, Axol Bio, R&D Systems, Lonza, ATCC, Irvine Scientific, CDI

Regions and Countries

The Middle East and Africa(GCC Countries and Egypt)North America(the United States, Mexico, and Canada)South America(Brazil etc.)Europe(Turkey, Germany, Russia UK, Italy, France, etc.)Asia-Pacific(Vietnam, China, Malaysia, Japan, Philippines, Korea, Thailand, India, Indonesia, and Australia)

Key Questions Answered

What is the size and CAGR of the global Progenitor Cell Product market?

Which are the leading segments of the global Progenitor Cell Product market?

What are the key driving factors of the most profitable regional market?

What is the nature of competition in the global Progenitor Cell Product market?

How will the global Progenitor Cell Product market advance in the coming years?

What are the main strategies adopted in the global Progenitor Cell Product market?

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Table of Contents

Table of Contents 1 Progenitor Cell Product Market Overview1.1 Progenitor Cell Product Product Overview1.2 Progenitor Cell Product Market Segment by Type1.2.1 Pancreatic progenitor cells1.2.2 Cardiac Progenitor Cells1.2.3 Intermediate progenitor cells1.2.4 Neural progenitor cells (NPCs)1.2.5 Endothelial progenitor cells (EPC)1.2.6 Others1.3 Global Progenitor Cell Product Market Size by Type1.3.1 Global Progenitor Cell Product Sales and Growth by Type1.3.2 Global Progenitor Cell Product Sales and Market Share by Type1.3.3 Global Progenitor Cell Product Revenue and Market Share by Type1.3.4 Global Progenitor Cell Product Price by Type1.4 North America Progenitor Cell Product by Type1.5 Europe Progenitor Cell Product by Type1.6 South America Progenitor Cell Product by Type1.7 Middle East and Africa Progenitor Cell Product by Type 2 Global Progenitor Cell Product Market Competition by Company2.1 Global Progenitor Cell Product Sales and Market Share by Company (2014-2019)2.2 Global Progenitor Cell Product Revenue and Share by Company (2014-2019)2.3 Global Progenitor Cell Product Price by Company (2014-2019)2.4 Global Top Players Progenitor Cell Product Manufacturing Base Distribution, Sales Area, Product Types2.5 Progenitor Cell Product Market Competitive Situation and Trends2.5.1 Progenitor Cell Product Market Concentration Rate2.5.2 Global Progenitor Cell Product Market Share of Top 5 and Top 10 Players2.5.3 Mergers & Acquisitions, Expansion 3 Progenitor Cell Product Company Profiles and Sales Data3.1 NeuroNova AB3.1.1 Company Basic Information, Manufacturing Base and Competitors3.1.2 Progenitor Cell Product Product Category, Application and Specification3.1.3 NeuroNova AB Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.1.4 Main Business Overview3.2 StemCells3.2.1 Company Basic Information, Manufacturing Base and Competitors3.2.2 Progenitor Cell Product Product Category, Application and Specification3.2.3 StemCells Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.2.4 Main Business Overview3.3 ReNeuron Limited3.3.1 Company Basic Information, Manufacturing Base and Competitors3.3.2 Progenitor Cell Product Product Category, Application and Specification3.3.3 ReNeuron Limited Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.3.4 Main Business Overview3.4 Asterias Biotherapeutics3.4.1 Company Basic Information, Manufacturing Base and Competitors3.4.2 Progenitor Cell Product Product Category, Application and Specification3.4.3 Asterias Biotherapeutics Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.4.4 Main Business Overview3.5 Thermo Fisher Scientific3.5.1 Company Basic Information, Manufacturing Base and Competitors3.5.2 Progenitor Cell Product Product Category, Application and Specification3.5.3 Thermo Fisher Scientific Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.5.4 Main Business Overview3.6 STEMCELL Technologies3.6.1 Company Basic Information, Manufacturing Base and Competitors3.6.2 Progenitor Cell Product Product Category, Application and Specification3.6.3 STEMCELL Technologies Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.6.4 Main Business Overview3.7 Axol Bio3.7.1 Company Basic Information, Manufacturing Base and Competitors3.7.2 Progenitor Cell Product Product Category, Application and Specification3.7.3 Axol Bio Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.7.4 Main Business Overview3.8 R&D Systems3.8.1 Company Basic Information, Manufacturing Base and Competitors3.8.2 Progenitor Cell Product Product Category, Application and Specification3.8.3 R&D Systems Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.8.4 Main Business Overview3.9 Lonza3.9.1 Company Basic Information, Manufacturing Base and Competitors3.9.2 Progenitor Cell Product Product Category, Application and Specification3.9.3 Lonza Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.9.4 Main Business Overview3.10 ATCC3.10.1 Company Basic Information, Manufacturing Base and Competitors3.10.2 Progenitor Cell Product Product Category, Application and Specification3.10.3 ATCC Progenitor Cell Product Sales, Revenue, Price and Gross Margin(2014-2019)3.10.4 Main Business Overview3.11 Irvine Scientific3.12 CDI 4 Progenitor Cell Product Market Status and Outlook by Regions4.1 Global Progenitor Cell Product Market Status and Outlook by Regions4.1.1 Global Progenitor Cell Product Market Size and CAGR by Regions4.1.2 North America4.1.3 Europe4.1.4 Asia-Pacific4.1.5 South America4.1.6 Middle East and Africa4.2 Global Progenitor Cell Product Sales and Revenue by Regions4.2.1 Global Progenitor Cell Product Sales Market Share by Regions (2014-2019)4.2.2 Global Progenitor Cell Product Revenue Market Share by Regions (2014-2019)4.2.3 Global Progenitor Cell Product Sales, Revenue, Price and Gross Margin (2014-2019)4.3 North America Progenitor Cell Product Sales, Revenue, Price and Gross Margin4.3.1 North America Progenitor Cell Product Sales by Countries4.3.2 United States4.3.3 Canada4.3.4 Mexico4.4 Europe Progenitor Cell Product Sales, Revenue, Price and Gross Margin4.4.1 Europe Progenitor Cell Product Sales by Countries4.4.2 Germany4.4.3 France4.4.4 UK4.4.5 Italy4.4.6 Russia4.5 Asia-Pacific Progenitor Cell Product Sales, Revenue, Price and Gross Margin4.5.1 Asia-Pacific Progenitor Cell Product Sales by Regions4.5.2 China4.5.3 Japan4.5.4 South Korea4.5.5 India4.5.6 Australia4.5.7 Indonesia4.5.8 Thailand4.5.9 Malaysia4.5.10 Philippines4.5.11 Vietnam4.6 South America Progenitor Cell Product Sales, Revenue, Price and Gross Margin4.6.1 South America Progenitor Cell Product Sales by Countries4.6.2 Brazil4.7 Middle East and Africa Progenitor Cell Product Sales, Revenue, Price and Gross Margin4.7.1 Middle East and Africa Progenitor Cell Product Sales by Countries4.7.2 Turkey4.7.3 GCC Countries4.7.4 Egypt4.7.5 South Africa 5 Progenitor Cell Product Application5.1 Progenitor Cell Product Segment by Application5.1.1 Medical care5.1.2 Hospital5.1.3 Laboratory5.2 Global Progenitor Cell Product Product Segment by Application5.2.1 Global Progenitor Cell Product Sales by Application5.2.2 Global Progenitor Cell Product Sales and Market Share by Application (2014-2019)5.3 North America Progenitor Cell Product by Application5.4 Europe Progenitor Cell Product by Application5.5 Asia-Pacific Progenitor Cell Product by Application5.6 South America Progenitor Cell Product by Application5.7 Middle East and Africa Progenitor Cell Product by Application 6 Global Progenitor Cell Product Market Forecast6.1 Global Progenitor Cell Product Sales, Revenue Forecast (2019-2025)6.1.1 Global Progenitor Cell Product Sales and Growth Rate Forecast (2019-2025)6.1.2 Global Progenitor Cell Product Revenue and Growth Rate Forecast (2019-2025)6.2 Global Progenitor Cell Product Forecast by Regions6.2.1 North America Progenitor Cell Product Sales and Revenue Forecast (2019-2025)6.2.2 Europe Progenitor Cell Product Sales and Revenue Forecast (2019-2025)6.2.3 Asia-Pacific Progenitor Cell Product Sales and Revenue Forecast (2019-2025)6.2.4 South America Progenitor Cell Product Sales and Revenue Forecast (2019-2025)6.2.5 Middle East and Africa Progenitor Cell Product Sales and Revenue Forecast (2019-2025)6.3 Progenitor Cell Product Forecast by Type6.3.1 Global Progenitor Cell Product Sales and Revenue Forecast by Type (2019-2025)6.3.2 Pancreatic progenitor cells Growth Forecast6.3.3 Cardiac Progenitor Cells Growth Forecast6.4 Progenitor Cell Product Forecast by Application6.4.1 Global Progenitor Cell Product Sales Forecast by Application (2019-2025)6.4.2 Global Progenitor Cell Product Forecast in Medical care6.4.3 Global Progenitor Cell Product Forecast in Hospital 7 Progenitor Cell Product Upstream Raw Materials7.1 Progenitor Cell Product Key Raw Materials7.1.1 Key Raw Materials7.1.2 Key Raw Materials Price7.1.3 Raw Materials Key Suppliers7.2 Manufacturing Cost Structure7.2.1 Raw Materials7.2.2 Labor Cost7.2.3 Manufacturing Expenses7.3 Progenitor Cell Product Industrial Chain Analysis 8 Marketing Strategy Analysis, Distributors8.1 Sales Channel8.2 Distributors8.3 Downstream Customers 9 Research Findings and Conclusion 10 Appendix10.1 Methodology/Research Approach10.1.1 Research Programs/Design10.1.2 Market Size Estimation10.1.3 Market Breakdown and Data Triangulation10.2 Data Source10.2.1 Secondary Sources10.2.2 Primary Sources10.3 Author List10.4 Disclaimer

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Seattle Genetics Highlights Data from Expanding Oncology Portfolio During Virtual Scientific Program of the 2020 ASCO Annual Meeting – BioSpace

By daniellenierenberg

Over the past six months, we have been able to deliver on our promise of bringing important new medicines to certain patients with HER2-positive metastatic breast cancer and metastatic urothelial cancer through two U.S. FDA approvals, said Clay Siegall, Ph.D., Chief Executive Officer at Seattle Genetics. We look forward to sharing data in the ASCO virtual scientific program that reinforce our ability to rapidly advance novel targeted agents across multiple tumor types.

An Expanding Portfolio of Marketed Therapies

Key data presentations will showcase progress for certain patients with HER2-positive metastatic breast cancer and metastatic urothelial cancer as well as for patients with classical Hodgkin lymphoma (HL). Highlights include:

TUKYSA Update in Patients with Brain Metastases

Results for TUKYSA in combination with trastuzumab and capecitabine in patients with brain metastases from the HER2CLIMB pivotal trial of previously treated patients with HER2-positive metastatic breast cancer will be featured in an oral session (Abstract #1005). Data will be presented from these exploratory analyses on findings from the TUKYSA arm of the study on reduction in the risk of death (OS), reduction in the risk of intracranial progression or death (CNS-PFS) and improvement of the intracranial confirmed objective response rate (ORR-IC) compared to trastuzumab and capecitabine. Data will be presented by Nancy U. Lin, Director of the Metastatic Breast Cancer Program in the Susan F. Smith Center for Womens Cancers at Dana-Farber in Boston, MA, during an oral presentation available on demand at 8:00 a.m. ET on May 29, 2020. A separate analysis of adverse events (AE) from the same trial will be presented (AbstractГ poster presentation).

PADCEV (enfortumab vedotin-ejfv) in Combination and in Other Solid Tumors

Additional results and durability data from the phase 1b EV-103 trial of PADCEV plus pembrolizumab in first-line metastatic urothelial cancer will be presented (Abstract #5044), and a separate Trials-in-Progress poster will provide details about a new randomized cohort added to the EV-103 study, Cohort K, which is evaluating PADCEV as monotherapy or in combination with pembrolizumab (#TPS5092). Both presentations will be featured in the Genitourinary CancerKidney and Bladder session. Data from the Cohort K, along with other data from the EV-103 trial evaluating PADCEV combined with pembrolizumab as first-line therapy for cisplatin-ineligible patients, could potentially support registration under accelerated approval regulations in the United States.

Additionally, information about the phase 2 EV-202 trial, which is studying PADCEV in six different types of locally advanced and metastatic solid tumors (HR-positive/HER2-negative and triple-negative breast cancers, squamous and non-squamous non-small cell lung cancers, head and neck cancer and gastroesophageal cancers), will be discussed in a Trials-in-Progress poster during the Developmental Therapeutics Molecularly Targeted Agents and Tumor Biology Poster Session (Abstracts #TPS3647).

ADCETRIS (brentuximab vedotin) Continues to Advance

Data to be presented on ADCETRIS will demonstrate the companys progress in efforts to continue expanding clinical research on combination regimens and monotherapy in a variety of HL and peripheral T-cell lymphoma (PTCL) patient populations, including in both older and younger disease settings. A poster presentation will highlight the potential of ADCETRIS in combination with nivolumab or dacarbazine and as a monotherapy for previously untreated older HL patients who typically have poorer outcomes than younger patients due to comorbidities and toxicities related to standard first-line chemotherapy (Abstract #8032). The primary analysis from an ongoing clinical trial evaluating ADCETRIS plus nivolumab in children, adolescents and young adults with standard-risk relapsed or refractory classical HL will also be presented (AbstractὍ poster discussion). Lastly, two Trials-in-Progress poster presentations will highlight ongoing clinical trials evaluating ADCETRIS as a monotherapy in frontline older HL or CD30-expressing PTCL patients and in a combination regimen in frontline advanced-stage HL patients (Abstracts #TPS8069 and #TPS8068).

A Strong, Diverse Pipeline of Investigational Therapies

An additional four Trials-in-Progress posters for investigational therapies will showcase the companys continued clinical development of pipeline candidates in first-line cervical cancer (Abstract #TPS6095), metastatic breast cancer (Abstract #TPS1104), metastatic pancreatic ductal adenocarcinoma (PDAC) (Abstract #TPS4671) and other solid tumors (Abstract #TPS3652).

The abstracts published in advance of the ASCO meeting were made available today on the ASCO website. All data presentations will be available on-demand on May 29, 2020.

Details of Key Seattle Genetics Presentations at ASCO20 Virtual:

Abstract Title

Abstract #

Presentation Type

Presenter

ADCETRIS (brentuximab vedotin)

Nivolumab and brentuximab vedotin (BV)-based, responseadapted treatment in children, adolescents, and young adults (CAYA) with standard-risk relapsed/refractory classical Hodgkin lymphoma (R/R cHL): Primary analysis

8013

Poster discussion

P. Cole

Frontline Brentuximab Vedotin as Monotherapy or in Combination for Older Hodgkin Lymphoma Patients

8032

Poster presentation

C. Yasenchak

PADCEV (enfortumab vedotin-ejfv)

Study EV-103: Durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma

5044

Poster presentation

J. Rosenberg

TUKYSA (tucatinib)

Tucatinib vs Placebo Added to Trastuzumab and Capecitabine for Patients with Previously Treated HER2+ Metastatic Breast Cancer with Brain Metastases (HER2CLIMB)

1005

Oral presentation

N. Lin

Management of adverse events in patients with HER2+ metastatic breast cancer treated with tucatinib, trastuzumab, and capecitabine (HER2CLIMB)

1043

Poster presentation

A. Okines

Trials-in-Progress

ADCETRIS (brentuximab vedotin)

Frontline brentuximab vedotin in Hodgkin lymphoma and CD30-expressing peripheral T-cell lymphoma for older patients and those with comorbidities

TPS8069

Poster presentation

C. Yasenchak

Brentuximab Vedotin in Combination with Nivolumab, Doxorubucin, and Dacarbazine in Newly Diagnosed Patients with Advanced Stage Hodgkin Lymphoma

TPS8068

Poster presentation

J. Friedman

PADCEV (enfortumab vedotin-ejfv)

Study EV-103: New randomized cohort testing enfortumab vedotin as monotherapy or in combination with pembrolizumab for locally advanced or metastatic urothelial carcinoma

TPS5092

Poster presentation

N. Mar

EV-202: A Phase 2 Study of Enfortumab Vedotin in Patients With Select Previously Treated Locally Advanced or Metastatic Solid Tumors

TPS3647

Poster presentation

J. Bruce

Investigational Therapies

Phase 1b/2 trial of tisotumab vedotin (TV) bevacizumab (BEV), pembrolizumab (PEM), or carboplatin (CBP) in recurrent or metastatic cervical cancer (innovaTV 205/ENGOT-cx8/GOG-3024)

TPS6095

Poster presentation

I. Vergote

SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer

TPS1104

Poster presentation

H. Beckwith

SGN228-001: A phase 1 open-label dose escalation and expansion study of SGN-CD228A in select advanced solid tumors

TPS3652

Poster presentation

A. Patnik

Phase 1 study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients (pts) with metastatic pancreatic ductal adenocarcinoma (PDAC)

TPS4671

Poster presentation

A. Coveler

About ADCETRIS (brentuximab vedotin)

ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seattle Genetics proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells. Seattle Genetics and Takeda are jointly developing ADCETRIS.

About PADCEV (enfortumab vedotin-ejfv)

PADCEV is an antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis). PADCEV is co-developed by Seattle Genetics and Astellas.

About TUKYSA (tucatinib)

TUKYSA is an oral medicine that is a tyrosine kinase inhibitor of the HER2 protein. In vitro (in lab studies), TUKYSA inhibited phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell growth (proliferation), and showed anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibited the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either medicine alone.

ADCETRIS (brentuximab vedotin) U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Administer G-CSF primary prophylaxis beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Most Common (20% in any study) Adverse Reactions

Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

Excerpt from:
Seattle Genetics Highlights Data from Expanding Oncology Portfolio During Virtual Scientific Program of the 2020 ASCO Annual Meeting - BioSpace

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Cardio Stem Cell Therapy Used to Treat Critically Ill Covid-19 Patients – Physician’s Weekly

By daniellenierenberg

Four of six patients in case series were weaned off respiratory support

An investigational allogeneic cell therapy using cardiosphere-derived cells (CDC) showed an acceptable safety profile with early evidence of efficacy in the treatment of very severe Covid-19 in a case series involving six patients treated at Cedars-Sinai Medical Center in Los Angeles.

All six patients treated with the intravenous allogeneic CDC formulation CAP-1002 (Capricor Therapeutics) as a compassionate therapy required respiratory support prior to treatment, with five on mechanical ventilation.

No adverse events related to the treatment were reported, and four of the six patients were successfully weaned from respiratory support and were discharged from the hospital as of late April.

The other two patients are still alive, but remain intubated, Cedars-Sinai cardiologist Raj Makkar, MD, confirmed to BreakingMED Wednesday, May 13.

While we are encouraged by these findings, it is important to point out that the only way that we can assess the efficacy of this treatment in a definitive way is with a randomized clinical trial, and that is what we intend to do, Makkar said.

He added that the clinical trial, which is in the planning stages, is likely to include Covid-19 patients who are not as critically ill as the six in the case series.

All of these patients required respiratory support and they were all on a downward trajectory when treated, he said. They were getting worse and we had nothing else to offer them.

Cardiosphere-derived cells are stromal/progenitor cells from heart tissue with a distinctive antigenic profile (CD105+, CD45-, CD90low).

In their case series, published in the journal Basic Research in Cardiology, Makkar and colleagues noted that the cells are entirely distinct from the controversial c-kit+ putative cardiac progenitors, which have been the subject of various retracted studies.

Since CDCs were first isolated in 2007, the cells have been tested in more than 200 patients in clinical trials for a variety of conditions with a good safety profile, including in young boys with Duchenne muscular dystrophy.

Makkar said the anti-inflammatory and antifibrotic properties of CDCs in animal models make them a possible target therapy for Covid-19.

The prior testing gave us reasonable confidence that this treatment was safe, he said, adding that there is also evidence of a favorable effect on the same type of proinflammatory cytokines that are up-regulated in Covid-19.

Comparisons to mesenchymal stem cells (MSCs) in pre-clinical models suggest that CDCs may also be more effective for paracrine factor secretion and myocardial remodeling.

Given the safety record of CDCs in humans, and the substantial body of evidence confirming relevant disease-modifying bioactivity, applicability to Covid-19 seemed compelling, particularly in the hyperinflammatory stage of the illness, the researchers wrote.

All six patients treated with the intravenous CDC formulation had severe, confirmed Covid-19 with respiratory failure and they were not receiving any other experimental agent, with the exception of hydroxychloroquine and tocilizumab.

Lack of clinical improvement or deterioration despite standard care was the primary reason for considering patients for treatment with CAP-1002. Exclusion criteria included known hypersensitivity to DMSO, which is a component of CAP-1002; prior stem cell therapy; pre-existing terminal illness; and need for mechanical circulatory support and dialysis.

In general, patients with multi-organ failure who were deemed to be too sick for any intervention were excluded from the study, Makkar and colleagues wrote.

All patients had acute respiratory distress syndrome (ARDS) prior to infusion, with decreased PaO2/FiO2 ratios (range 69-198; median 142), diffuse bilateral pulmonary infiltrates on chest imaging and evidence of preserved cardiac function on transthoracic echocardiography (LVEF range, 50-75%). SOFA scores ranged from 2 to 8 prior to stem cell treatment.

The six patients (age range, 19-75 years) had IV infusions of CAP-1002 containing 150 million allogeneic CDCs, and two of the six had a second dose of the treatment.

Following treatment, four patients (67%) were weaned from respiratory support and discharged from the hospital.

A contemporaneous control group of critically ill Covid-19 patients (n = 34) at our institution showed 18% overall mortality at a similar stage of hospitalization, the researchers wrote.

Ferritin was elevated in all patients at baseline (range of all patients 605.43-2991.52 ng/ml) and decreased in five of the six patients (range of all patients 252.891029.90 ng/ml).

Absolute lymphocyte counts were low in five of the six patients at baseline (range 0.260.82 103/l) but had increased in 3 of these five at last follow-up (range 0.231.02 103/l).

Administration of CAP-1002 as a compassionate therapy for patients with severe Covid-19 and significant comorbidities was safe, well tolerated without serious adverse events, and associated with clinical improvement, as evidenced by extubation (or prevention of intubation, the researchers wrote.

Stem cell therapy utilizing cardiosphere-derived cells (CDC) showed an acceptable safety profile with early evidence of efficacy in the treatment of very severe Covid-19 in an early case series involving 6 patients treated at Cedars-Sinai Medical Center, Los Angeles.

No adverse events related to the treatment were reported, and four of the six patients were successfully weaned from respiratory support and were discharged from the hospital.

Salynn Boyles, Contributing Writer, BreakingMED

Funding for this story was provided by the Smidt Family Foundation. The cell product, CAP-1002, was provided by manufacturer Capricor Therapeutics.

ResearcherEduardo Marban reported owning founders equity in Cariricor Therapeutics, and researcher Linda Marban reported being an employee and owning equity in the company.

Cat ID: 125

Topic ID: 79,125,254,930,287,728,932,570,574,730,933,125,190,926,192,927,151,928,925,934

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Doctors just discovered another promising coronavirus therapy – BGR

By daniellenierenberg

The novel coronavirus cant be killed or stopped with the current drugs that we have, the WHO said earlier this week. Dr. Anthony Fauci said separately that its virtually impossible to eradicate the virus. But there are plenty of therapies that can be used to reduce the severity of COVID-19 and shorten the recovery period.

The WHO is studying four or five of the best drugs for the new illness, but there are plenty of new lines of therapy that are discovered on a regular basis. The latest one consists of a treatment thats usually given to Duchenne muscular dystrophy patients.

Cedars-Sinai doctors have given six patients an experimental treatment consisting of cells grown from human heart tissues, according to ABC7. This therapy improved the overall condition of all patients, each of whom were critically ill before the Hail Mary treatment was administered. Four of them have come off ventilators and were discharged, while the other two are still in the hospital, but theyre alive.

Dr. Eduardo Marban and his colleagues were using the treatment for muscular dystrophy patients with heart failure before considering it for COVID-19. The novel coronavirus can do severe damage to the heart, and that may have been the reason why the doctors attempted this novel therapy.

This can only be considered anecdotal evidence at best, but the doctors are hoping that the FDA can approve a more extensive study that can evaluate the benefits of the therapy. The doctors have additional doses available in the freezer for the research.

Cells grown from human heart tissues sound a lot like stem cells, although the report doesnt refer to them as such. This wouldnt be the first time that stem cell use would prove to be helpful in COVID-19 cases. A few weeks ago, doctors from Mount Sinai reported theyve treated 12 patients using stem cells derived from bone marrow, and the therapy allowed 10 of them to come off ventilators. Those physicians also noted that further study is required.

Marban and his colleagues detailed the benefits of injections of cardiac progenitor cells (cardiosphere-derived cells or CDCs) for patients with muscular dystrophy in February 2018. Cardiosphere-derived cells are stem cells derived from cardiac tissue.

We unexpectedly found that treating the heart made the whole body better, Marban said at the time. These basic findings, which have already been translated to clinical trials, rationalize why treating the heart may also benefit skeletal muscle function in boys and young men with Duchenne.

The study showed the stem cells acted not just on the heart tissue, but also on skeletal muscle, and that the benefits persisted. We found that within a few weeks, the injected cells were undetectable, Marban said, but the benefits persisted for at least three months, which led us to discover that exosomes secreted by CDCs are responsible.

The same type of therapy was likely used to treat COVID-19 patients.

Image Source: John Minchillo/AP/Shutterstock

Chris Smith started writing about gadgets as a hobby, and before he knew it he was sharing his views on tech stuff with readers around the world. Whenever he's not writing about gadgets he miserably fails to stay away from them, although he desperately tries. But that's not necessarily a bad thing.

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bluebird bio to Present Data from Its Gene and Cell Therapy Programs During the Virtual Edition of the 25th European Hematology Association Annual…

By daniellenierenberg

Presentation of new and updated results from ongoing Phase 1/2 HGB-206 study of LentiGlobin for sickle cell disease will include additional patients treated in the study

New and updated data, including analysis of healthy red blood cell production in patients with transfusion-dependent -thalassemia following treatment with betibeglogene autotemcel (LentiGlobin for -thalassemia) to be shared

CAMBRIDGE, Mass. bluebird bio, Inc. (Nasdaq: BLUE) announced today that data from its gene therapy programs for sickle cell disease (SCD), transfusion-dependent -thalassemia (TDT) and its cell therapy program for relapsed and refractory multiple myeloma (RRMM) will be presented during the Virtual Edition of the 25th European Hematology Association (EHA25) Annual Congress.

New data from the companys Phase 1/2 HGB-206 study of LentiGlobin gene therapy for SCD will be presented, including updated data from patients in Group C.

bluebird bio will also present data from its ongoing clinical studies of betibeglogene autotemcel (formerly LentiGlobin gene therapy for -thalassemia), including the Phase 3 Northstar-2 (HGB-207) study in patients who do not have a 0/0 genotype and the Phase 3 Northstar-3 (HGB-212) study in patients who have 0/0, 0/+IVS-I-110, or +IVS-I-110/+IVS-I-110 genotypes.

Data from studies of idecabtagene vicleucel (ide-cel; bb2121), the companys anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in development with Bristol Myers Squibb, will be presented, including an encore presentation of results from the pivotal Phase 2 KarMMa study.

Sickle Cell Disease Data at EHA25

Oral Presentation: Outcomes in patients treated with LentiGlobin for sickle cell disease (SCD) gene therapy: Updated results from the Phase 1/2 HGB-206 group C study Presenting Author: Julie Kanter, M.D., University of Alabama at Birmingham, Birmingham, Ala.

Transfusion-Dependent -Thalassemia Data at EHA25

Oral Presentation: Improvement in erythropoiesis in patients with transfusion-dependent -thalassemia following treatment with betibeglogene autotemcel (LentiGlobin for -thalassemia) in the Phase 3 HGB-207 study Presenting Author: John B. Porter, MA, M.D., FRCP, FRCPath, University College London Hospital, London, UK

Poster: Betibeglogene autotemcel (LentiGlobin) in patients with transfusion-dependent -thalassemia and 0/0, +IVS-I-110/+IVS-I-110, or 0/+IVS-I-110 genotypes: Updated results from the HGB-212 study Presenting Author: Evangelia Yannaki, M.D., George Papanicolaou Hospital, Thessaloniki, Greece

Multiple Myeloma Data at EHA25

Oral Presentation:Phase II KarMMa study: Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T cell therapy, in patients with relapsed and refractory multiple myeloma Presenting Author: Jesus San-Miguel, M.D., Ph.D., Clinica Universidad de Navarra, Navarra, Spain

Poster: Quality of life in patients with relapsed and refractory multiple myeloma treated with the BCMA-targeted CAR T cell therapy Idecabtagene vicleucel (ide-cel; bb2121): results from the KarMMa Trial Presenting Author: Michel Delforge, M.D., Ph.D., Leuven University College, Brussels, Belgium

Poster: Matching-adjusted indirect comparisons of efficacy outcomes for idecabtagene vicleucel from the KarMMa study vs selinexor PLUS dexamethasone (STORM part 2) and belantamab mafodotin (DREAMM-2) Presenting Author: Paula Rodriguez-Otero, M.D., Clinica Universidad de Navarra, Navarra, Spain

Poster: Baseline and postinfusion pharmcodynamic biomarkers of safety and efficacy in patients treated with idecabtagene vicleucel (ide-cel; bb2121) in the KarMMa study Presenting Author: Justine DellAringa, Bristol Myers Squibb, Seattle, Wash.

Poster: Correlation of tumor BCMA expression with response and acquired resistance to idecabtagene vicleucel in the KarMMa study in relapsed and refractory multiple myeloma Presenting Author: Nathan Martin, Bristol Myers Squibb, Seattle, Wash.

Abstracts outlining bluebird bios accepted data at the EHA25 Virtual Congress have been made available on the EHA25 conference website. On Friday, June 12 at 8:30 AM CEST, the embargo will lift for poster and oral presentations accepted for EHA25.

About betibeglogene autotemcel The European Commission granted conditional marketing authorization (CMA) for betibeglogene autotemcel, marketed as ZYNTEGLO gene therapy, for patients 12 years and older with TDT who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available. On April 28, 2020, the European Medicines Agency (EMA) renewed the CMA for ZYNTEGLO, supported by data from 32 patients treated with ZYNTEGLO including three patients with up to five years of follow-up.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Betibeglogene autotemcel adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

Non-serious adverse events (AEs) observed during the clinical studies that were attributed to betibeglogene autotemcel were abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnoea, pain in extremity, and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for -thalassemia for TDT.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

The CMA for ZYNTEGLO is only valid in the 28 member states of the EU as well as Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted betibeglogene autotemcel Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT. Betibeglogene autotemcel is not approved in the United States.

Betibeglogene autotemcel continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207), NCT03207009 for Northstar-3 (HGB-212).

About LentiGlobin for Sickle Cell Disease LentiGlobin for sickle cell disease is an investigational gene therapy being studied as a potential treatment for SCD. bluebird bios clinical development program for LentiGlobin for SCD includes the ongoing Phase 1/2 HGB-206 study and the ongoing Phase 3 HGB-210 study.

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS), causing red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive crises (VOCs). For adults and children living with SCD, this means unpredictable episodes of excruciating pain due to vaso-occlusion as well as other acute complicationssuch as acute chest syndrome (ACS), stroke, and infections, which can contribute to early mortality in these patients.

LentiGlobin for SCD received Orphan Medicinal Product designation from the European Commission for the treatment of SCD.

The U.S. Food and Drug Administration (FDA) granted Orphan Drug status and Regenerative Medicine Advanced Therapy designation for LentiGlobin for the treatment of SCD.

LentiGlobin for SCD is investigational and has not been approved by the European Medicines Agency (EMA) or FDA.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of betibeglogene autotemcel and LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

About idecabtagene vicleucel (ide-cel; bb2121) Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 4-1BB and CD3- chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

In addition to the pivotal KarMMa trial evaluating ide-cel in patients with relapsed and refractory multiple myeloma, bluebird bio and Bristol Myers Squibbs broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

Ide-cel was granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) and PRIority Medicines (PRIME) designation, as well as Accelerated Assessment status, by the European Medicines Agency for relapsed and refractory multiple myeloma.

Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between Bristol Myers Squibb and bluebird bio.

Ide-cel is not approved for any indication in any geography.

About KarMMa KarMMa (NCT03361748) is a pivotal, open-label, single-arm, multicenter, multinational, Phase 2 study evaluating the efficacy and safety of ide-cel in adults with relapsed and refractory multiple myeloma in North America and Europe. The primary endpoint of the study is overall response rate as assessed by an independent review committee (IRC) according to the International Myeloma Working Group (IMWG) criteria. Complete response rate is a key secondary endpoint. Other efficacy endpoints include time to response, duration of response, progression-free survival, overall survival, minimal residual disease evaluated by Next-Generation Sequencing (NGS) assay and safety. The study enrolled 140 patients, of whom 128 received ide-cel across the target dose levels of 150-450 x 10P6P CAR+ T cells after receiving lymphodepleting chemotherapy. All enrolled patients had received at least three prior treatment regimens, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, and were refractory to their last regimen, defined as progression during or within 60 days of their last therapy.

About bluebird bio, Inc. bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

ZYNTEGLO, LentiGlobin, and bluebird bio are trademarks of bluebird bio, Inc.

Forward-Looking Statements This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to: regarding the potential for betibeglogene autotemcel to treat transfusion-dependent -thalassemia and the potential for LentiGlobin for sickle cell disease (SCD) to treat SCD; and the risk that the efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or planned clinical trials. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200514005234/en/

Contacts

Media: Catherine Falcetti, 339-499-9436 cfalcetti@bluebirdbio.com Victoria von Rinteln, 617-914-8774 vvonrinteln@bluebirdbio.com

Investors: Ingrid Goldberg, 410-960-5022 Ingrid.goldberg@bluebirdbio.com Elizabeth Pingpank, 617-914-8736 epingpank@bluebirdbio.com

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bluebird bio to Present Data from Its Gene and Cell Therapy Programs During the Virtual Edition of the 25th European Hematology Association Annual...

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Surplus antioxidants are pathogenic for hearts and skeletal muscle – The Mix

By daniellenierenberg

This discovery may have clinical importance in management of heart failure.

This discovery may have clinical importance in management of heart failure.Many heart diseases are linked to oxidative stress, an overabundance of reactive oxygen species. The body reacts to reduce oxidative stress where the redox teeter-totter has gone too far up through production of endogenous antioxidants that reduce the reactive oxygen species. This balancing act is called redox homeostasis.

But what happens if the redox teeter-totter goes too far down, creating antioxidative stress, also known as reductive stress? Rajasekaran Namakkal-Soorappan, Ph.D., associate professor in the University of Alabama at Birmingham Department of Pathology, and colleagues have found that reductive stress, or RS/AS, is also pathological. This discovery, they say, may have clinical importance in management of heart failure.

They report that RS causes pathological heart enlargement and diastolic dysfunction in a mouse model. This study, published in the journal Antioxidants and Redox Signaling, was led by Namakkal-Soorappan and Pei Ping, Ph.D., David Geffen School of Medicine at the University of California-Los Angeles.

Antioxidant-based therapeutic approaches for human heart failure should consider a thorough evaluation of antioxidant levels before the treatment, they said. Our findings demonstrate that chronic RS is intolerable and adequate to induce heart failure.

The study used transgenic mice that had upregulated genes for antioxidants in the heart, which increased the amounts of antioxidant proteins and reduced glutathione, creating RS. One mouse line had low upregulation, and one had high upregulation, creating chronic low RS and chronic high RS, respectively, in the hearts of the mice.

The mice with high RS showed pathological heart changes called hypertrophic cardiomyopathy, and had an abnormally high heart ejection fraction and diastolic dysfunction at 6 months of age. Sixty percent of the high-RS mice died by 18 months of age.

The mice with low RS had normal survival rates, but they developed the heart changes at about 15 months of age, suggesting that even moderate RS can lead to irreversible damage in the heart over time.

Giving high-RS mice a chemical that blocked biosynthesis of glutathione, beginning at about 6 weeks of age, prevented RS and rescued the mice from pathological heart changes.

Gobinath Shanmugam, Ph.D., postdoctoral fellow in the UAB Department of Pathology, and Namakkal-Soorappan point out that a 2019 survey found about 77 percent of Americans are consuming dietary supplements every day, and within this group, about 58 percent are consuming antioxidants as multivitamins. Thus, a chronic consumption of antioxidant drugs by any individual without knowing their redox state might result in RS, which can induce pathology and slowly damage the heart.

In a related study, published in the journal Redox Biology, Namakkal-Soorappan looked at the impact of RS on myosatellite cells, which are also known as muscle stem cells. These cells, located near skeletal muscle fibers, are able to regenerate and differentiate into skeletal muscle after acute or chronic muscle injury. The regulation of myosatellite cells is of interest given the loss of skeletal muscle mass during aging or in chronic conditions like diabetes and AIDS.

Recently, Namakkal-Soorappan reported that tilting the redox teeter-totter to oxidative stress impaired regeneration of skeletal muscle. Now, in the Redox Biology paper, he has shown that tilting the redox to RS also causes significant inhibition of muscle satellite cell differentiation.

Rather than genetic manipulation to induce RS, as was done in the heart study, the researchers used the chemical sulforaphane or direct augmentation of intracellular glutathione to induce RS in cultured mouse myoblast cells. Both treatments inhibited myoblast differentiation. Finally, authors attempted to withdraw antioxidative stress by growing cells in medium without sulforaphane, which removes the RS and accelerates the differentiation. Namakkal-Soorappan and colleagues found that a pro-oxidative milieu, through a mild generation of reactive oxygen species, was required for myoblast differentiation.

The researchers also showed that genetic silencing of a negative regulator of the antioxidant genes also inhibited myoblast differentiation.

Co-authors with Namakkal-Soorappan and Ping, and first-author Shanmugam, in the Antioxidants and Redox Signaling study, Reductive stress causes pathological cardiac remodeling and diastolic dysfunction, are Silvio H. Litovsky and Rajesh Kumar Radhakrishnan, UAB Department of Pathology; Ding Wang, UCLA; Sellamuthu S. Gounder, Kevin Whitehead, Sarah Franklin and John R. Hoidal, University of Utah School of Medicine; Jolyn Fernandes and Dean P. Jones, Emory University, Atlanta, Georgia; Thomas W. Kensler, Fred Hutch Cancer Research Center, Seattle, Washington; Louis DellItalia, UAB Department of Medicine; Victor Darley-Usmar, UAB Department of Pathology; and E. Dale Abel, University of Iowa.

In the Redox Biology study, Reductive stress impairs myogenic differentiation, co-authors with Namakkal-Soorappan are Sandeep Balu Shelar, UAB Department of Pathology; Dean P. Jones, Emory University; and John R. Hoidal, University of Utah School of Medicine.

Support for both studies came from National Institutes of Health grants HL118067 and AG042860, American Heart Association grant BGIA 0865015F, the University of Utah, and UAB.

In the two studies, Namakkal-Soorappans name is listed as Namakkal S. Rajasekaran.

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One year on, Capricor’s stem cell therapy appears to help DMD patients in small study, but investors balk at the data – Endpoints News

By daniellenierenberg

Repeated setbacks aside, little Capricor has suggested it has generated some long-term data to support its pursuit to garner approval for its stem cell therapy for Duchenne muscular dystrophy, although some of the data appeared to underwhelmed investors.

The data from the small, placebo-controlled mid-stage study, HOPE-2, tracked the effects of the companys stem cell therapy CAP-1002, which is designed to temper the inflammation associated with DMD, in 8 boys and young men who are in advanced stages of DMD. The remaining 12 enrolled patients received the placebo.

The main goal of the study was a measure that evaluates shoulder, arm and hand strength in patients who are generally non-ambulant (performance of the upper limb (PUL) 2.0), as suggested by the FDA, Capricor said. It is one of several ways Capricor quantified skeletal muscle improvement in the trial.

The intravenous infusion of CAP-1002, given every 3 months, induced a statistically meaningful improvement of 2.4 points (p=0.05) versus the placebo group, in which patient declines were consistent with natural history data. However, on another measure of upper limb function, the trend was in favor of the Capricor drug, but did not hit statistical significance.

The companys shares $CAPR were down nearly 13% to $6.89 in morning trading.

Click on the image to see the full-sized version

Meanwhile, there were also some encouraging data on cardiac function the genetic condition is characterized by progressive weakness and chronic inflammation of the skeletal, heart and respiratory muscles.

As reflected above, CAP-1002 elicited an improvement across different measures of cardiac function, although the effect was not always statistically significant. In particular, the drug also caused a reduction in the levels of the biomarker CK-MB, an enzyme that is only released when there is cardiac muscle cell damage.

Armed with these data and an RMAT and orphan drug designation from the FDA, Capricor is now hoping to eke out a plan with the FDA for marketing approval.

LA-based Capricor initially set out to test the potential of technology that Eduardo Marbn, CEO Linda Marbns husband, developed at Johns Hopkins. But repeated setbacks clobbered the company, which in 2014 traded north of $14 a share. In 2017, J&J walked away from a collaboration on a stem cell therapy for damaged hearts after it flopped in the clinic.

In late 2018, the company voluntarily halted a DMD clinical trial, following a severe allergic reaction that occurred during infusion. In February 2019, the company said it is exploring strategic alternatives for one or more of its products and cutting 21 jobs to keep financially afloat, but had resumed dosing in its DMD trial.

The first batch of positive data on CAP-1002, which consists of progenitor cells derived from donor hearts and is designed to exude exosomes that initiate muscle repair by suppressing inflammation and driving immunomodulation, came last July when the company announced the drug had generated a positive effect at the interim analysis juncture of HOPE-2. Capricor is now working on to flexing its therapeutic muscle with CAP-1002 to fight the Covid-19 pandemic.

DMD is a rare muscle-wasting disease caused by the absence of dystrophin, a protein that helps keep muscle cells intact. It disproportionately affects boys and affects roughly 6,000 in the United States.

Patients are essentially treated with steroids. Sarepta Therapeutics now has two exon-skipping drugs designed to treat certain subsets of the disease, although the magnitude of their effect is controversial given that approvals were not based on placebo-controlled data. Meanwhile, Sarepta and others are also pursuing one-time cures in the form of gene therapies to replace the missing dystrophin gene in patients.

Social: Linda Marbn, Capricor CEO (Twitter)

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ROCKET PHARMACEUTICALS : Management’s Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) – marketscreener.com

By daniellenierenberg

You should read the following discussion and analysis of our financial conditionand results of operations together with the condensed consolidated financialstatements and related notes that are included elsewhere in this QuarterlyReport on Form 10-Q and our Annual Report on Form 10-K for the fiscal year endedDecember 31, 2019 filed with the U.S. Securities and Exchange Commission, or theSEC, on March 6, 2020, or our 2019 Form 10-K. This discussion containsforward-looking statements based upon current plans, expectations and beliefsthat involve risks and uncertainties. Our actual results may differ materiallyfrom those anticipated in these forward-looking statements as a result ofvarious factors, including, but not limited to, those discussed in the sectionentitled "Risk Factors" and elsewhere in this Quarterly Report on Form 10-Q. Inpreparing this MD&A, we presume that readers have access to and have read theMD&A in our 2019 Form 10-K, pursuant to Instruction 2 to paragraph (b) of Item303 of Regulation S-K. Unless stated otherwise, references in this QuarterlyReport on Form 10-Q to "us," "we," "our," or our "Company" and similar termsrefer to Rocket Pharmaceuticals, Inc.

We are a clinical-stage, multi-platform biotechnology company focused on thedevelopment of first, only and best-in-class gene therapies, with directon-target mechanism of action and clear clinical endpoints, for rare anddevastating diseases. We currently have three clinical-stage ex vivo lentiviralvector ("LVV") programs currently enrolling patients in the US and EU forFanconi Anemia ("FA"), a genetic defect in the bone marrow that reducesproduction of blood cells or promotes the production of faulty blood cells,Leukocyte Adhesion Deficiency-I ("LAD-I"), a genetic disorder that causes theimmune system to malfunction and Pyruvate Kinase Deficiency ("PKD"), a rare redblood cell autosomal recessive disorder that results in chronic non-spherocytichemolytic anemia. Of these, both the Phase 2 FA program and the Phase 1/2 LAD-Iprogram are in registration-enabling studies in the US and EU. In addition, inthe US we have a clinical stage in vivo adeno-associated virus ("AAV") programfor Danon disease, a multi-organ lysosomal-associated disorder leading to earlydeath due to heart failure. Finally, we have a pre-clinical stage LVV programfor Infantile Malignant Osteopetrosis ("IMO"), a genetic disorder characterizedby increased bone density and bone mass secondary to impaired bone resorption -this program is anticipated to enter the clinic in 2020. We have globalcommercialization and development rights to all of these product candidatesunder royalty-bearing license agreements. Additional work in the discovery stagefor an FA CRISPR/CAS9 program as well as a gene therapy program for the lesscommon FA subtypes C and G is ongoing.

Recent Developments

On February 20, 2020, we entered into separate, privately negotiated exchangeagreements (the "Exchange Agreements") with certain holders of our outstanding5.75% Convertible Senior Notes due 2021 (the "2021 Convertible Notes") to extendthe maturity date by one year. Pursuant to the Exchange Agreements, we exchangedapproximately $39.35 million aggregate principal amount of the 2021 ConvertibleNotes (which represents approximately 76% of the aggregate outstanding principalamount of the 2021 Convertible Notes) for (a) approximately $39.35 millionaggregate principal amount of 6.25% Convertible Senior Notes due August 2022(the "2022 Convertible Notes") (an exchange ratio equal to 1.00 2022 ConvertibleNote per exchanged 2021 Convertible Note) and (b) $119,416 in cash to pay theaccrued and unpaid interest on the exchanged 2021 Convertible Notes from, andincluding, February 1, 2020 to February 20, 2020. The 2022 Convertible Noteswere issued in private placements exempt from registration in reliance onSection 4(a) (2) of the Securities Act of 1933, as amended (the "SecuritiesAct"). Upon completion of the exchange transactions, approximately $12.65million aggregate principal amount of 2021 Convertible Notes remainedoutstanding.

Gene Therapy Overview

Genes are composed of sequences of deoxyribonucleic acid ("DNA"), which code forproteins that perform a broad range of physiologic functions in all livingorganisms. Although genes are passed on from generation to generation, geneticchanges, also known as mutations, can occur in this process. These changes canresult in the lack of production of proteins or the production of alteredproteins with reduced or abnormal function, which can in turn result in disease.

Gene therapy is a therapeutic approach in which an isolated gene sequence orsegment of DNA is administered to a patient, most commonly for the purpose oftreating a genetic disease that is caused by genetic mutations. Currentlyavailable therapies for many genetic diseases focus on administration of largeproteins or enzymes and typically address only the symptoms of the disease. Genetherapy aims to address the disease-causing effects of absent or dysfunctionalgenes by delivering functional copies of the gene sequence directly into thepatient's cells, offering the potential for curing the genetic disease, ratherthan simply addressing symptoms.

We are using modified non-pathogenic viruses for the development of our genetherapy treatments. Viruses are particularly well suited as delivery vehiclesbecause they are adept at penetrating cells and delivering genetic materialinside a cell. In creating our viral delivery vehicles, the viral (pathogenic)genes are removed and are replaced with a functional form of the missing ormutant gene that is the cause of the patient's genetic disease. The functionalform of a missing or mutant gene is called a therapeutic gene, or the"transgene." The process of inserting the transgene is called "transduction."Once a virus is modified by replacement of the viral genes with a transgene, themodified virus is called a "viral vector." The viral vector delivers thetransgene into the targeted tissue or organ (such as the cells inside apatient's bone marrow). We have two types of viral vectors in development, LVVand AAV. We believe that our LVV and AAV-based programs have the potential tooffer a long-lasting and significant therapeutic benefit to patients.

Gene therapies can be delivered either (1) ex vivo (outside the body), in whichcase the patient's cells are extracted and the vector is delivered to thesecells in a controlled, safe laboratory setting, with the modified cells thenbeing reinserted into the patient, or (2) in vivo (inside the body), in whichcase the vector is injected directly into the patient, either intravenously("IV") or directly into a specific tissue at a targeted site, with the aim ofthe vector delivering the transgene to the targeted cells.

We believe that scientific advances, clinical progress, and the greaterregulatory acceptance of gene therapy have created a promising environment toadvance gene therapy products as these products are being designed to restorecell function and improve clinical outcomes, which in many cases includeprevention of death at an early age.

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The chart below shows the current phases of development of Rocket's programs andproduct candidates:

LVV Programs. Rocket's LVV-based programs utilize third-generation,self-inactivating lentiviral vectors to target selected rare diseases.Currently, Rocket is developing LVV programs to treat FA, LAD-I, PKD, and IMO.

Fanconi Anemia Complementation Group A (FANCA):

FA, a rare and life-threatening DNA-repair disorder, generally arises from amutation in a single FA gene. An estimated 60 to 70% of cases arise frommutations in the Fanconi-A ("FANCA") gene, which is the focus of our program. FAresults in bone marrow failure, developmental abnormalities, myeloid leukemiaand other malignancies, often during the early years and decades of life. Bonemarrow aplasia, which is bone marrow that no longer produces any or very few redand white blood cells and platelets leading to infections and bleeding, is themost frequent cause of early morbidity and mortality in FA, with a median onsetbefore 10 years of age. Leukemia is the next most common cause of mortality,ultimately occurring in about 20% of patients later in life. Solid organmalignancies, such as head and neck cancers, can also occur, although at lowerrates during the first two to three decades of life.

Although improvements in allogeneic (donor-mediated) hematopoietic stem celltransplant ("HSCT"), currently the most frequently utilized therapy for FA, haveresulted in more frequent hematologic correction of the disorder, HSCT isassociated with both acute and long-term risks, including transplant-relatedmortality, graft versus host disease ("GVHD"), a sometimes fatal side effect ofallogeneic transplant characterized by painful ulcers in the GI tract, livertoxicity and skin rashes, as well as increased risk of subsequent cancers. Ourgene therapy program in FA is designed to enable a minimally toxic hematologiccorrection using a patient's own stem cells during the early years of life. Webelieve that the development of a broadly applicable autologous gene therapy canbe transformative for these patients.

Each of our LVV-based programs utilize third-generation, self-inactivatinglentiviral vectors to correct defects in patients' HSCs, which are the cellsfound in bone marrow that are capable of generating blood cells over a patient'slifetime. Defects in the genetic coding of HSCs can result in severe, andpotentially life-threatening anemia, which is when a patient's blood lacksenough properly functioning red blood cells to carry oxygen throughout the body.Stem cell defects can also result in severe and potentially life-threateningdecreases in white blood cells resulting in susceptibility to infections, and inplatelets responsible for blood clotting, which may result in severe andpotentially life-threatening bleeding episodes. Patients with FA have a geneticdefect that prevents the normal repair of genes and chromosomes within bloodcells in the bone marrow, which frequently results in the development of acutemyeloid leukemia ("AML"), a type of blood cancer, as well as bone marrow failureand congenital defects. The average lifespan of an FA patient is estimated to be30 to 40 years. The prevalence of FA in the US and EU is estimated to be about4,000, and given the efficacy seen in non-conditioned patients, the addressableannual market opportunity is now thought to be in the 400 to 500 range.

We currently have one LVV-based program targeting FA, RP-L102. RP-L102 is ourlead lentiviral vector based program that we in-licensed from Centro deInvestigaciones Energticas, Medioambientales y Tecnolgicas ("CIEMAT"), whichis a leading research institute in Madrid, Spain. RP-L102 is currently beingstudied in our sponsored Phase 2 registrational enabling clinical trialstreating FA patients initially at the Center for Definitive and CurativeMedicine at Stanford University School of Medicine ("Stanford") and HospitalInfantil de Nino Jesus ("HNJ") in Spain. The Phase 2 portion of the trial isexpected to enroll ten patients total from the U.S. and EU. Patients willreceive a single IV infusion of RP-L102 that utilizes fresh cells and "ProcessB" which incorporates a modified stem cell enrichment process, transductionenhancers, as well as commercial-grade vector and final drug product.

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Table of ContentsIn October 2019, at the European Society of Cell and Gene Therapy ("ESGCT") 2019Annual Congress, long-term Phase 1/2 clinical data of RP-L102, from the clinicaltrial sponsored by CIEMAT, for FA "Process A", without the use of myeloablativeconditioning was presented demonstrating evidence of increasing and durableengraftment leading to bone marrow restoration exceeding the 10% thresholdagreed to by the FDA and EMA for the ongoing registration-enabling Phase 2trial. In patient 02002, who received what we consider adequate drug product,hemoglobin levels are now similar to those in the first year after birth,suggesting hematologic correction over the long term.

During the third quarter of 2019, we received alignment from the FDA on thetrial design and the primary endpoint. This alignment was similar to thatpreviously received from the European Medicines Agency ("EMA"). Resistance tomitomycin-C, a DNA damaging agent, in bone marrow stem cells at a minimum timepoint of one year to serve as the primary endpoint for our Phase II study. InDecember 2019, we announced that the first patient of the global Phase 2 studyfor RP-L102 "Process B" for FA received investigational therapy. There will betotal of 10 patients enrolled in the global Phase 2 studies.

In December 2019, we also announced preliminary results from two pediatricpatients treated with "Process B" RP-L102 prior to development of severe bonemarrow failure in our Phase 1 trial of RP-L102 for FA. To evaluate transductionefficiency, an analysis of the proportion of the MMC-resistant colony formingcells was conducted and both patients have thus far exhibited early signs ofengraftment, including increases in blood cell lineages in one patient. Nodrug-related safety or tolerability issues have been reported.

Leukocyte Adhesion Deficiency-I (LAD-I):

LAD-I is a rare autosomal recessive disorder of white blood cell adhesion andmigration, resulting from mutations in the ITGB2 gene encoding for the Beta-2Integrin component, CD18. Deficiencies in CD18 result in an impaired ability forneutrophils (a subset of infection-fighting white blood cells) to leave bloodvessels and enter into tissues where these cells are needed to combatinfections. As is the case with many rare diseases, true estimates of incidenceare difficult; however, several hundred cases have been reported to date.

Most LAD-I patients are believed to have the severe form of the disease. SevereLAD-I is notable for recurrent, life-threatening infections and substantialinfant mortality in patients who do not receive an allogeneic HSCT. Mortalityfor severe LAD-I has been reported as 60 to 75% by age two in the absence ofallogeneic HCST.

We currently have one program targeting LAD-I, RP-L201. RP-L201 is a clinicalprogram that we in-licensed from CIEMAT. We have partnered with UCLA to leadU.S. clinical development efforts for the LAD-I program. UCLA and its Eli andEdythe Broad Center of Regenerative Medicine and Stem Cell Research is servingas the lead U.S. clinical research center for the registrational clinical trialfor LAD-I, and HNJ is serving as the lead clinical site in Spain.

The ongoing open-label, single-arm, Phase 1/2 registration enabling clinicaltrial of RP-L201 has dosed one severe LAD-I patient in the U.S. to assess thesafety and tolerability of RP-L201. The first patient was treated with RP-L201in third quarter 2019. This study has received $6.5 million CLIN2 grant awardfrom the California Institute for Regenerative Medicine ("CIRM") to support theclinical development of gene therapy for LAD-I.

In December 2019, we announced initial results from the first pediatric patienttreated with RP-L201, demonstrating early evidence of safety. Analyses ofperipheral vector copy number ("VCN"), and CD18-expressing neutrophils wereperformed through three months after infusion of RP-L201 to evaluate engraftmentand phenotypic correction. The patient exhibited early signs of engraftment withVCN myeloid levels at 1.5 at three months and CD-18 expression of 45%. No safetyor tolerability issues related to RP-L201 administration (or investigationalproduct) had been identified as of that date. The study is expected to enrollnine patients globally.

Pyruvate Kinase Deficiency (PKD):

Red blood cell PKD is a rare autosomal recessive disorder resulting frommutations in the pyruvate kinase L/R ("PKLR") gene encoding for a component ofthe red blood cell ("RBC") glycolytic pathway. PKD is characterized by chronicnon-spherocytic hemolytic anemia, a disorder in which RBCs do not assume anormal spherical shape and are broken down, leading to decreased ability tocarry oxygen to cells, with anemia severity that can range from mild(asymptomatic) to severe forms that may result in childhood mortality or arequirement for frequent, lifelong RBC transfusions. The pediatric population isthe most commonly and severely affected subgroup of patients with PKD, and PKDoften results in splenomegaly (abnormal enlargement of the spleen), jaundice andchronic iron overload which is likely the result of both chronic hemolysis andthe RBC transfusions used to treat the disease. The variability in anemiaseverity is believed to arise in part from the large number of diverse mutationsthat may affect the PKLR gene. Estimates of disease incidence have rangedbetween 3.2 and 51 cases per million in the white U.S. and EU population.Industry estimates suggest at least 2,500 cases in the U.S. and EU have alreadybeen diagnosed despite the lack of FDA-approved molecularly targeted therapies.Enrollment is currently ongoing and we anticipate treating the first patient inthe third quarter of 2020.

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Table of ContentsWe currently have one LVV-based program targeting PKD, RP-L301. RP-L301 is aclinical stage program that we in-licensed from CIEMAT. The IND for RP-L301 toinitiate a global Phase 1 study was cleared by the FDA in October 2019. Thisprogram has been granted EMA orphan drug disease designation and FDA orphan drugdisease designation ("ODD").

This global Phase 1 open-label, single-arm, clinical trial is expected to enrollsix adult and pediatric transfusion-dependent PKD patients in the U.S. andEurope. Lucile Packard Children's Hospital Stanford will serve as the lead sitein the U.S. for adult and pediatric patients, and Hospital InfantilUniversitario Nio Jess will serve as the lead site in Europe for pediatricsand Hospital Universitario Fundacin Jimnez Daz will serve as the lead site inEurope for adult patients.

Infantile Malignant Osteopetrosis (IMO):

IMO is a genetic disorder characterized by increased bone density and bone masssecondary to impaired bone resorption. Normally, small areas of bone areconstantly being broken down by special cells called osteoclasts, then madeagain by cells called osteoblasts. In IMO, the cells that break down bone(osteoclasts) do not work properly, which leads to the bones becoming thickerand not as healthy. Untreated IMO patients may suffer from a compression of thebone-marrow space, which results in bone marrow failure, anemia and increasedinfection risk due to the lack of production of white blood cells. Untreated IMOpatients may also suffer from a compression of cranial nerves, which transmitsignals between vital organs and the brain, resulting in blindness, hearing lossand other neurologic deficits.

We currently have one LVV-based program targeting IMO, RP-L401. RP-L401 is apreclinical program that we in-licensed from Lund University, Sweden. Thisprogram has been granted ODD and Rare Pediatric Disease designation from theFDA. The FDA defines a "rare pediatric disease" as a serious andlife-threatening disease that affects less than 200,000 people in the U.S. thatare aged between birth to 18 years. The Rare Pediatric Disease designationprogram allows for a sponsor who receives an approval for a product topotentially qualify for a voucher that can be redeemed to receive a priorityreview of a subsequent marketing application for a different product. We havepartnered with UCLA to lead U.S. clinical development efforts for the IMOprogram and anticipate that UCLA will serve as the lead U.S. clinical site forIMO. We intend to file an IND for IMO and commence our clinical trial in thefourth quarter of 2020.

Danon disease is a multi-organ lysosomal-associated disorder leading to earlydeath due to heart failure. Danon disease is caused by mutations in the geneencoding lysosome-associated membrane protein 2 ("LAMP-2"), a mediator ofautophagy. This mutation results in the accumulation of autophagic vacuoles,predominantly in cardiac and skeletal muscle. Male patients often require hearttransplantation and typically die in their teens or twenties from progressiveheart failure. Along with severe cardiomyopathy, other Danon disease symptomscan include skeletal muscle weakness, liver disease, and intellectualimpairment. There are no specific therapies available for the treatment of Danondisease. RP-A501 is in clinical trials as an in vivo therapy for Danon disease,which is estimated to have a prevalence of 15,000 to 30,000 patients in the U.S.and the EU, however new market research is being performed and the prevalence ofpatients may be updated in the future.

In January 2019, we announced the clearance of our IND application by the FDAfor RP-A501, and in February 2019, we were notified by the FDA that we weregranted Fast Track designation for RP-A501. University of California San DiegoHealth is the initial and lead center for our Phase 1 clinical trial.

On May 2, 2019, we presented additional preclinical data at the ASCGT annualmeeting, indicating that high VCN, in Danon disease-relevant organs in both miceand non-human primates ("NHN's"), with high concentrations in heart and livertissue (for NHP, cardiac VCN was approximately 10 times higher on average thanin skeletal muscle and central nervous system), which is consistent withreported results in several studies of heart tissue across different species.There were no treatment-related adverse events or safety issues up to thehighest dose. We have dosed three patients in the RP-A501 phase 1 clinicaltrial. We will continue further enrollment with clinical data read-outs in thefourth quarter of 2020.

As of March 2020, we have dosed three patients in the RP-A501 phase 1 clinicaltrial. This completes the first low dose cohort of the Phase 1 study. Based onthe preliminary safety and efficacy data review of this completed cohort, boththe FDA and IDMC has provided clearance to advance to a higher dose cohort inPhase 1 Trial of RP-A501 for Danon Disease. We will continue further enrollmentwith clinical data read-outs in the second half of 2020.

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In addition to its LVV and AAV programs, we also have a program evaluatingCRISPR/Cas9-based gene editing for FA. This program is currently in thediscovery phase. CRISPR/Cas9-based gene editing is a different method ofcorrecting the defective genes in a patient, where the editing is very specificand targeted to a particular gene sequence. "CRISPR/Cas9" stands for Clustered,Regularly Interspaced Short Palindromic Repeats ("CRISPR") Associated protein-9.The CRISPR/Cas9 technology can be used to make "cuts" in DNA at specific sitesof targeted genes, making it potentially more precise in delivering genetherapies than traditional vector-based delivery approaches. CRISPR/Cas9 canalso be adapted to regulate the activity of an existing gene without modifyingthe actual DNA sequence, which is referred to as gene regulation.

Strategy

We seek to bring hope and relief to patients with devastating, undertreated,rare pediatric diseases through the development and commercialization ofpotentially curative first-in-class gene therapies. To achieve these objectives,we intend to develop into a fully-integrated biotechnology company. In the near-and medium-term, we intend to develop our first-in-class product candidates,which are targeting devastating diseases with substantial unmet need, developproprietary in-house analytics and manufacturing capabilities and continue tocommence registration trials for our currently planned programs. In the mediumand long-term, we expect to submit our first biologics license applications("BLAs"), and establish our gene therapy platform and expand our pipeline totarget additional indications that we believe to be potentially compatible withour gene therapy technologies. In addition, during that time, we believe thatour currently planned programs will become eligible for priority review vouchersfrom the FDA that provide for expedited review. We have assembled a leadershipand research team with expertise in cell and gene therapy, rare disease drugdevelopment and commercialization.

We believe that our competitive advantage lies in our disease-based selectionapproach, a rigorous process with defined criteria to identify target diseases.We believe that this approach to asset development differentiates us as a genetherapy company and potentially provides us with a first-mover advantage.

Financial Overview

Since our inception, we have devoted substantially all of our resources toorganizing and staffing the Company, business planning, raising capital,acquiring or discovering product candidates and securing related intellectualproperty rights, conducting discovery, research and development activities forthe programs and planning for potential commercialization. We do not have anyproducts approved for sale and have not generated revenue from product sales.From inception through March 31, 2020, we raised net cash proceeds ofapproximately $373.1 million from investors through both equity and convertibledebt financing to fund operating activities. As of March 31, 2020, we had cash,cash equivalents and investments of $275.9 million.

Since inception, we have incurred significant operating losses. Our ability togenerate product revenue sufficient to achieve profitability will depend heavilyon the successful development and eventual commercialization of one or more ofthe current or future product candidates and programs. We had net losses of$24.7 million for the three months ended March 31, 2020 and $77.3 million forthe year ended December 31, 2019. As of March 31, 2020, we had an accumulateddeficit of $207.8 million. We expect to continue to incur significant expensesand higher operating losses for the foreseeable future as we advance our currentproduct candidates from discovery through preclinical development and clinicaltrials and seek regulatory approval of our product candidates. In addition, ifwe obtain marketing approval for any of their product candidates, we expect toincur significant commercialization expenses related to product manufacturing,marketing, sales and distribution. Furthermore, we expect to incur additionalcosts as a public company. Accordingly, we will need additional financing tosupport continuing operations and potential acquisitions of licensing or otherrights for product candidates.

Until such a time as we can generate significant revenue from product sales, ifever, we will seek to fund our operations through public or private equity ordebt financings or other sources, which may include collaborations with thirdparties and government programs or grants. Adequate additional financing may notbe available to us on acceptable terms, or at all. We can make no assurancesthat we will be able to raise the cash needed to fund our operations and, if wefail to raise capital when needed, we may have to significantly delay, scaleback or discontinue the development and commercialization of one or more productcandidates or delay pursuit of potential in-licenses or acquisitions.

Because of the numerous risks and uncertainties associated with productdevelopment, we are unable to predict the timing or amount of increased expensesor when or if we will be able to achieve or maintain profitability. Even if weare able to generate product sales, we may not become profitable. If we fail tobecome profitable or are unable to sustain profitability on a continuing basis,then we may be unable to continue our operations at planned levels and be forcedto reduce or terminate our operations.

Revenue

To date, we have not generated any revenue from any sources, including fromproduct sales, and we do not expect to generate any revenue from the sale ofproducts in the near future. If our development efforts for product candidatesare successful and result in regulatory approval or license agreements withthird parties, we may generate revenue in the future from product sales.

--------------------------------------------------------------------------------

Research and Development Expenses

Our research and development program ("R&D") expenses consist primarily ofexternal costs incurred for the development of our product candidates. Theseexpenses include:

expenses incurred under agreements with research institutions that conduct

research and development activities including, process development,

preclinical, and clinical activities on Rocket's behalf;

costs related to process development, production of preclinical and clinical

materials, including fees paid to contract manufacturers and manufacturing

input costs for use in internal manufacturing processes;

consultants supporting process development and regulatory activities; and

costs related to in-licensing of rights to develop and commercialize our

product candidate portfolio.

We recognize external development costs based on contractual payment schedulesaligned with program activities, invoices for work incurred, and milestoneswhich correspond with costs incurred by the third parties. Nonrefundable advancepayments for goods or services to be received in the future for use in researchand development activities are recorded as prepaid expenses.

Our direct research and development expenses are tracked on a program-by-programbasis for product candidates and consist primarily of external costs, such asresearch collaborations and third party manufacturing agreements associated withour preclinical research, process development, manufacturing, and clinicaldevelopment activities. Our direct research and development expenses by programalso include fees incurred under license agreements. Our personnel, non-programand unallocated program expenses include costs associated with activitiesperformed by our internal research and development organization and generallybenefit multiple programs. These costs are not separately allocated by productcandidate and consist primarily of:

Our research and development activities are central to our business model.Product candidates in later stages of clinical development generally have higherdevelopment costs than those in earlier stages of clinical development. As aresult, we expect that research and development expenses will increasesubstantially over the next several years as we increase personnel costs,including stock-based compensation, support ongoing clinical studies, seek toachieve proof-of-concept in one or more product candidates, advance preclinicalprograms to clinical programs, and prepare regulatory filings for productcandidates.

We cannot determine with certainty the duration and costs to complete current orfuture clinical studies of product candidates or if, when, or to what extent wewill generate revenues from the commercialization and sale of any of our productcandidates that obtain regulatory approval. We may never succeed in achievingregulatory approval for any of our product candidates. The duration, costs, andtiming of clinical studies and development of product candidates will depend ona variety of factors, including:

the scope, rate of progress, and expense of ongoing as well as any future

clinical studies and other research and development activities that we

undertake;

future clinical trial results;

uncertainties in clinical trial enrollment rates;

changing standards for regulatory approval; and

the timing and receipt of any regulatory approvals.

We expect research and development expenses to increase for the foreseeablefuture as we continue to invest in research and development activities relatedto developing product candidates, including investments in manufacturing, as ourprograms advance into later stages of development and as we conduct additionalclinical trials. The process of conducting the necessary clinical research toobtain regulatory approval is costly and time-consuming, and the successfuldevelopment of product candidates is highly uncertain. As a result, we areunable to determine the duration and completion costs of research anddevelopment projects or when and to what extent we will generate revenue fromthe commercialization and sale of any of our product candidates.

Our future research and development expenses will depend on the clinical successof our product candidates, as well as ongoing assessments of the commercialpotential of such product candidates. In addition, we cannot forecast with anydegree of certainty which product candidates may be subject to futurecollaborations, when such arrangements will be secured, if at all, and to whatdegree such arrangements would affect our development plans and capitalrequirements. We expect our research and development expenses to increase infuture periods for the foreseeable future as we seek to complete development ofour product candidates.

The successful development and commercialization of our product candidates ishighly uncertain. This is due to the numerous risks and uncertainties associatedwith product development and commercialization, including the uncertainty of:

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Table of Contents

the scope, progress, outcome and costs of our clinical trials and other

research and development activities;

the efficacy and potential advantages of our product candidates compared to

alternative treatments, including any standard of care;

the market acceptance of our product candidates;

obtaining, maintaining, defending and enforcing patent claims and other

intellectual property rights;

significant and changing government regulation; and

the timing, receipt and terms of any marketing approvals.

A change in the outcome of any of these variables with respect to thedevelopment of our product candidates that we may develop could mean asignificant change in the costs and timing associated with the development ofour product candidates. For example, if the FDA or another regulatory authoritywere to require us to conduct clinical trials or other testing beyond those thatwe currently contemplate for the completion of clinical development of any ofour product candidates that we may develop or if we experience significantdelays in enrollment in any of our clinical trials, we could be required toexpend significant additional financial resources and time on the completion ofclinical development of that product candidate.

General and Administrative Expenses

General and administrative ("G&A") expenses consist primarily of salaries andrelated benefit costs for personnel, including stock-based compensation andtravel expenses for our employees in executive, operational, finance, legal,business development, and human resource functions. In addition, othersignificant general and administrative expenses include professional fees forlegal, patents, consulting, investor and public relations, auditing and taxservices as well as other expenses for rent and maintenance of facilities,insurance and other supplies used in general and administrative activities. Weexpect general and administrative expenses to increase for the foreseeablefuture due to anticipated increases in headcount to support the continuedadvancement of our product candidates. We also anticipate that we will incurincreased accounting, audit, legal, regulatory, compliance and director andofficer insurance costs as well as investor and public relations expenses.

Interest Expense

Interest expense is related to the 2021 Convertible Notes, which mature inAugust 2021, and the 2022 Convertible Notes, which mature in August 2022.

Interest Income

Interest income is related to interest earned from investments.

Critical Accounting Policies and Significant Judgments and Estimates

Our consolidated financial statements are prepared in accordance with generallyaccepted accounting principles in the U.S. The preparation of our financialstatements and related disclosures requires us to make estimates and judgmentsthat affect the reported amounts of assets, liabilities, costs and expenses, andthe disclosure of contingent assets and liabilities in our financial statements.We base our estimates on historical experience, known trends and events andvarious other factors that we believe are reasonable under the circumstances,the results of which form the basis for making judgments about the carryingvalues of assets and liabilities that are not readily apparent from othersources. We evaluate estimates and assumptions on an ongoing basis. Actualresults may differ from these estimates under different assumptions orconditions.

Our significant accounting policies are described in more detail in our 2019Form 10-K, except as otherwise described below.

Results of Operations

Link:
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Cell Therapy Technologies Market to Receive Overwhelming Hike in Revenues by 2023 – MENAFN.COM

By daniellenierenberg

(MENAFN - iCrowdNewsWire) May 8, 2020

According to the new market research report " Cell Therapy Technologies Market by Product (Consumables, Equipment, Software), Cell Type (Human Stem & Differentiated, Animal), Process Stages (Cell Processing, Distribution, Handling, QC), End User, and Region - Global Forecast to 2023, , published by MarketsandMarkets, The global cell therapy technologies market is projected to reach USD 19.9 billion by 2023 from USD 10.2 billion in 2018, at a CAGR of 14.4% during the forecast period.

Browse in-depth TOC on 'Cell Therapy Technologies Market" 75 - Table30 Figures116 Pages

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Rising government investments for cell-based research, the increasing number of GMP-certified production facilities, and the large number of oncology-oriented cell-based therapy clinical trials are the key factors driving the growth of this market. China, India, Japan, Korea, and Brazil are emerging markets for cell therapy instruments. These markets boast comparatively lenient standards and government regulations as opposed to developed markets in North America and the EU, and thus offer significant growth potential for providers. However, the high cost of cell-based research and the low success rate is expected to restrain market growth to some extent during the forecast period.

Consumables are expected to account for the largest cell therapy technologies market share in 2018 : By product, the cell therapy technologies market is segmented into consumables, equipment, and systems & software. The consumables segment is expected to account for the largest share of the market in 2018. Factors such as increasing investments by companies to develop advanced products as well as government initiatives for enhancing cell-based research are contributing to the growth of the cell therapy consumables market.

Cell processing segment to witness the highest growth during the forecast period :

Based on process, the cell therapy technologies market is segmented into cell processing; cell preservation, distribution, and handling; and process monitoring and quality control. The cell processing segment is expected to account for the largest market share in 2018 and is projected to witness the highest CAGR during the forecasted period.

Human cells segment accounts for the large share of the cell therapy instruments market, by cell type :

Based on cell type, the market is segmented into human cells and animal cells. In 2018, the human cells segment is expected to account for the largest share of the cell therapy technologies market. The rising adoption of human cells over animal cells for cell therapeutics research, technological advancements, and the rising incidence of diseases such as cancer and cardiac abnormalities are the key factors driving the growth of this segment.

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North America to dominate the cell therapy technologies market during the forecast period : The market is segmented into four major regions, namely, North America, Europe, Asia Pacific, and the Rest of the World (RoW). North America is expected to dominate the market in 2018 owing to the high burden of chronic diseases and increasing R & D activities in the pharmaceutical and biotechnology industries. The Asia Pacific region is expected to register the highest CAGR during the forecast period.

The major players in the western blotting market are Beckman Coulter (US), Becton, Dickinson and Company (US), GE Healthcare (US), Lonza (Switzerland), Merck KGaA (Germany), Miltenyi Biotec (Germany), STEMCELL Technologies, Inc. (Canada), Terumo BCT (US), and Thermo Fisher Scientific (US).

MENAFN0805202000703403ID1100139731

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Mrieux Equity Partners and Korys Announce the Launch of OMX Europe Venture Fund, Dedicated to Venture Investment Within the Healthcare and Nutrition…

By daniellenierenberg

LYON, France & HALLE, Belgium--(BUSINESS WIRE)--Mrieux Equity Partners and Korys announce the launch of a new investment platform in Venture Capital to support innovative companies in the healthcare and nutrition sectors, in Europe and North America.

OMX Europe Venture Fund FPCI (OMX Europe) was launched with a significant financial commitment representing more than two thirds of the target size of the fund (EUR 90 million) with the support of Korys and Mrieux Dveloppement as sponsors and the contribution of new third party subscribers. The fund will benefit from the solid expertise and network of its sponsors and will be operated by a dedicated team covering direct investments in Venture Capital.

OMX [-miks] refers to a field of study in biology ending in -omics, such as genomics, proteomics, metabolomics or microbiomics. The promise of precision medicine and a biology-led industrial revolution hinge on the ability to reduce the complex interconnections of large, multi-omic data sets into useful products, services and information to enable a more personalized healthcare and nutrition.

The crisis caused by COVID-19 has raised significant public and government awareness around the importance of biology, for a better understanding of infectious diseases but also for providing adequate solutions in the field of prevention, diagnostic and therapeutic intervention. The OMX Europe investment fund focuses on entrepreneurs and life science companies driving breakthroughs in this field at international level, ultimately contributing to a better and cost-effective healthcare while also addressing global challenges.

A number of investments have already been completed by the fund:

OMX Europe will be managed by Mrieux Equity Partners in Europe, with the operational support of Korys Life Science team as a key advisor to the fund. Mrieux Equity Partners currently employs four FTEs dedicated to venture investment and plans to expand its team over the coming months. To add additional geographic and sector expertise a strategic partnership was recently established with a team of senior business executives who have co-invested on several venture deals in the United States with Mrieux Equity Partners over the last ten years. The US-based OMX Ventures investment team, composed of Craig Asher, Nick Haft and Dan Fero, with the support of Paul Conley, operating as Senior Advisor to the fund, will bring an outstanding track record and deep experience in the life science sector.

The American OMX Ventures team have established OMX Ventures Fund I (OMX US) in the US to support innovative companies, with a similar investment strategy to that of the OMX Europe fund and a privileged right of co-investment with OMX Europe. Targeting at least USD 100 million, OMX US has recently completed an initial closing and secured over two thirds of the funding for OMX Ventures Fund I.

We are honored to welcome Korys as a sponsor and key advisor to the fund. Together with Mrieux Dveloppements sponsorship, privileged access to the experience and industrial network of Korys will bring real additional value to our portfolio of fast growing companies, said Valrie Calenda, Partner at Mrieux Equity Partners.

Our collaboration with Mrieux Equity Partners is based on an entrepreneurial history spanning several generations, common values and the shared ambition to dedicate significant, long-term resources within the healthcare and nutrition sectors. We look forward to a successful partnership, said Christoph Waer from Korys.

Thanks to significant support from Mrieux Dveloppement, Korys and the contribution of our business partners in North America, we are increasing our investment capacity in the life science sector, at a time when understanding and mastering biology is more important than ever, added Franois Valencony, President of Mrieux Equity Partners.

About Mrieux Equity Partners - http://www.merieux-partners.com

Mrieux Equity Partners is a management company registered with the Autorit des Marchs Financiers (AMF) since June 2018 that is dedicated to growth equity and venture capital investments. Mrieux Equity Partners currently operates with an international team of 20 employees and regional partners based in Europe and North America. With over EUR 650 million under management, Mrieux Equity Partners actively supports entrepreneurs and industrial companies whose products and services bring differentiated and innovative solutions in the healthcare and nutrition sectors by providing privileged access to its expertise and the industrial, scientific and commercial network of Institut Mrieux, in compliance with the current regulations.

About Korys - http://www.korys.be

Korys is the investment company of the Colruyt family. Today, it has more than EUR 4.5 billion of assets under management. Besides holding a significant participation in the Colruyt Group, a leading retail company in Belgium and France, it actively manages participations in privately held companies and in private equity funds. Korys has also set up proprietary funds to manage its portfolio of listed investments. Across its activities, Korys investment decisions are taken with a long-term perspective and on basis of strict economic (Profit), social (People) and ecological (Planet) criteria. Korys aims to create sustainable value in three major ecosystems: Life Sciences, Energy Transition and Conscious Consumer. To do this, Korys can count on a motivated team of 30 professionals based in Belgium and Luxembourg.

This press release is not a marketing communication in the European Union member states or non-member states. This press release is not an offer of securities for sale in the United States. Securities may not be offered or sold in the United States absent registration or an exemption from registration. Any public offering of securities made in the United States will be made by means of a prospectus that may be obtained from the issuer and will contain detailed information about the company and management, as well as financial statements.

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FDA Approves AstraZeneca’s Farxiga for Heart Failure in Adults with Reduced Ejection Fraction – BioSpace

By daniellenierenberg

Alexanderstock23 / Shutterstock

The U.S. Food and Drug Administration (FDA) announced on Tuesday that it has approved dapagliflozin, also known under the brand name Farxiga, for the treatment of heart failure in adults with reduced ejection fraction. The drug can potentially reduce the risk of cardiovascular death and hospitalization for heart failure.

AstraZenecas Farxiga is now the first in its drug class of sodium-glucose co-transporter 2 (SGLT2) inhibitors to be approved to treat adults with the New York Heart Associations functional class II-IV heart failure with reduced ejection fraction. AstraZeneca was granted with the approval of Farxiga related to heart failure by the FDA.

In a clinical trial, Farxiga appeared to improve survival and reduce the need for hospitalization in adults with heart failure and reduced ejection fraction.

To determine the efficacy of the drug, researchers looked at the number of instances of cardiovascular death, hospitalization for heart failure and urgent heart failure visits. Some trial participants were given a once-daily dose of 10mg of Farxiga, while others were given a placebo. After approximately 18 months, those who were given Farxiga had fewer cardiovascular deaths, hospitalizations for heart failure and urgent heart failure visits compared to their counterparts.

Heart failure is a serious health condition that contributes to one in eight deaths in the U.S. and impacts nearly 6.5 million Americans, said Norman Stockbridge, M.D., Ph.D., director of the Division of Cardiology and Nephrology in the FDAs Center for Drug Evaluation and Research. This approval provides patients with heart failure with reduced ejection fraction an additional treatment option that can improve survival and reduce the need for hospitalization.

Farxiga can cause side effects including dehydration, urinary tract infections and genetical yeast infections. It can also potentially result in serious cases of necrotizing fasciitis of the perineum in people with diabetes and low blood sugar when combined with insulin.

On Tuesday, BioCardia, Inc. also announced positive preclinical data supporting its new drug application for anti-inflammatory cell therapy for heart failure. BioCardias allogenic neurokinin 1 receptor positive mesenchymal stem cell (NK1R+ MSC) therapy appeared to improve heart function in a study. NK1R+ MSC is being marketed under the name CardiALLO.

Researchers looked at 26 animals treated with both low dose and high dose CardiALLO in their study. Echocardiographic measures of cardiac ejection fraction, fractional shortening and cardiac outflow all notably improved in the animals.

In light of these positive data on our allogenic NK1R+ MSC therapy, we expect to meet our internal timeline to complete our submission to the FDA for our first indication for CardiALLO, and potentially receive IND acceptance by the end of the second quarter, said BioCardia Chief Scientific Officer Ian McNiece, PhD. The MSCs that were studied are subtypes of MSC that we have delivered previously in our co-sponsored trials, which we believe have enhanced potency over MSC generated from unselected bone marrow cells. We look forward to seeing additional data from this animal study that are currently being analyzed, including histology and pathology of the heart and lungs.

BioCardia also intends to submit an IND for the use of NK1R+ MSC delivered via intravenous infusion for the treatment of Acute Respiratory Distress Syndrome caused by COVID-19.

Approximately 6.5 million adults in the U.S. are living with heart failure, according to the Centers for Disease Control and Protection. In 2017, it was a contributing cause of death in one out of eight people.

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Merck to Present New Data from its Broad Oncology Portfolio and Pipeline at the ASCO20 Virtual Scientific Program – Business Wire

By daniellenierenberg

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that new data from its oncology program will be presented at the 2020 American Society of Clinical Oncology (ASCO20) Virtual Scientific Program from May 29-31. More than 80 abstracts in nearly 20 types of solid tumors and blood cancers have been accepted across Mercks broad cancer portfolio and investigational pipeline, including KEYTRUDA, Mercks anti-PD-1 therapy; LENVIMA (in collaboration with Eisai); LYNPARZA (in collaboration with AstraZeneca); and MK-6482 (formerly PT2977), an investigational, oral hypoxia-inducible factor-2 alpha (HIF-2) inhibitor.

Despite the challenges we all face due to the COVID-19 pandemic, Merck remains fully committed to supporting the cancer community and to advancing important scientific research from our clinical program, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. The data to be presented at this years ASCO demonstrate how our deep and diverse oncology portfolio continues to show meaningful outcomes for patients in new tumor types and stages of disease, while long-term survival data for KEYTRUDA in non-small cell lung cancer, renal cell carcinoma and melanoma further support its important role in these types of cancer.

Key abstracts including late-breakers, oral sessions, and select poster discussions and posters to be presented at ASCO include:

Merck Investor Event

Merck will hold a virtual investor event in conjunction with the ASCO20 Virtual Scientific Program on Tuesday, June 2 at 2 p.m. ET. Details will be provided at a date closer to the event at http://investors.merck.com/home/default.aspx.

Details on Abstracts Listed Above, Additional Presentations and Key Abstracts with Mercks Collaboration Partners

KEYTRUDA

Breast Cancer

Bladder Cancer

Classical Hodgkin Lymphoma

Colorectal Cancer

Lung Cancer

Renal Cell Carcinoma

Prostate Cancer

Melanoma

Ovarian Cancer

Head and Neck Cancer

KEYTRUDA plus LENVIMA (in collaboration with Eisai)

Hepatocellular Carcinoma

Renal Cell Carcinoma

Endometrial Cancer

LYNPARZA (in collaboration with AstraZeneca)

Ovarian Cancer

MK-6482

Renal Cell Carcinoma

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,200 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [combined positive score (CPS) 10], as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause adrenal insufficiency (primary and secondary), hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Adrenal insufficiency occurred in 0.8% (22/2799) of patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (<0.1%). Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of adrenal insufficiency, hypophysitis (including hypopituitarism), thyroid function (prior to and periodically during treatment), and hyperglycemia. For adrenal insufficiency or hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 adrenal insufficiency or hypophysitis and withhold or discontinue KEYTRUDA for Grade 3 or Grade 4 adrenal insufficiency or hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barr syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptorblocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

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Merck to Present New Data from its Broad Oncology Portfolio and Pipeline at the ASCO20 Virtual Scientific Program - Business Wire

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50 Aussie research projects to beat coronavirus – Tweed Daily News

By daniellenierenberg

Australian researchers are at the forefront of world efforts to find vaccines, treatments and new tests for coronavirus with more than 50 projects already under way.

The Australian Association of Medical Research Institutes has compiled a list of major COVID-19 research projects in every state.

Apart from the University of Queensland's project to develop a vaccine, there are trials under way that repurpose existing drugs to treat COVID-19 patients, teams of scientists are developing new antiviral drugs, others are working on monoclonal antibody treatments that harness the body's immune system to fight the virus.

Burnet Institute in Victoria is screening ACE 2 inhibitor drugs for blood pressure to see if they can prevent or treat COVID-19 infection.

They plan to turn the best performing drugs into formulations that can be inhaled to deliver the drug directly to where the virus is in the lungs.

It is also developing monoclonal antibodies essential for profiling the immune response in humans infected with COVID-19 to help develop point of care tests.

Hudson Institute in Victoria, in collaboration with Biotech company Noxopharm, has found a cancer drug Veyonda could block pathways that causes a deadly inflammatory reaction in COVID-19 patients called a cytokine storm.

Noxopharm is seeking approval from the US FDA for a clinical trial in COVID-19 patients of Veyonda.

The Walter and Eliza Hall Institute in Melbourne is developing 'biologics' medicines for coronavirus infections.

The race for a COVID-19 cure is on and Australia is at the forefront. Picture: Shutterstock

These mimic antibodies to fight infection and are already in clinical use for diseases such as cancer and auto-immune conditions.

The Institute is also leading COVID-19 SHIELD, Australia's first clinical trial to assess whether the drug hydroxychloroquine is effective in preventing COVID-19 in frontline healthcare workers.

Doherty Institute Melbourne was the first group outside China to grow the COVID-19 virus, it is conducting the testing for COVID-19 in patients and validating commercial tests for the virus.

The institute's experts have been conducting pandemic modelling for the government on the spread of COVID-19.

It is helping Melbourne University run the ASCOT trial that will initially test two treatments for hospitalised COVID-19 patients, using drugs that are currently used to treat HIV (lopinavir/ritonavir) and malaria (hydroxychloroquine).

It is also developing a vaccine for COVID-19.

CSIRO is running animal trials of two potential COVID-19 vaccines, it has helped test the University Queensland vaccine on mice.

It is conducting research into genetic changes in the virus and doing computer modelling to understand how the virus behaves.

It is tracing where the virus came from and how it jumped from animals to humans and is working on how it spread so quickly.

The Monash Biomedicine Discovery Institute (BDI) and the Doherty Institute in Victoria have shown that head lice treatment ivermectin kills the COVID-19 in a test tube.

It is now checking whether it works at doses that are safe to use in humans and will then trial it on animals.

Garvan Institute in Sydney in collaboration with UNSW Sydney's Kirby Institute, is developing antibodies designed to target proteins the virus needs to infect human cells.

The potential antiviral therapy could help the elderly and chronically ill and be administered as a preventative therapy to health workers on the frontline.

Victor Chang Cardiac Research Institute Sydney in collaboration with St Vincent's Hospital Sydney and two hospitals in Victoria are planning a clinical trial of a stem cell to dampen down the hyperactivity of the immune system that causes severe heart and lung problems in patients with COVID-19.

The Kirby Institute at UNSW Sydney is researching hyperimmune globulin-based therapy based on the blood plasma of people who have recovered from the virus, it is engineering monoclonal antibodies for COVID-19 protection and therapy and is working on a treatment that could be delivered direct to the lungs via an inhaler or puffer.

There are more than 50 vaccines underway in Australia alone. Picture: Marieke De Lorijn/Supplied

QMIR Berghofer is conducting a randomised controlled trial of anti-inflammatory drug tocilizumab on critically ill patients with COVID-19 in the hope it can prevent the cytokine storm that is killing some COVID-19 patients.

It is also testing existing, widely used, and safe drugs to reduce COVID-19's ability to infect cells and help the immune system fight the disease and it is adapting its patented liquid biopsy assay system that has been successfully used in cancer patients to predict disease progression in patients with COVID-19.

It is developing antiviral gene-based drugs, looking factors that make some people more susceptible to severe COVID-19 symptoms.

It is using its 'human-heart-muscle-in-a-dish' to examine how COVID-19 causes cardiotoxicity and screen for drugs to limit heart injury in COVID-19 patients.

It is collecting information on COVID-19 from 80,000 Australians for whom researchers already have detailed genetic data will enable them to rapidly and cheaply identify genetic risk factors that might fast-track targets for drug development.

It is researching the way people with blood cancers respond to COVID-19.

Blood cancer treatments target immune cells that make antibodies to fight viruses.

It is developing a test to detect who has immunity to the virus.

The Institute for Glycomics (QLD), building on many years of vaccine development in streptococcus and malaria, is trying to identify critical target points on the coronavirus that may be susceptible to immune attack and to use that information to develop a highly focused vaccine.

Griffith Institute for Drug Discovery's rapid response technologies that allow fast design and manufacture of vaccines to combat pandemic threats has found five COVID-19 vaccine candidates that have been designed and manufactured and are currently being evaluated in animal trials.

The South Australian Health and Medical Research Institute is studying the protein-making pathway that are activated by coronavirus in an attempt to slow the growth of the virus.

They already know how to inhibit this pathway using a drug that is already in phase 2 clinical trials and cleared for use in humans.

Originally published as 50 Aussie research projects to beat coronavirus

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50 Aussie research projects to beat coronavirus - Tweed Daily News

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What is the Value of iPSC Technology in Cardiac… – The Doctor Weighs In

By daniellenierenberg

According to the World Health Organization (WHO), cardiovascular disease, specifically ischemic heart disease, is one of the leading causes of death worldwide. Cardiovascular diseases result in an estimated 17.9 million deaths each year. This is about 31% of all deaths worldwide (1). Medical researchers are continually working on ways to reduce those numbers, including the development of new technologies to combat premature deaths from cardiovascular diseases. This article will focus, in particular, on the value of induced pluripotent stem cells (iPSCs) in cardiac research.

iPSCs are a type of pluripotent stem cell. These are master cells that can differentiate into any cell or tissue the body needs. They are generated directly from somatic cells through ectopic expression of various transcription factors, such as

Theyve become key tools to model biological processes, particularly in cell types that are difficult to access from living donors. Many research laboratories are working to enhance reprogramming efficiency by testing different cocktails of transcription factors.

iPSCs have become essential in a number of different research fields, including cardiac research.

They are a valuable and advantageous technologic development for two main reasons:

Most people have heard of embryonic stem cells, which are one variation of pluripotent cells. Like iPSCs, they can be used to replace or restore tissues that have been damaged.

The problem is that embryonic stem cells are only found in preimplantation stage embryos (3). Whereas iPSCs are adult cells that have been genetically modified to work like embryonic stem cells. Thus, the term, inducedpluripotent stem cells.

The development of iPSCs was helpful because embryos are not needed. This reduces the controversy surrounding the creation and use of stem cells. Further, iPSCs from human donors are also more compatible with patients than animal iPSCs, making them even closer to their embryonic cousins.

The Japanese inventor of iPSCs, Professor Shinya Yamanaka earned a Nobel Prize in 2012 for the discovery that mature cells can be reprogrammed to become pluripotent. (4) The Prize was awarded to Dr. Yamanaka because of the significant medical and research implications this technology holds.

iPSCs hold a lot of promise for transplantation medicine. Further, they are highly useful in drug development and modeling of diseases.

iPSCs may become important in transplantation medicine because the tissues developed from them are a nearly identical match to the cell donors. This can potentially reduce the chances of rejection by the immune system (5).

In the future, and with enough research, it is highly possible that researchers may be able to perfect the iPSC technology so that it can efficiently reprogram cells and repair damaged tissues throughout the body.

iPSCs forgo the need for embryos and can be made to match specific patients. This makes them extremely useful in both research and medicine.

Every individual with damaged or diseased tissues could have their own pluripotent stem cells created to replace or repair them. Of course, more research is needed before that becomes a reality. To date, the use of iPSCs in therapeutic transplants has been very limited.

One of the most significant areas where iPSCs are currently being used is in cardiac research. With appropriate nutrients and inducers, iPSC can be programmed to differentiate into any cell type of the body, including cardiomyocyte. This heart-specific cell can then serve as a great model for therapeutic drug screening or assay development.

Another notable application of iPSCs in cardiac research is optical mapping technology. Optical mapping technology employs high-speed cameras and fluorescence microscopy to examines the etiology and therapy of cardiac arrhythmias in a patient-like environment. This is typically done by looking into electrical properties of multicellular cardiac preparations., e.g. action potential or calcium transient, at high spatiotemporal resolution (6).

Optical mapping technology can correctly record or acquire data from iPSCs. iPSCs are also useful in mimicking a patients cardiomyocytes with their specific behaviors, resulting in more reliable and quality data of cardiac diseases.

iPSCs are vital tools in cardiac research for the following reasons:

iPSCs are patient-specific because they are 100% genetically identical with their donors. This genomic make-up allows researchers to study patients pathology further and develop therapeutic agents for treating their cardiac diseases.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), help researchers predict the cardiotoxicity of drugs like with widely used chemotherapy reagents (10). Predictions like this were close to impossible before iPSC technology entered the research game.

iPSCs really come into play with their ability to model diseases. Because iPSCs are genetic matches to their living donors, they are uniquely useful for the study of genetic cardiac diseases like monogenic disorders. iPSCs help researchers understand how disease genotypes at the genetic level manifest as phenotypes at the cellular level (5).

Long QT syndrome, a condition that affects the repolarization of a patients heart after a heartbeat, is a notable example of iPSC-based disease modeling (7). This syndrome has been successfully modeled using iPSCs and is an excellent model for other promising target diseases (7).

Long QT syndrome is not the only disease that has been modeled by iPSCs. Other cardiac diseases like Barth syndrome-associated cardiomyopathy and drug-induced kidney glomerular injuries have been modeled as well (8).

The advent of iPSC technology has created a wealth of new opportunities and applications in cardiovascular research and treatments. In the near future, researchers hope that iPSC-derived therapies will be an option for thousands, if not millions of patients worldwide.

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What is the Value of iPSC Technology in Cardiac... - The Doctor Weighs In

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BioCardia Announces Positive Preclinical Results Supporting Investigational New Drug Application for Anti-Inflammatory Cell Therapy in Heart Failure -…

By daniellenierenberg

SAN CARLOS, Calif., May 05, 2020 (GLOBE NEWSWIRE) -- BioCardia, Inc.[Nasdaq: BCDA], a leader in the development of comprehensive solutions for cardiovascular regenerative therapies, today announced data from a recent animal study performed by the Company that demonstrate meaningful improvements in heart function for subjects treated with its allogenic (from another donor, or off the shelf) neurokinin 1 receptor positive mesenchymal stem cell (NK1R+ MSC) program for heart failure, known as CardiALLO. In addition, the Company is planning further exploration and discussion with the U.S. Food and Drug Administration (FDA) on the use of its allogenic cells for COVID-19 related Acute Respiratory Distress Syndrome (ARDS).

In the 26 animals treated with both low dose and high dose NK1R+ MSC, echocardiographic measures of cardiac ejection fraction, fractional shortening and cardiac outflow were meaningfully improved, with all three measures being statistically significant for both dosage levels over control animals.

The CardiALLO cell therapy is being developed initially to treat heart failure patients whose cells do not qualify for its lead autologous cell therapy, CardiAMP (BCDA-01).

BioCardia Chief Scientific Officer Ian McNiece, PhD, said, In light of these positive data on our allogenic NK1R+ MSC therapy, we expect to meet our internal timeline to complete our submission to the FDA for our first indication for CardiALLO, and potentially receive IND acceptance by the end of the second quarter. The MSCs that were studied are subtypes of MSC that we have delivered previously in our co-sponsored trials, which we believe have enhanced potency over MSC generated from unselected bone marrow cells. We look forward to seeing additional data from this animal study that are currently being analyzed, including histology and pathology of the heart and lungs.

COVID-19 Induced Acute Respiratory Distress Syndrome (ARDS) Exploration

The Company also intends to submit an IND for the use of its NK1R+ MSC delivered via intravenous (IV) infusion for Acute Respiratory Distress Syndrome (ARDS) caused by COVID-19.

Based on preliminary clinical reports on COVID-19, respiratory failure complicated by ARDs is the leading cause of death for COVID-19 patients.1 ARDS is a type of respiratory failure characterized by the rapid onset of widespread inflammation in the lungs.

The anti-inflammatory effects of MSC have been well-documented and MSC have been shown to reduce inflammation and injury in models of lung disease.2 The specific MSCs used in BioCardias allogenic cell therapy are expanded from cells selected for the presence of the NK1 receptor, which is known to bind to substance P, an important neuropeptide associated with inflammation throughout the body and a primary mediator of inflammation in the airways.3,4

Our NK1R+ allogenic MSC may have more potential than other MSC approaches being advanced today due to their interaction with Substance P, said BioCardia CEO Peter Altman, PhD. This COVID-19 related work will be the Companys first clinical investigation outside of the cardiac space and our first exploring therapy for the lung. A recent patent publication (US 2020/0101113 A1) shows that BioCardia has long intended for these remarkable reparative cells to be targeted for respiratory disorders, in addition to cardiovascular disease. Addressing inflammation in the lungs is an important contribution we may be able to make using our NK1R+ allogenic MSC therapy.

The Companys allogenic cells are expected to be manufactured at BioCardias clinical stage cell manufacturing facility in San Carlos, California.

About BioCardiaBioCardia, Inc., headquartered in San Carlos, California, is developing regenerative biologic therapies to treat cardiovascular disease. CardiAMP and CardiALLO cell therapies are the Companys biotherapeutic product candidates in clinical development. The Company's approved products include the Helix transendocardial delivery system and its steerable guide and sheath catheter portfolio. BioCardia also partners with other biotherapeutic companies to provide its Helix System and clinical support to their programs studying therapies for the treatment of heart failure, chronic myocardial ischemia and acute myocardial infarction.

Forward Looking Statements This press release contains forward-looking statements that are subject to many risks and uncertainties. Forward-looking statements include, among other things, references to the development of NK1R+ cells for the treatment of heart failure and ARDS secondary to COVID-19, potential FDA IND acceptances, and potential FDA filings, statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations. Such risks and uncertainties include, among others, the inherent uncertainties associated with developing new products or technologies. These forward-looking statements are made as of the date of this press release, and BioCardia assumes no obligation to update the forward-looking statements.

We may use terms such as believes, estimates, anticipates, expects, plans, intends, may, could, might, will, should, approximately or other words that convey the uncertainty of future events or outcomes to identify these forward-looking statements. Although we believe that we have a reasonable basis for each forward-looking statement contained herein, we caution you that forward-looking statements are not guarantees of future performance and that our actual results may differ materially from the forward-looking statements contained in this press release. As a result of these factors, we cannot assure you that the forward-looking statements in this press release will prove to be accurate. Additional factors that could materially affect actual results can be found in BioCardias Form 10-K filed with the Securities and Exchange Commission on April 9, 2020, under the caption titled Risk Factors. BioCardia expressly disclaims any intent or obligation to update these forward-looking statements, except as required by law.

Media Contact: Michelle McAdam, Chronic Communications, Inc.michelle@chronic-comm.com(310) 902-1274

Investor Contact: David McClung, Chief Financial Officerinvestors@BioCardia.com(650) 226-0120

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BioCardia Announces Positive Preclinical Results Supporting Investigational New Drug Application for Anti-Inflammatory Cell Therapy in Heart Failure -...

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Evaluating Nelipepimut-S in the Treatment of Breast Cancer: A Short Report on the Emerging Data – Oncology Nurse Advisor

By daniellenierenberg

Abstract:Vaccine therapies for treatment andprevention of cancer have seen modest degrees of efficacy with wide variationrelated to the tumor type, vaccine type, adjuvants and clinical setting fortheir study. Over the course of the last two decades, various peptide vaccinesfor breast cancer have been studied. The current leading peptide vaccine forhuman application is a HER2-based vaccine known as Nelipepimut-S, which hasdemonstrated immune activity and promising clinical activity in some settings.This review covers the development of this newer peptide vaccine for both HER2amplified and non-amplified breast cancer.

Keywords:vaccine, breast cancer, HER2, peptide,human

INTRODUCTION

The human epidermal growth factor receptor 2 (HER2) proteinhas been one of the most extensively studied and targeted markers in oncologyin the last 30 years. The identification of the HER2 receptor and thedevelopment of antibodies to target it such as trastuzumab, pertuzumab andothers, are among the most successful advances in the treatment of breastcancer in the past 50 years. The research community learned that HER2signalling through its membrane-bound tyrosine kinase domain results indownstream activation of a cascade of events leading to angiogenesis, cellularinvasiveness, proliferation and survival proficiency. It is well known thatabout 20 percent of breast cancers will have marked overexpression of the HER2receptor and will benefit from HER2 targeting agents. It is generally acceptedthat most of the other 80% of breast cancers will express HER2, but at lowerlevels. There remains debate about the potential role of the HER2 protein andHER2 targeting in lower expressing breast cancers. Nevertheless, as a targetfor either passive or active immunotherapy, HER2 has been immunogenic due toantigens such as HER2369-377(also known as the E75 peptide)that are easily recognized by T cells and dendritic cells.

The currently available agents approved for HER2-overexpressing breast cancer include: trastuzumab, ado-trastuzumab, pertuzumab, lapatinib, neratinib, most recently trastuzumab deruxtecan, and five trastuzumab biosimilars (as of 1/2020). Additionally, the novel HER2 targeted monoclonal antibody, margetuximab, and a small molecule inhibitor, tucatinib, are currently being reviewed by the US FDA for possible approvals. While some of those drugs have been tested in HER2-low settings and non-breast settings, none have been approved to date for an indication outside of HER2-high or HER2 over-expressed cancer. Likewise, vaccine strategies have tested peptides, whole cell vaccines, dendritic cell vaccines, DNA vaccines and multipeptide vaccine in both HER2-high and HER2-low settings. The present review will examine the activity, development, efficacy and safety of the E75 peptide (also known as Nelipepimut-S when combined with GMCSF) as a peptide vaccine for breast cancer. Nelipepimut-S is currently in Phase III clinical development (NCT01479244) and has strong evidence of immunologic activity, though there is mixed evidence to date of clinical activity against early stage HER2-overexpressed breast cancer and there is little clinical activity reported against advanced metastatic disease. There is emerging data on Nelipepimut-S for HER2-low and triple negative breast cancer that will be reviewed.1

METHODS: LITERATURE SEARCH, INCLUSION AND EXCLUSION CRITERIA

We performed a systematic search of peer-reviewed literaturedatabases from 11/1/2019 to 12/9/2019. This review was limited to manuscripts,abstracts and chapters available in the English language and catalogued inPubmed, Web of Science, Scopus and proceedings of national meetings including:ASCO, SITC, SABCS, ESMO (American Society of Clinical Oncology, Society forImmunoTherapy of Cancer, San Antonio Breast Cancer Symposium, and EuropeanSociety of Medical Oncology). We searched for keywords including: HER2peptide E75 peptide, Nelipepimut-S, Neu-vax, breast cancer. Weexcluded trials examining cancers other than breast cancer and other related peptidesoutside the studied amino acid sequence from HER2369-377.Multipeptide vaccine studies were included for completeness.

BACKGROUND OF NELIPEPIMUT-S

The aim of a cancer vaccine is to stimulate a cancerpatients immune system to recognize tumor associated antigens via activeimmunotherapy. Successful active immunotherapy results in T cell recognitionand killing of cells expressing the antigen of interest. Ideally, successful Tcell mediated tumor killing should lead to epitope spreading to increase therepertoire of T cells for cytolysis, and lead to long term T cell memory.Several peptide vaccines have been investigated for these purposes, and apeptide sequence that is successful to date is the E75 HER2 peptide vaccine,otherwise known as Nelipepimut-S.2This vaccine has severalpublished clinical and preclinical reports and has been studied in aregistrational phase III study.3Nelipepimut-S, or the E75vaccine, is a 9 amino acid sequence from the extracellular domain of the HER2receptor (residues 369377 of HER2neu: KIFGSLAFL4). This 9 aminoacid sequence has long been known to be the immunologically dominant epitope ofthe protein and is presented both by HLA-A2 and HLA-A3 (HLA restricted).2,5,6Thesetwo alleles represent a majority of patients with breast cancer. HER2 is ofcourse a self-antigen, but overexpression is largely limited to breast cancers(and occasionally lung, gastric and colon cancers). Surprisingly, there doesnot appear to be negative thymic selection of HER2369-377specificT cells as shown by several groups.710Thus the E75 antigenfrom HER2 is a reasonable target for a variety of immunotherapies.

During in vitro preclinical development, the E75 peptide wasrecognized by CD8+ T lymphocytes. Subsequently, it was demonstrated thatE75-stimulated cytotoxic T lymphocytes were capable of lysis of HER2-expressingcancer cell lines.4,10,11The specificity of pulsed T cells forHER2 expressing cells was replicated in mouse models of cancer.8,12Additionally,it was found by multiple groups that lymphocytes in circulation occasionallyharbor pre-existing responses against the E75, 9 amino acid sequence HER2neu369-377usedin the subsequent development of Nelipepimut-S.6,11-13Likewise,dendritic cells from normal donor blood sources have been shown to be able topresent the E75 peptide and to generate E75-specific T cells.14

CLINICALS TRIALS WITH THE E75 PEPTIDE

The earliest Phase I pilot study of the E75 peptide inhumans also incorporated a MUC1 peptide (M1.2) in an autologous dendritic cellvaccine in breast and ovarian cancer.14Among 10 patients, CD8responses to E75 and M1.2 were observed (via intracellular interferon assay andchromium release assays) in 5 patients. The authors also reported evidence ofepitope spreading in two patients after repeat vaccination.

A study by Zaks and Rosenberg (Table 1) examined theactivity of the single E75 peptide formulated with incomplete Freunds adjuvantin various solid tumors, including breast cancer. CD8 responses were againobserved in human leukocyte antigen (HLA) -A2 and HLA-A3 patients, but anergyrather than memory was the long term outcome,15possibly due tooverstimulation related to incomplete Freunds adjuvant.

Subsequently, the E75 peptide was combined with GM-CSF toattempt to overcome the anergy suspected to be due to the incomplete Freundsadjuvant in the prior study. When combined with GM-CSF, the vaccine is termedNelipepimut-S (also previously called Neu-vax). Two phase I studies of 6 and 14patients respectively with advanced disease were completed using Nelipepimut-Sby intradermal injection, and safety was observed for up to 1000 micrograms(mcg) of Nelipepimut-S along with 250mcg of GM-CSF. Immune response wasobserved by means of ELIspot and delayed type hypersensitivity analysis.16,17Patientsreceived monthly vaccinations for up to 10 months and no dose limiting toxicitywas observed.

Given the challenge of developing an immunotherapy inheavily pre-treated metastatic patients, the Nelipepimut-S was subsequentlytested in early stage, surgically resected breast cancer patients. Testing inearly stage disease was expected to be safe given the excellent safety profileobserved in the metastatic setting. Thus, a paired set of trials (NCT00841399,NCT00584789) were performed for stage II or stage III, HER2-expressing breastcancer as defined as any immunohistochemical (IHC) staining from 1+ to 3+. Thesister clinical trials (phase II) were performed in the United States and havesince been published.7,18,19In the studies, all patients wereclinically disease-free and were permitted to use concomitant endocrinetherapies as well as prior Trastuzumab therapy. The dose and schedule wereoptimized in these early adjuvant trials. Ultimately, 195 patients wereenrolled and followed for 60 months.18,19There were 100patients vaccinated and 95 control patients. In the primary analysis, with amedian 20 months follow-up after vaccination, the recurrence rates were 5.6% vs14.2% in vaccinated vs unvaccinated participants (p=0.04).20Thusthe studies met their primary endpoint. However, for secondary analysis it wasfound that the short-term recurrence difference observed at 20 months did notpersist at any of the later analyses. For example, there was no difference inrecurrence at the 26month analysis (p=0.15) nor at 60 months (p=0.08). Therewas no difference in overall survival (OS) with p value=0.1. The authorssuggested that waning immunity due to lack of boosting contributed to the lackof long term benefit of the vaccine strategy.20Interestingly,there was a higher rate of visceral metastases in the vaccine-treated patientswhen they recurred. The toxicities of this vaccine strategy included flu-likesymptoms, fatigue, and bone pain. Less than 2% of patients experienced any highgrade toxicity (highest grade=3). The study concluded that an optimal dosewould be 1000mcg and that a potential phase III trial should be performed.

In the sister Phase II trials, boosting was explored and asuggestion of benefit was observed with boosting once every 6 months.Exploratory analysis also showed that the low-grade breast cancers seemed toderive greater benefit from Nelipepimut-S vaccination than higher grade breastcancers. In a late followup report, there was only one recurrence observed inthe 21 participants with optimal dosing of booster vaccines.18

Following completion of the phase II studies, a phase IIIstudy of Nelipepimut-S as a single agent, was designed and given the acronym,PRESENT. The PRESENT study (NCT01479244) fully accrued across 197 researchsites by Galena Biopharma Inc. PRESENT was a registrational study of 758patients with early stage, node positive breast cancer with low to intermediateHER2 expression with a primary endpoint of 3 year disease free survival (DFS).Patients received either Nelipepimut-S with GM-CSF or GM-CSF alone over thecourse of six intradermal injections followed by boosting every 6 months for 3years.3The interim analysis was published in 2019 anddemonstrated no overall difference in disease free survival (DFS) between armsat 16 months follow-up. There was a numerically higher number ofimaging-detected recurrences in the Nelipepimut-S vaccinated patients (54.1%)compared to placebo (29.2%).3The phase III PRESENT study wasdiscontinued due to futility in 2016, based on that interim analysis and thedata monitoring committee recommendation. No new safety signals were reported,and no cardiac signals were seen. The protocol design required empiriccross-sectional body imaging yearly in all patients. This imaging requirementwas a deviation from the existing standard of care (which would be for no crosssectional imaging unless symptoms arise). The required cross sectional imagingmay have impacted on the early termination of the study. The control arm had arecurrence rate comparable to rates seen in contemporary trials in early stagepatients. There is some speculation about whether pseudoprogression findingsmight have been observed in the radiographic recurrences, but biopsyconfirmation was not undertaken, so no conclusion can be drawn. Given anegative phase III result in PRESENT, there is unclear future for thedevelopment of Nelipepimut-S in the node positive, HER2-low, adjuvant breastcancer population.

COMBINATION CLINICAL TRIALS WITH NELIPEPIMUT-S

Given the challenge and phase III disappointment ofdeveloping Nelipepimut-S as a stand-alone therapy, it is now also beingexamined in combinatorial studies. Preclinical data had suggested thattrastuzumab could increase cross presentation of the E75 epitope and moreefficient expansion of specific CD8+T cells. The first phaseIIb combination trial of E75 and trastuzumab (NCT01570036) enrolled 275patients with HER2 low (IHC 1+ or 2+) breast cancer in the United States andcombined Nelipepimut-S with trastuzumab.1The patients receivedeither Nelipepimut-S with trastuzumab or trastuzumab/GM-CSF. The study designwas based on the observation, during the early phase Nelipepimut-S studies,that 12 patients were concurrently exposed to trastuzumab as a standard of careand none of those 12 patients experienced recurrent breast cancer.21Inthis newer phase IIb combinatorial study of Nelipepimut-S with trastuzumab,overall, there was no statistically significant difference in DFS (p=0.18),although there was a benefit seen in the subgroup of patients deemed to betriple negative. In this subset of 97 patients, the DFS for Nelipepimut-S plustrastuzumab was 92.6% compared with 71.9% for the trastuzumab/GM-CSF group (HR=0.26, p=0.01).1This encouraging subset finding has reportedlyled to the design of an upcoming clinical trial in the triple-negative earlystage setting.

NELIPEPIMUT-S WITH TRASTUZUMAB IN HER2 IHC3+ BREAST CANCER

In a recently completed randomized phase II trial (NCT02297698), 100 patients with traditionally-defined HER2 overexpression (IHC 3+) and otherwise high risk, non-metastatic breast cancer were enrolled to 1 to 1 randomized study of trastuzumab Nelipepimut-S and followed for DFS. This study completed accrual in 2017, and interim results demonstrated that Nelipepimut-S was well tolerated, and no significant difference in side effect profile nor cardiac ejection fraction was observed between the two arms of the study.22Clinical results have not been released to date.

TRIAL OF NELIPEPIMUT-S IN DCIS OF THE BREAST

A phase II study (NCT02636582) termed the VADIS study isassessing Nelipepimut-S against GM-CSF for ductal carcinoma in situ (DCIS) inthe neo-adjuvant window of opportunity design.23The premisefor this is supported by work published by Lowenfeld et al.24Inthis ongoing VADIS study, Nelipepimut-S or GM-CSF is given as two injectionsprior to definitive breast surgery. The primary endpoint is circulating immuneresponse at 6 months after vaccination. Secondary endpoints are toxicity andsafety. The study completed accrual in July 2019, and findings are stillpending.

OTHER E75 STUDIES IN BREAST CANCER

The potential promise of Nelipepimut-S vaccines, butnegative results in the large phase III trial, raise questions of whetheralternate vaccine formulations may induce stronger and more effective immuneresponses. A recently published study created and tested a liposomalformulation of the vaccine by attaching the E75 peptide to the surface ofdistearoyl phosphocholine and distearoyl phophoglycerol of nano-liposomes forvaccination.25ELISpot analysis and flow cytometry demonstratedsignificantly enhanced antitumor responses as well as tumor inhibition andprolonged survival time in the mouse TUBO model, which is a cell line thatoverexpresses the rHER/neu protein. Thus, this approach offers promise fortranslation to human clinical trials. There is also an ongoing autologous dendriticcell vaccine of the E75 peptide in combination with vinorelbine and trastuzumabin human cancer patients at the University of North Carolina (NCT00266110).26Finally,a series of four clinical trials performed at the University of Virginiaincorporated the E75 peptide into multipeptide vaccines for breast and ovariancancer, and using either polyICLC or incomplete Freunds adjuvant, rather thanGM-CSF (NCT00892567, NCT00304096, NCT01532960, NCT00091273). Immune responseswere detected, but clinical activity was not observed.27,28

DISCUSSION

The Nelipepimut-S vaccine alone demonstrates immune activityin patients expressing HLA-A2 or HLA-A3. As detailed above, the use of theNelipepimut-S vaccine in adjuvant breast cancer settings has not led toclinically meaningful improvements in overall survival or disease free survivalin a large randomized trial to date. Nevertheless, there are hints that thisparticular vaccine may hold potential clinical value in selected settings. Forexample, a meta-analysis of the 5 human clinical trials that involvedrandomization was performed in an effort to combine data from the smallertrials. In a published meta-analysis, the delayed hypersensitivity (DTH)responses and DFS combined data across trials suggested significant benefits tovaccination over control (p<0.05 and p=0.001 respectively). The combineddata for OS and recurrence were suggested to also have relevance (p=0.863 andp=0.388).29The conclusions of the meta-analysis do notablydiffer from some of the individual trials and obviously the patient populationshad major differences, thus rendering the impact of a meta-analysis unclear.Despite the criticisms of aggregation of data in the meta-analysis, it doessuggest that in appropriate settings that the Nelipepimut-S may have clinicalbenefits for some patients without untoward toxicity. Raw data from the large750 patient randomized phase III PRESENT trial, which was stopped for futility,was not available for analysis in that meta-analysis.

Thus, vaccine researchers in breast cancer are leftwondering which direction to focus limited resources on. Clearly there isimmunogenicity when vaccinating with the E75 peptide, and it tends todemonstrate synergy with passive antibody-based immunotherapy (ie, trastuzumabcombinations). It is also intriguing that the triple negative early stagebreast cancer population may have the greatest relative benefit afterNelipepimut-S vaccination. To date, there has been little traction indeveloping combinatorial strategies with checkpoint inhibitors or with myeloidsuppressing immunotherapy strategies. With checkpoint inhibitors approved inthe metastatic triple negative setting and expected in the triple negativeadjuvant setting, it is unclear what role peptide vaccination strategies may beable to play in the future triple negative treatment landscape.

Some remaining concerns for the E75 HER2 peptide developmentinclude the criticism that the peptide is HLA restricted and thus not availableuniversally to all patients. Also there is an unresolved question about how toaddress waning immunity and the need for long-term boosting strategies. Finally,the question about how best to select patients, especially in light of majorimmune system modulation that occurs during and immediately following adjuvantchemotherapy. It remains unknown whether the rebounding immune system in the 6months following cytotoxic chemotherapy presents a stimulatory or suppressiveenvironment for peptide vaccine generally and specifically for thisNelipepimut-S vaccine. Likewise, since HER2 targeting antibodies also impact onthe immune recognition of antigens from HER2, it is further unclear whetherearly adjuvant vaccination at the time of adjuvant HER2 antibodies or followingthe course of HER2 maintenance antibodies will be optimal.

CONCLUSION

Nelipepimut-S demonstrated immune activity against HER2positive breast cancer and suggestion of activity against triple negativebreast cancer. Its development in the adjuvant HER2 low to intermediatepopulation might be unlikely to continue based on the negative phase IIIPRESENT trial. Nevertheless, several important studies are yet to be performedfor the Nelipepimut-S and related E75 vaccines, such as combinatorial studies,novel adjuvant studies, boosting strategies, and biomarker driven studies.Recently there is rising interest in vaccine therapy for breast cancer, so thisor related vaccine strategies are likely to continue to be explored. Optimalpatient selection and monitoring may aid in future development of this cancertherapy.

Acknowledgments

Drs. Dillon, Brenin and Slingluff are supported by NCIsupport grant: 2P30CA044579-26 for the University of Virginia Cancer Center.

Disclosure

Drs. Dillon and Slingluff have published studies on peptidesreferenced in this manuscript. The University of Virginia was a subsite for aclinical trial referenced in this manuscript. Dr Dillon participated in aclinical trial for Galena Pharmaceuticals. Dr. Slingluff is an inventor onlicensed patents held by the University of Virginia Licensing and Venturesgroup for peptides used in melanoma vaccines. Dr Slingluff reports grants,non-financial support from Celldex for providing antibodies for clinical trialsand for preclinical studies. He also reports grants and/or non-financialsupport from Merck, Immatics, Polynoma, and GlaxoSmithKline; non-financialsupport from Theraclion, outside the submitted work. Dr Slingluff also in theprocess of joining the scientific advisory board with CureVac. In addition, DrSlingluff has patents on peptides used in cancer vaccines with royalties paid,a pending patent on biomarkers, a patent for a surgical device issued. Theauthors report no other conflicts of interest in this work.

Patrick M. Dillon,1Christiana M. Brenin,1Craig L. Slingluff Jr2

1University of Virginia, Division of Hematology/Oncology, Charlottesville, VA 22908, USA;2University of Virginia, Department of Surgery, Charlottesville, VA 22908, USA

Correspondence: Patrick M DillonDivision of Hematology/Oncology, University of Virginia, Box 800716, Charlottesville, VA 22908, USATel +1-434-982-1495Fax +1-434-244-7534Email Pmd5b@hscmail.mcc.virginia.edu

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6.Fisk B, Savary C, Hudson JM, et al. Changes in an HER-2 peptide upregulating HLA-A2 expression affect both conformational epitopes and CTL recognition: implications for optimization of antigen presentation and tumor-specific CTL induction.J Immunother Emphasis Tumor Immunol. 1995;18(4):197209. doi:10.1097/00002371-199511000-00001

7.Amin A, Benavides LC, Holmes JP, et al. Assessment of immunologic response and recurrence patterns among patients with clinical recurrence after vaccination with a preventive HER2/neu peptide vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.Cancer Immunol Immunother. 2008;57(12):18171825. doi:10.1007/s00262-008-0509-2

8.Brossart P, Stuhler G, Flad T, et al. Her-2/neu-derived peptides are tumor-associated antigens expressed by human renal cell and colon carcinoma lines and are recognized by in vitro induced specific cytotoxic T lymphocytes.Cancer Res. 1998;58(4):732736.

9.Holmes JP, Clifton GT, Patil R, et al. Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.Cancer. 2011;117(3):463471. doi:10.1002/cncr.25586

10.Kawashima I, Hudson SJ, Tsai V, et al. The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors.Hum Immunol. 1998;59(1):114. doi:10.1016/S0198-8859(97)00255-3

11.Kono K, Takahashi A, Sugai H, et al. Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer.Clin Cancer Res. 2002;8(11):33943400.

12.Lustgarten J, Theobald M, Labadie C, et al. Identification of Her-2/Neu CTL epitopes using double transgenic mice expressing HLA-A2.1 and human CD.8.Hum Immunol. 1997;52(2):109118. doi:10.1016/S0198-8859(96)00292-3

13.Kuerer HM, Peoples GE, Sahin AA, et al. Axillary lymph node cellular immune response to HER-2/neu peptides in patients with carcinoma of the breast.J Interferon Cytokine Res. 2002;22(5):583592. doi:10.1089/10799900252982061

14.Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells.Blood. 2000;96(9):31023108. doi:10.1182/blood.V96.9.3102

15.Zaks TZ, Rosenberg SA. Immunization with a peptide epitope (p369-377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors.Cancer Res. 1998;58(21):49024908.

16.Knutson KL, Schiffman K, Cheever MA, Disis ML. Immunization of cancer patients with a HER-2/neu, HLA-A2 peptide, p369-377, results in short-lived peptide-specific immunity.Clin Cancer Res. 2002;8(5):10141018.

17.Murray JL, Gillogly ME, Przepiorka D, et al. Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369-377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer.Clin Cancer Res. 2002;8(11):34073418.

18.Mittendorf EA, Clifton GT, Holmes JP, et al. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients.Ann Oncol. 2014;25(9):17351742. doi:10.1093/annonc/mdu211

19.Peoples GE, Gurney JM, Hueman MT, et al. Clinical trial results of a HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer patients.J clin oncol. 2005;23(30):75367545. doi:10.1200/JCO.2005.03.047

20.Peoples GE, Holmes JP, Hueman MT, et al. Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high-risk breast cancer patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02.Clin Cancer Res. 2008;14(3):797803. doi:10.1158/1078-0432.CCR-07-1448

21.Mittendorf EA, Clifton GT, Holmes JP, et al. Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.Cancer. 2012;118(10):25942602. doi:10.1002/cncr.26574

22.Peace KM, Litton JK, Murthy RK, et al. Pre-specified interim analysis in a prospective, randomized phase II trial of trastuzumab vs trastuzumab + NeuVax to prevent breast cancer recurrence in HER2+ breast cancer patients.Paper presented at: American Association of Cancer Researchers, Annual Meeting; 2017;Washington, DC.

23.Mittendorf Elizabeth A, Plitas G, Garber J, et al. Abstract OT3-01-04: VADIS trial: phase II trial of the nelipepimut-S peptide vaccine in women with DCIS of the breast.Paper presented at: San Antonio Breast Cancer Symposium; 2016;San Antonio, TX.

24.Lowenfeld L, Mick R, Datta J, et al. Dendritic cell vaccination enhances immune responses and induces regression of HER2(pos) DCIS independent of route: results of randomized selection design trial.Clin Cancer Res. 2017;23(12):29612971. doi:10.1158/1078-0432.CCR-16-1924

25.Arab A, Behravan J, Razazan A, et al. A nano-liposome vaccine carrying E75, a HER-2/neu-derived peptide, exhibits significant antitumour activity in mice.J Drug Target. 2018;26(4):365372. doi:10.1080/1061186X.2017.1387788

26.Serody J; 2020. Vaccine Therapy, Trastuzumab, and Vinorelbine in Treating Patients With Locally Recurrent or Metastatic Breast Cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT00266110.AccessedMarch11, 2020.

27.Chianese-Bullock KA, Irvin WPJr., Petroni GR, et al. A multipeptide vaccine is safe and elicits T-cell responses in participants with advanced stage ovarian cancer.J Immunother. 2008;31(4):420430. doi:10.1097/CJI.0b013e31816dad10

28.Dillon PM, Petroni GR, Smolkin ME, et al. A pilot study of the immunogenicity of a 9-peptide breast cancer vaccine plus poly-ICLC in early stage breast cancer.J Immunother Cancer. 2017;5(1):92. doi:10.1186/s40425-017-0295-5

29.Chamani R, Ranji P, Hadji M, Nahvijou A, Esmati E, Alizadeh AM. Application of E75 peptide vaccine in breast cancer patients: a systematic review and meta-analysis.Eur J Pharmacol. 2018;831:8793. doi:10.1016/j.ejphar.2018.05.010

Source: Breast Cancer: Targets and Therapy.Originally published April 3, 2020.

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Teva and Celltrion Healthcare Announce the Launch of TRUXIMA (rituximab-abbs) Injection for Rheumatoid Arthritis, the Only Biosimilar to Rituxan…

By daniellenierenberg

TEL AVIV, Israel & PARSIPPANY, N.J. & INCHEON, South Korea--(BUSINESS WIRE)-- Teva Pharmaceuticals USA, Inc., a U.S. affiliate of Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA), and Celltrion Healthcare, Co., Ltd. (KRX KOSDAQ:091990), today announced that TRUXIMA (rituximab-abbs) injection is now available in the United States for the treatment of:

TRUXIMA is the only biosimilar to the reference product Rituxan1 (rituximab) available to treat rheumatoid arthritis in the United States. See important safety information below including Boxed Warning regarding fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation and progressive multifocal leukoencephalopathy.

We are proud to make TRUXIMA available to patients and providers as a treatment option for these indications, especially as this is the only rituximab biosimilar indicated for rheumatoid arthritis, said Brendan OGrady, Executive Vice President, North America Commercial, Teva. Following the launch of our other biosimilar earlier this year, we remain focused on our commitment to lower healthcare costs and increase price competition through the availability of biosimilars.

Celltrion Healthcare and Teva Pharmaceutical Industries Ltd. entered into an exclusive partnership in October 2016 for Teva to commercialize TRUXIMA in the U.S. and Canada. In May 2019, TRUXIMA was approved by the U.S. Food and Drug Administration (FDA) to match all of the reference products oncology indications described below.

We are pleased that patients in the United States can now have access to TRUXIMA for these new indications, said Mr. Hyoung-Ki Kim, Vice Chairman at Celltrion Healthcare. We believe that the continued use of biosimilars in the U.S. market will contribute to addressing unmet needs for patients and providers.

Earlier this year, the Centers for Medicare and Medicaid Services (CMS) granted pass-through status for TRUXIMA in the hospital outpatient setting. The Wholesale Acquisition Cost (WAC or list price) for TRUXIMA will be 10 percent lower than the reference product. TRUXIMA is expected to be available through primary wholesalers at a WAC of $845.55 per 100mg vial and $4,227.75 per 500mg vial. Actual costs to individual patients and providers for TRUXIMA are anticipated to be lower than WAC because WAC does not account for additional rebates and discounts that may apply. Savings on out-of-pocket costs may vary depending on the patients insurance payer and eligibility for participation in the assistance program.

Teva also offers dedicated patient support services through the CORE program. CORE is available to help eligible patients, caregivers and healthcare professionals navigate the reimbursement process. CORE offers a range of services, including benefits verification and coverage determination, support for precertification and prior authorization, assistance with coverage guidelines and claims investigation, and support through the claims and appeals process. A savings program is also available for eligible commercially insured patients. To learn more, please visit TevaCORE.com.

Please see the Important Safety Information below including the Boxed Warning regarding fatal infusion-related reactions, severe mucocutaneous reactions, hepatitis B virus reactivation and progressive multifocal leukoencephalopathy. For more information, please see the full prescribing information.

Indications TRUXIMA (rituximab-abbs) is indicated for the treatment of adult patients with:

Non-Hodgkins Lymphoma (NHL)

Chronic Lymphocytic Leukemia (CLL)

Rheumatoid Arthritis (RA)

Granulomatosis with Polyangiitis (GPA) (Wegeners Granulomatosis) and Microscopic Polyangiitis (MPA)

Important Safety Information

WARNING: FATAL INFUSION-RELATED REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Infusion-Related Reactions: Administration of rituximab products, including TRUXIMA, can result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of rituximab infusion have occurred. Approximately 80% of fatal infusion-related reactions occurred in association with the first infusion. Monitor patients closely. Discontinue TRUXIMA infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion-related reactions

Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab products

Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with rituximab products, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with TRUXIMA. Discontinue TRUXIMA and concomitant medications in the event of HBV reactivation

Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab products

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions - Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30-120 minutes. Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death

Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA, GPA, and MPA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue TRUXIMA. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (25,000/mm3)

Severe Mucocutaneous Reactions - Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue TRUXIMA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined

Hepatitis B Virus Reactivation - Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive)

HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur

Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with TRUXIMA. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during TRUXIMA treatment

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following TRUXIMA therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy

In patients who develop reactivation of HBV while on TRUXIMA, immediately discontinue TRUXIMA and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming TRUXIMA treatment in patients who develop HBV reactivation. Resumption of TRUXIMA treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV

Progressive Multifocal Leukoencephalopathy (PML) - JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies. The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were diagnosed within 12 months of their last infusion of rituximab

Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture

Discontinue TRUXIMA and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML

Tumor Lysis Syndrome (TLS) - Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of rituximab products in patients with NHL. A high number of circulating malignant cells ( 25,000/mm3) or high tumor burden, confers a greater risk of TLS

Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated

Infections - Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue TRUXIMA for serious infections and institute appropriate anti-infective therapy. TRUXIMA is not recommended for use in patients with severe, active infections

Cardiovascular Adverse Reactions - Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of TRUXIMA for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina

Renal Toxicity - Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and TRUXIMA is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue TRUXIMA in patients with a rising serum creatinine or oliguria

Bowel Obstruction and Perforation - Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur

Immunization - The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment

Prior to initiating TRUXIMA physicians should ensure patients vaccinations and immunizations are up-to-date with guidelines. Administration of any non-live vaccines should occur at least 4 weeks prior to a course of TRUXIMA

Embryo-Fetal Toxicity - Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving TRUXIMA and for 12 months following the last dose of TRUXIMA

Concomitant Use With Other Biologic Agents and DMARDS Other Than Methotrexate

Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly as limited safety data is available.

Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with rituximab products

Use in RA Patients Who Have Not Had Prior Inadequate Response to TNF Antagonists

TRUXIMA should only be used in patients who have had a prior inadequate response to one or more TNF antagonist

Most common adverse reactions in clinical trials of NHL (25%) were: infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia

Most common adverse reactions in clinical trials of CLL (25%) were: infusion-related reactions and neutropenia

Most common adverse reactions in clinical trials of RA (10%) were: upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis (other important adverse reactions include infusion-related reactions, serious infections, and cardiovascular events)

Most common adverse reactions in clinical trials of GPA and MPA (15%) were: infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, and infusion-related reactions

Nursing Mothers - There are no data on the presence of rituximab in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs including antibodies are present in human milk, advise a lactating woman not to breastfeed during treatment and for at least 6 months after the last dose of TRUXIMA due to the potential for serious adverse reactions in breastfed infants

About TRUXIMA TRUXIMA (rituximab-abbs) is a U.S. Food and Drug Administration (FDA)-approved biosimilar to RITUXAN (rituximab) for the treatment of: adult patients with CD20-positive, B-cell NHL to be used as a single agent or in combination with chemotherapy or CLL in combination with fludarabine and cyclophosphamide (FC); for rheumatoid arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies; and granulomatosis with polyangiitis (GPA) (Wegeners Granulomatosis) and microscopic polyangiitis (MPA) in adult patients in combination with glucocorticoids

TRUXIMA has the same mechanism of action as Rituxan and has demonstrated biosimilarity to Rituxan through a totality of evidence.

About Celltrion Healthcare, Co. Ltd. Celltrion Healthcare conducts the worldwide marketing, sales and distribution of biological medicines developed by Celltrion, Inc. through an extensive global network that spans more than 120 different countries. Celltrion Healthcares products are manufactured at state-of-the-art mammalian cell culture facilities, designed and built to comply with the US Food and Drug Administration (FDA) cGMP guidelines and the EU GMP guidelines.

About Teva Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) has been developing and producing medicines to improve peoples lives for more than a century. We are a global leader in generic and specialty medicines with a portfolio consisting of over 3,500 products in nearly every therapeutic area. Around 200 million people around the world take a Teva medicine every day, and are served by one of the largest and most complex supply chains in the pharmaceutical industry. Along with our established presence in generics, we have significant innovative research and operations supporting our growing portfolio of specialty and biopharmaceutical products. Learn more at http://www.tevapharm.com.

Teva's Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 regarding the launch of TRUXIMA Injection for Rheumatoid Arthritis in the United States, which are based on managements current beliefs and expectations and are subject to substantial risks and uncertainties, both known and unknown, that could cause our future results, performance or achievements to differ significantly from that expressed or implied by such forward-looking statements. Important factors that could cause or contribute to such differences include risks relating to:

and other factors discussed in our Annual Report on Form 10-K for the year ended December 31, 2019, including in the sections captioned "Risk Factors and Forward Looking Statements. Forward-looking statements speak only as of the date on which they are made, and we assume no obligation to update or revise any forward-looking statements or other information contained herein, whether as a result of new information, future events or otherwise. You are cautioned not to put undue reliance on these forward-looking statements.

1 RITUXAN is a registered trademark of Genentech and Biogen.

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Teva and Celltrion Healthcare Announce the Launch of TRUXIMA (rituximab-abbs) Injection for Rheumatoid Arthritis, the Only Biosimilar to Rituxan...

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