Name: Timesia HartAge: 58Hometown: Port Arthur, TexasTime Cycling: 10 yearsOccupation: Disabled Veteran and CEO/Founder of Living to Win FoundationReason for cycling: After surviving neuromyelitis optica (an autoimmune disease and central nervous system disorder that affects eye nerves and the spinal cord) and completing grueling physical, occupational, and speech therapy, I realized I would have to live with disabilities and had a decision to make. I could sit around feeling sorry for myself, or take the life God gave me and positively make an impact on society. Thankfully, cycling was what challenged me and helped me to help others by defying the odds.

Before my neuromyelitis optica (NMO) diagnosis, I prided myself for being physically fit. I could run, walk, hikeI did what I wanted to do, albeit with some pain from back injuries while in the Army. I cooked well, ate well, and used food as the fuel for my well maintained body. But my NMO came out of nowhere. I literally went to bed and the next day felt weakness in my lower extremities, and by the end of the day I had been transported to a huge neurological center because I was paralyzed from my shoulders to my toes.

In 2009, I was misdiagnosed with multiple sclerosis (MS), and the treatment wreaked havoc on my body. My body was toxic by the time the right diagnosis of NMO was discoveredthe neurologist began every known treatment, but nothing worked for me. Doctors said the sooner I accepted that Id be in a remote controlled wheel chair, the better off Id be, and that I should spend whatever time I had left with familythat was the best they could offer me. Never did I accept that, and its very much why Im alive and well today.

As a last resort, I was accepted into a clinical trial at Northwestern Memorial Hospital for a hematopoietic clinical trial stem cell transplant (HCST), in which they used my bone marrow to replace the bad cells causing the NMO neurological attacks with new cells. I received the transplant in 2013, and I was fortunate to regain some mobility.

No matter what youre looking to improve in your riding life, find it with Bicycling All Access!

After going through extensive physical, occupational, and speech therapy, I said I wasnt strong enough to go to the gym on my own, but my therapist recommended I start cycling. I started on a stationary bike in 2014, and by 2015 I was still barely able to stay on the bike. Therapy was difficult in the beginning, and I wasnt able to do much. But my attitude made a big difference, along with my determination.

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As my body began responding, therapy became much easier. I gradually gained enough strength and confidence to start to ride safely outside. I also went through the Livestrong programa 12-week exercise plan to get survivors back on their feettwice, and then mentored two cycles afterward. Now I can sit on a bike, balance, and ride up to 25 miles. I enjoy riding even more now, and it is my new form of physical fitness. I ran track in college and ran while in the military, but Ill unlikely run again. So riding is the next best thing for me.

In 2017, I recorded some music and released an EP called Endure, and with the revenue generated from it, I started the Living to Win foundation, where we support NMO patients and their families. We motivate them to fight and survive. I started an annual bike race, and we will have our 4th annual Biking to Win event in August where we bike 20 miles around Bentonville, Arkansas, where I now live. It is a family event, and parents ride with children and decorate their bikes. We put on a biking parade, and all the proceeds go towards supporting others with this debilitating disease. My goal is to have a state to state Biking to Win event.

To date, my longest ride has been 25 miles. I dont race, mountain bike, or any of the crazy stuff, but my average of 80+ miles a week is pretty impressive. The community I live in in Northwest Arkansas has many trails, and my favorite ride is from Bella Vista to Springdale by way of the Greenway.

Riding is so freeing to me. Im not supposed to be able to walk, let alone ride. I pray that by riding, othersno matter what their issues arewill be inspired to keep pushing and do something. I always say I dont have a disability, but rather the ability to do things differently.

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How Cycling Changed Me | Timesia Hart Cycles to Inspire Others - Bicycling

Spinal Cord Stem Cells Comments Off on How Cycling Changed Me | Timesia Hart Cycles to Inspire Others – Bicycling | July 7th, 2021

Cardiovascular disease, any of the diseases, whether congenital or acquired, of the heart and blood vessels. Among the most important are atherosclerosis, rheumatic heart disease, and vascular inflammation. Cardiovascular diseases are a major cause of health problems and death.

This micrograph shows a cross section of a coronary artery narrowed by an atherosclerotic plaque (purplish matter inside the artery). The extensive buildup of plaque impedes the flow of blood through the artery and to the heart's tissues.

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Life depends on the functioning of the heart; thus, the heart is involved in all death, but this does not account for its prominence in causing death. To some degree, as medical science advances, more people are saved from other illnesses only to die from one of the unsolved and uncontrolled disorders of the cardiovascular system. Some forms of cardiovascular diseases are becoming less frequent causes of death, and continued research and preventive measures may provide even greater benefits. However, changes in lifestyle and diet, including the adoption of more sedentary lifestyles and the consumption of fried foods and foods high in sugar, have resulted in increases in the incidence of otherwise preventable cardiovascular-related illness and death.

Heart disease as such was not recognized in non-technological cultures, but the beating heart and its relationship to death have always been appreciated. Sudden death, now usually attributed to heart disease, was recognized as early as the 5th century bce by the Greek physician Hippocrates and was noted to be more common in the obese. The role of disease in affecting the heart itself did not become apparent until the 17th century, when examination of the body after death became acceptable.

Gradually, the involvement of the heart valves, the blood vessels, and the heart muscle was observed and categorized in an orderly fashion. The circulation of the blood through the heart was described in 1628 by the British physician William Harvey. The recognition of the manifestations of heart failure came later, as did the ability to diagnose heart ailments by physical examination through the techniques of percussion (thumping), auscultation (listening) with the stethoscope, and other means. It was not until early in the 20th century that the determination of arterial blood pressure and the use of X-rays for diagnosis became widespread.

In 1912 James Bryan Herrick, a Chicago physician, first described what he called coronary thrombosis (he was describing symptoms actually caused by myocardial infarction). Angina pectoris had been recorded centuries earlier. Cardiovascular surgery in the modern sense began in the 1930s, and open-heart surgery began in the 1950s.

The exact incidence of heart disease in the world population is difficult to ascertain, because complete and adequate public health figures for either prevalence or related deaths are not available. Nonetheless, in the 21st century, in many parts of the world, cardiovascular disease was recognized as a leading cause of death. In the more technologically developed countries of the worldsuch as the United Kingdom and most continental European countriesarteriosclerotic heart disease (heart disease resulting from thickening and hardening of the artery walls) was one of the most common forms of cardiovascular disease. In the early 21st century in the United States, an estimated one-half of the adult population was affected by some form of cardiovascular disease; while heart disease and stroke accounted for a significant proportion of this disease burden, high blood pressure was the most common condition. In other areas of the world, such as the countries of Central Africa, other forms of heart disease, often nutritional in nature, were a common cause of death. In Asia and the islands of the Pacific, hypertensive cardiovascular disease, disease involving high blood pressure, constituted a major health hazard.

The hearts complicated evolution during embryological development presents the opportunity for many different types of congenital defects to occur. Congenital heart disease is one of the important types of diseases affecting the cardiovascular system, with an incidence of about 8 per 1,000 live births. In most patients the causes appear to fit in the middle of a continuum from primarily genetic to primarily environmental.

Of the few cases that have a genetic nature, the defect may be the result of a single mutant gene, while in other cases it may be associated with a chromosomal abnormality, the most common of which is Down syndrome, in which about 50 percent of afflicted children have a congenital cardiac abnormality. In the even smaller number of cases of an obvious environmental cause, a variety of specific factors are evident. The occurrence of rubella (German measles) in a woman during the first three months of pregnancy is caused by a virus and is associated in the child with patent ductus arteriosus (nonclosure of the opening between the aorta and the pulmonary artery). Other viruses may be responsible for specific heart lesions, and a number of drugs, including antiepileptic agents, are associated with an increased incidence of congenital heart disease.

In most cases, congenital heart disease is probably caused by a variety of factors, and any genetic factor is usually unmasked only if it occurs together with the appropriate environmental hazard. The risk of a sibling of a child with congenital heart disease being similarly affected is between 2 and 4 percent. The precise recurrence can vary for individual congenital cardiovascular lesions.

Prenatal diagnosis of congenital cardiovascular abnormalities is still at an early stage. The most promising technique is ultrasonography, used for many years to examine the fetus in utero. The increasing sophistication of equipment has made it possible to examine the heart and the great vessels from 16 to 18 weeks of gestation onward and to determine whether defects are present. Amniocentesis (removal and examination of a small quantity of fluid from around the developing fetus) provides a method by which the fetal chromosomes can be examined for chromosomal abnormalities associated with congenital heart disease. In many children and adults the presence of congenital heart disease is detected for the first time when a cardiac murmur is heard. A congenital cardiovascular lesion is rarely signaled by a disturbance of the heart rate or the heart rhythm.

Congenital cardiac disturbances are varied and may involve almost all components of the heart and great arteries. Some may cause death at the time of birth, others may not have an effect until early adulthood, and some may be associated with an essentially normal life span. Nonetheless, about 40 percent of all untreated infants born with congenital heart disease die before the end of their first year.

Congenital heart defects can be classified into cyanotic and noncyanotic varieties. In the cyanotic varieties, a shunt bypasses the lungs and delivers venous (deoxygenated) blood from the right side of the heart into the arterial circulation. The infants nail beds and lips have a blue colour due to the excess deoxygenated blood in the system. Some infants with severe noncyanotic varieties of congenital heart disease may fail to thrive and may have breathing difficulties.

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cardiovascular disease | Symptoms, Causes, Treatment ...

Cardiac Stem Cells Comments Off on cardiovascular disease | Symptoms, Causes, Treatment … | July 7th, 2021

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved an expanded label for KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the treatment of patients with locally advanced cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation. This approval is based on data from the second interim analysis of the Phase 2 KEYNOTE-629 trial, in which KEYTRUDA demonstrated an objective response rate (ORR) of 50% (95% CI, 36-64) (n=54), including a complete response rate of 17% and a partial response rate of 33% in the cohort of patients with locally advanced disease. Among the 27 responding patients, 81% had a duration of response (DOR) of six months or longer, and 37% had a DOR of 12 months or longer. In June 2020, KEYTRUDA was granted its first indication in cSCC, as monotherapy for the treatment of patients with recurrent or metastatic disease that is not curable by surgery or radiation.

This approval is great news for these patients and further demonstrates Mercks commitment to the skin cancer community. KEYTRUDA has shown meaningful efficacy in patients with locally advanced or recurrent or metastatic cutaneous squamous cell carcinoma that cannot be cured by surgery or radiation, said Dr. Vicki Goodman, vice president, clinical research, Merck Research Laboratories. This expanded indication reinforces the role of KEYTRUDA in this cancer type, which is the second most common form of non-melanoma skin cancer.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

Data Supporting the Approval

The approval was based on data from KEYNOTE-629 (ClinicalTrials.gov, NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial that enrolled patients with recurrent or metastatic cSCC or locally advanced cSCC. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression.

Patients received KEYTRUDA 200 mg intravenously every three weeks until documented disease progression, unacceptable toxicity or a maximum of 24 months. Patients with initial radiographic disease progression could receive additional doses of KEYTRUDA during confirmation of progression unless disease progression was symptomatic, rapidly progressive, required urgent intervention, or occurred with a decline in performance status.

Assessment of tumor status was performed every six weeks during the first year and every nine weeks during the second year. The major efficacy outcome measures were ORR and DOR as assessed by blinded independent central review (BICR) according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

Among the 54 patients with locally advanced cSCC treated, the study population characteristics were: median age of 76 years (range, 35 to 95), 80% age 65 or older; 72% male; 83% white, 13% race unknown; 41% Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 and 59% ECOG PS of 1. Twenty-two percent received one or more prior lines of therapy; 63% received prior radiation therapy.

The ORR was 50% (95% CI, 36-64), including a complete response rate of 17% and a partial response rate of 33%, for patients treated with KEYTRUDA. After a median follow-up of 13.4 months, the median DOR had not yet been reached (range, 1.0+ to 17.2+ months). Among the 27 responding patients, 81% had a DOR of six months or longer, and 37% had a DOR of 12 months or longer.

Among the 159 patients with advanced cSCC (recurrent or metastatic or locally advanced disease) enrolled in KEYNOTE-629, the median duration of exposure to KEYTRUDA was 6.9 months (range, 1 day to 28.9 months). Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in 2,799 patients with melanoma or non-small cell lung cancer treated with KEYTRUDA as a single agent. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence included lymphopenia (10%) and decreased sodium (10%).

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (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 1,500 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 in the U.S.

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.

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 (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 HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

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. 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 (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 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-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient 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)solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options

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.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. 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.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or 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 locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

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.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. 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 TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently 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. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

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 an antiPD-1/PD-L1 treatment 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

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

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FDA Approves Expanded Indication for Merck's KEYTRUDA (pembrolizumab) in Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC) - Business Wire

Cardiac Stem Cells Comments Off on FDA Approves Expanded Indication for Merck’s KEYTRUDA (pembrolizumab) in Locally Advanced Cutaneous Squamous Cell Carcinoma (cSCC) – Business Wire | July 7th, 2021

Clinical trial data supporting the safety of the CRISPR-Cas9 genomic editing tool was presented on Monday by Intellia Therapeutics (NASDAQ:NTLA) for its lead product, NTLA-2001. The data was highly encouraging. However, despite NTLA-2001's positive early results as a potential treatment for the rare disease transthyretin (TTR) amyloidosis, there's still a long way to go before Intellia could bring it to market.

In transthyretin amyloidosis, cells in the liver produce misfolded TTR proteins, which accumulate throughout the body, causing debilitating complications that can involve the digestive system, nervous system, and heart. Once symptoms appear, they grow progressively worse, and the disease leads to death within a median of 4 to 17 years among patients with nervous system involvement, and 2 to 6 years among patients with cardiac involvement.

NTLA-2001 edits the genes in those liver cells, removing the segment that produces those lethal misfolded proteins.

Worldwide, an estimated 250,000-550,000 people suffer from some form of amyloidosis.

IMAGE SOURCE: GETTY IMAGES.

An interim readout from Intellia's ongoing phase 1 trial found that a single high-dose infusion of NTLA-2001 led to an 87% mean reduction in the amount of misfolded TTR in patients' bloodstreams, with a maximum reduction of 96% by day 28 in one patient. Encouragingly, no serious adverse events were observed in the six study participants. While this is a small pilot study, in previous studies of NTLA-2001 in mice, the maximum reductions in TTR persisted for 12 months after a single treatment.

All of this data provides an early indication that CRISPR gene therapies are safe and efficacious as treatments for at least some genetic diseases.

There are other treatments on the market for TTR amyloidosis, but one thing that would set CRISPR apart is the relative simplicity of administering it. And that factor could lead insurers to favor CRISPR treatments for certain rare and debilitating diseases such as TTR amyloidosis and hemophilia.

For example, Alnylam's (NASDAQ:ALNY) RNA-silencing therapy Onpattro requires an infusion every three weeks at a clinician's office. Ionis Pharmaceuticals' (NASDAQ:IONS) Tegsedi requires regular injections, though they can be self-administered. Both are priced in the neighborhood of $345,000 per year, and Onpattro comes with the additional costs associated with going to a medical office and having an infusion set up. Then there is Pfizer's (NYSE:PFE) once-daily oral medication Vyndamax, which costs $225,000 annually.

As a one-time infusion, gene therapy may become a compelling option for both patients and insurers, particularly given the high prices of currently available treatments. Though TTR amyloidosis treatments are a niche market, in 2020, Onpattro generated sales of $306 million, Tegsedi just under $70 million, and Vyndamax $429 million. Assuming that Intellia charges more for NTLA-2001 -- a one-time treatment with bluebird bio's (NASDAQ:BLUE) gene therapy for beta-thalassemia, Zynteglo, costs about $1.8 million -- TTR amyloidosis treatment could easily become a multibillion-dollar addressable market for the biotech.

Notably, CRISPR therapy for TTR amyloidosis may also put less stress on the healthcare system than the lentivirus and adenovirus gene therapies that are further along in clinical trials. Consider, for instance, Zynteglo, which requires a significant amount of effort and processing prior to treatment. First, physicians must extract stem cells from the patient, which must then be transported to and treated by bluebird bio. In the meantime, the patient undergoes "myeloablative conditioning" -- essentially knocking down the patient's bone marrow in preparation for a transplant of the edited stem cells, which will contain a repaired version of the gene that (when mutated) causes beta-thalassemia. This complicated process requires treatment at a qualified transplant center.

By comparison, for TTR amyloidosis, NTLA-2001 requires pre-medication with steroids and antihistamines. That's it. No prolonged patient preparation at the hospital. No bone marrow suppression. No shipping the patient's stem cells to a lab. The relative simplicity of administering CRISPR therapies is just one reason for the degree of excitement they are generating.

It may also give them a lower total cost of treatment than current gene therapies, which could make these therapies more palatable to insurers. If NTLA-2001 pans out, we may see a new biotech boom, with Intellia leading the charge.

Before investors get their hopes up too much, remember that these results were from a six-person, phase 1 trial, and that Intellia now holds a market cap of roughly $11 billion. In fact, its valuation rose by about $2.8 billion in a single trading session after the interim trial data was made public. That gain was more than the current $2.1 billion market cap of bluebird bio, which already has an approved gene therapy on the market as well as a CAR-T therapy, and has two more candidates in phase 3 trials.

For further context, bluebird bio announced phase 1 results for Zynteglo in December 2014. While Zynteglo was approved for use in the EU in late 2019, bluebird bio faced some backlash on pricing, and the company isn't selling it in Germany because the two sides could not agree on pricing.

Moreover, the NTLA-2001 study excluded patients who had previously received RNA-silencing therapy, and none of these patients had previously taken Vyndamax either. How previous treatments will affect the way patients respond to NTLA-2001 is not yet known. And with hundreds of millions of dollars in revenue annually on the line, it is doubtful that Alynam, Ionis, or Pfizer will surrender this market without a fight.

In sum, Intellia will still need to conduct several years of trials, leap many regulatory hurdles, and outmaneuver an array of rivals stand before it can declare the CRISPR-Cas9 platform a winner. Not only that, but -- recognizing that future studies won't be cheap -- Intellia has already proposed another public offering of $400 million worth of common stock this week, diluting its current shareholders.

So while long-term Intellia shareholders have reason to celebrate, let bluebird bio serve as a cautionary tale. That biotech was once flying high on positive trial data, hitting a market cap of around $15.5 billion in March 2018. Since then, its shares have nose-dived by more than 80%. This despite the fact that it now has two approved therapies and two more candidates in phase 3 trials.

As such, I would be concerned about investing new money in Intellia now. I suspect it will soon reach its peak for the foreseeable future. Biotech investing can be gut-wrenchingly fickle, and investors may want to consider taking a basket approach to high-risk clinical-stage biotechs, rather than investing too heavily in a single player.

This article represents the opinion of the writer, who may disagree with the official recommendation position of a Motley Fool premium advisory service. Were motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.

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2 Reasons to Buy Intellia -- and 1 Big Reason Why I Won't - The Motley Fool

Cardiac Stem Cells Comments Off on 2 Reasons to Buy Intellia — and 1 Big Reason Why I Won’t – The Motley Fool | July 7th, 2021

MarketQuest.biz has recently added a report titled Global Autologous Stem Cell Based Therapies Market 2021 by Company, Regions, Type and Application, Forecast to 2026 describes the crucial aspects of the market by conducting an in-depth analysis of the current trend, emerging threats, and future market assessment. The report presents a thorough study of the current trends leading to this vertical trend in various regions. The report highlights important details related to global Autologous Stem Cell Based Therapies market share, market size, applications, and statistics. It sheds light on market dynamics and demonstrates a superior forecast for the development of the market.

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Global Autologous Stem Cell Based Therapies Market 2021 Outlook and Study of Top Players Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM...

Cardiac Stem Cells Comments Off on Global Autologous Stem Cell Based Therapies Market 2021 Outlook and Study of Top Players Regeneus, Mesoblast, Pluristem Therapeutics Inc, US STEM… | July 7th, 2021

Why is the Development of Disease-Modifying Osteoarthritis Drugs (DMOADs) Required?Disease Burden

Osteoarthritis (OA) is the most prevalent arthritis globally and represents a major challenge for twenty-first century health care systems.1,2 The Global Burden of Disease 2020 report showed an increase of 9.3% and 8.2% in the age-standardized OA point prevalence and annual incidence rate from 1990 to 2017.3 The prevalence rises with increasing age; in the USA (United States of America), OA was found in 13.9% of adults aged 25 years and 33.6% for those aged 65 years respectively in 2005.4 The lifetime risk of having symptomatic knee OA is about 40% in men and 47% in women, and the risk increases to 60.5% among obese persons.5 By the year 2040, an estimated 25.9% of the total adult population will have doctor-diagnosed arthritis in the USA.6

Globally, 80% of patients with OA suffer from limitations in movement, and 25% from difficulty in performing their major daily activities of life; representing a significant impact of OA on functional impairment and disability.7 In terms of economic burden, mean per-person earnings losses caused by OA were, on average, 7548 US$ per year from 2008 to 2011.8 The mean all-cause health care utilization of working-age patients with OA is $14,521 US$ per year.9 The socio-economic costs of OA were reported to range between 0.25% and 0.50% of a countrys GDP.10 In an individual patient data meta-analysis, the pooled estimate for premature mortality revealed a 23% increased risk (95% CI 1.07, 1.42) in patients with knee OA and a 20% increased risk (95% CI 1.04, 1.37) in hip OA.11

Current OA treatment options are focused on symptomatic improvement in pain and joint function and include paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, and intra-articular medications such as steroids and hyaluronic acids.14 Surgical treatments are typically indicated only for patients with end-stage OA, as a last resort. Recently, paracetamol and opioids are only conditionally or not recommended by several scientific organisations,12,13 highlighting the importance of finding new effective treatments for OA. In addition, outcomes for patients with OA are usually suboptimal and patients remain vulnerable to the clinical consequences of the disease on pain and physical function.14

OA was previously regarded as a degenerative disorder resulting from cartilage damage;15 however, the development and utilization of modern imaging methods revealed that it results from the failure of the joint organ with a heterogeneous involvement of the whole joint structures, including cartilage damage, subchondral bone remodeling, synovial inflammation and osteophyte development.16 Therefore, OA can be defined as a complex heterogeneous syndrome with multiple joint tissue involvement of varying severity. In part as a consequence, it is a huge challenge to develop a single one size fits all therapy that may be suitable and effective for all patients with OA.17

The central hallmark in the pathologic process of OA disease is the progressive deterioration in the biological, structural and mechanical properties and function of the joint tissues, and an effective medical treatment should possess the ability to delay these processes or ideally even halt them completely. Such pharmaceutical agents that will alter the natural history of disease progression by arresting joint structural change and ameliorating symptoms, either by reducing pain or improving physical function are termed as DMOADs.18

Currently, regulatory bodies such as US Food and Drug Administration (FDA)19 and the European Medicines Agency (EMA)20 have not approved any drug as an effective DMOAD, as the approval guide requires a potential DMOAD to demonstrate a slowing in the loss of knee or hip joint space width (JSW) on x-ray with associated symptomatic improvement.17 Therefore, current OA trials for DMOAD development pipeline need to meet both clinically meaningful symptom improvement with concomitant structural benefits according to US FDAs published draft industry guidance on structural endpoints for OA published in 2018.18

Because OA is characterised by its extraordinary inter-patient variability in clinical and structural manifestations, identification of patient/disease subtypes appropriate for targeted therapy is probably one of the promising ways forward in drug development research.21,22 In addition, structural changes in OA result from complex interactions among different pathobiological pathways, which implicate a variety of catabolic factors and cytokines in the different joint tissues (molecular cross-talk).23 Therefore, a new model of classifying OA based on pathophysiological disease subtypes is needed.

These subtypes can be clinical phenotypes or molecular/mechanistic endotypes.24 A clinical phenotype can be defined as a group of observable traits (ie aetiologic factors, risk factors) that can identify and characterize a subtype in a defined population.25,26 In other words, these subgroups of patients have similar clinically observable characteristics for better identifying individuals who are at higher risk of progression (prognostic) or who are more likely to respond to a specific intervention (prescriptive).27,28

An endotype is a disease subtype defined by distinct pathophysiologic mechanisms, including cellular, molecular and biomechanical signalling pathways.29 Therefore, the endotype is distinct from a phenotype, and indicates the presence of a well-defined molecular mechanism. A given clinical phenotype of OA may comprise overlapping molecular endotypes (ie, different mechanisms giving rise to the same manifestation at varying degrees during different phases of the disease).24

From the point of view of targeted drug discovery, where identifying and directing the right pathobiological mechanism and structural manifestations of disease is key for success, drug development in OA should be based on the endotypes as the basis of the main drivers of OA disease.30 In this review, we will, therefore, focus on currently ongoing phase 2 and 3 clinical trials of active drug development (Figure 1) related to three main molecular/mechanistic endotypes: 1) Cartilage-driven endotype, 2) Bone-driven endotype, 3) Inflammation-driven endotype. While each drug has been assigned to and is discussed under one endotype based on its predominant activity, a particular therapeutic may have broader endotype-effects and where present, these are duly noted.

Figure 1 Active drugs related to the three main molecular or mechanistic OA endotypes (phase 2 and 3).

One author (WMO) conducted electronic and manual searches on the https://clinicaltrials.gov/ for identifying ongoing phase 2/3 clinical trials in active drug development pipelines, as well as electronic database searches in the PubMed and Embase via Ovid for published reports of phase-2/3 clinical trials results from the inception of these databases to 31st March 2021 using the following MESH or keywords: osteoarthritis OR osteoarthrosis AND DMOAD/ OR structure modification OR disease-modifying osteoarthritis drugs/.

Cartilage damage is considered as a central part of OA disease process, which involves a variety of catabolic and reparative mechanisms at the molecular level. The pharmaceutical drugs in phase 2 and 3 stages of development for cartilage-driven endotype are summarized in Table 1.

Matrix-degrading enzymes in the joint such as collagenases and aggrecanases are responsible for proteolysis of extracellular matrix components such as type II collagen and aggrecan, which is the most abundant proteoglycan in cartilage.31 Proteinases such as matrix metalloproteinase 13 (MMP13) and ADAMTS5 (a Disintegrin And Metalloproteinase with ThromboSpondin-motif-5) are involved in cartilage destruction and progression of cartilage damage in OA pre-clinical models.32,33 The potential benefits of MMP inhibitors in preserving the OA joint have been investigated. However, in patients with knee OA, broad-spectrum MMP inhibitors such as PG-116800 showed reversible musculoskeletal toxicities in a dose-dependent manner without clinical benefits, leading to the termination of further development of this drug.34

S201086/GLPG1972 is a potent and highly selective active site inhibitor of ADAMTS5. It possesses an excellent selectivity profile in animal models and high stability in dog and human liver microsomes and hepatocytes.35 Phase-1 clinical studies revealed favorable pharmacokinetics as well as a strong and consistent target engagement in both healthy subjects and OA patients (n=171).36 In a phase-2 study (Roccella study) which investigated the efficacy and safety profile of three different once-daily oral doses of GLPG1972/S201086 (n=932), the change in cartilage thickness [in mm (SD)] of central medial tibiofemoral compartment of the target knee via quantitative MRI was 0.116 (0.27) for the placebo group and 0.068 (0.20), 0.097 (0.27) and 0.085 (0.22), for the low, medium and high dose, respectively. There was no statistically significant difference versus placebo in both MRI and clinical outcome measures.37 Another ADAMTS5-targeting agent, M6495 an anti-ADAMTS5 Nanobody (Ablynx), showed an acceptable safety profile and dose-dependent effects in a phase-1 study.38

Sprifermin is a recombinant human fibroblast growth factor 18 (FGF18) which binds to fibroblast growth factor receptor-3 (FGFR-3) in cartilage.39 It stimulates the proliferation of articular chondrocytes and induces hyaline extracellular matrix synthesis in rat OA models.40 At the cellular level, intermittent administration may transiently promote an anabolic effect, while continuous administration may stimulate other signalling pathways, leading to a weaker effect.41

Lohmander et al reported in 2014 that intra-articular (IA) sprifermin administration did not improve medial tibiofemoral cartilage-thickness over 12 months quantified by MRI (n=168) possibly as follow-ups were too short for detection of the full disease-modifying effect of treatment.39 However, a significant dose-dependent response was detected in total and lateral tibiofemoral cartilage-thickness and radiographic JSW over 12 months. The authors speculated that the dynamic loading implicated in predominantly medial tibiofemoral involvement seems to impede attempts to prevent cartilage loss or regenerate cartilage tissue. Sprifermin had no major local or systemic adverse events compared with placebo. Conference abstracts published in 2015 and 2016 reported the structure-modifying effects on cartilage thickness and bone marrow lesions (BMLs) on MRI on 12-month follow-up, using post-hoc analyses of the same study.42,43

In another clinical trial in which Sprifermin was administered up to 300 g for advanced knee OA, it was reported in 2016 that no significant benefits were detected for cartilage outcomes on histology, synovitis, effusion, BMLs on MRI and JSW on X-ray. However, the study was underpowered as MRI was only available in 30 out of 52 patients and the follow-up period was only 24 weeks, which may be too short for capturing the structure-modifying effects.44

In a 5-year, phase 2 dose-finding, multicenter randomized clinical trial [FGF18 Osteoarthritis Randomized Trial with administration of Repeated Doses (FORWARD) study], the effects of Sprifermin on changes in total femorotibial joint cartilage thickness (n=549) on MRI was evaluated at 2-year follow-up (NCT01919164). Hochberg et al reported in 2019 that three once-weekly IA injection of 100 g sprifermin provided a significant improvement in total femorotibial joint cartilage thickness [0.05 mm (95% CI, 0.03 to 0.07 mm)] for participants administered every 6 months and [0.04 mm (95% CI, 0.02 to 0.06 mm)] for participants administered every 12 months, compared with the placebo saline injection provided every 6 months (0.02 mm).45 No significant improvement in total WOMAC scores was detected, compared with placebo. The most frequently reported treatment-emergent adverse event was arthralgia and showed no difference from the placebo group (43%). An exploratory analysis of the same study at 3 year-follow-up (n=442) reveals significant differences (0.05 mm [95% CI, 0.030.07 mm]) in total femorotibial joint cartilage thickness over MRI between Sprifermin (100 g of Sprifermin every 6 months) and placebo (saline every 6 months).45 However, the clinical significance of a 0.05-mm increase of cartilage thickness in this study remains unclear in terms of reducing risk for knee replacement, delaying time towards knee replacement, or both.46 No significant change in total WOMAC scores in this study may be attributed to using intra-articular saline injections as a control since the IA saline injection may act as an active placebo,47 masking symptomatic benefits. In addition, a large number of patients with low baseline pain and/or high baseline cartilage thickness may result in a potential floor effect on symptoms as 32% of this study had <40/100 points on WOMAC pain score at baseline and 50% had medial minimum joint space width (mJSW) >4.0 mm on baseline X-rays. Therefore, analysis of a more selective subgroup, featuring baseline characteristics associated with rapid structural and symptomatic OA progression should be investigated. In a 2019 ACR conference abstract, it was reported that in a subgroup at risk (n=161) of structural and symptomatic progression with a baseline medial or lateral mJSW between 1.5 and 3.5 mm and WOMAC pain score of 4090 out of 100, WOMAC pain was significantly improved on 3 year follow-up [8.8 (22.4, 4.9)] in the group administered with the 100 g Sprifermin (n=34) compared with the placebo (n=33)48 suggesting that, in this subgroup, the drug effect reaches the absolute minimal clinically important improvement for the WOMAC pain subscore which ranges 69.49

In a recent 2020 paper using a post-hoc analysis of the same data from the FORWARD study, thinning/thickening scores and ordered values of femorotibial cartilage thickness change on MRI over 24 months were analyzed by applying location-independent (ie not region-specific) analysis methodology in the knee joint.50 With administration of 100g Sprifermin every 6 months cartilage thickening is more than double [856m (717 to 996) vs 356m (313 to 398)] and cartilage thinning almost reduced to [432m (521 to 343) vs 335m (381 to 288)] that in healthy reference subjects from the Osteoarthritis Initiative dataset (n=82). The authors concluded that the finding supported the evidence of substantial structure-protective action of Sprifermin. However, as this is a post-hoc analysis, further study will be required to confirm its structure-modifying effect.

At a molecular level, the regulation of Wnt signalling determines osteoblast and chondrocyte lineage specification and their homeostasis.51 Increased Wnt signaling predisposes MSCs to an osteogenic lineage fate and induces generation of metalloproteinases which can cause cartilage degradation in OA.52 Increased expression and activation of the Wnt pathway in articular cartilage chondrocytes in OA similarly promotes cartilage degradation, while elevated Wnt signalling in subchondral bone enhances bone formation and sclerosis.5355 Therefore, pharmacological modulation of Wnt signaling might have potential benefits in repairing osteochondral dysregulation detected in OA disease process. Moreover, increased Wnt signaling in the synovium may potently lead to the OA progression via increased production of MMPs as well as activation of osteoclast differentiation and enhanced subchondral bone turnover.56,57

Lorecivivint (SM04690) is a small-molecule CLK/DYRK1A inhibitor that blocks Wnt signalling at the transcriptional level.58 It showed induction of chondrogenesis and reduction in cartilage degradation in preclinical studies.5860 In a 52-week, multicenter, phase-2 trial (n=455) (NCT02536833), the primary end point, a significant improvement in the WOMAC pain score compared with placebo at week 13, was not met, compared with IA placebo saline injection, However, at 52-week follow-up, intra-articular administration of 0.07 mg demonstrated a significant benefit in pain and functional scores [between-group difference versus placebo, 8.73, 95% CI (17.44, 0.03) and 10.26, 95% CI (19.82, 0.69)], as well as improvement in mJSW on X-rays [between-group difference versus placebo, +0.39 mm, 95% CI (0.06, 0.72)] in patients with unilateral knee OA. Serious adverse events were reported in 17 (3.7%) patients.61 The most common SAEs included infections and cardiac disorders and were deemed unrelated to the study drug by the investigators.62

Another phase-2 trial evaluated in 700 patients for 24 weeks was completed (NCT03122860) where the 0.07 mg lorecivivint treatment group demonstrated more favorable reductions in both WOMAC indices as compared with placebo.63 Recently, the investigators reported the safety data after the combined analysis of the two trials, which included 848 Lorecivivint-treated and 360 control subjects in total. The incidence of adverse effects or serious adverse effects was similar in treatment (41.3% and 2.4%) and control groups (38.3% and 1.1%), respectively. The most commonly reported AE in both groups was arthralgia (7.6% vs 7.2%).64 Two small phase-2 (NCT03727022, NCT03706521) and three phase-3 (NCT03928184, NCT04385303, NCT04520607) trials are still active.

Transforming growth factor- (TGF-) induces extracellular matrix protein synthesis and modulates cartilage development. A variety of TGF- signalling pathways are crucial for early cartilage growth, maintaining cartilage homeostasis in later life and may also possess anti-inflammatory and immunosuppressive properties.65 Impaired TGF- function in cartilage might be related to an increased susceptibility to OA.66 However, the biological effect of TGF- is under complex control, and may switch from being protective in normal joints to detrimental in OA as a result of changes in the predominant cell-surface receptors and intra-cellular signalling pathways in various joint tissues (cartilage, bone, synovium).67 In addition, osteocyte TGF- signaling could regulate the osteogenic and osteoclastic activity of mesenchymal stem cells and may be associated with the remodeling of subchondral bone in advanced OA.68

TissueGene-C (TG-C) uses a cell-mediated cytokine gene therapy approach and includes non-irradiated allogeneic human chondrocytes and irradiated allogeneic human GP2-293 cells in a ratio of 3:1, retrovirally transduced to promote TGF-beta1 transcription (hChonJb#7 cells).6971 A recent study reported as a possible mechanism of action that TG-C induced an M2 macrophage-dominant pro-anabolic micro-environment in a rat model, thereby providing a beneficial effect on cartilage regeneration.72 At one-year follow-up after a single IA administration, there were significant improvements in pain, sports activities and quality of life but structure-modifying effects on the cartilage were insignificant (n=156).73 In a phase-2 trial (NCT01221441) including 57 patients in the treatment group and 29 patients in the placebo group, the TG-C administration caused less progression (47.9% vs 34.6%; adjusted RR 0.7, 95% CI 0.51.1) of cartilage damage than placebo over 12-months.69 In a phase-3 trial (NCT02072070) which included 163 patients, symptomatic benefit was detected.74

The two pivotal phase-3 trials (NCT03203330, NCT03291470) had been on hold in April 2019 while the regulators were investigating chemistry, manufacturing, and control issues related with the potential mislabeling of ingredients.75 This clinical hold was lifted in April 2020, and trial enrollments have been reinitiated later in 2020.76 Recently, analysis of the safety data from an observational long-term safety follow-up trial showed that there is no evidence to suggest that injection of TG-C was associated with increased risk of cancer nor generated any long-term safety concerns over an average 10 years.71

Senescence is characterized mainly by altered responses to cellular stress and proliferation arrest of cells.77 Senescent cells (SnCs) are a newly implicated factor in the OA pathogenic process78 by promoting pathological age-related deterioration via the production of proinflammatory cytokines, chemokines, extracellular proteases, and growth factors (termed the senescence-associated secretory phenotype (SASP))79 and altering the function of neighbouring cells (termed secondary or paracrine senescence).80 Therefore, senotherapeutics which are directed at SnCs are an emerging therapy for treating diseases related to ageing. Senotherapeutics can be classified into of 3 types: 1) senolytics which kill and destroy SnCs selectively; 2) senomorphics which modulate or even reverse the phenotype of SnCs to those of young cells by blocking SASP; 3) senoinflammation, the immune system-mediated clearance of SnCs.81 Several senolytic pharmaceutical drugs such as Fisetin and UBX0101 are emerging.

Fisetin is a polyphenol extracted from fruits and vegetables and shows potential senolytic and anti-inflammatory activities.82 Fisetin inhibited IL-1-induced MMP13 and ADAMTS5 expression in human OA chondrocytes in vitro, and reduced cartilage damage along with subchondral bone thickening and synovitis in a mouse OA model induced by destabilization of the medial meniscus (DMM).83 Two phase-2 clinical trials (NCT 04210986, NCT04815902) are under investigation in patients with knee OA and estimated to be completed in 2022 and 2025, respectively.

UBX0101 is a small molecule inhibitor of the MDM2/p53 protein interaction, which possesses a potent senolytic candidate. In a preclinical study, UBX0101 improved chondrogenesis in human OA tissue in vitro, and in an anterior cruciate ligament transection (ACLT) OA model in mice UBX0101 attenuated SnCs by stimulating apoptosis, and reduced cartilage damage and joint pain.84 The amount SnCs in human OA synovial tissues positively correlated with knee pain, disease severity and synovitis severity.85 A phase-1 study (n=48) revealed that a single intra-articular injection of UBX0101 at different doses up to 4 mg had a favorable safety profile and dose-dependent, clinically meaningful improvements in pain on Numeric Rating Scale (010) [3.95 (95% CI, 4.74, 3.16)] and WOMAC function [1.05 (95% CI, 1.36,-0.74)] compared with placebo injection. Recently, UNITY Biotechnology announced 12-week data from UBX0101 Phase-2 Clinical Study (NCT04129944) which did not detect a significant change in pain and function in 183 patients with painful knee OA.86 A follow-up observational study of the previous trial (NCT04349956) was terminated in November 2020 due to failure to meet the trial outcomes.

Subchondral change in OA involves an uncoupled remodelling process, which is characterized by both increased osteoblast activation and bone formation but simultaneously macrophage infiltration and osteoclast formation.87 Activation of osteoclasts can result in pain genesis through developing acidic conditions at the osteochondral junction, thereby activating acid-sensing receptors of sensory neurons.88,89 Subchondral bone also undergoes remarkable alterations in both composition and structural organization, leading to adverse effects on the overlying articular cartilage.90 Therefore, targeting the pathways that modify subchondral bone turnover is an attractive option for DMOAD research.89 The pharmaceutical drugs in phase 2 and 3 stages of development for bone-driven endotype are summarized in Table 2.

Table 2 The Registered Phase 2/3 Clinical Trials on Compounds with Potential Disease-Modifying Effects on Subchondral Bone

Cathepsin K is a cysteine protease which induces bone resorption and cartilage damage through the breakdown of key bone matrix proteins.91,92 Cathepsin K knock out mice had attenuated cartilage damage in OA induced by DMM, and inhibition of Cathepsin K in rabbits by daily oral dosing with L-006235 reduced cartilage damage and subchondral bone remodelling in an ACLT model of OA.93,94

MIV-711 is a selective cathepsin K inhibitor, and in a 6-month phase 2 clinical trial (NCT02705625) (n=244), significantly reduced femoral bone disease progression and reduced cartilage loss, although there was no improvement in pain outcome.95 Infrequent musculoskeletal symptoms, infections and rashes were reported. A further 6-month open-level extension study showed the maintenance of structural benefit with symptomatic improvement (n=50).96 However, as most of the participants in the extension sub-study were selected because their symptoms did not worsen, a treatment benefit may be due to positive selection bias.95

Recombinant human PTH, teriparatide, is a 134 amino-acid fragment acquired from human PTH). Its anabolic action on bone production is used for osteoporosis management. In OA, it exhibits the ability to maintain articular cartilage health,97 stimulate the synthesis of extracellular matrix and induce chondrocyte proliferation in pre-clinical injury-induced OA models.98 PTH can increase subchondral bone mineral density, which could exert a negative effect on OA progression. In this sense, PTH could be an excellent drug in OA patients with osteoporosis and low subchondral sclerosis.99 Additionally, intermittent parathyroid hormone treatment attenuates OA pain in a DMM model, in association with inhibiting subchondral sensory innervation, subchondral bone deterioration, and articular cartilage degeneration.100 A phase-2 study is currently ongoing to evaluate the efficacy of PTH in knee OA participants (NCT03072147).

TPX-100 is a novel 23-amino-acid peptide derived from MEPE, a member of the Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) protein family, involved in subchondral bone remodeling.101 TPX-100 provided symptomatic improvements in patellofemoral OA knees administered with 4 weekly 200 mg injections compared with placebo injection in the contralateral knees (n=93), but only 14% of knees showed changes in cartilage thickness/volume measured on MRI over 12 months with no evidence of structural modification. No drug-related SAEs occurred in this study.102 Another 2020 OARSI conference abstract reported a statistically significant decrease in pathologic bone shape change in the femur at both 6 and 12 months using 3D femoral bone shape change.103

Antiresorptive drugs have shown reduction in bone remodeling and improvement in trabecular microarchitecture and bone mineralization. In clinical trials investigating the structure-modifying effects of bisphosphonates (alendronate, risedronate, zoledronic acid), the results are inconsistent across the studies and their outcomes presented a great heterogeneity.17,104 In a recent systematic review including preclinical studies (n=26) over the past two decades (20002020), these drugs showed better chondroprotective effects at high doses with a dose-dependent manner as well as depending on the timing of treatment initiation in relation to OA stage (time-dependency).105 Therefore, these agents may still be of potential benefits in certain OA endotypes with high rates of subchondral bone turnover. This phenotype-dependency has been demonstrated in pre-clinical research, where bisphosphonates are differentially effective in reducing pain and not only bone but also cartilage pathology in OA models with high versus low bone turnover.106109 Recently, clodronate (n=74)110 and neridronate (n=64)111 have been successfully used for the treatment of knee and hand OA, with an interesting efficacy on BMLs, although the sample sizes are small. An individual patient data meta-analysis for examining their efficacy in specific knee OA subtypes is still ongoing.112

In a multicentre, randomised controlled trial involving knee OA patients with significant knee pain and MRI-detected BMLs (n = 223), 2 annual infusions with 5 mg of zoledronic acid (the most potent of all bisphosphonates) did not significantly reduce cartilage volume loss, knee pain or BML size although the study was designed for detecting effects on the bone-driven subgroup with BMLs which may likely have potential benefits from this therapy.113 It was noted that more knee replacement procedures were performed in the zoledronic acid group compared with the placebo group (9% vs 2%) in contrast with other population-based studies.114,115

Another study involving Osteoarthritis Initiative (OAI) female participants (n=346) showed that bisphosphonate therapy may be protective of radiographic knee OA progression in nonoverweight patients with earlystage OA.116 Currently, a Phase 3 study (NCT04303026) to examine its effects in hip OA is ongoing. A phase 2 study examining the effects of another anti-resorptive, denosumab, in hand OA is expected to finish in 2021 (NCT02771860).

Vitamin D has a direct impact on cartilage by inducing proteoglycan synthesis in mature chondrocytes,117 and enhances chondrocyte viability and reduces their inflammatory cytokine synthesis through activating AMPK/mTOR and autophagy.118 Active vitamin D administration reduced cartilage degradation and inflammation in models of OA in mice and rats induced by meniscal injury/meniscectomy and ACLT.118120 Out of two recently published systematic reviews, one review showed the association of vitamin D deficiency with knee OA in patients but inconsistent evidence for its role in the prevention of incidence and progression of radiographic OA,121 while the other argued that inconsistent results may be attributed to factors such as severity of knee OA, baseline level of serum vitamin D, duration of treatment, and vitamin D dosages.122 There is a need for multicentric and well-conducted randomized studies using larger samples to determine its efficacy. A small Phase 4 clinical trial is currently active (NCT04739592).

Synovial inflammation (synovitis) is an important contributing factor to the OA pathogenesis through increased local production of pro-inflammatory cytokines, chemokines, and mediators of joint tissue damage123,124 which may be amenable to a range of anti-inflammatory drugs commonly used in inflammatory rheumatic diseases. The pharmaceutical drugs in phase 2 and 3 stages of development for inflammation-driven endotype are summarized in Table 3.

Diacerein is a purified anthraquinone derivative. It involves an inhibitory action on IL-1 and its signalling pathway, possesses an anticatabolic effect on OA tissues and reduces generation of metalloproteases.125 In animal models of OA (sheep meniscectomy, canine ACLT, rabbit ACLT and partial meniscectomy) diacerein has generally shown limited long-term effect on cartilage composition or pathology, but some evidence of reducing synovitis.126129 In a 2014 Cochrane review, the authors concluded that diacerein demonstrated only a minimal symptomatic improvement in patients with unclear benefits in JSW on X-rays, compared with placebo. Diarrhoea was the main adverse event with an absolute difference of 26%.130

The EMAs Pharmacovigilance Risk Assessment Committee suspended diacerein across Europe in 2013 due to its harms overweighing benefits,131 and then re-evaluated the drug in 2014, suggesting that it remain available with restrictions to limit risks of severe diarrhoea and hepatotoxicity.132 In 2016, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) reported that diacerein had efficacy similar to that of NSAIDs with slower onset of action, suggesting that it might have some benefits for patients with contraindication to NSAID.133

Recently, results of a phase-3 clinical trial (NCT02688400) were reported where the authors explored the comparative efficacy and safety of diacerein vs celecoxib in patients with moderate and severe knee OA using a non-inferiority trial design [(6-months of diacerein 50 mg once daily for 1 month and twice daily thereafter (n = 187), or celecoxib 200 mg once daily (n = 193)]. Diacerein was non-inferior to celecoxib in reducing pain, stiffness, or functional limitations. The diacerein group had a higher number of emergent AEs (26.3%) compared with the celecoxib group (17.4%), mainly due to higher diarrhoea events (10.2% vs 3.7%). One patient in the diacerein group had three SAEs (abdominal pain, elevated transaminase and gamma-glutamyl transferase, collectively suggestive of hepatitis) which resolved spontaneously following drug withdrawal.134

In in vitro and in vivo preclinical studies, interleukin-1 (IL-1), tumor necrosis factor- (TNF-), IL-6, IL-15, IL-17, and IL-18 exhibit pro-inflammatory actions, leading to the initiation and progression of cartilage damage and joint inflammation. So far, IL-1 and TNF- have been the most extensively studied cytokines in pre-clinical research.135,136 Despite this favorable evidence in animal OA models, most clinical trials investigating the disease-modifying effects demonstrated by inhibitors of IL-1 and TNF- in OA patients failed to meet the primary and secondary endpoints such as in cases of Gevokizumab (XOMA-052),137 AMG108,138 Lutikizumab (ABT-981),139,140 anakinra,141 adalimumab142144 and etanercept.145 In a meta-analysis evaluating the efficacy of disease-modifying anti-rheumatic drugs in OA, neither IL1-inhibitors nor TNF-inhibitors possess symptomatic benefits irrespective of the joint site affected or the inflammatory phenotype (erosive or non-erosive OA).146

These failed trial results may suggest the implication of a more complicated interaction among various cytokines in the OA pathogenic process. One of the reasons for failure may be that the clinical trials were designed to detect an effect on symptoms rather than on joint structure, which is conversely the main outcome evaluated in preclinical studies, or that they are underpowered or have not followed participants for long enough to find meaningful structural effects such as proposed in the recent CANTOS trial.147 In a recent exploratory analysis of the CANTOS trial involving patients with elevated high-sensitivity C-reactive protein (hs-CRP) levels 2 mg/L and a history of myocardial infarction (n=10061), IL-1 inhibition using canakinumab may render a substantial reduction of THR/TKR rates as well as OA-related symptoms on an averaged 3.7 years follow-up.147 Although the study had some positives such as a large sample size and long-term follow-up, it was not primarily designed to investigate the DMOAD efficacy of canakinumab and many relevant OA outcomes were missing, necessitating further confirmatory studies.

IL-6 can increase the risk of radiographic OA and associated with knee cartilage damage,148 suggesting the potential role of low-level inflammation in the pathogenesis of OA. IL-6R blockage with tocilizumab contributes to cartilage preservation and increases bone volume in a mouse model of ischemic osteonecrosis,149 and reduced cartilage lesions, osteophyte formation and synovitis in DMM-induced OA in mice.150 However, male IL-6 knock out mice have increased cartilage damage and age-related OA.151 In local joint tissues, IL-6 classic signaling produces structure-protective effects, while trans-signaling leads to catabolic effects.152 This finding might suggest that selective inhibition of IL-6 trans-signaling could be a superior treatment strategy as this may inhibit deleterious IL-6 effects in OA, while maintaining protective IL-6 signaling via the classic pathway.153 Recently, in a phase-3 trial evaluating the efficacy of tocilizumab in hand OA for 12 weeks (n=104), it revealed no more effectiveness than placebo for pain relief (7.9 vs 9.9 on VAS score in the tocilizumab and placebo groups).154

Interleukin-10 (IL-10) is an anti-inflammatory cytokine that potently and broadly suppresses proinflammatory cytokine activity. It also possesses chondroprotective effects, via reduced production of matrix metalloproteases155 as well as inhibition of chondrocyte apoptosis.156 Therefore, IL-10 could have potential benefits in OA management, both for pain improvement and suppression of the cartilage-damaging processes. Currently, there is a phase-2 clinical trial evaluating the safety and efficacy of a single injection of XT-150 (a plasmid DNA with a variant of human IL-10 transgene) in patients with knee OA (NCT04124042), and it is estimated to be complete in 2022.

In this section, we briefly put forward the reasons for failures in OA clinical trials and possible steps to overcome these barriers (Figure 2).

Figure 2 Reasons for DMOAD trial failures.

The drug will be required to demonstrate symptomatic benefits (pain and/or function) coupled with structural modifications to meet regulatory requirements as a disease-modifying agent.19,20 To date, no agent has been approved by the regulatory agencies.17 Some argue that the improvements in structural change (in the absence of any meaningful symptomatic benefits) should be a meaningful target for approval, in and of itself. However, this is unlikely to meet consumers needs as their primary reason for clinical presentation relates to symptomatic complaints.30

On the other hand, OA is a slowly progressive disease and only 14% of patients with incident OA have measurable disease progression over a 1-year period (Figure 2).157 Therefore, structure-modifying effects using targeted therapy would be optimal to delay or even avoid disease worsening and joint replacement. In OA, symptom-structure discordance is often described.158 Analysis of data from the Osteoarthritis Initiative revealed that changes in bone structure over 2 years do not translate into pain worsening until 4 years,159 suggesting that a structure-modifying drug may need longer follow-up to detect symptomatic benefit. In addition, a variety of disease outcomes using different OA subtypes (genotypes, phenotypes and endotypes) are needed to demonstrate the ability of a structure-modifying drug to directly predict for symptomatic benefits to overcome the regulatory hurdles.18

In addition, FDAs formal recognition of OA as a serious disease paves the way for using surrogate outcome measures for regulatory approval of DMOADs under accelerated approval regulations. However, two challenges need to be addressed: 1) selection/qualification of appropriate surrogate outcome measures, and 2) appropriate designs for post-marketing confirmatory studies. To overcome the first challenge, the Foundation for NIH (FNIH) OA Biomarkers Consortium initiative was established.160 For addressing the second challenge, Kraus et al proposed two major study design scenarios: 1) prospective trial continuation which continue all patients on initial drug allocation into the post-marketing approval trial until a failure threshold is achieved; and 2) separate post-marketing approval study which use different study population administered with active treatment only.161

The imaging standard in OA clinical trials has been radiographically measured mJSW which is notoriously unresponsive to change as well as possessing several other drawbacks such as issues with alignment, positioning and assuming JSW as the composite contribution of changes in other structures in this heterogeneous OA with multiple-tissue involvement.162,163 Therefore, utilization of this insensitive-to-change measure may limit our opportunity to detect any modification in what oftentimes is a slow-moving disease.

In 2015 OARSI published recommendations related to the applications of knee imaging in knee OA trials to set standards and improve quality assurance.164 Although a range of different MRI approaches have been developed to evaluate changes in overall joint structure,165167 further validation studies and evaluation of their clinimetrics are required to gain acceptance by regulatory authorities as a suitable surrogate endpoint which is the focus of the FNIH OA Biomarkers Consortium.160

In addition, the emergence of approved surrogate outcomes would allow pharmaceutical companies to examine the efficacy of the DMOADs in a shorter duration of clinical trials and reduce drug development costs. In this way, there is a possibility of instituting accelerated approval based on surrogate imaging endpoints and post-marketing approval studies to prove the longitudinal benefit-to-harm profile and the durability of the potential new therapies.161

In the study design for post-marketing approval which uses observational outcomes such as time-to-event of joint replacement surgery, considerable barriers exist in terms of need for large sample sizes due to low annual incidence rates (1.611.9%),14 long study follow-ups (>5 years at least),46 and the impact of non-disease and other subjective factors on the outcome (ie, comorbidities and/or age of the patient, costs, insurance cover, etc.).168,169 There is a lack of universal consensus criteria for guiding patient recommendations regarding joint replacement surgery, leading to differences even among treatment centres within the same region. These issues need to be adequately addressed by study design.161 There is a need for developing a criteria set to define appropriateness for total knee replacement or a virtual total knee replacement.170

Instead of utilizing the systemic route of administration which may produce undesirable systemic toxicity and off-target effects, many of the agents in the development pipeline are focused on an intra-articular route for drug delivery. This can also potentially enhance the local bioavailability, thereby maximizing therapeutic effects locally in the joint with a higher safety profile compared to systemic exposure.171 On the other hand, the marked placebo effect generated by local intraarticular administration is well-documented in the literature,172 making the assessment of symptom efficacy more challenging.30

Another issue related with the intra-articular therapy is that drugs have a short residence time within the joint.171,173 To overcome this barrier, a variety of drug delivery systems were proposed to prolong drug residence time while providing a stable concentration within the therapeutic window, leading to a reduction of side effects and better patient compliance.174 It remains unclear how long particular drugs have to remain in the joint for a meaningful symptomatic relief and/or structure-modification after an intra-articular administration. An ideal drug delivery system should comply with adequate disease modification, biocompatibility, and biodegradability while responding to its physiological environment.175

In the randomized clinical trials for IA drugs, saline is commonly used as the placebo in the control group. A recent meta-analysis examining the effects of IA saline in 50 clinical trials (n=4076) revealed significant improvement of pain severity on 0100 VAS up to 6 months [13.4 (21.7/5.1)] and WOMAC function sub-score [10.1 (12.2,-8.0)]. The pooled responder rate after saline injections using the OMERACT-OARSI criteria is 48% at 3 months and 56% at 6 months,47 challenging the concept of saline being a mere placebo.176 However, there is no evidence supporting hypotheses advocating the disease-modifying role of saline injection. Future scientifically robust studies which examined the effects of sham injections compared with saline injections are required to shed new light on this issue.

The IA therapies show a considerably larger therapeutic effect after the adjustment for the effects of IA saline, suggesting an inappropriate underestimating of the true effect of the active medication.177 Further research is required to determine the underlying mechanisms and the factors influencing the placebo response and ways to overcome it. In addition, the mechanisms of pain genesis in OA are poorly understood and thought to involve a complex interaction among local pathological processes in the OA joint and neuronal mechanisms and alterations of pain processing (ie central sensitization, especially in advanced OA).178 Further studies should focus on the effects of these interactions on the outcomes in the placebo-controlled clinical trials. It is also necessary to strictly report in each clinical trial what placebo has been used as well as the presence or absence of any additional blinded clinical evaluator, even more, if considering clinical trials with intra-articular therapies.

As OA is a heterogeneous disease with a combination of different endotypes in varying degree at different stages of the disease process, a one size fits all approach using a single therapeutic agent targeting a single target within a single endotype may be unlikely to succeed in the management of OA.179 Therefore, as in the oncology therapeutic area, combinations of drugs targeting different hallmarks of OA pathogenic process should be considered. Further research examining the potential synergistic action of combining anabolic therapies with those that downregulate catabolic factors will be required.

OA is well known for marked variations of disease expression,180 involves a variety of tissue pathologies as a whole joint disease16 and presents with different pathobiological manifestations,181 suggesting the potential value of personalised and precision medicine from the treatment perspective. Personalized medicine is used for treatment focusing on the patient based on their individual clinical characterization, considering the diversity of symptoms, severity, and genetic traits.182 In precision medicine, the molecular information maximizes the accuracy with which the patients are categorized and treated, typically applying large amounts of data for identification of patient subtypes which possess sharing specific relevant characteristics to predict diagnosis, progression, or treatment response, and to utilize appropriate therapeutic targets.183 The use of precision medicine in OA remains limited.

The implementation of private/ public initiatives, such as the Osteoarthritis Initiative, the FNIH biomarkers consortium, the European APPROACH ((Applied Public-Private Research enabling OsteoArthritis Clinical Headway)) project have contributed greatly to moving the field forward. Clinical phenotypes, endotypes, and molecular and imaging biomarkers are being identified, but the exact interplay among them and underlying mechanisms of each remain to be elucidated.24 While these biomarkers may have potential benefits in detecting those patients with the greatest risk for structural progression, their use still needs to be translated into more efficient clinical trial design and widespread clinical application.184

There remains an immense unmet need for effective and safe targeted interventions to inhibit both pain and disease progression. The complex overlapping interplay among the pathobiological OA processes and heterogeneity of clinical presentations of patients with OA, call for a universally accepted classification of phenotypes and endotypes for developing targeted disease-modifying therapy and providing the appropriate treatment in clinical setting. Although challenges exist towards the eventual management of OA by applying the concepts of personalized and precision medicine, the lessons learned through failed clinical trials, the ongoing developments of more advanced imaging and sophisticated biomarkers tools and effective drug delivery systems are leading to substantial progress in our field.

WMO is supported by the Presidential Scholarship of Myanmar for his PhD course. DJH is supported by the NHMRC Investigator Grant. VD is supported by a University of Sydney Postgraduate Award scholarship.

DJH provides consulting advice on scientific advisory boards for Pfizer, Lilly, TLCBio, Novartis, Tissuegene, Biobone. CL has provided consulting advice for Merck Serono and Galapagos Pharmaceuticals, and receives research funding from numerous pharmaceutical companies (Fidia Farmaceutici, Inter-K Peptide Therapeutics Ltd, Taisho Pharmaceutical Co. Ltd, Concentric Analgesics Inc, Cynata Therapeutics, CEVA Animal Health, Regeneus) through specific services/testing contract research agreements between and managed by The University of Sydney or the NSLHD. The authors report no other conflicts of interest in this work.

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23. Karsdal MA, Michaelis M, Ladel C, et al. Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future. Osteoarthritis Cartilage. 2016;24(12):20132021. doi:10.1016/j.joca.2016.07.017

24. Mobasheri A, Saarakkala S, Finnil M, Karsdal MA, Bay-Jensen A-C, van Spil WE. Recent advances in understanding the phenotypes of osteoarthritis. F1000Res. 2019;8:F1000Faculty Rev2091. doi:10.12688/f1000research.20575.1

25. DellIsola A, Allan R, Smith SL, Marreiros SS, Steultjens M. Identification of clinical phenotypes in knee osteoarthritis: a systematic review of the literature. BMC Musculoskelet Disord. 2016;17(1):425. doi:10.1186/s12891-016-1286-2

26. Van Spil WE, Kubassova O, Boesen M, Bay-Jensen AC, Mobasheri A. Osteoarthritis phenotypes and novel therapeutic targets. Biochem Pharmacol. 2019;165:4148. doi:10.1016/j.bcp.2019.02.037

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28. Deveza LA, Nelson AE, Loeser RF. Phenotypes of osteoarthritis: current state and future implications. Clin Exp Rheumatol. 2019;37 Suppl 120(5):6472.

29. Mobasheri A, van Spil WE, Budd E, et al. Molecular taxonomy of osteoarthritis for patient stratification, disease management and drug development: biochemical markers associated with emerging clinical phenotypes and molecular endotypes. Curr Opin Rheumatol. 2019;31(1):8089. doi:10.1097/BOR.0000000000000567

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Disease-modifying therapies for osteoarthritis | DDDT - Dove Medical Press

Cardiac Stem Cells Comments Off on Disease-modifying therapies for osteoarthritis | DDDT – Dove Medical Press | July 7th, 2021

An industry centered around unproven stem cell therapies is flourishing due to misinformation.

Why it matters: Stem cells offer a tantalizing potential to address a large number of diseases, like Parkinson's, ALS, cancers and bodily injuries. But only a small number of therapies have been found safe and effective through clinical trials, while misinformation continues to proliferate.

The latest: The Pew Charitable Trusts issued a brief in early June that describes a rising number of reported adverse events.

Background: Clinics with unregulated stem cell products or therapies began emerging in the early 2000s all over the world, "taking advantage of the media hype around stem cells and patients hope and desperation," says Mohamed Abou-el-Enein, executive director of the Joint USC/CHLA Cell Therapy Program at USC's Keck School of Medicine.

Regulatory agencies like the FDA need to crack down on these misinformation campaigns, several experts say.

What they're saying: Turner says in that period the FDA contacted about 400 businesses to warn of noncompliance and issued several warning letters, but adds that was "probably of very little consequence. ... A one-year period could be justified, but three years is basically like a security guard walking away from the post, and you can guess what's going to happen."

The big picture: This is a global threat as well, Master and Abou-el-Enein say. In a recent perspective in the journal Stem Cell Reports, they argue for the WHO to establish an expert advisory committee to explore global standards.

What's next: Researchers are still hopeful stem cell therapies can be effective but emphasize the need for more research into how stem cells work and how they can be manipulated for therapies.

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The growing global "infodemic" around stem cell therapies - Axios

Spinal Cord Stem Cells Comments Off on The growing global "infodemic" around stem cell therapies – Axios | June 25th, 2021

Hear from the CEO of NurExone Biologic Ltd, Israel's promising new start-up which aims to utilize innovative Exosome-based technology and smart delivery platforms in order to revolutionize the way spinal cord injury (SCI) is treated around the world

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June22, 20215 min read

Opinions expressed by Entrepreneur contributors are their own.

On Wall Street and prominent global stock exchanges, the emergence of innovative start-up companies has become an Israeli phenomenon. Today, the innovation nation gains unprecedented international recognition as well as investment for a country the size of the (US) state of New Jersey. Based in the northern city of Haifa, one of the newest Israeli startups building upon the countrys profound reputation is NurExone Biologic Ltd. The company, founded just last year, aims to change the way spinal cord injury (SCI) is treated around the world by utilizing exosomes as smart delivery platforms.

Over the past few decades, stem cells have become a significant interest for the scientific community as well as popular culture, and the preliminary results have been incredible. Now, stem cell research and therapy development are at an all-time high with accompanying experimental trials to apply decades of analysis into real-life medicinal practice. In regard to treating SCI, traumatic and non-traumatic, Stem Cells were tested on patients, which some of the patients have benefitted from the use of the stem cells, but due to various challenges, the treatment was not approved yet. However, NurExone promising exosome-based research proof of concept results, shown on animal, has to offer new treatment to SCI patients as well as same potential in traumatic brain injury.

NurExone is led by CEO Dr. Lior Shaltiel, who maintains an impressive background in biotech entrepreneurship, in addition to biomedical engineering, pharmacology and the advancement of smart delivery systems all of which are vital components to the companys mission. The formula behind NurExones solution is a two-prong strategy to concentrate exosome technology as the main fuel and practically treating SCI patients via a smart delivery platform. This combination, which is planned to medically transferred into the body through the nose, has a natural effect in targeting neuron damage. According to Shaltiel, while many companies are using stem cells which release exosomes naturally and attempt to regenerate neurons through local injections, our loaded exosomes have the potential to be transferred into the body nasally which is a considerable game-changer for the industry.

Furthermore, NurExone is equipped with an experienced Board of Directors, including from some of Israels leading pharmaceutical and biotech brands listed on international stock exchanges such as Executive Chairman Ron Mayron of Teva (NYSE: TEVA) and Founder & Director Yoram Drucker of Pluristem (NASDAQ: PSTI) and Brainstorm (BCLI). These substantial decision-makers in the medical technology as well as the Israeli innovation scene is indispensable and attests to the potential of the offer of the company from global operational management to strategic marketing to attracting major investors.

From its inception, NurExones extensive research and ability to conduct experimental testing comes from the companys collaboration with top professors from two of Israels elite universities Technion (noted as Israels MIT) and Tel Aviv University. As part of the companys Co-founders and Scientific Advisory Board, NurExone has partnered with Professor Daniel Offen, Head of Tel Aviv Universitys Neurology Lab, and Professor Shulamit Levenberg, the former Dean of Technions Biomedical Engineering Department and Director of the Technion Center for 3D Bioprinting. The board also features Professor Nashson Knoller, MD, Head of the Neurosurgery Department at Sheba Hospital.

This month, NurExone also implemented notable moves to prepare the company for the subsequent stage developing a promising product for the clinical phase. The company has received important approvals, which allow them to further their developing SCI treatments around the world. This significant advancement in the Israeli start-ups early focus on next stage financial efforts will play a principal role in persuading interested parties and serious investors to the table to help the company progress to become listed on international stock exchanges.

According to Shaltiel, while it usually will take several years for companies during the research and development (R&D) phase to secure investment, we are progressing with our funding model due to the exponential potential of our product. At the moment, NurExones plans to move towards entering the Toronto Stock Venture Exchange (TSXV), a Mecca-like market for penny stocks and new companies attempting to build an investor following for more global exchanges in the future.

In the world of start-up and innovation companies, a companys infrastructure, vision, and basis for research development is crucial to the success and longevity of the business. For NurExone, the companys successful Board of Directors, ambitious and experienced CEO Dr. Lior Shaltiel, together with the Scientific Advisory Board should not merely satisfy these prerequisites but galvanize the biotech community. While the company, after only a few months, has provided an important genesis for potential investors as well as medical professionals to learn from it also shows the teams efficiency and maturity. In order for NurExone to change how SCI is treated around the world, its next pragmatic step will be to analyze and optimize the product to take another step towards making its goal to treat SCI closer to becoming a reality.

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This Startup is Changing the Way Spinal Cord Injury Is Treated Around the World - Entrepreneur

Spinal Cord Stem Cells Comments Off on This Startup is Changing the Way Spinal Cord Injury Is Treated Around the World – Entrepreneur | June 25th, 2021

New York, June 23, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Nerve Repair and Regeneration Devices Industry" - https://www.reportlinker.com/p05957490/?utm_source=GNW The rapid rise in the incidence of nerve injuries worldwide, increasing prevalence of various neurological disorders, especially in the expanding elderly population, and development of advanced technology-based nerve repair and regeneration products are fueling growth in the global market. The constant increase in incidence of nerve injuries is leading to high demand for nerve repair and regeneration products. The growing incidence of chronic nervous system disorders such as Parkinson`s and Alzheimer`s disease is also driving demand for nerve repair and regeneration procedures and devices. There is also increased funding for clinical trials aimed at development of effective and safe therapies for treatment of various neurological disorders. Initiatives such as stem cells in umbilical blood infusion for cerebral palsy; and the use of Polyethylene glycol (PEG) drug for promoting axonal fusion technique for repairing peripheral nerve injuries are favoring market growth.

- Amid the COVID-19 crisis, the global market for Nerve Repair and Regeneration Devices estimated at US$6.6 Billion in the year 2020, is projected to reach a revised size of US$11.8 Billion by 2026, growing at a CAGR of 10% over the analysis period. Neurostimulation & Neuromodulation Devices, one of the segments analyzed in the report, is projected to grow at a 9.7% CAGR to reach US$10.9 Billion by the end of the analysis period. After a thorough analysis of the business implications of the pandemic and its induced economic crisis, growth in the Biomaterials segment is readjusted to a revised 11.7% CAGR for the next 7-year period. This segment currently accounts for a 13.8% share of the global Nerve Repair and Regeneration Devices market. The neurostimulation and neuromodulation devices segment growth will be fueled by rising incidence of peripheral nerve injuries, development of technologically advanced products and favorable reimbursement scenario. Within the segment, internal neurostimulation and neuromodulation devices category is being driven due to the devices` ability to lower occurrence of post-surgical complications and reducing duration of hospitalization. Biomaterials segment is expected to witness high growth, driven by broadening application range, increased availability of government funding for innovations, and development of advanced products.

The U.S. Market is Estimated at $2.2 Billion in 2021, While China is Forecast to Reach $1.8 Billion by 2026

- The Nerve Repair and Regeneration Devices market in the U.S. is estimated at US$2.2 Billion in the year 2021. The country currently accounts for a 30.45% share in the global market. China, the world`s second largest economy, is forecast to reach an estimated market size of US$1.8 Billion in the year 2026 trailing a CAGR of 13% through the analysis period. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 7.7% and 8.8% respectively over the analysis period. Within Europe, Germany is forecast to grow at approximately 9.2% CAGR while Rest of European market (as defined in the study) will reach US$2 Billion by the end of the analysis period. Increasing incidence of neurological diseases and expanding geriatric population, increasing spending on healthcare sector, positive reimbursement framework and presence of several leading industry players are fueling growth in the North America region. Asia-Pacific is poised to grow at a robust pace, driven by sizeable patient pool, favorable healthcare initiatives and high unmet healthcare needs. The Asia-Pacific market is expected to gain from notable surge in aging population, increasing awareness regarding neurological disorders, and rising incidence of cancer and osteoporosis. Select Competitors (Total 61 Featured)

Read the full report: https://www.reportlinker.com/p05957490/?utm_source=GNW

CONTENTS

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEW Impact of Covid-19 and a Looming Global Recession 2020 Marked as a Year of Disruption & Transformation EXHIBIT 1: World Economic Growth Projections (Real GDP, Annual % Change) for 2019 to 2022 Global Nerve Repair & Regeneration Market Buckles under COVID- 19 Strain Covid-19 Patients in Prone Position Suffering Nerve Damage Bodes Well for Market Growth Nerve Repair and Regeneration Market Set for a Robust Growth Neurostimulation & Neuromodulation Devices Hold Commanding Slot in Nerve Repair & Regeneration Market Biomaterials to Exhibit Rapid Growth Nerve Repair and Regeneration Market by Application US and Europe Dominate the Market Asia-Pacific and other Emerging Regions Display Impressive Growth Potential Recent Market Activity

2. FOCUS ON SELECT PLAYERS

3. MARKET TRENDS & DRIVERS High Incidence of Neurological Disorders: A Key Market Driver EXHIBIT 2: Annual Incidence of Adult-Onset Neurologic Disorders in the US Effects of COVID-19 on the Nervous System Sheds Focus on Neuromodulation Applications Increasing Cases of Peripheral Nerve Injuries Drive the Nerve Repair and Regeneration Market Growing Number of Vehicular Accidents Drive the Peripheral Nerve injuries Repair Market Rising Geriatric Population and Subsequent Growth in Prevalence of Neurological Disorders EXHIBIT 3: Global Population Statistics for the 65+ Age Group in Million by Geographic Region for the Years 2019, 2025, 2035 and 2050 Growing Incidence of Neurodegenerative Diseases Propels the Market for Deep Brain Stimulation Devices EXHIBIT 4: Global Alzheimers Prevalence by Age Group EXHIBIT 5: Diagnosed Prevalence Cases of Parkinson?s Disease Across Select Countries EXHIBIT 6: Global DBS Market by Leading Player (2020E): Market Share Breakdown of Revenues for Medtronic, Boston Scientific, and Abbott Select Available Deep Brain Stimulation Devices Available in the Market Intensified Research Activity Across Various Neural Disciplines Induces Additional Optimism Stem Cell Therapy: A Promising Avenue for Nerve Repair and Regeneration Increasing Cases of Epilepsy Drives the Demand for Vagus Nerve Stimulation Devices EXHIBIT 7: Epilepsy Incidence by Type (2019): Percentage Share Breakdown for Idiopathic and Symptomatic Epilepsy EXHIBIT 8: Symptomatic Epilepsy Incidence by Type (2019): Percentage Share Breakdown of Congenital, Degenerative, Infective, Neoplastic, Trauma, and Vascular Epilepsy Spinal Cord Injuries Propel the Demand for Spinal Cord Stimulation Devices Recent Developments in Spinal Cord Injury Treatment Biomaterials (Nerve Conduits and Nerve Wraps) to Witness Rapid Growth New Biomaterials Pave the Way for Innovative Neurodegeneration Therapies Role of Nerve Conduits in the Treatment of Peripheral Nerve Injury Innovative Nerve Conduits from Stryker TENS (Transcutaneous electrical nerve stimulation devices) Market Witnesses Rapid Growth Non-Invasiveness of TMS (Transcranial Magnetic Stimulation) Propelling the adoption of TMS devices Nerve Grafts for Bridging Larger Nerve Gaps Role of Nerve Grafting in Treatment of Peripheral Nerve Injuries FDA-approved Nerve Tubes for Peripheral Nerve Repair

4. GLOBAL MARKET PERSPECTIVE Table 1: World Current & Future Analysis for Nerve Repair and Regeneration Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 2: World Historic Review for Nerve Repair and Regeneration Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 3: World 15-Year Perspective for Nerve Repair and Regeneration Devices by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets for Years 2012, 2020 & 2027

Table 4: World Current & Future Analysis for Neurostimulation & Neuromodulation Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 5: World Historic Review for Neurostimulation & Neuromodulation Devices by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 6: World 15-Year Perspective for Neurostimulation & Neuromodulation Devices by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 7: World Current & Future Analysis for Biomaterials by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 8: World Historic Review for Biomaterials by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 9: World 15-Year Perspective for Biomaterials by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 10: World Current & Future Analysis for Neurostimulation & Neuromodulation Surgeries by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 11: World Historic Review for Neurostimulation & Neuromodulation Surgeries by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 12: World 15-Year Perspective for Neurostimulation & Neuromodulation Surgeries by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 13: World Current & Future Analysis for Neurorrhaphy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 14: World Historic Review for Neurorrhaphy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 15: World 15-Year Perspective for Neurorrhaphy by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 16: World Current & Future Analysis for Nerve Grafting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 17: World Historic Review for Nerve Grafting by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 18: World 15-Year Perspective for Nerve Grafting by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 19: World Current & Future Analysis for Stem Cell Therapy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 20: World Historic Review for Stem Cell Therapy by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 21: World 15-Year Perspective for Stem Cell Therapy by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 22: World Current & Future Analysis for Hospitals & Clinics by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 23: World Historic Review for Hospitals & Clinics by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 24: World 15-Year Perspective for Hospitals & Clinics by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

Table 25: World Current & Future Analysis for Ambulatory Surgery Centers by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 26: World Historic Review for Ambulatory Surgery Centers by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 27: World 15-Year Perspective for Ambulatory Surgery Centers by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific, Latin America, Middle East and Africa for Years 2012, 2020 & 2027

III. MARKET ANALYSIS

UNITED STATES Table 28: USA Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 29: USA Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 30: USA 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 31: USA Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 32: USA Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 33: USA 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 34: USA Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 35: USA Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 36: USA 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

CANADA Table 37: Canada Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 38: Canada Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 39: Canada 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 40: Canada Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 41: Canada Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 42: Canada 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 43: Canada Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 44: Canada Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 45: Canada 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

JAPAN Table 46: Japan Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 47: Japan Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 48: Japan 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 49: Japan Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 50: Japan Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 51: Japan 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 52: Japan Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 53: Japan Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 54: Japan 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

CHINA Table 55: China Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 56: China Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 57: China 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 58: China Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 59: China Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 60: China 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 61: China Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 62: China Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 63: China 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

EUROPE Table 64: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by Geographic Region - France, Germany, Italy, UK, Spain, Russia and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 65: Europe Historic Review for Nerve Repair and Regeneration Devices by Geographic Region - France, Germany, Italy, UK, Spain, Russia and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 66: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK, Spain, Russia and Rest of Europe Markets for Years 2012, 2020 & 2027

Table 67: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 68: Europe Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 69: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 70: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 71: Europe Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 72: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 73: Europe Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 74: Europe Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 75: Europe 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

FRANCE Table 76: France Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 77: France Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 78: France 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 79: France Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 80: France Historic Review for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 81: France 15-Year Perspective for Nerve Repair and Regeneration Devices by Application - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy for the Years 2012, 2020 & 2027

Table 82: France Current & Future Analysis for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 83: France Historic Review for Nerve Repair and Regeneration Devices by End-Use - Hospitals & Clinics and Ambulatory Surgery Centers Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 84: France 15-Year Perspective for Nerve Repair and Regeneration Devices by End-Use - Percentage Breakdown of Value Sales for Hospitals & Clinics and Ambulatory Surgery Centers for the Years 2012, 2020 & 2027

GERMANY Table 85: Germany Current & Future Analysis for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 86: Germany Historic Review for Nerve Repair and Regeneration Devices by Product - Neurostimulation & Neuromodulation Devices and Biomaterials Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2012 through 2019 and % CAGR

Table 87: Germany 15-Year Perspective for Nerve Repair and Regeneration Devices by Product - Percentage Breakdown of Value Sales for Neurostimulation & Neuromodulation Devices and Biomaterials for the Years 2012, 2020 & 2027

Table 88: Germany Current & Future Analysis for Nerve Repair and Regeneration Devices by Application - Neurostimulation & Neuromodulation Surgeries, Neurorrhaphy, Nerve Grafting and Stem Cell Therapy - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

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Global Nerve Repair and Regeneration Devices Market to Reach $11. 8 Billion by 2026 - GlobeNewswire

Spinal Cord Stem Cells Comments Off on Global Nerve Repair and Regeneration Devices Market to Reach $11. 8 Billion by 2026 – GlobeNewswire | June 25th, 2021

Cases of mucormycosis or "black fungus," a rare but serious fungal infection, are climbing in India among some coronavirus patients, per news reports.

Infections have risen to over 30,000 in three weeks, with at least 2,100 deaths, the New York Times reported, compounding the need to protect the country's population, a large percentage of which remain unvaccinated against COVID-19 ahead of a feared third wave this fall.

The infection is caused by a group of molds called mucormycetes which live throughout the environment and typically do not agitate otherwise healthy people, according to the Centers for Disease Control and Prevention (CDC).

However, in those who have health problems, or take medications that lower the bodys ability to fight off germs and sickness, it could infect the sinuses or lungs when inhaled through the air or on injured skin. Diabetes, cancer, organ transplants, stem cell transplants, low white blood cells, long-term corticosteroid use, injection drug use, too much iron, skin injury and premature or low birth weight are all considered to be risk factors.

INDIA'S CORONAVIRUS DOCTORS REPORT BLACK FUNGUS INFECTIONS AMONG SOME PATIENTS

Doctors in India suspect the countrys overwhelmed hospitals and shortage of medical oxygen left patients vulnerable to the fungal infection. Dr. Bela Prajapati, in charge of treatment for hundreds of mucormycosis patients, told the Times that doctors excessive use of steroids to fight inflammation in coronavirus patients, to help them breathe easier, in turn spiked blood sugar levels and left diabetes patients at risk of infection.

Researcher and microbiologist Dr. Arunaloke Chakrabarti noted many doctors didnt have time to question patients over underlying conditions before turning to the steroids.

"Doctors hardly had any time to do patient management," Chakrabarti told the newspaper. "They were all looking at how to take care of the respiratory tract."

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'Black fungus' infections on the rise in India: report - Yahoo News

Skin Stem Cells Comments Off on ‘Black fungus’ infections on the rise in India: report – Yahoo News | June 25th, 2021

Express News Service

Both internal and external factors cause the skin to age. As we age, collagen and other supportive tissues in the deeper layers of the skin decrease, causing the skin to lose its elasticity. Excessive sun exposure, air pollution, stress and chronic ill-health can hasten the process. Aesthetic and surgical treatments for men are now coming into prominence. Here are some:

Laser treatments: New technology is giving laser treatments an impetus, which are good to treat pigmentation and other skin problems. Carbon dioxide and erbium lasers are good options. Botulinum toxin and dermal filler injections: Fat is a very good, popular and natural filler. Botox is a protein that paralyses muscles and prevents them from contracting, thus smoothening fine lines and wrinkles.

Platelet Rich Plasma (PRP) therapy: This is a simple, quick and effective therapy that restores radiance. A small amount of blood is drawn from the patient, centrifuged (spun at fast speed) to separate the platelet-rich plasma and is then injected into the facial skin using a fine needle.

Autologous fat grafting: Fat is harvested from one part of the body, purified and injected into the facial area. With new techniques, the fat can be treated to extract fat stem cells, which have better rejuvenating and repairing potential. This technique is called Nano fat grafting and can be combined with micro-needling.

Thermage: Also known as the lunchtime facelift, it is a quick, non-invasive facial rejuvenation technique. A handpiece delivers radiofrequency heat energy into the collagen-containing layers of the skin, stimulating the collagen to renew and repair itself, and thus adding volume and improving the texture of the facial skin.

HIFU skin tightening: It is a new cosmetic treatment that is a non-invasive and painless replacement for facelifts. Surgical facelift: This is useful when the degree of sagging and wrinkles is unlikely to be corrected by non-surgical techniques. It is done under general anaesthesia.

The author is a SeniorConsultant and Cosmetic Surgeon, Apollo Hospital, New Delhi

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Mens Guide to Cosmetic Beauty - The New Indian Express

Skin Stem Cells Comments Off on Mens Guide to Cosmetic Beauty – The New Indian Express | June 25th, 2021

Continued, heavy thunderstorms along the Gulf Coast will further flash flooding concerns left by the tropical storm. Accuweather

Planning a hike or a nature walk? You probably know to avoid poison ivy by its distinguishable three leaves on a single stem or stinging nettle by its tiny hair-like projections. But there may be one seemingly innocuous plant not on your radar, as one Facebook post claims.

"(It's) about that time of the year again and we are terrified of the kidscoming into contact with Wild Parsnip. Please, please be aware of how dangerous this plant really is!" claims the May 31, 2019, post,since shared over 142,000 times on the social media platform.

The poster says the yellow flowering plant, resembling an upturned umbrella in accompanying pictures, produces a sapthat reacts violently with skin after exposure to sunlight, causing blisters, burns and potentially blindness.

Large, fluid-filled blisters on the chest, hands and arms of an unidentified child, purportedly the poster's son, are included, emphasizing the need for awareness and caution.

Fact check: Brood X cicadas are infected with a sexually transmitted fungus

"I have heard about Wild Parsnip but never knew it was this bad. Poor little guy," commented one Facebook user.

"Oh my gosh, (I) had this in the field behind my house last year, wonder if it comes back every year," said another.

Wild parsnip, an invasive plant species from Europe and Asia likely brought by European settlers to North America for its edible root, is a widespread problem in Canada and in states like Ohio, New Yorkand Minnesota. USA TODAY cannot verify the images shared in the post, but its word of warning about the plant is indeed scientifically true.

Standing at almost 5-feet tall with a single, deeply ridged stem about 2- to 5-centimetersthick, wild parsnip is found throughout southern Canada and the northern U.S. All parts of the plant from the stems, leaves and flowers contain phytochemicals called psoralens, which kill skin cells by inserting themselves into our DNA.

Normally, our skin shields us from a type of radiation emitted by the sun called long-wave ultraviolet radiation, or LWUVR. But with psoralens essentially hijacking our genetic code, they boost the amount of LWUVR our skin absorbsand stop cellular growth.

This may sound bad, and does result in a condition called phytophotodermatitis characterized by angry-looking blisters and burn-like symptoms, but psoralens in combination with ultraviolet light therapy havebeen usedto safely treat skin diseases like psoriasis and vitiligo since the 1970s.

Fact check: Image of human-elephant hybrid is art, doesn't show real baby

Other conditions resulting from coming into contact with wild parsnipcan include blindness if the sap gets into your eyes.

The plant can also inflict injury in animals; livestock that eat it tend to lose weight and may have fertility issues.

Wild parsnip grows in a whole range of environments butis commonly foundalong roadsides, pastures, abandoned fields and any place where soil has been disturbed and native vegetation has yet to be established, according tothe New York Invasive Species Information Clearinghouse.

It's advised if you do come into contact with the yellow-flowered planttoget out of the sun as soon as possible or immediately cover the affected areas before washing with warm water and soap. While photosensitivity and discoloration typically last up to eight hours, these symptoms can linger for up to two years.

Based on our research, we rate TRUE the claim wild parsnip sap can cause skin blisters. A phytochemical secreted by wild parsnip, called psoralens, reacts when exposed to sunlight, affecting cell growth, which results in blisters, other burn-like symptoms and even blindness if the sap gets in the eyes.

Thank you for supporting our journalism. You can subscribe to our print edition, ad-free app or electronic newspaper replica here.

Our fact check work is supported in part by a grant from Facebook.

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Fact check: Contact with wild parsnip harmful to humans and animals - USA TODAY

Skin Stem Cells Comments Off on Fact check: Contact with wild parsnip harmful to humans and animals – USA TODAY | June 25th, 2021

ABU DHABI, 22nd June, 2021 (WAM) -- The Ministry of Health and Prevention (MoHAP) and the Emirates Health Services (EHS) recently revealed innovative immunotherapy for cancer and viral infections in cooperation with Japans Kyoto University.

This came during the participation of the ministry and the EHS at the Arab Health 2021 which began in Dubai on 21st June and concludes on 24th June.

The treatment is based on the clinical application of the therapy using T cell preparation after it was discovered that such cells can fight cancer and viral infections. The T cell medicine will be produced using the iPS cell technology.

T Cell makes up a group of lymphocytes present in the blood and plays a major role in cellular immunity. It is possible to produce T cells in large numbers and store them in appropriate conditions to be administered to patients when needed.

Thus, by the success of this project, patients with cancer or viral infection may have great merit in which they can make very easy access to T cell therapy.

Strategic partnerships Dr. Youssef Mohamed Al Serkal, Director-General of the Emirates Health Services, spoke about the commitment of the ministry and the EHS to having strategic partnerships with the most prestigious medical research centres while keeping an eye on the sustainable investment in future healthcare services.

"Although the prevalence of cancer in the UAE is considered lower than in other parts of the world, we work hard to make a qualitative shift in cancer and viral infection healthcare," Al Serkal stated, adding, "This is part of our strategy to provide healthcare services in innovative and sustainable ways and implement the national strategy to reduce cancer mortality rates."

Al Serkal pointed out that the ministry and EHS support the National Cancer Control Programme and prepare a road map to achieve the target indicator. They also analyse the current status of cancer diseases and their diagnostic and therapeutic pathways, support research and studies on the control of cancer diseases and viral infections, and back workshops and educational and training activities. awareness campaigns, and innovative initiatives.

Dr. Kalthum Al Balushi, Director of Hospitals Department, said, "The ground-breaking treatment technology for cancer and viral infections, in cooperation with the Kyoto University, represents a paradigm shift in health services provided by the Ministry and the EHS."

The treatment is based on stimulating immune cells to fight cancer cells using pluripotent stem cells, which is a recent global trend that has begun to open great prospects for improving the quality of life of patients, Al Balushi added.

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MoHAP, EHS reveal immunotherapy for cancer, viral infections at Arab Health 2021 - WAM EN

IPS Cell Therapy Comments Off on MoHAP, EHS reveal immunotherapy for cancer, viral infections at Arab Health 2021 – WAM EN | June 25th, 2021

BOSTON--(BUSINESS WIRE)--Gamida Cell Ltd. (Nasdaq: GMDA), an advanced cell therapy company committed to cures for blood cancers and serious hematologic diseases, today announced that the results of a Phase 3 clinical study of omidubicel have been published in Blood, the official journal of the American Society of Hematology. Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell transplant solution for patients with hematologic malignancies.

The results demonstrate that transplantation with omidubicel leads to faster neutrophil and platelet recovery compared to a standard umbilical cord blood graft, and results in fewer early bacterial and viral infections and less time in the hospital.

We are pleased that the data from this well-conducted international Phase 3 trial have been published in Blood, the highly respected, peer-reviewed journal of the American Society of Hematology, said Ronit Simantov, M.D., chief medical officer of Gamida Cell. The robust results of this clinical trial have demonstrated that omidubicel could provide an important new option for patients with hematologic malignancies in need of a bone marrow transplant.

Data from this study were previously presented at the Transplantation & Cellular Therapy Meetings of the American Society of Transplantation and Cellular Therapy and Center for International Blood & Marrow Transplant Research, and most recently during the Presidential Symposium at the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation. The pivotal study was an international, multi-center, randomized Phase 3 trial designed to compare the safety and efficacy of omidubicel to standard umbilical cord blood transplant in patients with high-risk hematologic malignancies undergoing a bone marrow transplant.

Previous studies have shown that engraftment with omidubicel is durable, with some patients in the Phase 1/2 study now a decade past their transplant. The Phase 3 data reinforce omidubicels potential to be a new standard of care for patients who are in need of stem cell transplantation but do not have access to an appropriate matched donor, said Mitchell Horwitz, M.D., lead author of the paper and a professor of medicine at the Duke Cancer Institute.

The full Blood manuscript is available here: https://ashpublications.org/blood/article/doi/10.1182/blood.2021011719/476235/Omidubicel-Versus-Standard-Myeloablative-Umbilical.

Details of Phase 3 Efficacy and Safety Results Shared in Blood

The intent-to-treat analysis included 125 patients aged 1365 years with a median age of 41. Forty-four percent of the patients treated on study were non-Caucasian, a population known to be underrepresented in adult bone marrow donor registries. Patient demographics and baseline characteristics were well-balanced across the two study groups. Patients with acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome or lymphoma were enrolled at more than 30 clinical centers in the United States, Europe, Asia, and Latin America.

Gamida Cell previously reported in May 2020 that the study achieved its primary endpoint, showing that omidubicel demonstrated a statistically significant reduction in time to neutrophil engraftment, a measure of how quickly the stem cells a patient receives in a transplant are established and begin to make healthy new cells and a key milestone in a patients recovery from a bone marrow transplant. The median time to neutrophil engraftment was 12 days for patients randomized to omidubicel compared to 22 days for the comparator group (p<0.001).

All three secondary endpoints, details of which were first reported in December 2020, demonstrated a statistically significant improvement among patients who were randomized to omidubicel compared to patients randomized to standard cord blood graft. Platelet engraftment was significantly accelerated with omidubicel, with 55 percent of patients randomized to omidubicel achieving platelet engraftment at day 42, compared to 35 percent for the comparator (p = 0.028). Hospitalization in the first 100 days after transplant was also reduced in patients randomized to omidubicel, with a median number of days alive and out of hospital for patients randomized to omidubicel of 61 days, compared to 48 days for the comparator (p=0.005). The rate of infection was significantly reduced for patients randomized to omidubicel, with the cumulative incidence of first grade 2 or grade 3 bacterial or invasive fungal infection for patients randomized to omidubicel of 37 percent, compared to 57 percent for the comparator (p=0.027). Additional data reported in the manuscript included a comparison of infection density, or the number of infections during the first year following transplantation, which showed that the risk for grade 2 and grade 3 infections was significantly lower among recipients of omidubicel compared to control (risk ratio 0.5, p<0.001).

Data from the study relating to exploratory endpoints also support the clinical benefit demonstrated by the studys primary and secondary endpoints. There was no statistically significant difference between the two patient groups in incidence of grade 3/4 acute GvHD (14 percent for omidubicel, 21 percent for the comparator) or all grades chronic GvHD at one year (35 percent for omidubicel, 29 percent for the comparator). Non-relapse mortality was shown to be 11 percent for patients randomized to omidubicel and 24 percent for patients randomized to the comparator (p=0.09).

These clinical data results form the basis of a Biologics License Application (BLA) that Gamida Cell plans to submit to the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2021.

About Omidubicel

Omidubicel is an advanced cell therapy under development as a potential life-saving allogeneic hematopoietic stem cell (bone marrow) transplants for patients with hematologic malignancies (blood cancers), for which it has been granted Breakthrough Status by the FDA. Omidubicel is also being evaluated in a Phase 1/2 clinical study in patients with severe aplastic anemia (NCT03173937). The aplastic anemia investigational new drug application is currently filed with the FDA under the brand name CordIn, which is the same investigational development candidate as omidubicel. For more information on clinical trials of omidubicel, please visit http://www.clinicaltrials.gov.

Omidubicel is an investigational therapy, and its safety and efficacy have not been established by the FDA or any other health authority.

About Gamida Cell

Gamida Cell is an advanced cell therapy company committed to cures for patients with blood cancers and serious blood diseases. We harness our cell expansion platform to create therapies with the potential to redefine standards of care in areas of serious medical need. For additional information, please visit http://www.gamida-cell.com or follow Gamida Cell on LinkedIn or Twitter at @GamidaCellTx.

Cautionary Note Regarding Forward Looking Statements

This press release contains forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995, including with respect to the potential for omidubicel to become a new standard of care and the anticipated submission of a BLA for omidubicel, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to Gamida Cells ability to prepare regulatory filings and the review process therefor; complications in Gamida Cells plans to manufacture its products for commercial distribution; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in the Risk Factors section and other sections of Gamida Cells Annual Report on Form 20-F, filed with the Securities and Exchange Commission (SEC) on March 9, 2021, as amended on March 22, 2021, and other filings that Gamida Cell makes with the SEC from time to time (which are available at http://www.sec.gov), the events and circumstances discussed in such forward-looking statements may not occur, and Gamida Cells actual results could differ materially and adversely from those anticipated or implied thereby. Any forward-looking statements speak only as of the date of this press release and are based on information available to Gamida Cell as of the date of this release.

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Gamida Cell Announces Publication in Blood, the Journal of the American Society of Hematology, of the First Pivotal Trial to Evaluate a Cell Therapy...

Bone Marrow Stem Cells Comments Off on Gamida Cell Announces Publication in Blood, the Journal of the American Society of Hematology, of the First Pivotal Trial to Evaluate a Cell Therapy… | June 25th, 2021

FRIDAY, June 18, 2021 (HealthDay News) -- It's been more than six months since Brandy Compton last landed in a hospital emergency room.

That's an amazing medical achievement, brought about by scientific breakthroughs that have been unfortunately overshadowed by the coronavirus pandemic, experts say.

Compton, 31, was born with sickle cell disease, a genetic condition that primarily affects people of African descent.

The disease causes episodes of pain so bad that in the past, Compton had to be hospitalized frequently for full blood transfusions.

"In grade school, I was in the hospital for a week, I'd get out of the hospital for maybe a good week and a half, two weeks, and then I'd be back in the hospital for another week," recalls Compton, who lives in Hartford, Conn. "It was constant."

But last year Compton started on a once-monthly IV drug called Adakveo (crizanlizumab), one of a handful of new sickle cell drugs approved by the U.S. Food and Drug Administration just before the pandemic hit.

The drug has cut in half the amount of blood Compton requires during a transfusion, and has prevented the sort of pain crisis that would send her to an ER, she said.

As the pandemic subsides, sickle cell disease experts are now trying to spread the word about these handful of treatments that could improve and potentially extend the lives of patients.

"In the last three years or so, three new medicines got approved by the FDA with different ways of working that could actually be used together and give more preventive, disease-modifying types of approaches rather than just waiting for the bad complications to occur," said Dr. Lewis Hsu, chief medical officer of the Sickle Cell Disease Association of America.

Progress also is being made on cures that would fix the genetic error that causes sickle cell, either through a donor bone marrow transplant or gene therapy that would fix the patient's own stem cells, Hsu added.

'Jagged rocks shredding your veins'

Sickle cell disease affects the shape of a person's red blood cells, which are normally disc-shaped and flexible enough to move easily through blood vessels.

The red blood cells of a person with sickle cell are crescent-shaped, resembling a sickle. The cells are stiff and sticky, and cause pain episodes and other health problems when they clump together in different parts of the body. They also are less capable of carrying oxygen to a person's tissues, causing chronic fatigue.

"Sickle cell feels like jagged rocks shredding the inside of your veins, and your bones being crushed," Compton says.

Sickle cell disproportionately affects Black people in the United States. About 1 in 13 Black babies is born with the genetic trait for sickle cell, and about 1 in every 365 Black babies is born with sickle cell disease, according to the U.S. National Institutes of Health.

For a long time, there was no treatment at all for sickle cell, Hsu said, outside of regular blood transfusions.

"At the age of 13, I started getting blood transfusions," Compton recalls. "After that, it started getting under control. I would be able to go about a month without having to be hospitalized. That time got longer as I got older."

In 1998, the FDA approved hydroxyurea, an oral medicine that can reduce or prevent sickle cell complications in people with specific subtypes of the disease. But following that, there was a "long gap" in new treatments, Hsu said.

That ended in 2017 with the approval of L-glutamine powder, sold under the brand name Endari. Patients sprinkle a packet of this purified amino acid powder on their food or drink twice a day, Hsu said.

"Particularly, it help the red cells be healthier and have better energy stores," Hsu said.

But the two real breakthroughs occurred in November 2019, on the cusp of the pandemic, with FDA approval of two new drugs -- Adaveko and Oxbryta (voxelotor).

Adaveko essentially creates an "oil slick" in the bloodstream that keeps sickled red blood cells from clumping, explained Genice Nelson, program director of the New England Sickle Cell Institute at the University of Connecticut. She also leads Compton's care.

"It helps to improve blood flow by having the cells move along better, gliding instead of sticking to each other," Hsu said.

Showing promise at a high price

Thanks to Adaveko, Compton now only needs four units of blood every four weeks, down from seven, and does not suffer frequent pain episodes.

The other drug, Oxbryta, improves the ability of deformed red blood cells to hold onto oxygen, Nelson said.

"It inhibits the deformation of the red blood cell, so it's able to hold onto oxygen," Nelson said. "Because the red blood cell is able to hold onto oxygen, it's able to give that oxygen to the tissues within the body."

Because these drugs act in different ways, the hope is that a sickle cell patient taking two or more would receive added benefits, Hsu said.

Unfortunately, the new drugs are expensive and insurance companies have balked at paying for them, Hsu said.

For example, Adakveo costs about $10,000 a month for a patient, Nelson said. It seems like a great expense, but is likely cheaper than regular ER visits.

"If someone is in the hospital several days out of the month every month, dollar for dollar you'd rather invest it in preventing them from being in the hospital rather than trying to treat them once they're in the hospital," Nelson said.

Despite this, insurance companies have dragged their feet accepting the new drugs.

"We have great, great difficulty prescribing them and getting them authorized," Hsu said. "It's a case-by-case issue for every single prescription. It takes two months or so to get the authorizations, and then we go for refills or another prescription and they have to go through the same process again."

Experts hope that the track record of these drugs will lead insurance companies to relent.

"The data is clear there is benefit to patients being on disease-modifying therapies," said Dr. Alexis Thompson, head of hematology for the Ann & Robert Lurie Children's Hospital in Chicago. "The natural history of sickle cell disease is devastating. To not think about where the opportunities are to intervene early, to modify the natural history of the disease and really reduce suffering, is something we all need to be committed to."

Great progress also has been made in cures for sickle cell, Hsu added.

Transplants tricky, but improvements underway

For a long time, the only potential cure was a full bone marrow transplant from a genetically matched donor, usually a sibling, Hsu said. Only children could handle the stress of this cure, because their existing bone marrow had to be killed off through chemotherapy prior to the transplant.

But improved medications that inhibit immune system rejection now have made transplants also available to children who have a half-matched relative. These drugs selectively inhibit immune attack cells without harming the healthy stem cells being transplanted, Hsu said.

Over the past decade, even adult sickle cell patients have been receiving transplants, through a method that replaces most but not all of the person's bone marrow.

"This is a mixture that's enough to allow the donor to supply most of the red cells that are floating around, so they're not sickle red cells, and the tiny portion of host red cells are diluted heavily," Hsu said. "This has found to be successful and stable."

Five to seven research groups also are working on what could be the ultimate cure for sickle cell, a gene therapy that would take the person's own bone marrow and fix it to remove the genetic anomaly that causes the disease.

"You'd no longer have to find a donor for the stem cells," Hsu said. "You basically do your own donation of stem cells."

Research efforts are focused on fixing the stem cells by treating them with a genetically modified virus, or by using newly discovered methods of gene editing, Hsu said. In both cases, the person's bone marrow is removed, treated in a lab, and then put back inside them.

These efforts have met with some hurdles, with the gene therapy causing leukemia in something like 2 of every 47 cases in some instances, Hsu said.

"We do need to keep working on ways to limit the side effects or toxicity of those approaches, but one cannot argue that the early data is quite remarkable," Thompson said.

Compton, now the mother of a healthy 9-year-old boy, is hopeful that these efforts will lead to a cure, even though she doesn't expect to benefit from one at her age.

"I know about gene therapy and things like that," Compton said. "I do hope there would be a cure available."

More information

The Mayo Clinic has more about sickle cell disease.

SOURCES: Brandy Compton, Hartford, Conn.; Lewis Hsu, MD, PhD, chief medical officer, Sickle Cell Disease Association of America; Alexis Thompson, MD, MPH, head, hematology, Ann & Robert Lurie Children's Hospital, Chicago; Genice Nelson, DNP, program director, New England Sickle Cell Institute, University of Connecticut, Farmington

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Sickle Cell Plagues Many Black Americans, But There's Hope for Better Treatments - HealthDay News

Bone Marrow Stem Cells Comments Off on Sickle Cell Plagues Many Black Americans, But There’s Hope for Better Treatments – HealthDay News | June 25th, 2021

Imagine being able to reverse blindness, cure multiple sclerosis (MS), or rebuild your heart muscles after a heart attack. For the past few decades, research into stem cells, the building blocks of tissues and organs, has raised the prospect of medical advances of this kind yet it has produced relatively few approved treatments. But that could be about to change, says Robin Ali, professor of human molecular genetics of Kings College London. Just as gene therapy went from being a fantasy with little practical value to becoming a major area of treatment, stem cells are within a few years of reaching the medical mainstream. Whats more, developments in synthetic biology, the process of engineering and re-engineering cells, could make stem cells even more effective.

Stem cells are essentially the bodys raw material: basic cells from which all other cells with particular functions are generated. They are found in various organs and tissues, including the brain, blood, bone marrow and skin. The primary promise of adult stem cells lies in regenerative medicine, says Professor Ali.

Stem cells go through several rounds of division in order to produce specialist cells; a blood stem cell can be used to produce blood cells and skin stem cells can be used to produce skin cells. So in theory you can take adult stem cells from one person and transplant them into another person in order to promote the growth of new cells and tissue.

In practice, however, things have proved more complicated, since the number of stem cells in a persons body is relatively limited and they are hard to access. Scientists were also previously restricted by the fact that adult stem cells could only produce one specific type of cell (so blood stem cells couldnt produce skin cells, for instance).

In their quest for a universal stem cell, some scientists initially focused on stem cells from human embryos, but that remains a controversial method, not only because harvesting stem cells involves destroying the embryo, but also because there is a much higher risk of rejection of embryonic stem cells by the recipients immune system.

The good news is that in 2006 Japanese scientist Shinya Yamanaka of Kyoto University and his team discovered a technique for creating what they call induced pluripotent stem cells (iPSC). The research, for which they won a Nobel Prize in 2012, showed that you can rewind adult stem cells development process so that they became embryo-like stem cells. These cells can then be repurposed into any type of stem cells. So you could turn skin stem cells into iPSCs, which could in turn be turned into blood stem cells.

This major breakthrough has two main benefits. Firstly, because iPSCs are derived from adults, they dont come with the ethical problems associated with embryonic stem cells. Whats more, the risk of the body rejecting the cells is much lower as they come from another adult or are produced by the patient. In recent years scientists have refined this technique to the extent that we now have a recipe for making all types of cells, as well as a growing ability to multiply the number of stem cells, says Professor Ali.

Having the blueprint for manufacturing stem cells isnt quite enough on its own and several barriers remain, admits Professor Ali. For example, we still need to be able to manufacture large numbers of stem cells at a reasonable cost. Ensuring that the stem cells, once they are in the recipient, carry out their function of making new cells and tissue remains a work in progress. Finally, regulators are currently taking a hard line towards the technology, insisting on exhaustive testing and slowing research down.

The good news, Professor Ali believes, is that all these problems are not insurmountable as scientists get better at re-engineering adult cells (a process known as synthetic biology). The costs of manufacturing large numbers of stem cells are falling and this can only speed up as more companies invest in the area. There are also a finite number of different human antigens (the parts of the immune system that lead a body to reject a cell), so it should be possible to produce a bank of iPSC cells for the most popular antigen types.

While the attitude of regulators is harder to predict, Professor Ali is confident that it needs only one major breakthrough for the entire sector to secure a large amount of research from the top drug and biotech firms. Indeed, he believes that effective applications are likely in the next few years in areas where there are already established transplant procedures, such as blood transfusion, cartilage and corneas. The breakthrough may come in ophthalmology (the treatment of eye disorders) as you only need to stimulate the development of a relatively small number of cells to restore someones eyesight.

In addition to helping the body repair its own tissues and organs by creating new cells, adult stem cells can also indirectly aid regeneration by delivering other molecules and proteins to parts of the body where they are needed, says Ralph Kern, president and chief medical officer of biotechnology company BrainStorm Cell Therapeutics.

For example, BrainStorm has developed NurOwn, a cellular technology using peoples own cells to deliver neurotrophic factors (NTFs), proteins that can promote the repair of tissue in the nervous system. NurOwn works by modifying so-called Mesenchymal stem cells (MSCs) from a persons bone marrow. The re-transplanted mesenchymal stem cells can then deliver higher quantities of NTFs and other repair molecules.

At present BrainStorm is using its stem-cell therapy to focus on diseases of the brain and nervous system, such as amyotrophic lateral sclerosis (ALS, also known as Lou Gehrigs disease), MS and Huntingtons disease. The data from a recent final-stage trial suggests that the treatment may be able to halt the progression of ALS in those who have the early stage of the disease. Phase-two trial (the second of three stages of clinical trials) of the technique in MS patients also showed that those who underwent the treatment experienced an improvement in the functioning of their body.

Kern notes that MSCs are a particularly promising area of research. They are considered relatively safe, with few side effects, and can be frozen, which improves efficiency and drastically cuts down the amount of bone marrow that needs to be extracted from each patient.

Because the manufacture of MSC cells has become so efficient, NurOwn can be used to get years of therapy in one blood draw. Whats more, the cells can be reintroduced into patients bodies via a simple lumbar puncture into the spine, which can be done as an outpatient procedure, with no need for an overnight stay in hospital.

Kern emphasises that the rapid progress in our ability to modify cells is opening up new opportunities for using stem cells as a molecular delivery platform. Through taking advantage of the latest advances in the science of cellular therapies, BrainStorm is developing a technique to vary the molecules that its stem cells deliver so they can be more closely targeted to the particular condition being treated. BrainStorm is also trying to use smaller fragments of the modified cells, known as exosomes, in the hope that these can be more easily delivered and absorbed by the body and further improve its ability to avoid immune-system reactions to unrelated donors. One of BrainStorms most interesting projects is to use exosomes to repair the long-term lung damage from Covid-19, a particular problem for those with long Covid-19. Early preclinical trials show that modified exosomes delivered into the lungs of animals led to remarkable improvements in their condition. This included increasing the lungs oxygen capacity, reducing inflammation, and decreasing clotting.

Overall, while Kern admits that you cant say that stem cells are a cure for every condition, there is a lot of evidence that in many specific cases they have the potential to be the best option, with fewer side effects. With Americas Food and Drug Administration recently deciding to approve Biogens Alzheimers drug, Kern thinks that they have become much more open to approving products in diseases that are currently considered untreatable. As a result, he thinks that a significant number of adult stem-cell treatments will be approved within the next five to ten years.

Adult stem cells and synthetic biology arent just useful in treatments, says Dr Mark Kotter, CEO and founder of Bit Bio, a company spun out of Cambridge University. They are also set to revolutionise drug discovery. At present, companies start out by testing large numbers of different drug combinations in animals, before finding one that seems to be most effective. They then start a process of clinical trials with humans to test whether the drug is safe, followed by an analysis to see whether it has any effects.

Not only is this process extremely lengthy, but it is also inefficient, because human and animal biology, while similar in many respects, can differ greatly for many conditions. Many drugs that seem promising in animals end up being rejected when they are used on humans. This leads to a high failure rate. Indeed, when you take the failures into account, it has been estimated that it may cost as much to around $2bn to develop the typical drug.

As a result, pharma companies are now realising that you have to insert the human element at a pre-clinical stage by at least using human tissues, says Kotter. The problem is that until recently such tissues were scarce, since they were only available from biopsies or surgery. However, by using synthetic biology to transform adult stem cells from the skin or other parts of the body into other types of stem cells, researchers can potentially grow their own cells, or even whole tissues, in the laboratory, allowing them to integrate the human element at a much earlier stage.

Kotter has direct experience of this himself. He originally spent several decades studying the brain. However, because he had to rely on animal tissue for much of his research he became frustrated that he was turning into a rat doctor.

And when it came to the brain, the differences between human and rat biology were particularly stark. In fact, some human conditions, such as Alzheimers, dont even naturally appear in rodents, so researchers typically use mice and rats engineered to develop something that looks like Alzheimers. But even this isnt a completely accurate representation of what happens in humans.

As a result of his frustration, Kotter sought a way to create human tissues. It initially took six months. However, his company, Bit Bio, managed to cut costs and greatly accelerate the process. The companys technology now allows it to grow tissues in the laboratory in a matter of days, on an industrial scale. Whats more, the tissues can also be designed not just for particular conditions, such as dementia and Huntingdons disease, but also for particular sub-types of diseases.

Kotter and Bit Bio are currently working with Charles River Laboratories, a global company that has been involved in around 80% of drugs approved by the US Food and Drug Administration over the last three years, to commercialise this product. They have already attracted interest from some of the ten largest drug companies in the world, who believe that it will not only reduce the chances of failure, but also speed up development. Early estimates suggest that the process could double the chance of a successful trial, effectively cutting the cost of each approved drug by around 50% from $2bn to just $1bn. This in turn could increase the number of successful drugs on the market.

Two years ago my colleague Dr Mike Tubbs tipped Fate Therapeutics (Nasdaq: FATE). Since then, the share price has soared by 280%, thanks to growing interest from other drug companies (such as Janssen Biotech and ONO Pharmaceutical) in its cancer treatments involving genetically modified iPSCs.

Fate has no fewer than seven iPSC-derived treatments undergoing trials, with several more in the pre-clinical stage. While it is still losing money, it has over $790m cash on hand, which should be more than enough to support it while it develops its drugs.

As mentioned in the main story, the American-Israeli biotechnology company BrainStorm Cell Therapeutics (Nasdaq: BCLI) is developing treatments that aim to use stem cells as a delivery mechanism for proteins. While the phase-three trial (the final stage of clinical trials) of its proprietary NurOwn system for treatment of Amyotrophic lateral sclerosis (ALS, or Lou Gehrigs disease) did not fully succeed, promising results for those in the early stages of the disease mean that the company is thinking about running a new trial aimed at those patients. It also has an ongoing phase-two trial for those with MS, a phase-one trial in Alzheimers patients, as well as various preclinical programmes aimed at Parkinsons, Huntingtons, autistic spectrum disorder and peripheral nerve injury. Like Fate Therapeutics, BrainStorm is currently unprofitable.

Australian biotechnology company Mesoblast (Nasdaq: MESO) takes mesenchymal stem cells from the patient and modifies them so that they can absorb proteins that promote tissue repair and regeneration. At present Mesoblast is working with larger drug and biotech companies, including Novartis, to develop this technique for conditions ranging from heart disease to Covid-19. Several of these projects are close to being completed.

While the US Food and Drug Administration (FDA) controversially rejected Mesoblasts treatment remestemcel-L for use in children who have suffered from reactions to bone-marrow transplants against the advice of the Food and Drug Administrations own advisory committee the firm is confident that the FDA will eventually change its mind.

One stem-cell company that has already reached profitability is Vericel (Nasdaq: VCEL). Vericels flagship MACI products use adult stem cells taken from the patient to grow replacement cartilage, which can then be re-transplanted into the patient, speeding up their recovery from knee injuries. It has also developed a skin replacement based on skin stem cells.

While earnings remain relatively small, Vericel expects profitability to soar fivefold over the next year alone as the company starts to benefit from economies of scale and runs further trials to expand the range of patients who can benefit.

British micro-cap biotech ReNeuron (Aim: RENE) is developing adult stem-cell treatments for several conditions. It is currently carrying out clinical trials for patients with retinal degeneration and those recovering from the effects of having a stroke. ReNeuron has also developed its own induced pluripotent stem cell (iPSC) platform for research purposes and is seeking collaborations with other drug and biotech companies.

Like other small biotech firms in this area, it is not making any money, so it is an extremely risky investment although the rewards could be huge if any of its treatments show positive results from their clinical trials.

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Investing in stem cells, the building blocks of the body - MoneyWeek

Bone Marrow Stem Cells Comments Off on Investing in stem cells, the building blocks of the body – MoneyWeek | June 25th, 2021

REDWOOD CITY, Calif. and NEW YORK and BASEL, Switzerland, June 21, 2021 /PRNewswire/ --Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, andAruvant Sciences, a private company focused on developing gene therapies for rare diseases, today announced that they have entered a non-exclusive research collaboration to evaluate the use of JSP191, Jasper's anti-CD117 monoclonal antibody, as a targeted, non-toxic conditioning agent with ARU-1801, Aruvant's investigational lentiviral gene therapy for sickle cell disease (SCD). The objective of the collaboration is to evaluate the use of JSP191 as an effective and more tolerable conditioning agent that can expand the number of patients who can receive ARU-1801, a potentially curative treatment for SCD.

"This research collaboration with Aruvant is the first to use a clinical-stage antibody-based conditioning agent and a novel clinical-stage gene therapy, giving this combination a clear advantage by moving beyond the harsh conditioning agents currently used for gene therapy and establishing this next-generation potentially curative treatment as a leader in sickle cell disease," said Kevin N. Heller, M.D., executive vice president, research and development of Jasper. "Our goal is to establish JSP191 as a potential new standard of care conditioning agent, broadly in autologous gene therapy and allogeneic hematopoietic stem cell transplantation."

Gene therapies and gene editing technologies generally require that a patient's own hematopoietic stem cells first be depleted from the bone marrow to facilitate the engraftment of the new, gene-modified stem cells through a process called conditioning. Other investigational gene therapies and gene editing approaches in SCD use a high-dose chemotherapy such as busulfan for the conditioning regimen, which can place patients at prolonged risk for infection and bleeding, secondary malignancy and infertility. ARU-1801 is currently the only gene therapy that has demonstrated durable efficacy using both a lower dose of chemotherapy and a different agent than busulfan with a more limited side effect profile. The Aruvant-Jasper partnership is focused on evaluating the potential of using JSP191, a highly targeted anti-CD117 (stem cell factor receptor) monoclonal antibody agent, as the foundationof a novel conditioning regimen for use in combination with ARU-1801 to further reduce the negative side effects while maintaining efficacy.

"The unique attributes of ARU-1801 enable us to bring a potentially curative one-time therapy to individuals with sickle cell disease that can be delivered in the safest way possible," said Will Chou, M.D., Aruvant chief executive officer. "By partnering with Jasper to evaluate the use of JSP191 with ARU-1801, we are one step closer to developing a next-generation definitive therapy with an even more patient-friendly conditioning regimen. We believe that this combination may be able to further expand the number of patients who can benefit from ARU-1801 in the future, including potentially those with more moderate disease."

About JSP191 JSP191 is a humanized monoclonal antibody in clinical development as a conditioning agent that blocks stem cell factor receptor signaling leading to clearance of hematopoietic stem cells from bone marrow, creating an empty space for donor or gene-corrected transplanted stem cells to engraft. While hematopoietic cell transplantation can be curative for patients, its use is limited because standard high dose myeloablative conditioning is associated with severe toxicities and standard low dose conditioning has limited efficacy. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients. It is currently enrolling in two clinical trials for myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) and severe combined immunodeficiency (SCID) and expects to begin enrollment in four additional studies in 2021 for severe autoimmune disease, sickle cell disease, chronic granulomatous disease and Fanconi anemia patients undergoing hematopoietic cell transplantation.

About ARU-1801 ARU-1801 is designed to address the limitations of current curative treatment options, such as low donor availability and the risk of graft-versus-host disease (GvHD) seen with allogeneic stem cell transplants. Unlike investigational gene therapies and gene editing approaches which require fully myeloablative conditioning, the unique characteristics of ARU-1801 allow it to be given with reduced intensity conditioning ("RIC"). Compared to myeloablative approaches, the lower dose chemotherapy regimen underlying RIC has the potential to reduce not only hospital length of stay, but also the risk of short- and long-term adverse events such as infection and infertility. Preliminary clinical data from the MOMENTUMstudy, an ongoing Phase 1/2 trial of ARU-1801 in patients with severe sickle cell disease, demonstrate continuing durable reductions in disease burden.

The MOMENTUM Study Aruvant is conducting the MOMENTUM study, which is evaluating ARU-1801, a one-time potentially curative investigational gene therapy for patients with SCD. This Phase 1/2 study is currently enrolling participants, and information may be found at momentumtrials.comwhich includes a patient brochure, an eligibility questionnaireand information for healthcare providers.

About Jasper Therapeutics Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, a first-in-class anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplantation. It is designed to enable safer and more effective curative allogeneic and autologous hematopoietic cell transplants and gene therapies. In parallel, Jasper Therapeutics is advancing its preclinical engineered hematopoietic stem cell (eHSC) platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

About Aruvant Sciences Aruvant Sciences, part of the Roivant family of companies, is a clinical-stage biopharmaceutical company focused on developing and commercializing gene therapies for the treatment of rare diseases. The company has a talented team with extensive experience in the development, manufacturing and commercialization of gene therapy products. Aruvant has an active research program with a lead product candidate, ARU-1801, in development for individuals suffering from sickle cell disease (SCD). ARU-1801, an investigational lentiviral gene therapy, is being studied in a Phase 1/2 clinical trial, the MOMENTUM study, as a one-time potentially curative treatment for SCD. Preliminary clinical data demonstrate engraftment of ARU-1801 and amelioration of SCD is possible with one dose of reduced intensity chemotherapy. The company's second product candidate, ARU-2801, is in development to cure hypophosphatasia, a devastating, ultra-orphan disorder that affects multiple organ systems and leads to high mortality when not treated. Data from pre-clinical studies with ARU-2801 shows durable improvement in disease biomarkers and increased survival. For more information on the ongoing ARU-1801 clinical study, please visit http://www.momentumtrials.comand for more on the company, please visit http://www.aruvant.com. Follow Aruvant on Facebook, Twitter @AruvantSciencesand on Instagram @Aruvant_Sciences.

About Roivant Roivant's mission is to improve the delivery of healthcare to patients by treating every inefficiency as an opportunity. Roivant develops transformative medicines faster by building technologies and developing talent in creative ways, leveraging the Roivant platform to launch Vants nimble and focused biopharmaceutical and health technology companies. For more information, please visit http://www.roivant.com.

SOURCE Aruvant Sciences andJasper Therapeutics

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Jasper Therapeutics and Aruvant Announce Research Collaboration to Study JSP191, an Antibody-Based Conditioning Agent, with ARU-1801, a Novel Gene...

Bone Marrow Stem Cells Comments Off on Jasper Therapeutics and Aruvant Announce Research Collaboration to Study JSP191, an Antibody-Based Conditioning Agent, with ARU-1801, a Novel Gene… | June 25th, 2021

Heart muscle regeneration researchers (left to right) Naoto Muraoka, Elaheh Karbassi, and Chuck Murry. (University of Washington Photo)

Human stem cell scientists have long dreamed of repairing damaged hearts, but have been stymied by researchshowing that the cells yield irregular heartbeats in laboratory animals. A new genetic engineering approach overcomes this barrier, according to a report at the annual meeting of the International Society for Stem Cell Research by scientists at the University of Washington and Sana Biotechnology, a Seattle-based company.

A heart attack typically kills about one billion cells, said Charles Murry, director of the Institute for Stem Cell and Regenerative Medicine at the UW, who presented the data Monday. Such massive cell death can lead to downstream effects such as heart failure, an often-debilitating condition that affects about 6.2 million people in the U.S. Using stem cells to repair the damage after a heart attack has long been a goal in his lab.

One major challenge in the field is that implanting cells into the hearts of laboratory animals can nudge the whole heart into beating rapidly, a condition called engraftment arrhythmia, said Murry, who is also a senior vice president and head of cardiometabolic cell therapy at Sana, which went public earlier this year.

This engraftment arrhythmia, where the heart races too quickly, has been one of the major hurdles weve been trying to overcome en route to clinical trials, said Murry in a press release.

In their study, Murry and his colleagues quelled engraftment arrhythmia using a genetic engineering strategy in cells implanted into pig hearts. Their next step is to see if the cells can repair heart damage in macaques if those studies work, the researchers will initiate clinical trials in people, he said.

To quell the arrhythmia, Murry and his colleagues turned to CRISPR, the Nobel Prize-winning technique to knock out genes. They knocked out three genes in stem cells encoding different ion channels, molecules embedded in the cell membrane that mediate impulses that propagate heart beats. They also added DNA for another ion channel, KCNJ2, which mediates the movement of potassium across the membrane, Its a chill out channel, Murry told GeekWire, It tells the heart cell not to be so excitable.

The engineered stem cells, derived from human embryonic stem cells, were coaxed in a petri dish to produce heart muscle cells, which were then implanted into pigs via open heart surgery or a catheter. The result was an even heartbeat the genetically altered cells did not cause engraftment arrhythmia.

The researchers landed on this strategy after years of effort, assessing which channels were present in the cells during arrhythmia, and knocking out multiple types of channels until they hit the right combination.

In their next set of experiments in macaques, We want to make sure these cells are still effective, said Murry, They look good beating in culture, so I think they are going to be OK. Moving forward, the researchers will also use induced human pluripotent stem cells, obtainable from adults and more amenable longer-term for clinical use.

In another recent study, published in Cell Systems, scientists at the Allen Institute for Cell Science took a close look at cardiac muscle cells derived from stem cells. They found that they could classify the state of the cells, such as how mature they were, by assessing both cell structure and which genes were turned on.

This paints a broader picture of our cells. If someone wants to really understand and characterize a cells state, we found that having both of these types of information can be complementary, said Kaytlyn Gerbin, a scientist at the Allen Institute for Cell Science in a statement. The findings provide a fine-tooth analysis of cell state, which may guide future experiments on cardiac muscle and other cell types.

Murrys research was conducted primarily at the UW, with financial support from Sana. In addition to its cardiac program, Sana has cell and gene therapy programs in diabetes, blood disorders, immunotherapy and other areas.

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Univ. of Washington and Sana researchers use gene editing to prep stem cells for heart repair - GeekWire

Cardiac Stem Cells Comments Off on Univ. of Washington and Sana researchers use gene editing to prep stem cells for heart repair – GeekWire | June 25th, 2021

This Autologous Stem Cell Based Therapies market report provides vital info on survey data and the present market place situation of each sector. The purview of this Autologous Stem Cell Based Therapies market report is also expected to involve detailed pricing, profits, main market players, and trading price for a specific business district, along with the market constraints. This anticipated market research will benefit enterprises in making better judgments.

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Key global participants in the Autologous Stem Cell Based Therapies market include:Med cell Europe US STEM CELL, INC. Tigenix Mesoblast Pluristem Therapeutics Inc Brainstorm Cell Therapeutics Regeneus

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Segmentation on the Basis of Application:Neurodegenerative Disorders Autoimmune Diseases Cardiovascular Diseases

Market Segments by TypeEmbryonic Stem Cell Resident Cardiac Stem Cells Umbilical Cord Blood Stem Cells

Table of Content1 Report Overview1.1 Product Definition and Scope1.2 PEST (Political, Economic, Social and Technological) Analysis of Autologous Stem Cell Based Therapies Market2 Market Trends and Competitive Landscape3 Segmentation of Autologous Stem Cell Based Therapies Market by Types4 Segmentation of Autologous Stem Cell Based Therapies Market by End-Users5 Market Analysis by Major Regions6 Product Commodity of Autologous Stem Cell Based Therapies Market in Major Countries7 North America Autologous Stem Cell Based Therapies Landscape Analysis8 Europe Autologous Stem Cell Based Therapies Landscape Analysis9 Asia Pacific Autologous Stem Cell Based Therapies Landscape Analysis10 Latin America, Middle East & Africa Autologous Stem Cell Based Therapies Landscape Analysis 11 Major Players Profile

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Autologous Stem Cell Based Therapies Market to Eyewitness Huge Growth by 2027 with Covid-19 Impact The Manomet Current - The Manomet Current

Cardiac Stem Cells Comments Off on Autologous Stem Cell Based Therapies Market to Eyewitness Huge Growth by 2027 with Covid-19 Impact The Manomet Current – The Manomet Current | June 25th, 2021

While widespread vaccination is key in our fight against COVID-19, people who are infected still need better treatment to improve their chance of survival and making a full recovery.

Early on, the world had high hopes for a range of repurposed medications which had previously been approved to treat other conditions including hydroxychloroquine, remdesivir and ivermectin to treat COVID-19. But the results have been disappointing.

Diseases caused by viruses are among the most difficult to treat, due to their ability to invade and repurpose infected cells. This limits the ability for drugs to directly act on the virus.

Read more: Developing antiviral drugs is not easy here's why

Yet researchers around the world are finding ways to overcome these barriers and directly target the coronavirus, including in Australia. So whats being developed here and how do they work?

Researchers at Queenslands Menzies Health Institute, in collaboration with scientists from the United States, have developed a novel treatment which targets key genes of the coronavirus, stopping the viruss ability to replicate.

The treatment uses an engineered particle called a small interfering RNA (si-RNA), which detects and binds to areas of the hosts genome, where the virus resides.

The si-RNA is encased in a nanoparticle to protect it as it travels through the bloodstream. It enters all cells in the hosts body, but will only act on the cells infected by the virus.

Read more: Have Australian researchers developed an effective COVID-19 treatment? Potentially, but we need to wait for human trials

Studies in mice showed the treatment reduced the amount of the virus in the lungs by more than 90%.

Its unclear if the results will translate to humans, but if they do, it could potentially protect infected people from severe disease and make them less likely to transmit the illness to others.

If it is successful, the researchers estimate the treatment could be available in 2023.

Another strategy is to block the virus from invading all together.

A number of research teams across Australia are working on engineered antibody treatments, which hunt out and bind to the virus before it enters a cell, effectively blocking it out.

Researchers at the Garvan and Kirby institutes in New South Wales are building on research developed after the 2003 SARS outbreak to create treatments using monoclonal antibodies. These antibodies are generated in the lab and mimic the immune system response to infection.

Once these monoclonal antibodies are injected into an infected person, they bind to the virus and stop it from invading host cells. They also mark it for destruction by the other immune cells.

While this research is in the pre-clinical (lab testing) phase, the researchers at Garvan are already working with clinicians at the Kirby institute to identify the best antibodies and move them through to human clinical trials.

As monoclonal antibody treatments are widely used in a range of diseases, these could potentially be deployed quickly for patients with COVID-19, or to protect people who have been exposed to the virus, to stop them getting sick and becoming infectious.

Another team at the Walter and Elizabeth Hall Institute in Melbourne is harnessing unique nanobodies, which are significantly smaller than human antibodies, derived from the immune system of alpacas.

These nanobodies have powerful and specific binding capacity. By vaccinating the alpacas with a synthetic component of the SARS-CoV-2 virus, nanobodies targeting the virus can be identified and synthesised for human use.

While these treatments are in the very early stages of development, they could prove revolutionary for all kinds of infectious and non-infectious diseases.

While some treatments aim to neutralise the virus, others are being developed to protect patients from the consequences of COVID-19.

One of the most severe reactions to an infection with the coronavirus is a widespread inflammatory reaction known as a cytokine storm, causing severe damage to the lungs.

While potent anti-inflammatory drugs such as hydrocortisone can help to prevent this response, they also can have severe side-effects such as bone weakening, immune system weakening, psychiatric symptoms and insomnia.

Researchers at the Victor Chang Cardiac Institute and St Vincents hospital in Sydney are proposing to trial a novel stem cell therapy, in an attempt to counteract this inflammatory storm.

While they havent disclosed specifically which cells they are planning to use, human studies show stem cell treatments can suppress inflammatory responses from the immune system.

The researchers are seeking approval for clinical studies and are using a stem cell that has been used in humans previously potentially speeding the pathway to clinical use.

Read more: Could a simple pill beat COVID-19? Pfizer is giving it a go

Another anti-inflammatory drug to control the damaging levels of immune response to the viral infection is being developed by Implicit Bioscience.

Its drug has already shown promising preliminary results in small trials for acute lung injury and amyotrophic lateral sclerosis (AML, a rare neurological disease also known as motor neurone disease), with phase 2 trials for AML due to be completed in 2021.

Two trials at major medical centres, one led by the US National Institutes of Health and the other by Quantum Leap Healthcare Collaborative, are now underway to test whether the drug is effective in patients with severe COVID-19.

Australian biotech company Ena Respiratory is developing a nasal spray to fight COVID-19.

These nasal sprays contain a compound designed to trigger a rapid immune response in the upper airways. This allows the immune system to destroy the virus and infected cells before serious disease can occur.

Ena Respiratorys product, called INNA-051, has produced promising results in animal models, with up to a 96% decrease in SARS-CoV-2 virus replication.

The next step is to see if these results translate to humans.

Australia has a long history of strong performance on the world stage in research. Fortunately, this has continued through the COVID-19 pandemic, with a number of key developments and innovations as described, which show promise for translation to human clinical trials.

Developments are continuing, including research by Vasso and her team into novel re-purposed and experimental drugs aimed at stopping coronavirus replication. This is a collaboration between Victoria University and researchers from the United States and Greece, and the team hopes to be able to report on its progress soon.

Read more: I'm a lung doctor testing the blood plasma from COVID-19 survivors as a treatment for the sick a century-old idea that could be a fast track to treatment

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Stopping, blocking and dampening how Aussie drugs in the pipeline could treat COVID-19 - The Conversation AU

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