StemCell Therapy

Chronic obstructive pulmonary disease (COPD) continues to be a major cause of disability and is one of the leading causes of mortality worldwide. While there are numerous treatment options for the lung disease, the available treatments focus on symptoms secondary to inflammation, and are not curative. In a review published in the American Journal of Physiology Lung Cellular and Molecular Physiology, experts focus on potential disease-relevant pathways and emphasize the important of developing new treatments for patients with COPD.1

The objective of the review was to summarize COPD pathology, available treatment options and additional potential pathways and targets for new therapeutic development.

Cigarette smoke contains thousands of injurious agents and is the key cause of COPD worldwide as these induce tissue damage and inflammatory process leading to destruction of alveolar tissue, loss of extracellular matrix and alveolar cells, along with airway remodeling.2 As COPD may progress in patients despite smoking cessation it was suggested that persistent airway inflammation in these patients is related to repair of smoke-induced tissue damage in the airways.3 Failure to achieve normal lung function in early adulthood followed by age-appropriate rates of decline causes up to half of COPD cases.4

The 2020 Global Initiative for Chronic Obstructive Lung Disease guidelines recommend that the management strategy of COPD should be based on the assessment of symptoms and future risk of exacerbations and the main goals of pharmacological therapy for COPD are to reduce symptoms and frequency and severity of exacerbations, as well as to improve exercise tolerance and health status. However, at this point there is no evidence that any of the available medications can modify the long-term decline in lung function.5

The commonly used maintenance medications in COPD are short- and long-acting beta-2 agonists and anti-cholinergics, methylxanthines, inhaled or systemic corticosteroids, phosphodiesterase (PDE)-4 inhibitors and mucolytic agents.5 As these medications are mainly focused on relieving symptoms and reducing the risk for exacerbations, more effective treatment strategies are needed. COPD is a complex disease and precision medicine strategy, that considers biologic and psychosocial factors, may improve disease outcomes.4

New Treatment Targets

There is a real need to uncover new biology in order to advance more precision-based therapeutic strategies for patients with COPD. New disease-specific strategies in development are focusing on inflammatory pathways, hoping this will help to address disease onset. Early reports suggest there are several promising targets that can address inflammatory complications, including oxidative stress, kinase-mediates pathways, phosphodiesterase inhibitors, interleukins and chemokines.

Oxidative Stress a common denominator for aging and cellular senescence, resulting in macromolecular damage and DNA damage.2 With cigarette smoke exposure there is an increased oxidative stress, associated with an increase in Nrf2 activity which declines with the progression of COPD.6 As several studies have implicated Nrf2 in COPD pathology, this pathway is a potential important therapeutic target. Several agents may change Nrf2 expression and activity in airway cell, including aspirin-triggered resolvin D1, crocin, sulforaphane, and schisandrin B.1,6

Kinase-mediated Pathways as various kinases, including MAPK, receptor-tyrosine kinases, phosphoinositide-3-kinases, JAK, and NF-B, may induce chronic inflammation, they may serve as new targets for COPD treatment. There are several drugs that target different kinases but these are not approved for clinical use. Drugs with a more specific action, such as RV568 that inhibits p38, was well tolerated in a 14-day clinical trial and showed promising results with potent anti-inflammatory effects on cell and animal models relevant to COPD, with evidence for improvement in lung function and anti-inflammatory effects on sputum biomarkers.7

Phosphodiesterase Inhibitors inhibiting PDE leads to an increase in intracellular cAMP levels that may have anti-inflammatory effects. Roflumilast is an oral PDE-4 inhibitor already in use for more severe cases of COPD, but more potent medications are being developed, including several inhaled formulations, such as CHF6001, which was reported to have significant anti-inflammatory properties in the lungs of patients with COPD already receiving triple inhaled therapy (8). Ensifentrine is a PDE3/PDE4 inhibitor with anti-inflammatory and bronchodilator properties and when combined with short-acting bronchodilators or tiotropium caused additional improvement in lung function, reduced gas trapping, and improved airway conductance.9

Inflammatory Mediators exposure to inhaled irritants and tobacco smoke results in an increase in various interleukins (IL) that increase the number of immune cells and induce inflammatory responses. Hence, treatment directed against these mediators may reduce inflammation.1 Mepolizumab, reslizumab, and benralizumab are antibodies directed against IL-5 and its receptor and reduced eosinophil-related inflammation. These medications are approved for use for asthma, and were not effective in COPD, but may be valuable for patients with COPD with eosinophilia. Dupilumab, a monoclonal antibody directed against IL-4 and IL-13 receptor, is another potential candidate for future use. microRNAs are also involved in inflammation regulation, and miR-155 expression was shown to be increased in COPD, but at this point there are no available miRNA-based therapeutics for COPD.10

Additional Potential Treatment Targets

While multiple medications under development for COPD are focusing on the inflammatory pathways, they are not expected to reverse the lung damage. For this reason, it is important to study the upstream pathways that may help to identify strategies to reverse exiting lung damage, including targets that can lead to lung repair and regeneration.

These potential breakthrough targets may include treatments directed against mitochondrial dysfunction; structural integrity of airway epithelium such as proteins that comprise tight junctions or the extracellular matrix; various ion channels that are responsible for airway hydration; and pro-regenerative strategies, including stem cell and tissue-engineering treatments to repair lung damage.1

Animal models and 3D human-based disease models have an important role in the efforts to better understand disease process and identify specific therapeutic targets and pathways.11,12 These models improve our knowledge about the basic mechanisms underlying COPD physiology, pathophysiology and treatment. Although they can only mimic some of the features of the disease, they are valuable for further investigation of mechanisms involved in human COPD.11

Several different types of 3D cell culture models have been developed in recent years, and these have gained increasing interest in drug discovery and tissue engineering due to their evident advantages in providing more physiologically relevant information and more predictive data. Ex vivo modeling using primary human material can improve translational research activities by fostering the mechanistic understanding of human lung diseases while reducing animal usage. It is believed that using new model organisms may allow exploring new avenues and treatments approached for human disease, and these are especially promising.12

COPD is a major public health concern, and as it continues to be a global burden, the importance of developing new treatments is apparent. Current treatments are not curative, and while new strategies and drugs are in the pipeline, they still address mostly secondary inflammatory pathways of the disease. An additional major complication in COPD drug development likely comes from the essential dependency on surrogate endpoints like FEV1 to assess the impact of a therapeutic strategy. Thus, any new therapeutic strategy will ultimately require long-term studies to confirm that the surrogate endpoints accurately reflect efficacy on disease outcome, concluded the researchers.

References

1.Nguyen JMK, Robinson DN, Sidhaye VK. Why new biology must be uncovered to advance therapeutic strategies for chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2021;320(1):L1-L11. doi:10.1152/ajplung.00367.2020

2.Tuder RM, Petrache I. Pathogenesis of chronic obstructive pulmonary disease. J Clin Invest. 2012;122(8):2749-55. doi:10.1172/JCI60324

3.Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Postma DS, Timens W. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 2005;26(5):835-45. doi:10.1183/09031936.05.00108904

4.Sidhaye VK, Nishida K, Martinez FJ. Precision medicine in COPD: where are we and where do we need to go? Eur Respir Rev. 2018;27(149):180022. doi:10.1183/16000617.0022-2018

5.Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease 2020 report [Online]. Global Initiative for Chronic Obstructive Lung Disease. https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.1wms.pdf. Accessed January 25, 2021.

6.Cuadrado A, Rojo AI, Wells G, et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov. 2019;18(4):295-317. doi:10.1038/s41573-018-0008-x

7.Charron CE, Russell P, Ito K, et al. RV568, a narrow-spectrum kinase inhibitor with p38 MAPK- and - selectivity, suppresses COPD inflammation. Eur Respir J. 2017;50(4):1700188. doi:10.1183/13993003.00188-2017

8.Singh D, Beeh KM, Colgan B, et al. Effect of the inhaled PDE4 inhibitor CHF6001 on biomarkers of inflammation in COPD. Respir Res. 2019;20(1):180. doi:10.1186/s12931-019-1142-7

9.Singh D, Abbott-Banner K, Bengtsson T, Newman K. The short-term bronchodilator effects of the dual phosphodiesterase 3 and 4 inhibitor RPL554 in COPD. Eur Respir J. 2018;52(5):1801074. doi:10.1183/13993003.01074-2018

10.Barnes PJ. Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol. 2018;18(7):454-466. doi:10.1038/s41577-018-0006-6

11.Ghorani V, Boskabady MH, Khazdair MR, Kianmeher M. Experimental animal models for COPD: a methodological review. Tob Induc Dis. 2017;15:25. doi:10.1186/s12971-017-0130-2

12.Zscheppang K, Berg J, Hedtrich S, et al. Human pulmonary 3D models For translational research. Biotechnol J. 2018;13(1):1700341. doi:10.1002/biot.201700341

Continue reading here:
The Need for New Biological Targets for Therapeutic Intervention in COPD - Pulmonology Advisor

Following the Food and Drug Administration (FDA)s emergency use authorization of the Pfizer-BioNTech COVID-19 Vaccine on Friday, many patients with cancer who are actively receiving treatment, and those who no longer have signs of active disease, are sure to have questions as to what they should know about the vaccine.

In fact, Dr. Debu Tripathy, chair of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center and editor in chief of CURE, said he and his colleagues were getting questions about the distribution of the vaccine prior to its authorization by the FDA and Centers for Disease Control and Prevention.

We have been getting questions more and more frequently; all our patients want to know what the schedule is for when they might get a vaccine, said Tripathy in an interview with CURE.

To address any questions patients with cancer and survivors may have regarding the vaccine, CURE recently spoke with Drs. Debu Tripathy and Roy Chemaly, chief infection control officer and a professor in the department of infectious diseases, infection control and employee health at The University of Texas MD Anderson Cancer Center.

On Monday, the first of many high-risk health care workers started receiving the vaccine across the United States. Many frontline workers will continue to receive it over the next several weeks, including those who work directly with patients with cancer who are at a high risk for infection.

After those frontline workers, there is a process for which patients will begin to receive the vaccine, according to Tripathy.

Patients with underlying conditions at high risk for complications of COVID-19 infection will likely be a top priority to receive the vaccine. However, for patients with cancer receiving therapy, in particular, those receiving more intensive therapies like a stem cell transplant, there are still some details that need to be ironed out.

We haven't gotten into the nitty gritty in terms of how we're going to divide (the vaccine) to some extent, said Tripathy. We're going to have the physicians be involved in prioritizing this based on their knowledge because they're the ones who know the patients the best.

Chemaly also noted that the vaccine will likely be administered to patients on a case-by-case basis.

Now for cancer patients who are still under active treatment with chemo or radiation, or early after stem cell transplantation, there is no data on how effective the vaccine is, and should it be used, he said. So we're going to be a little bit more cautious and take it case by case to recommend these vaccines to our cancer patients, as we wait for more data to come out from the general population, then see how safe it is and how effective (it is) in order to really extrapolate to our cancer patients.

If a patient is no longer receiving active treatment and there are no signs of active cancer, Chemaly said, they should have a good response to the vaccine, and it will likely be safe for them to receive it as well.

Now, for other patients who (are) still in the follow-up period, not really called survivors of cancer, we're going to probably provide some guidance, for example, for recipients of a stem cell transplantation. If it's been six months from allogeneic transplantation, they're stable and recovering well from after transplant, then it is probably be safe to give it to these patients, he said. Autologous transplant could be three months from the transplantation if they have no active issues, if they are still in remission and they're stable enough to receive a vaccine.

As with any vaccine, Tripathy said, some people will have reactions, but at least there are data from healthy individuals that can be shared with patients with cancer. When those data are shared with patients with cancer, however, there will be some unknowns. For instance, will patients with cancer be able to generate antibodies and develop the same protection, and might there be unique side effects that this patient population will experience.

These are things that we will have to learn as we go, and we will, Tripathy said. As the cancer centers and practices start immunizing their patients, were going to be tracking their outcomes.

In fact, just like with any drug that receives FDA approval, there will be a process for reporting and compiling any side effects that occur when a patient receives the vaccine.

As for the individuals who developed severe allergic reactions to the vaccine in the United Kingdom, Chemaly noted that those individuals had a history of anaphylaxis, or severe allergic reactions to different antigens. And two out of those three individuals who experienced the severe reactions were already carrying an EpiPen (epinephrine), which helps to combat serious allergic reactions.

And we're prepared to intervene if someone develop(s) this kind of reaction when we give the vaccine, Chemaly said.

Everyone not just patients with cancer should expect to follow all the public health measures from wearing a mask to social distancing and frequent hand hygiene for at least another six months to one year even if vaccinated, according to Chemaly.

We need to create herd immunity (because) without herd immunity, we're not going to eliminate this virus, he said. Second, even if (you) get (a) vaccine, (it) doesn't mean (youre) not going to be exposed to the virus in the community or in your workplace. At that point, you may carry the virus and not getting sick from it or get admitted to the hospital but (you) can still transmit the virus to other people. This why masking is still so important.

Chemaly said hes received questions from patients and employees every day about their worry of receiving the vaccine. And while he said its understandable, he assures the public that the trials have been conducted under a microscope, meaning so many eyes have been watching everything that has happened.

No one is hiding anything, he said. Based on that, I advise my patients, my colleagues (and) other health care workers in the health care setting, that, what we know is (the vaccine is) safe and is effective there is no long-term side effect up to two or three months from receiving the vaccine. I, myself, feel very comfortable taking it, and I'm going to be lining up to get the vaccine as soon as it is available.

I think that we are witnessing an incredible moment in history where we rallied to do something that had never been done, and that is to get a vaccine from scratch in less than one year, Tripathy said. That is a pretty astounding technologic feat that not many people would have believed it was possible when all this started that in this short period of time; we did it.

Now, its up to patients to make an informed decision as to whether to get the vaccine, although the available data point to its potential effectiveness.

Nothing works unless you get the vaccine, he said. If you don't get the vaccine, all of this was for nothing.

However, Tripathy acknowledged why some people may be concerned and reluctant to receive the vaccine.

Things have happened in medical history where that might give some people pause, he said. There's a lot of concern about people that are underserved and minorities because there is a history of them not receiving fair treatment when it comes to medicine and clinical trials. And so, we have to go the extra mile to reassure patients. But we can't pretend that we can reassure people 100%. Just like many other decisions you make in life, you take the best information you have and you make a recommendation for other people or for yourself. All we can do is be truthful, present our recommendations and hope that a majority of people do get vaccinated.

For more news on cancer updates, research and education, dont forget tosubscribe to CUREs newsletters here.

Originally posted here:
What Patients With Cancer, Survivors Need to Know About the Emergency Use Authorization of COVID-19 Vaccine - Curetoday.com

18 months into the first serious clinical trials of CRISPR gene therapy for sickle cell disease and beta-thalassemiaand all patients are free from symptoms and have not needed blood transfusions.

Sickle cell disease (SCD) can cause a variety of health problems including episodes of severe pain, called vaso-occlusive crises, as well as organ damage and strokes.

Patients with transfusion-dependent thalassemia (TDT) are dependent on blood transfusions from early childhood.

The only available cure for both diseases is a bone marrow transplant from a closely related donor, an option that is not available for the vast majority of patients because of difficulty locating matched donors, the cost, and the risk of complications.

In the studies, the researchers goal is to functionally cure the blood disorders using CRISPR/Cas9 gene-editing by increasing the production of fetal hemoglobin, which produces normal, healthy red blood cells as opposed to the misshapen cells produced by faulty hemoglobin in the bodies of individuals with the disorders.

The clinical trials involve collecting stem cells from the patients. Researchers edit the stem cells using CRISPR-Cas9 and infuse the gene-modified cells into the patients. Patients remain in the hospital for approximately one month following the infusion.

Prior to receiving their modified cells, the seven patients with beta thalassemia required blood transfusions approximately every three to four weeks and the three patients with SCD suffered episodes of severe pain roughly every other month.

All the individuals with beta thalassemia have been transfusion independent since receiving the treatment, a period ranging between two and 18 months.

Similarly, none of the individuals with SCD have experienced vaso-occlusive crises since CTX001 infusion. All patients showed a substantial and sustained increase in the production of fetal hemoglobin.

15 months on, and the first patient to receive the treatment for SCD, Victoria Gray, has even been on a plane for the first time.

Before receiving CRISPR gene therapy, Gray worried that the altitude change would cause an excruciating pain attack while flying. Now she no longer worries about such things.

She told NPR of her trip to Washington, D.C: It was one of those things I was waiting to get a chance to do It was exciting. I had a window. And I got to look out the window and see the clouds and everything.

MORE: MIT Researchers Believe Theyve Developed a New Treatment for Easing the Passage of Kidney Stones

This December, theNew England Journal of Medicinepublishedthe first peer-reviewed research paperfrom the studyit focuses on Gray and the first TDT patient who was treated with an infusion of billions of edited cells into their body.

There is a great need to find new therapies for beta thalassemia and sickle cell disease, saidHaydar Frangoul, MD,Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute, HCA Healthcares TriStar Centennial Medical Center. What we have been able to do through this study is a tremendous achievement. By gene editing the patients own stem cells we may have the potential to make this therapy an option for many patients facing these blood diseases.

READ: For the First Time in the US, Surgeons Pump New Life into Dead Donor Heart for Life-Saving Transplant

Because of the precise way CRISPR-Cas9 gene editing works, Dr. Frangoul suggested the technique could potentially cure or ameliorate a variety of diseases that have genetic origins.

As GNN has reported, researchers are already using CRISPR to try and treat cancer, Parkinsons, heart disease, and HIV, as well.

Source: American Society of Hematology

Read the original here:
Every Patient Treated With CRISPR Gene Therapy for Blood Diseases Continues to Thrive, More Than a Year On - Good News Network

In March 2020, the World Health Organization declared COVID-19, the disease caused by the SARS-CoV-2 virus, a pandemic.

Since then, COVID-19 has affected tens of millions of people around the world, leading to new discoveries about the symptoms that can accompany the disease.

Recently, multiple case studies have suggested that persistent hiccups may be a potentially rare and unusual manifestation of COVID-19.

In this article, well discuss whether hiccups are a sign of the new coronavirus, when to contact your doctor about frequent hiccups, and other important information you should know about COVID-19.

According to the research, it is possible that hiccups are a rare sign of COVID-19.

In one recent 2020 case study, a 64-year-old man was found to have persistent hiccups as the only symptom of COVID-19.

In this situation, the subject of the study visited an outpatient clinic after experiencing a bout of hiccups for 72 hours.

Both blood testing and lung imaging were performed. They revealed evidence of infection in both lungs and low white blood cells. Follow-up testing for COVID-19 revealed a positive diagnosis.

In a different 2020 case study, a 62-year-old man was also found to have experienced hiccups as a symptom of the new coronavirus.

In this case, the subject had been experiencing hiccups for a period of 4 days before presentation to the emergency room.

Upon admission, further testing showed similar findings in their lungs, as well as low white blood cells and platelets. Again, testing for COVID-19 confirmed a positive diagnosis.

It is important to note that the studies mentioned above are only two individual case studies. They only demonstrate a potentially rare side effect of COVID-19.

More research is still needed to determine the link between chronic hiccups and the new coronavirus.

Hiccups are quite common and happen when your diaphragm involuntarily spasms or contracts. Your diaphragm is your muscle directly beneath your lungs that separates your chest from your abdomen.

Hiccups can be caused by everything from eating to swallowing air to stress, and much more.

While they can be somewhat annoying, hiccups are rarely a sign of anything dangerous. Generally, hiccups only last a few minutes although in some cases, they have been known to last for hours.

According to the National Health Service, hiccups that last longer than 48 hours are considered a cause for concern and should be addressed by a doctor.

Medical treatment options for hiccups are generally reserved for people with chronic hiccups that dont resolve on their own. Some of these treatment options may include:

For most people, hiccups will resolve on their own they generally only become a concern if they become chronic or cause other health concerns.

You should talk with a doctor if your hiccups last longer than 48 hours, as this may be a sign of an underlying health condition.

You may also need to talk with a doctor if your hiccups cause you to be unable to eat, breathe, or do anything else you would typically be able to do.

According to the Centers for Disease Control and Prevention (CDC), the most common symptoms of COVID-19 include:

Symptoms of COVID-19 can appear anywhere from 2 to 14 days after exposure to the SARS-CoV-2 virus. Depending on the severity of the disease, the symptoms can range from asymptomatic (no symptoms at all) to severe.

In some situations, COVID-19 can cause uncommon symptoms that are not listed above, such as dizziness or rash.

Even rarer, case studies like those mentioned above have shown how other unusual symptoms can be a sign of the new coronavirus.

If you are experiencing new symptoms and concerned that you may have developed COVID-19, speak with your doctor as soon as possible for testing.

While not everyone needs to be tested for COVID-19, the CDC recommends getting tested if:

There are two types of testing available for COVID-19: viral testing and antibody testing. Viral testing is used to diagnose a current infection, while antibody testing can be used to detect a past infection.

Tests are available nationwide at most local or state health departments, doctors offices, and pharmacies. Some states also currently offer drive-thru testing and 24-hour emergency testing when necessary.

We all play an important role in preventing the spread of the SARS-CoV-2 virus. The best way to reduce your risk of contracting, or spreading, this new coronavirus is to practice personal hygiene and physical distancing.

This means following the CDC guidelines for preventing the spread of COVID-19 and being mindful of your own health and testing status.

Staying informed about current and developing COVID-19 news is also important you can keep up to date with Healthlines live coronavirus updates here.

Below, youll find some CDC recommended guidelines to protect yourself and prevent the spread of COVID-19:

According to the CDC, in December 2020, a vaccine from Pfizer was granted emergency use authorization and approval for a vaccine from Moderna is expected to follow.

It may take months before most people have access to this vaccine, but there are also treatment options available.

The current treatment recommendation for mild cases of COVID-19 is recovery at home. In more severe cases, certain medical treatments may be used, such as:

As the COVID-19 situation continues to develop, so do new treatment options to help combat the disease.

Many of the symptoms of COVID-19 are commonly experienced among people who have developed the disease. However, research has suggested that some people may experience other rare and unusual symptoms.

In two recent case studies, persistent hiccups were the only outward sign of the new coronavirus. While this indicates that hiccups may be a potential symptom of COVID-19, more research is needed on this rare side effect.

Excerpt from:
Are Hiccups a Sign of the New Coronavirus? - Healthline

The Covid-19 can damage the heart both directly and indirectly, and lead to complications ranging from inflammation of the heart (myocarditis), injury to heart cells (necrosis), heart rhythm disorders (arrhythmias), heart attack, and muscle dysfunction that can lead to acute or protracted heart failure, experts said.

Covid-19 is a vascular disease that injures heart cells and muscle. It also leads to the formation of blood clots, both in the microvasculature and large vessels, which can block blood supply to the heart, brain and lungs and lead to stroke, heart attack and respiratory failure, said Dr Ravi R Kasliwal, chairman of clinical and preventive cardiology department at Medanta -The Medicity Hospital.

Also Read: Few Covid-19 deaths in Indias old-age homes, survey finds

A US study using MRI found cardiac abnormalities in 78 of 100 patients who had recently recovered from Covid-19, including 12 of 18 asymptomatic patients. Sixty patients had ongoing myocardial inflammation consistent with myocarditis, found the study, which was published in the Journal of American Medical Association Cardiology in July.

Even people with mild disease or no symptoms can develop life-threatening cardiovascular complications. Whats worrying is that this holds true for healthy adults with no pre-existing risk factors, which raise their risk of complications, said Dr Kasliwal, who recommends that everyone who has recovered from Covid-19 be screened for heart damage

Cardiac trouble

Extensive cardiac involvement is what differentiates Sars-CoV-2, the virus that causes Covid-19, from the six other coronaviruses that cause infection in humans, writes cardiologist Dr Eric J Topol, founder, director and professor of molecular medicine at the Scripps Research Translational Institute in La Jolla, California, in the journal Science.

The four human coronaviruses that cause cold-like symptoms have not been associated with heart abnormalities, though there have been isolated reports linking the Middle East Respiratory Syndrome (MERS) caused by MERS-CoV) with myocarditis, and cardiac disease with the Severe Acute Respiratory Syndrome (SARS) caused by Sars-CoV.

Also Read| Extraordinary uncertainties: Harvard prof on Covid-19, impact on mental health

Sars-CoV-2 is structurally different from Sars-CoV. The virus targets the angiotensin-converting enzyme 2 (Ace2) receptor throughout the body, facilitating cell entry by way of its spike protein, along with the cooperation of proteases. The heart is one of the many organs with high expression of Ace2. The affinity of Sars-CoV-2 to Ace2 is significantly greater than that of SARS, according to Dr Topol.

Topol notes the ease with which Sars-CoV-2 infects heart cells derived from induced pluripotent stem cells (iPSCs) in vitro, leading to a distinctive pattern of heart muscle cell fragmentation evident in autopsy reports. Besides directly infecting heart muscle cells, Sars-CoV-2 also enters and infects the endothelial cells that line the blood vessels to the heart and multiple vascular beds, leading to a secondary immune response. This causes blood pressure dysregulation, and activation of a proinflammatory response leading to a cytokine storm, which is a potentially fatal systemic inflammatory syndrome associated with Covid-19.

Persisting problems

Studies have found that injury to heart cells reflected in blood concentrations of a cardiac muscle-specific enzyme called troponin affects at least one in five hospitalised patients and more than half of those with pre-existing heart conditions, which raises the risk of death. Patients with higher troponin amounts also have high markers of inflammation (including C-reactive protein, interleukin-6, ferritin, lactate dehydrogenase), high neutrophil count, and heart dysfunction, all of which heighten immune response.

The heightened systemic inflammatory responses and diminished blood supply because of clotting, endotheliitis (blood vessel inflammation), sepsis, or hypoxemia (oxygen deprivation) because of acute lung infection leads to indirect cardiac damage, said Dr Kasliwal.

The cardiovascular damage associated with Sars-CoV-2 infection can persist beyond recovery. Since the virus affects the heart as much as the respiratory tract, further research is needed to understand why some people are more vulnerable to heart damage than others.

See the rest here:
Covid-19 can have impact on heart too, say experts - Hindustan Times

First Overall Survival Analysis for KEYTRUDA Plus LENVIMA Combination in a Phase 3 Study in Advanced Endometrial Cancer

KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Combination Demonstrated Statistically Significant Improvement in Overall Survival, Progression-Free Survival and Objective Response Rate Versus Chemotherapy in Patients With Advanced Endometrial Cancer Following Prior Systemic Therapy in Phase 3 Study

Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced that the pivotal Phase 3 KEYNOTE-775/Study 309 trial evaluating the investigational use of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, met its dual primary endpoints of overall survival (OS) and progression-free survival (PFS) and its secondary efficacy endpoint of objective response rate (ORR) in patients with advanced endometrial cancer following at least one prior platinum-based regimen. These positive results were observed in the mismatch repair proficient (pMMR) subgroup and the intention-to-treat (ITT) study population, which includes both patients with endometrial carcinoma that is pMMR as well as patients whose disease is microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR). Based on an analysis conducted by an independent Data Monitoring Committee, KEYTRUDA plus LENVIMA demonstrated a statistically significant and clinically meaningful improvement in OS, PFS and ORR versus chemotherapy (treatment of physicians choice [TPC] of doxorubicin or paclitaxel). The safety profile of the KEYTRUDA plus LENVIMA combination was consistent with previously reported studies. Merck and Eisai will discuss these data with regulatory authorities worldwide, with the intent to submit marketing authorization applications based on these results, and plan to present these results at an upcoming medical meeting.

Women with advanced endometrial cancer are faced with high mortality rates and limited treatment options following initial systemic therapy, said Dr. Gregory Lubiniecki, Associate Vice President, Oncology Clinical Research, Merck Research Laboratories. These are the first results from a Phase 3 trial of a combination regimen including immunotherapy in advanced endometrial carcinoma that have shown a statistically significant improvement in overall survival, progression-free survival and objective response rate versus chemotherapy. Merck and Eisai are dedicated to continuing to research the KEYTRUDA plus LENVIMA combination and discover new approaches to address unmet needs for devastating diseases such as endometrial carcinoma.

We are encouraged by the data observed in KEYNOTE-775/Study 309, which represent a possible step forward for patients impacted by advanced endometrial carcinoma and support the results seen in the advanced endometrial cancer cohort of KEYNOTE-146/Study 111, said Dr. Takashi Owa, Vice President, Chief Medicine Creation Officer and Chief Discovery Officer, Oncology Business Group at Eisai. As more clinical data from the LEAP (LEnvatinib And Pembrolizumab) program are revealed, we cannot help but be energized by the trajectory of our collaboration with Merck and the benefits we hope to provide to patients together. Most importantly, we are grateful for the trust that the patients and healthcare professionals who participated in this trial have shown us.

KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported the U.S. Food and Drug Administrations (FDA) 2019 accelerated approval of the KEYTRUDA plus LENVIMA combination for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This accelerated approval was based on tumor response rate and durability of response and was the first approval granted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among its international partners. Under Project Orbis, Health Canada and Australias Therapeutic Goods Administration (TGA) granted conditional and provisional approvals, respectively, for this indication.

Merck and Eisai are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in 13 different tumor types across 20 clinical trials, including a Phase 3 trial evaluating the combination in the first-line setting for patients with advanced endometrial carcinoma (LEAP-001).

About KEYNOTE-775/Study 309

KEYNOTE-775/Study 309 is a multicenter, randomized, open-label, Phase 3 trial ( ClinicalTrials.gov , NCT03517449 ) evaluating KEYTRUDA in combination with LENVIMA in patients with advanced endometrial cancer following at least one prior platinum-based regimen. The dual primary endpoints are OS and PFS, as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors Version (RECIST) v1.1. Select secondary endpoints include objective response rate (ORR) by BICR per RECIST v1.1 and safety/tolerability. Of the 827 patients enrolled, 697 patients had tumors that were non-MSI-H or pMMR, and 130 patients had tumors that were MSI-H or dMMR. Patients were randomized 1:1 to receive:

About Endometrial Cancer

Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. In 2018, it was estimated there were more than 382,000 new cases and nearly 90,000 deaths from uterine body cancers worldwide (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In the U.S., it is estimated there will be almost 66,000 new cases of uterine body cancer and nearly 13,000 deaths from the disease in 2020. The five-year survival rate for advanced or metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,300 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 patients 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.

Small Cell Lung Cancer

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

Head and Neck Squamous Cell Cancer

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

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

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

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

Microsatellite Instability-High 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)

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 first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

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

Esophageal Cancer

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

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Endometrial Carcinoma

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

Tumor Mutational Burden-High

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) 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.

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, 42% of these patients 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 (

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 (

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, which was 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 (

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 (

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

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

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

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 (

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 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.

See the original post:
KEYTRUDA Plus LENVIMA Combination Demonstrated Statistically Significant Improvement in Overall Survival, Progression-Free Survival and Objective...

COVID-19 is currently the leading cause of death in the United States killing more people each day than heart disease or cancer.

To help stem the tide of this life-threatening disease, scientists around the world have been working to develop vaccines.

Last week, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the first of these vaccines, developed by Pfizer and BioNTech.

The EUA allows for the distribution of the Pfizer-BioNTech COVID-19 vaccine across the United States. This vaccine has been developed to prevent COVID-19 in people age 16 years and older.

Getting 2 doses of the vaccine may drastically reduce your chances of developing COVID-19.

Even if youve had COVID-19, getting the vaccine may help prevent reinfection and lower your risk of getting sick again.

Were really happy to have a safe and effective tool [against COVID-19], Dr. Iahn Gonsenhauser, chief quality and patient safety officer at The Ohio State University Wexner Medical Center in Columbus, Ohio, told Healthline.

Were encouraging everybody to explore their opportunity to access the COVID vaccine as soon as thats made available to them, he said.

When someone develops COVID-19, their immune system learns to recognize the virus and begins to produce antibodies to fight against it.

If that person recovers from the disease, they may have immunity against reinfection with the virus for a period of time afterwards.

However, questions remain about how long that immunity lasts.

We dont know how long the immunity triggered by infection persists, and someone infected in the spring may no longer be immunologically protected now in December, Dr. David Hirschwerk, an infectious disease specialist at Northwell Health in Manhasset, New York, told Healthline.

It does stand to reason that somebody with COVID-19 infection is likely immune for 3 to 4 months at least, he said, but we dont have firm data to support this yet.

Cases of reinfection with the virus that causes COVID-19 have been reported.

Getting vaccinated may help to strengthen immunity against COVID-19.

In an ongoing clinical trial, Pfizer and BioNTech have studied their vaccine in people with and without a history of exposure to the virus.

Their research to date has found the vaccine is 95 percent effective at preventing COVID-19.

Their findings suggest it may help prevent reinfection in people who have already been exposed to the virus, as well as lowering the risk of infection in people with no history of exposure.

Data from the phase 2/3 trial for the Pfizer-BioNTech vaccine suggest that the vaccine is safe and likely effective in persons with previous evidence of SARS-CoV-2 infection, said Dr. Miriam Smith, chief of infectious disease at Long Island Jewish Forest Hills in Queens, New York.

[The] vaccine should be offered to all persons regardless of history of prior symptomatic or asymptomatic infection, she said.

The Centers for Disease Control and Prevention (CDC) currently advises that people with a known history of COVID-19 may wait up to nearly 90 days after their prior infection to get vaccinated, if they prefer to do so.

While more research is needed, available evidence suggests that reinfection with this virus is rare within 90 days of initial infection.

If someone currently has active symptoms of COVID-19, the CDC recommends they wait to get vaccinated until theyve recovered and met the criteria for ending isolation.

The Pfizer-BioNTech COVID-19 vaccine carries some risk of side effects.

However, ongoing research suggests the side effects tend to be mild and short-lived.

The way that we generally approach these questions in healthcare is through risk-benefit analysis, Gonsenhauser said.

In this case, the risk of some adverse response to the vaccine is low, and the benefit of knowing that you have a potentially extended or refreshed immunity to COVID is significant, he said.

With that, were recommending that people get the vaccine, even if theyve already had a COVID exposure and infection, he continued.

The most commonly reported side effect associated with the Pfizer-BioNTech COVID-19 vaccine is pain around the injection site.

Some people who received the vaccine developed other side effects such as fatigue, headache, and muscle aches, which tend to resolve within a day or so.

The risk of severe adverse events following the vaccine appears to be very low. However, some groups of people might face higher risk of adverse reactions than others.

For example, if you have a history of severe allergic reaction to any of the ingredients contained in the vaccine, the FDA recommends that you not receive it.

Talk with your doctor to learn more about the potential benefits and risks of getting vaccinated against COVID-19.

More here:
Even if You've Had COVID-19 You Still Need the Vaccine - Healthline

SynDevRx is working to address the unmet medical need in the field of metabo-oncology by developing treatments for cancer patients who are overweight or have systemic metabolic dysfunction. Technology Networks recently spoke with Jim Shanahan,co-founder, vice president of business development and director of SynDevRx, to explore the impact of metabolic dysfunction on treatment outcomes and learn more about the companys lead compound SDX-7320.Laura Lansdowne (LL): Could you tell us about the link between cancer and metabolic hormone dysfunction?Jim Shanahan (JS): It is commonly understood that obesity increases the risk for certain cancers. What drives this effect has to do with adipose (fat) tissue, which produces a variety of hormones and cytokines that, when dysregulated (as in obesity), stimulate tumor growth and metastasis. Two of the most common and potent metabolic drivers of cancer are insulin and leptin.Insulin, produced by the pancreas in response to elevated blood glucose, stimulates tumor growth via the PI3K/Akt/mTOR pathway. Insulin resistance, often seen in people who are obese or even simply those who have excess visceral adipose tissue (i.e., belly fat) is a pathological state where peripheral tissues (i.e., liver, adipose tissue, skeletal muscle) are less responsive or unresponsive to insulin, leading to chronically high levels of fasting insulin. In the US, an estimated 88 million people have insulin resistance and in the UK, an estimated 12 million are at risk for Type 2 diabetes. This is not a new problem; almost 20 years ago, Dr Pamela Goodwin, a leader in the field, reported that High levels of fasting insulin identify women with poor outcomes in whom more effective treatment strategies should be explored. A large recent study of > 20,000 post-menopausal women showed a significantly increased risk of cancer-specific mortality with elevated insulin resistance. Despite the abundance of research showing insulin is a bad actor in cancer, insulin levels are rarely ever measured in cancer patients.Leptin is an adipocyte-derived hormone whose levels are in direct proportion to fat mass. Leptin acts as a primary regulator of normal metabolic physiology and energy metabolism. The binding of leptin to its specific receptor activates multiple signaling pathways, including the Janus kinase 2(JAK2)/ signal transducer and activator of transcription 3 (STAT3), insulin receptor substrate (IRS)/phosphatidylinositol 3 kinase (PI3K), SH2-containing protein tyrosine phosphatase 2 (SHP2)/mitogen-activated protein kinase (MAPK) and 5' adenosine monophosphate-activated protein kinase (AMPK)/ acetyl-CoA carboxylase (ACC), in the central nervous system and peripheral tissues. Importantly many of these pathways are validated oncogenic pathways commonly targeted by cancer drugs since they overlap with growth factor signaling (e.g., VEGF and bFGF, Her2). More recently it was found that leptin receptors are highly expressed on cancer cells and leptin has been shown to increase cell proliferation, inhibit apoptosis, promote angiogenesis and induce anti-cancer drug resistance. These characteristics are associated with a subset of cells in both liquid and solid tumors known as cancer stem cells (CSCs), or tumor-initiating cells, leading to the formation of metastatic lesions.Conversely, in patients with metabolic dysfunction, the secretion of a key protective adipokine called adiponectin, is reduced. Adiponectin increases insulin sensitivity, thereby reducing levels of fasting insulin. Through its receptor interactions, adiponectin may exert its anti-carcinogenic effects including regulating cell survival, apoptosis and metastasis via a plethora of signaling pathways. Adiponectin has also been shown to directly inhibit tumor growth and counter-act the tumor-promoting effects of leptin. Furthermore, levels of circulating adiponectin are inversely associated with survival outcomes in breast cancer.The role that metabolic syndrome and metabolic hormones play in cancer is significant yet frequently ignored and entirely underappreciated.LL: Some anti-cancer drugs can cause metabolic dysfunction what impact does this have on efficacy and overall treatment success?JS: The short answer is that metabolic dysfunction (independent of origin) has a decidedly negative impact on treatment outcomes and patient quality of life. Many common anti-cancer treatments induce insulin resistance, obesity, Type 2 diabetes and metabolic syndrome, such as doxorubicin, Taxol, platinum-based drugs, aromatase inhibitors, gonadotropin-releasing hormone agonist as well as newer targeted therapies, such as the PI3K inhibitor Piqray (alpelisib, Novartis), mTOR inhibitors and steroids among others. What is emerging is an understanding that these treatment-induced metabolic complications blunt the impact of the anti-cancer treatment itself and can even cause treatment resistance. Hyperglycemia and the subsequent hyperinsulinemia are common in cancer treatment. Yet, insulin levels, which are highly stimulative to many cancers, are rarely monitored and therefore rarely treated. Its an oversight in clinical practice that needs to be remedied urgently.LL: How can metabolic dysfunction and cancer growth be counteracted pharmacologically?JS: At the moment, there are no drugs for targeting tumors sensitive to metabolic hormones. This is the gap in cancer treatment we are targeting with our lead drug SDX-7320. As a stopgap, many oncologists give their patients metformin, as it has been shown to have a modest effect on cancer treatment-induced metabolic dysfunction and may even improve cancer outcomes. Occasionally, oncologists refer their cancer patients to endocrinologists for more acute metabolic care via anti-diabetic drugs like SGLT2 inhibitors. While these anti-diabetics may have clinical utility in helping control hyperglycemia, they generally have only a modest effect on hyperinsulinemia/insulin resistance or high circulating leptin levels. As difficult as they are to maintain, diet and exercise are still the best weapons in the battle against cancer treatment-induced metabolic dysfunction.LL: Can you tell us more about the companys lead compound SDX-7320, in terms of its design, mechanism of action, the indications it is being investigated for and the clinical programs currently underway?JS: SynDevRxs lead compound is SDX-7320 a polymer-drug conjugate consisting of a small molecule MetAP2 inhibitor attached via a peptide linker to a high molecular weight polymer backbone. SDX-7320 is itself inert, but in vivo, the pharmacologically active small molecule fumagillol-derivative is released from the polymer/peptide linker upon contact with lysosomal enzymes. The concept behind the drugs design was to improve the safety profile of the active small molecule by preventing it from crossing the bloodbrain barrier a known and challenging side effect of MetAP2 inhibitors. Another objective of the polymer-conjugation approach was to improve its drug-like properties, as fumagillin is unstable and poorly soluble.The active small molecule is based on fumagillin, a natural product isolated from the fungus Aspergillus fumigatus Fresenius. Fumagillin and its derivatives are potent and selective inhibitors of the enzyme, MetAP2. Covalent modification of MetAP2 by the fumagillin pharmacophore not only inhibits the aminopeptidase activity of MetAP2, but also results in decreased turnover and thus the accumulation of the inhibited protein. This results in multiple beneficial downstream effects including cell cycle arrest, modified angiogenic growth factors, improvements to the tumor immune micro-environment and amelioration of dysregulated metabolic hormones.The polymer conjugation technology yields a number of advantages of SDX-7320 over traditional small molecule fumagillin-based MetAP2 inhibitors, for example dramatically superior water solubility, excellent stability, and a highly favorable PK profile which allows for a patient-friendly dosing schedule and administration by subcutaneous injection a first for a polymer-drug conjugate. Additionally, the high average molecular weight of SDX-7320 has proven effective at minimizing the historic, class-specific CNS adverse effect observed with small-molecule fumagillin analogs.Interestingly, our expectations for the polymer-drug conjugate were that we would see absolute doses increase significantly, with respect to the small molecule doses. Decades of polymer-drug conjugation research suggested doses should increase by as much as 10x (compared to the small molecule) with little to no change in safety. In fact, we saw the opposite. In multiple head-to-head experiments, we saw greater activity with lower doses of the conjugate (in absolute drug weight terms) compared to the small molecule and with a better safety profile.SDX-7320 is being developed for the treatment of cancers that are sensitive to metabolic hormones, with our first indication being breast cancer. A Phase 1 trial of SDX-7320 was completed in 2020, in patients with advanced solid tumors. The results of this trial defined the recommended Phase 2 dose and schedule as well as demonstrated favorable effects on metabolic and angiogenic biomarkers. Clinical trials are planned in combination with standards of care in triple-negative breast cancer (TNBC) as well as in ER+/Her2- breast cancer in combination with a PI3K inhibitor (Piqray/alpelisib) in patients with a PIK3CA mutation.Jim Shanahan was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.

Read more here:
The Link Between Cancer and Metabolic Dysfunction - Technology Networks

STOCKHOLM, Dec. 16, 2020 /PRNewswire/ -- Diamyd Medical and the Critical Path Institute (C-Path) are proud to announce their collaboration to significantly improve the scientific community's insight into type 1 diabetes (T1D) through Diamyd Medical's contribution of fully anonymized data from a European Phase III trial to the Trial Outcome Measures Initiative (TOMI) T1D integrated database.

The Phase III trial evaluated the use of the diabetes vaccine Diamyd, an antigen-specific immunotherapy based on the auto-antigen GAD (glutamic acid decarboxylase), to induce immunological tolerance and stop the autoimmune destruction of insulin producing cells. The Data Contribution Agreement between Diamyd Medical and C-Path will allow for this unique set of fully anonymized clinical trial data to be integrated into an ever-growing list of committed trial data sets within the TOMI-T1D project.

TOMI-T1D is an international partnership between academia, the pharmaceutical industry and nonprofit organizations. It is funded by the world's leading charities dedicated to diabetes research, JDRF, and Diabetes UK, guided by both organizations' strong commitment to facilitate deep interrogation of consolidated community-wide trial data as a means to accelerate clinical research and therapeutic development for T1D. TOMI-T1D aims to create a clinical trial simulation tool (CTST) with large and diverse clinical datasets from the T1D community. The project also seeks to engage the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to identify opportunities for regulatory endorsement of such drug development tools.

The Diamyd Medical data includes relevant information about disease progression, drug effects and clinical trial design. Contribution of these robust data sets from industry led trials is critical to TOMI-T1D's work in developing innovative and quantitative tools that can facilitate clinical development efforts and be endorsed by regulators for future use by the pharmaceutical industry to optimize the design of future clinical trials.

"Progress towards the establishment of approved therapies for people with T1D is critically reliant on participation from our partners in industry with their data", said Simi Ahmed and Elizabeth Robertson, on behalf of the charity partnership.

"This is indeed a right step in that direction", said Colin Dayan, lead PI at Cardiff University.

"We are thrilled that Diamyd Medical is taking a leading role and championing precompetitive collaborations advancing type 1 diabetes regulatory science solutions", said Inish O'Doherty Executive Director at C-Path. "Their data will help in the construction and evaluation of a clinical trial simulation tool to assist in the development of novel therapies for type 1 diabetes patients".

"We are very honored to be part of this important collaboration -involving key stakeholders within the type 1 diabetes landscape, said Ulf Hannelius, President & CEO of Diamyd Medical. "As we are moving into an era of precision medicine in type 1 diabetes, we can expect to see significant therapeutic advances, and access to high quality data will be integral to maximizing these efforts".

To learn more about the TOMI-T1D project visit: https://c-path.org/programs/tomi-t1d/

About Critical Path Institute

Critical Path Institute (C-Path) is an independent, nonprofit organization established in 2005 as a public and private partnership. C-Path's mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, C-Path has established numerous global consortia that currently include more than 1,600 scientists from government and regulatory agencies, academia, patient organizations, disease foundations, and dozens of pharmaceutical and biotech companies. C-Path US is headquartered in Tucson, Arizona and C-Path, Ltd. EU is headquartered in Dublin, Ireland, with additional staff in multiple other locations. For more information, visit c-path.org and c-path.eu.

About JDRF

JDRF's mission is to accelerate life-changing breakthroughs to cure, prevent, and treat T1D and its complications. To accomplish this, JDRF has invested more than $2.5 billion in research funding since our inception. We are an organization built on a grassroots model of people connecting in their local communities, collaborating regionally for efficiency and broader fundraising impact and uniting on a national stage to pool resources, passion and energy. We collaborate with academic institutions, policymakers and corporate and industry partners to develop and deliver a pipeline of innovative therapies to people living with T1D. Our staff and volunteers throughout the United States and our five international affiliates are dedicated to advocacy, community engagement and our vision of a world without T1D. For more information, please visit jdrf.org or follow us on Twitter: @JDRF

About Diabetes UK

1. Diabetes UK's aim is creating a world where diabetes can do no harm. Diabetes is the most devastating and fastest growing health crisis of our time, affecting more people than any other serious health condition in the UK - more than dementia and cancer combined. There is currently no known cure for any type of diabetes. With the right treatment, knowledge and support people living with diabetes can lead a long, full and healthy life. For more information about diabetes and the charity's work, visit http://www.diabetes.org.uk

2. Diabetes is a condition where there is too much glucose in the blood because the body cannot use it properly. If not managed well, both type 1 and type 2 diabetes can lead to devastating complications. Diabetes is one of the leading causes of preventable sight loss in people of working age in the UK and is a major cause of lower limb amputation, kidney failure and stroke.

3. People with type 1 diabetes cannot produce insulin. About 10 per cent of people with diabetes have type 1. No one knows exactly what causes it, but it's not to do with being overweight and it isn't currently preventable. It's the most common type of diabetes in children and young adults, starting suddenly and getting worse quickly. Type 1 diabetes is treated by daily insulin doses - taken either by injections or via an insulin pump. It is also recommended to follow a healthy diet and take regular physical activity.

4. People with type 2 diabetes don't produce enough insulin or the insulin they produce doesn't work properly (known as insulin resistance). Around 90 per cent of people with diabetes have type 2. They might get type 2 diabetes because of their family history, age and ethnic background puts them at increased risk. They are also more likely to get type 2 diabetes if they are overweight. It starts gradually, usually later in life, and it can be years before they realise they have it. Type 2 diabetes is treated with a healthy diet and increased physical activity. In addition, tablets and/or insulin can be required.

For more information on reporting on diabetes, download our journalists' guide: Diabetes in the News: A Guide for Journalists on Reporting on Diabetes (PDF, 3MB).

About Diamyd Medical

Diamyd Medical develops therapies for type 1 diabetes. The diabetes vaccine Diamyd is an antigen-specific immunotherapy for the preservation of endogenous insulin production. Significant results have been shown in a genetically predefined patient group in a large-scale metastudy as well as in the Company's European Phase IIb trial DIAGNODE-2, where the diabetes vaccine is administered directly into a lymph node in children and young adults with newly diagnosed type 1 diabetes. A new facility for vaccine manufacturing is being set up in Ume for the manufacture of recombinant GAD65, the active ingredient in the therapeutic diabetes vaccine Diamyd. Diamyd Medical also develops the GABA-based investigational drug Remygen as a therapy for regeneration of endogenous insulin production and to improve hormonal response to hypoglycaemia. An investigator-initiated Remygen trial in patients living with type 1 diabetes for more than five years is ongoing at Uppsala University Hospital. Diamyd Medical is one of the major shareholders in the stem cell company NextCell Pharma AB.

Diamyd Medical's B-share is traded on Nasdaq First North Growth Market under the ticker DMYD B. FNCA Sweden AB is the Company's Certified Adviser; phone: +46 8-528 00 399, e-mail: info@fnca.se

CONTACT:

For further information, please contact:

Ulf Hannelius, President and CEO

Phone: +46 736 35 42 41

E-mail: ulf.hannelius@diamyd.com

This information was brought to you by Cision http://news.cision.com

https://news.cision.com/diamyd-medical-ab/r/diamyd-medical-and-critical-path-institute-announce-data-sharing-collaboration-to-develop-advanced-d,c3255392

The following files are available for download:

View original content:http://www.prnewswire.com/news-releases/diamyd-medical-and-critical-path-institute-announce-data-sharing-collaboration-to-develop-advanced-drug-development-tools-in-type-1-diabetes-301193791.html

SOURCE Diamyd Medical AB

Company Codes: Frankfurt:DMN, ISIN:SE0005162880, Munich:DMN, Stockholm:DMYD, Stockholm:DMYD-B.ST

Originally posted here:
Diamyd Medical and Critical Path Institute announce data sharing collaboration to develop advanced drug development tools in type 1 diabetes -...

For Evie Junior, living with sickle cell disease has been like running a marathon.

"But it's a marathon where as you keep going, the trail gets rockier and then you lose your shoes," the 27-year-old said. "It gets harder as you get older. Things start to fail and all you can think about is how much worse it's going to get down the road."

In sickle cell disease, a genetic mutation causes the blood-forming stem cells -- which give rise to all blood and immune cells -- to produce hard, sickle-shaped red blood cells. These misshapen cells die early, leaving an insufficient number of red blood cells to carry oxygen throughout the body. Because of their sickle shape, these cells also get stuck in blood vessels, blocking blood flow and resulting in excruciating bouts of pain that come on with no warning and can leave patients hospitalized for days.

The disease affects 100,000 people in the United States and millions around the world, the majority of whom are of African or Hispanic descent. It can ultimately lead to strokes, organ damage and early death.

As a child growing up in the Bronx, New York, Junior had to have his gall bladder and spleen removed due to complications from the disease, but he refused to let his condition limit him. He played football, basketball and baseball during the day, even though on some nights he experienced pain crises so severe he couldn't walk.

"It was just really routine if I had a sickle cell crisis," he said. "Going to the emergency room, staying in the hospital, coming out in a few days and then getting back to normal life."

'I want to create a better future'

When he was 24 and living in Portland, Oregon, Junior began working as an emergency medical technician. He adopted the same mentality -- trying to treat his pain episodes the best he could, and hoping they would resolve overnight so he could get back to work. Around that time, though, the crises became harder to manage. He developed pericarditis, an inflammation in the layers of tissue around his heart, and needed six weeks to recover.

"The big worry with sickle cell disease is that you're going to die young from some type of complications or damage to your organs," he said. "In the last couple of years, I've been seeing that slowly happen to me and I can only suspect that it's going to keep getting worse. I want to create a better future for myself."

In July 2019, in pursuit of that future, Junior enrolled in a clinical trial for an experimental stem cell gene therapy for sickle cell disease. The study is led by UCLA Broad Stem Cell Research Center physician-scientists Dr. Donald Kohn and Dr. Gary Schiller and funded by the California Institute for Regenerative Medicine.

The therapy, developed by Kohn over the past 10 years, is intended to correct the mutation in patients' blood-forming stem cells to allow them to produce healthy red blood cells. Kohn has already applied the same concept to successfully treat several immune system deficiencies, including a cure for a form of severe combined immune deficiency, also known as bubble baby disease.

But sickle cell disease has proven more difficult to treat with gene therapy than those other conditions. Junior volunteered for the trial knowing there was a chance the therapy wouldn't cure him.

"Even if it doesn't work for me, I'm hoping that it can be a cure later down the road for millions of people," he said.

In July 2020, Junior received an infusion of his own blood-forming stem cells that had been genetically modified to overcome the mutation that causes his disease.

"The goal of this treatment is to give him a future, let him plan for college, family or whatever he wants without worrying about getting hospitalized because of another pain crisis," said Kohn, a distinguished professor of microbiology, immunology and molecular genetics, pediatrics, and molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

Reason for optimism

Three months after his treatment, blood tests indicated that 70% of Junior's blood stem cells had the new corrected gene. Kohn and Schiller estimate that even a 20% correction would be enough to prevent future sickle cell complications. Junior said he hasn't had a pain crisis since undergoing the treatment and he has more energy and feels out of breath less often.

"I noticed a big difference in my cardiovascular endurance in general -- even going for a light jog with my dogs, I could feel it," he said.

Junior and his doctors are cautiously optimistic about the results.

"It's too early to declare victory, but it's looking quite promising at this point," Kohn said. "Once we're at six months to a year, if it looks like it does now, I'll feel very comfortable that he's likely to have a permanent benefit."

After a lifetime of dealing with the unwelcome surprises of the disease, Junior is even more cautious than his doctors. But as the weeks pass, he's slowly allowing a glimmer of hope that he could soon be someone who used to have sickle cell disease. For him, that hope feels like "a burst of happiness" that's followed by thoughts of all the things he could do with a healthy future: pursue his dream of becoming a firefighter, get married and start a family.

"I want to be present in my kids' lives, so I've always said I'm not going to have kids unless I can get this cured," he said. "But if this works, it means I could start a family one day."

Read more from the original source:
Gene therapy gives man with sickle cell disease the chance for a better future - Science Codex

This article was originally published here

J Vasc Interv Radiol. 2020 Nov 25:S1051-0443(20)30769-7. doi: 10.1016/j.jvir.2020.09.003. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate safety and efficacy of angiogenesis induced by intraarterial autologous bone marrow-derived stem cell (BMSC) injection in patients with severe peripheral arterial disease (PAD).

MATERIALS AND METHODS: Eighty-one patients with severe PAD (77 men), including 56 with critical limb ischemia (CLI) and 25 with severe claudication, were randomized to receive sham injection (group A) or intraarterial BMSC injection at the site of occlusion (group B). Primary endpoints included improvement in ankle-brachial index (ABI) of > 0.1 and transcutaneous pressure of oxygen (TcPO2) of > 15% at mid- and lower foot at 6 mo. Secondary endpoints included relief from rest pain, > 30% reduction in ulcer size, and reduction in major amputation in patients with CLI and > 50% improvement in pain-free walking distance in patients with severe claudication.

RESULTS: Technical success was achieved in all patients, without complications. At 6 mo, group B showed more improvements in ABI of > 0.1 (35 of 41 [85.37%] vs 13 of 40 [32.50%]; P < .0001) and TcPO2 of > 15% at the midfoot (35 of 41 [85.37%] vs 17 of 40 [42.50%]; P = .0001] and lower foot (37 of 41 [90.24%] vs 19 of 40 [47.50%]; P < .0001). No patients with CLI underwent major amputation in group B, compared with 4 in group A (P = .0390). No significant difference was observed in relief from rest pain or > 30% reduction in ulcer size among patients with CLI or in > 50% improvement in pain-free walking distance among patients with severe claudication.

CONCLUSIONS: Intraarterial delivery of autologous BMSCs is safe and effective in the management of severe PAD.

PMID:33248918 | DOI:10.1016/j.jvir.2020.09.003

Read more here:
Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Safety and Therapeutic Efficacy of Angiogenesis Induced by Intraarterial Autologous...

(TNS) - Scientists at Bay Area universities, laboratories, biotechnology companies and drug manufacturers are fashioning drug concoctions out of blood plasma, chimpanzee viruses and cells taken from bone marrow in the race to rid the world of COVID-19.

The microbial treasure hunt is not just to find a cure which may not be possible but to control the debilitating health problems caused by the coronavirus.

Major progress has been made this year. The antiviral drug remdesivir, produced in Foster City, has improved recovery times, and the steroid dexamethasone has cut the number of deaths in severely ill patients.

What follows is a list of some of the most promising medications and vaccines with ties to the Bay Area:

Antibodies

and Immunity

Mesenchymal stem cells / UCSF and UC Davis Medical Center:

UCSF Dr. Michael Matthay is leading a study of whether a kind of stem cell found in bone marrow can help critically ill patients with severe respiratory failure, known as ARDS. Matthay hopes the stem cells can help reduce the inflammation associated with some of ARDS' most dire respiratory symptoms, and help patients' lungs recover.

In all, 120 patients are being enrolled at UCSF Medical Center, Zuckerberg San Francisco General Hospital, the UC Davis Medical Center in Sacramento and hospitals in Oregon and Texas. He said the trial, which includes a small number of ARDS patients who don't have COVID-19, should have results by summer or fall 2021. So far, 28 patients are enrolled in San Francisco.

Lambda-interferon / Stanford University:

Lambda-interferon is a manufactured version of a naturally occurring protein that had been used to treat hepatitis, and researchers hoped it would help patients in the early stages of COVID-19.

Stanford researchers completed their trial of lambda-interferon and found that it did not boost the immune system response to coronavirus infections.

"That trial did not find any difference in outcomes between the treatment and placebo," said Yvonne Maldonado, chief of pediatric infectious diseases at Lucile Packard Children's Hospital at Stanford, where 120 patients were enrolled in the trial. "It didn't work."

Antiviral drugs

Remdesivir / Gilead Sciences ( Foster City):

Remdesivir, once conceived as a potential treatment for Ebola, was approved by the Food and Drug Administration in October for use on hospitalized COVID-19 patients.

Trademarked under the name Veklury, the drug interferes with the process through which the virus replicates itself. It was one of the drugs given to President Trump and has been used regularly in hospitals under what is known as an emergency use authorization.

It was approved after three clinical trials showed hospitalized coronavirus patients who received remdesivir recovered five days faster on average than those who received a placebo. Patients who required oxygen recovered seven days faster, according to the studies.

Gilead now plans to conduct clinical trials to see how remdesivir works on pediatric patients, from newborns to teenagers, with moderate to severe COVID-19 symptoms. Remdesivir is also being studied with steroids and other drugs to see if it works better as part of a medicinal cocktail. An inhalable form of the drug is also being developed.

Favipiravir / Fujifilm Toyama Chemical ( Stanford University):

This antiviral drug, developed in 2014 by a subsidiary of the Japanese film company to treat influenza, is undergoing numerous clinical studies worldwide, including a trial involving 180 patients at Stanford University.

Stanford epidemiologists are testing favipiravir to see if it prevents the coronavirus from replicating in human cells, halts the shedding of the virus and reduces the severity of infection. Unlike remdesivir, it can be administered orally, so it can be used to treat patients early in the disease, before hospitalization is necessary.

The Stanford study has so far enrolled about 90 patients, who are given the drug within 72 hours of when they were first diagnosed with COVID-19. Half of them get a placebo. People can enroll by emailing treatcovid@stanford.edu.

Monoclonal antibodies

REGN-COV2 / Regeneron Pharmaceuticals / Stanford School of Medicine:

The REGN-COV2 cocktail is the same one Trump received, and Stanford is one of dozens of locations nationwide where clinical trials are being held. Two separate trials are under way at Stanford one for hospitalized patients, the other for outpatients. A third trial is about to begin for people who aren't sick but are in contact with carriers of the virus.

Regeneron halted testing on severely ill patients requiring high-flow oxygen or mechanical ventilation after the independent Data and Safety Monitoring Board determined that the drug was unlikely to help them.

The drug is a combination of two monoclonal antibodies lab-made clones of the antibodies produced naturally in people who have recovered from COVID-19. The antibodies bind to the virus' spike protein and block the virus' ability to enter cells.

Dr. Aruna Subramanian, professor of infectious diseases at Stanford and lead investigator for the inpatient trial, said the 21 hospitalized patients in the study receive a high dose like Trump, a lower dose or a placebo. Subramanian plans to expand the inpatient trial to 45 patients. The outpatient study has enrolled a little more than 40 of the 60 patients researchers intend to sign up.

"There's enough promising evidence that it helps people early in the infection," Subramanian said. "What we don't know is whether it helps people who are pretty sick but not critically ill."

Bamlanivimab / Eli Lilly / Stanford and UCSF:

Stanford and UCSF are testing the Eli Lilly monoclonal antibodies on outpatients after the pharmaceutical company halted trials on hospitalized COVID-19 patients because of adverse results.

Dr. Andra Blomkalns, chair of emergency medicine at Stanford and the lead in the Eli Lilly outpatient trial, said she is now enrolling older people with comorbidities like heart disease, chronic lung disease, a history of strokes and severe obesity shortly after they test positive.

The hypothesis is that the bamlanivimab monotherapy, which is very similar to the Regeneron monoclonals, might work best early in the infection. Although about 400 patients have been enrolled in the Lilly phase 3 trials nationwide, to date fewer than 10 have been enrolled at Stanford and UCSF.

Matthay, who headed up the Lilly monoclonal study with LY-CoV555 at UCSF, said the cancellation of this inpatient trial was disappointing, but "just because this one did not work, doesn't mean another one won't work for hospitalized patients."

Blomkalns said the testing criteria has been changing. She expects the outpatient trial to open soon to adolescents ages 12 and up to determine whether the drug can be used as a preventive.

Designer monoclonal antibodies / Vir Biotechnology, San Francisco:

Scientists at Vir are studying several types of monoclonal antibodies, including a type engineered to activate T cells, which can search out and destroy cells infected with the coronavirus. A study published in the journal Nature in October found that monoclonals, modified to bind with certain receptors, stimulated T cells and improved the human immune response.

"By observing and learning from our body's powerful natural defenses, we have discovered how to maximize the capacity of antibodies through the amplification of key characteristics that may enable more effective treatments for viral diseases," said Herbert Virgin, the chief scientific officer at Vir and co-author of the study.

A similarly modified monoclonal antibody, leronlimab, is being studied in coronavirus clinical trials by its Washington state drugmaker, CytoDyn, which has developed drugs to treat HIV. The company's chief medical officer is in San Francisco, and the company that does laboratory tests of leronlimab is in San Carlos.

Anti-inflammatory drugs

Colchicine / UCSF ( San Francisco and New York):

The anti-inflammatory drug commonly used to treat gout flare-ups is being studied by scientists at UCSF and New York University. The drug short-circuits inflammation by decreasing the body's production of certain proteins, and researchers hope that it will reduce lung complications and prevent deaths from COVID-19.

Preliminary results from a clinical trial found that "Colchicine can be effective in reducing systemic symptoms of COVID-19 by inhibiting inflammatory biomarkers."

Selinexor / Kaiser Permanente:

Kaiser hospitals in San Francisco, Oakland and Sacramento are studying selinexor, an anticancer drug that blocks a key protein in the cellular machinery for DNA processing. Preliminary findings during the trials indicated that low doses of selinexor helped hospitalized patients with severe COVID-19. The drug has both antiviral and anti-inflammatory properties, and it's administered orally, according to Kaiser's Dr. Jacek Skarbinski.

Vaccines

VXA-COV2-1 / Vaxart, South San Francisco:

The biotechnology company Vaxart is testing VXA-COV2-1, the only potential vaccine in pill form. It uses the genetic code of the coronavirus to trigger a defensive response in mucous membranes. The hope is that the newly fortified membranes will prevent the virus from entering the body.

"It's the only vaccine (candidate) that activates the first line of defense, which is the mucosa," said Andrei Floroiu, Vaxart's chief executive. He said intravenous vaccines kill the virus after it is inside the body, but this one stops it beforehand.

View original post here:
Coronavirus Updates: The Latest Treatments and Vaccines - GovTech

Graft Versus Host Disease (GVHD) Epidemiology

According to the National Cancer Institute (NCI), Graft versus host disease (GVHD) is a disease caused when cells from a donated stem cell graft attack the normal tissues of the transplant patient. Symptoms include jaundice, skin rash or blisters, a dry mouth, or dry eyes. GVHD occurs when particular types of white blood cells (T cells) in the donated bone marrow or stem cells attack the host body cells because the donated cells (the graft) see the host cells as foreign and attack them.

GVHDhas two types Acute GVHDand Chronic GvHD. Acute GvHD is also known as fulminant GVHD and occurs usually in the initial 2-3 months after transplantation. Chronic GVHD occurs around 3-4 months after the transplantation has happened, and has more diverse complications. This type affects the liver, stomach, vagina, joints, lungs, gut, mouth and glands secreting mucus or saliva.

Get FREE sample copy at:https://www.delveinsight.com/sample-request/graft-versus-host-disease-gvhd-epidemiology-forecast

DelveInsights Graft Versus Host Disease (GVHD) Epidemiology Forecast to 2030 report delivers an in-depth understanding of the disease, historical and forecasted Graft Versus Host Disease (GVHD) epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan.The DelveInsight Graft Versus Host Disease (GVHD) epidemiology report gives a thorough understanding of the Graft Versus Host Disease (GVHD) disease symptoms and causes, along with the risk factors, diagnosis, pathophysiology associated with the disease, and. It also provides treatment algorithms and treatment guidelines for Graft Versus Host Disease (GVHD) in the US, Europe, and Japan. The report covers the detailed information of the Graft Versus Host Disease (GVHD) epidemiology scenario in seven major countries (US, EU5, and Japan).

Key Highlights Of The Report

As per a study by Elgaz S. et al., (2019), GVHDoccurs in 3050% of recipients and 14% of all patients suffer severe GVHDgrades 34. Chronic GVHDaffects 3070% of patients receiving allo-SCT.

As per a study by Jacobsohn and Vogelsang (n.d.) titled Acute graft versus host disease, in the United States, approximately 5,500 patients/year can develop acute GVHD and in 2003, the incidence of grade II-IV acute GVHD was roughly 3550%.

As per Orphanet, about 35%-50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute Graft versus host disease (GVHD). And about 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD.

Graft Versus Host Disease (GVHD) Epidemiology

Scope of the Report

Key Benefit of Graft Versus Host Disease (GVHD) Epidemiology Report

The Graft Versus Host Disease (GVHD) Epidemiology report will allow the user to

Get FREE sample copy at:https://www.delveinsight.com/sample-request/graft-versus-host-disease-gvhd-epidemiology-forecast

Table of Contents

*The table of contents is not exhaustive; will be provided in the final report

Related ReportsGraft versus host disease (GVHD)- Market Insight, Epidemiology and Market Forecast -2030DelveInsight s Graft versus host disease (GVHD) Market Insights, Epidemiology and Market Forecast 2030 report provides a detailed overview of the disease and in depth understanding of historical and forecasted epidemiology.

Graft versus host disease (GVHD) Pipeline Insights, 2020Graft versus host disease (GVHD) Pipeline Insight, 2020 report by DelveInsight outlays comprehensive insights of present clinical development scenario and growth prospects across the Graft versus host disease (GVHD) market.

About DelveInsightDelveInsight is a leading Business Consultant, and Market Research Firm focused exclusively on life sciences. It supports pharma companies by providing end to end comprehensive solutions to improve their performance.

Contact usShruti Thakur[emailprotected]+91-9650213330https://www.delveinsight.com/LinkedIn | Facebook | TwitterGraft Versus Host Disease (GVHD) Epidemiology Report:https://www.delveinsight.com/sample-request/graft-versus-host-disease-gvhd-epidemiology-forecast

Here is the original post:
Graft Versus Host Disease (GVHD) Patient Population, Treatment Algorithm, Medical Practices And Epidemiology Forecast To 2030 - The Market Feed

Ottawa: There are more than 300,000 Canadians living with type 1 diabetes (T1D), an autoimmune disease with no known cause or cure, resulting in the dysfunction, damage or loss of pancreatic beta cells that produce insulin in our bodies. People with T1D must treat themselves with insulin several times per day to keep their blood glucose levels normal, and despite their best efforts, they often experience serious, and even life-threatening, complications.

To mark the end of Diabetes Awareness Month, Sonia Sidhu, Member of Parliament for Brampton South, on behalf of the Honourable Patty Hajdu, Minister of Health, announced an investment of $6 million through the CIHR-JDRF Partnership to Defeat Diabetes for two Canadian research teams to accelerate the development of stem cell-based therapies for the treatment of T1D.

Stem cells show great promise as a source of insulin-producing cells that could be transplanted to provide a new source of insulin, to replace dysfunctional, damaged or lost pancreatic beta cells. Canada has a remarkable legacy in leading discoveries in this area. Stem cells were discovered in Toronto in 1961, and in 2000, a team in Edmonton were the first to pioneer transplantation of pancreatic islets (the part of the pancreas that contains insulin-producing cells). These achievements represent important steps toward a treatment that will allow people with T1D to live healthy lives without daily insulin injections.

The research teams are led by Dr. Maria Cristina Nostro at the University Health Network and the University of Toronto and Dr. Francis Lynn at the BC Childrens Hospital Research Institute and the University of British Columbia. The teams will build on Canadas demonstrated research excellence and leadership in clinical islet transplantation, stem cell biology, diabetes, immunology and genetic engineering to accelerate stem cell-based therapies for T1D. They will work in collaboration with other Canadian researchers to tackle some of the biggest scientific challenges that impede our progress in this area and move us closer to a future where people with T1D will no longer rely on insulin therapy.

This funding was provided by the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD), and JDRF Canada, through the CIHR-JDRF Partnership to Defeat Diabetes established in 2017. Each partner will invest $3 million over five years. This investment is part of a large research initiative, 100 Years of Insulin: Accelerating Canadian Discoveries to Defeat Diabetes, funded by CIHR and partners. This initiative commemorates the 100th anniversary of the discovery of insulin to be marked in 2021a discovery that changed the lives of millions of Canadians and people around the world and won researchers Sir Frederick Banting and John Macleod the Nobel Prize in Physiology or Medicine.

See the original post:
Government of Canada and JDRF Canada announce new research funding to accelerate stem cell-based therapies for type 1 diabetes - India Education Diary

Organ and stem cell transplants are proven and frequently used methods in everyday modern clinical practice. However, even when performed regularly in specialized centers, some patients still experience a number of serious complications afterwards. Among other things, infections with fungi and viruses can jeopardize therapeutic success. For example, coinfection with cytomegalovirus, which belongs to the family of Herpes viruses, and the fungus Aspergillus fumigatus can be critical. This combination of pathogens poses a serious medical threat in organ and stem cell transplantation.

When viruses and fungi join forces

A team of scientists from several German research institutions and clinics has now developed a new method to examine these two pathogens, their interaction with each other and with the human cells infected by them. The central result: coinfection with the two pathogens is more "than the sum of its parts". Viruses and fungi interact synergistically in the human organism, where they trigger certain genes that only become active when infected with both pathogens simultaneously.

The study involved scientists from the Julius Maximilian University of Wrzburg (JMU), the Wrzburg University Hospital (UKW), the Leibniz Institute for Natural Product Research and Infection Biology in Jena and the Helmholtz Institute for RNA-based Infection Research (HIRI) in Wrzburg, a site of the Braunschweig Helmholtz Centre for Infection Research (HZI). The results have now been published in the journal Cell Reports.

New insights thanks to a novel technology

"For our study, we have developed a method called Triple RNA-seq," explains Alexander Westermann. He is junior professor at the Chair of Molecular Infection Biology I at JMU, as well as group leader at the HIRI. Together with Jrgen Lffler from UKW and Sascha Schuble he is one of the senior authors of the study. The scientists have advanced an established method that has been an integral part of infection research for years: dual RNA-seq.

The term "RNA-seq" is short for RNA-sequencing: This technique enables the simultaneous and precise determination of the activities of thousands of genes at the RNA level in a high-throughput process, thus enabling the identification and better understanding of the changes occurring in the course of diseases. The development of dual RNA sequencing has made it possible to document not only the gene activity of a pathogen, but also the reaction of the host cell affected by it. This has enabled scientists to trace complex causal chains over the course of an infection.

Research on immune cells

Now, Triple RNA sequencing dissects the gene expression of three players and their interplay in infection processes. "Up to now, science has in many cases not known why an infection with a certain pathogen can make the affected person more susceptible to an infection with a second pathogen," explains Jrgen Lffler, molecular biologist at the Medical Clinic II of the UKW. In such cases, dual RNA-seq was insufficient to provide the desired answers.

In their study, the researchers used the triple RNA-seq method they developed to investigate what happens when certain cells of the immune system (known as monocyte-derived dendritic cells) are infected with both Aspergillus fumigatus and the human cytomegalovirus.

They were able to prove that the two pathogens influence each other, whilst also simultaneously affecting the immune cell in a different way than one pathogen alone otherwise would. For example, the cytomegalovirus weakened the fungal-mediated activation of pro-inflammatory signals, while Aspergillus affects viral clearance - the time it takes for the virus to become undetectable in tests.

Hope for a biomarker

At the same time, the team has identified specific genes in immune cells whose expression profiles differ significantly during an infection with both pathogens, compared to a single infection. These genes could thus serve as biomarkers for the timely identification of a co-infection after transplantation.

The scientists now hope that the triple RNA-seq technology will also help to better understand other cases of common infections, such as viruses and bacteria, and to prevent their potentially serious consequences. "Promising models for understanding how an infection makes the host more susceptible to another pathogen include certain strains of Salmonella and the human immunodeficiency virus (HIV), streptococci and influenza virus, or Chlamydia and human herpes virus," says Westermann. As a next step, Westermann plans to use the triple RNA-seq technique to investigate infections in which two different types of bacteria jointly influence the course of the disease.

View original post here:
Coinfection: more than the sum of its parts - Science Codex

SAN DIEGO, Nov. 11, 2020 /PRNewswire/ -- Angiocrine Bioscience Inc., a clinical-stage biopharmaceutical company today announced that the U.S. Food and Drug Administration (FDA) granted the Regenerative Medicine Advanced Therapy (RMAT) designation for AB-205, for "the treatment of organ vascular niche injuries to prevent or reduce severe regimen-related toxicities (SRRT) in patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) undergoing high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation".Based on its Phase 2 trial results, Angiocrine expects to initiate a single pivotal registration Phase 3 trial in 2021 involving leading cancer centers in North America and Europe.

Angiocrine Bioscience Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to AB-205

"The RMAT designation speaks to the clinical meaningfulness and the promising efficacy data and safety profile of AB-205 based on our Phase 1b/2 study.This is an important step in accelerating the development of AB-205 towards its first market approval," commented Paul Finnegan, MD, Angiocrine's CEO."We appreciate the thorough assessment provided by the FDA reviewers and the support from our partner, the California Institute for Regenerative Medicine."Angiocrine was awarded a $6 million grant from CIRM in 2019 for the clinical development of AB-205.

About Regenerative Medicine Advanced Therapy (RMAT) DesignationEstablished under the 21st Century Cures Act, the RMAT designation was established to facilitate development and expedite review of cell therapies and regenerative medicines intended to treat serious or life-threatening diseases or conditions. Advantages include the benefits of the FDA's Fast Track and Breakthrough Therapy Designation programs, such as early interactions with the FDA to discuss potential surrogate or intermediate endpoints to support accelerated approval.

About HDT-AHCT High-dose therapy and autologous hematopoietic cell transplantation (HDT-AHCT) is considered a standard-of-care therapy for patients with aggressive systemic Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).Although efficacious and considered a potential cure, HDT-AHCT is associated with severe regimen-related toxicities (SRRT) that increase patient morbidity and risk for mortality, especially in the aging population. Effective prevention of SRRT may lead to more patients being eligible for a potential cure through HDT and stem cell transplantation.

About SRRT Consequences of Diffuse Injury to the Organ Vascular NichesThe human body is capable of renewing, healing and restoring organs.For example, the human oral-GI tract renews its lining every 3 to 7 days. Both the organ renewal and healing processes are dependent on organ stem cell vascular niches made up of stem cells, endothelial cells (cells that line blood vessels) and supportive cells.When tissues are injured, the vascular niche endothelial cells direct the stem cells, via angiocrine factor expression, to repair and restore the damaged tissue. This restorative capacity is most active during childhood and youth but starts to diminish with increasing age.HDT provided to eradicate cancer cells also cause diffuse, collateral damage to vascular niches of multiple healthy organs. In particular, the organs with the highest cell turnover (ones with most active vascular niches) are severely affected.Specifically, the oral-GI tract, dependent on constant renewal of its mucosal lining, starts to break down upon vascular niche injury.The mucosal breakdown can cause severe nausea, vomiting and diarrhea. In addition, the bacteria in the gut may escape into the circulation, resulting in patients becoming ill with endotoxemia, bacteremia or potentially lethal sepsis.HDT-related vascular niche damage can also occur in other organs resulting in severe or life-threatening complications involving the lung, heart, kidney, or the liver.Collectively, these complications are known as severe regimen-related toxicities or SRRT.SRRT can occur as frequently as 50% in lymphoma HDT-AHCT patients, with increased rate and severity in older patients.

About AB205AB-205 is a first-in-class engineered cell therapy consisting of proprietary 'universal' E-CEL (human engineered cord endothelial) cells.The AB-205 cells are intravenously administered after the completion of HDT on the same day as when the patient's own (autologous) blood stem cells are infused. AB-205 acts promptly to repair injured vascular niches of organs damaged by HDT.By repairing the vascular niches, AB-205 restores the natural process of tissue renewal, vital for organs such as oral-GI tract and the bone marrow. Successful and prompt organ restoration can prevent or reduce SRRT, an outcome that is beneficial to quality of life and cost reductive to the healthcare system.

About CIRMThe California Institute for Regenerative Medicine (CIRM) was established in November, 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The statewide ballot measure provided $3 billion in funding for California universities and research institutions.With over 300 active stem cell programs in their portfolio, CIRM is the world's largest institution dedicated to stem cell research. For more information, visit http://www.cirm.ca.gov.

About Angiocrine Bioscience Inc.Angiocrine Bioscience is a clinical-stage biotechnology company developing a new and unique approach to treating serious medical conditions associated with the loss of the natural healing and regenerative capacity of the body.Based on its novel and proprietary E-CEL platform, Angiocrine is developing multiple therapies to address unmet medical needs in hematologic, musculoskeletal, gastrointestinal, soft-tissue, and degenerative/aging-related diseases.A Phase 3 registration trial is being planned for the intravenous formulation of AB-205 for the prevention of severe complications in lymphoma patients undergoing curative HDT-AHCT.This AB-205 indication is covered by the Orphan Drug Designation recently granted by the US FDA.In addition, Angiocrine is conducting clinical trials of local AB-205 injections for the treatment of: (1) rotator cuff tear in conjunction with arthroscopic repair; and, (2) non-healing perianal fistulas in post-radiation cancer patients.

For additional information, please contact:

Angiocrine Bioscience, Inc.John R. Jaskowiak(877) 784-8496IR@angiocrinebio.com

Originally posted here:
Angiocrine Bioscience Announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation Granted to AB-205 (Universal E-CEL Cell Therapy) to...

First Approval for KEYTRUDA in the Breast Cancer Setting

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 KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (Combined Positive Score [CPS] 10) as determined by an FDA-approved test. The approval is based on results from the Phase 3 KEYNOTE-355 trial, where KEYTRUDA in combination with chemotherapy paclitaxel (pac), paclitaxel protein-bound (commonly known as nab-paclitaxel) or gemcitabine (gem) and carboplatin (carbo) significantly reduced the risk of disease progression or death by 35% for patients whose tumors express PD-L1 (CPS 10) versus the same chemotherapy regimens alone (HR=0.65 [95% CI, 0.49, 0.86]; p=0.0012). Events were observed in 62% (n=136220) of these patients receiving KEYTRUDA in combination with pac, nab-paclitaxel or gemcarbo versus 77% (n=79103) with the same chemotherapy regimens alone. In the trial, 38% of patients had tumors expressing PD-L1 with CPS 10. This indication is approved under accelerated approval based on progression-free survival (PFS); continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Approximately 15-20% of patients with breast cancer are diagnosed with triple-negative breast cancer, which is a difficult-to-treat and aggressive cancer, said Dr. Hope Rugo, director of Breast Oncology and Clinical Trials Education, University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center. Notably, in KEYNOTE-355, KEYTRUDA was combined with three different chemotherapy regimens: paclitaxel, nab-paclitaxel or gemcitabine and carboplatin. The approval of KEYTRUDA in combination with chemotherapy gives physicians an important new option for appropriate patients.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or 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.

Todays approval is a significant milestone, as it represents the first approval for KEYTRUDA in the breast cancer setting, said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. In the study supporting this approval, KEYTRUDA in combination with paclitaxel, nab-paclitaxel or gemcitabine and carboplatin significantly improved progression-free survival for patients with advanced triple-negative breast cancer whose tumors express PD-L1 with CPS greater than or equal to 10 compared with the same chemotherapy regimens alone.

Data Supporting the Approval

The accelerated approval was based on data from KEYNOTE-355 (ClinicalTrials.gov, NCT02819518 ), a multicenter, double-blind, randomized, placebo-controlled trial conducted in 847 patients with locally recurrent unresectable or metastatic TNBC, regardless of tumor PD-L1 expression, who had not been previously treated with chemotherapy in the metastatic setting. Patients were randomized (2:1) to receive either KEYTRUDA (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with the following chemotherapy; all medications were administered via intravenous infusion:

Randomization was stratified by chemotherapy treatment (pac or nab-paclitaxel vs. gem and carbo), tumor PD-L1 expression (CPS 1 vs. CPS

The study population characteristics were: median age of 53 years (range, 22 to 85), 21% age 65 or older; 100% female; 68% White, 21% Asian and 4% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1; and 68% were post-menopausal. Seventy-five percent of patients had tumor PD-L1 expression CPS 1 and 38% had tumor PDL1 expression CPS 10.

In KEYNOTE-355, efficacy results were in patients who were PDL1 positive with a CPS 10 (n=323) and randomized to receive KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo compared with the same chemotherapy regimens alone. KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo (n=220) reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.49, 0.86]; p=0.0012), with a median PFS of 9.7 months (95% CI, 7.6, 11.3) versus 5.6 months (95% CI, 5.3, 7.5) with the same chemotherapy regimens alone (n=103). For PFS, 62% (n=136) of patients experienced an event with KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo versus 77% (n=79) with the same chemotherapy regimens alone. For patients who received KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo, the ORR was 53% (95% CI, 46, 60), with a complete response rate of 17% and a partial response rate of 36%. For patients treated with the same chemotherapy regimens alone, the ORR was 40% (95% CI, 30, 50), with a complete response rate of 13% and a partial response rate of 27%. Median DOR was 19.3 months (95% CI, 9.9, 29.8) with KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo versus 7.3 months (95% CI, 5.3, 15.8) with the same chemotherapy regimens alone.

In the study, the median duration of exposure to KEYTRUDA was 5.7 months (range, 1 day to 33.0 months). Fatal adverse reactions occurred in 2.5% of patients (n=596) receiving KEYTRUDA in combination with chemotherapy, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with pac, nab-paclitaxel, or gem/carbo. Serious adverse reactions observed in 2% of patients were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued for adverse reactions in 11% of patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (1%) were increased alanine aminotransferase (ALT) (2.2%), increased aspartate aminotransferase (AST) (1.5%), and pneumonitis (1.2%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 50% of patients. The most common adverse reactions leading to interruption of KEYTRUDA (2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%), leukopenia (5%), decreased white blood cell count (3.9%), and diarrhea (2%). The most common adverse reactions (all grades 20%) for KEYTRUDA in combination with pac, nab-paclitaxel or gem/carbo were: fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

About Triple-Negative Breast Cancer (TNBC)

Triple-negative breast cancer is an aggressive type of breast cancer that characteristically has a high recurrence rate within the first five years after diagnosis. While some breast cancers may test positive for estrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three. Approximately 15-20% of patients with breast cancer are diagnosed with TNBC.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

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

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,300 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 patients 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.

Small Cell Lung Cancer

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

Head and Neck Squamous Cell Cancer

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

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

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

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

Microsatellite Instability-High 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)

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 first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

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

Esophageal Cancer

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

Cervical Cancer

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

Hepatocellular Carcinoma

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

Merkel Cell Carcinoma

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

Renal Cell Carcinoma

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

Tumor Mutational Burden-High

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) 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.

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, 42% of these patients 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 (

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 (

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, which was 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 (

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 (

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

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

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

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 (

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 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.

Continue reading here:
FDA Approves Merck's KEYTRUDA in Combination With Chemotherapy for Patients With Locally Recurrent Unresectable or Metastatic Triple?Negative Breast...

This article was originally published here

Stem Cells Transl Med. 2020 Nov 14. doi: 10.1002/sctm.20-0385. Online ahead of print.

ABSTRACT

Anti-inflammatory and immune-modulatory therapies have been proposed for the treatment of COVID-19 and its most serious complications. Among others, the use of mesenchymal stromal cells (MSCs) is under investigation given their well-documented anti-inflammatory and immunomodulatory properties. However, some critical issues regarding the possibility that MSCs could be infected by the virus have been raised. Angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2) are the main host cell factors for the Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) entry but so far it is unclear if human MSCs express or do not these two proteins. To elucidate these important aspects, we evaluated if human MSCs from both fetal and adult tissues constitutively express ACE2 and TMPRSS2 and, most importantly, if they can be infected by SARS-CoV-2. We evaluated human MSCs derived from amnios, cord blood, cord tissue, adipose tissue and bone marrow. ACE2 and TMPRSS2 were expressed by the SARS-CoV-2-permissive human pulmonary Calu-3 cell line but not by all the MSCs tested. MSCs were then exposed to SARS-CoV-2 wild strain without evidence of cytopathic effect. Moreover, we also excluded that the MSCs could be infected without showing lytic effects since their conditioned medium after SARS-CoV-2 exposure did not contain viral particles. Our data, demonstrating that MSCs derived from different human tissues are not permissive to SARS-CoV-2 infection, support the safety of MSCs as potential therapy for COVID-19. AlphaMed Press 2020 SIGNIFICANCE STATEMENT: Human mesenchymal stromal cells (hMSCs) are currently under investigation for the treatment of COVID-19. However, the potential safety profile of hMSCs in this context has never been defined since none has described if they express ACE2 and TMPRSS2, the main host cell factors for SARS-CoV-2 entry, and if they can be infected by SARS-CoV-2. We provide the first evidence that ACE2 and TMPRSS2 are not expressed in hMSCs derived from both adult and fetal human tissues and, most importantly, that hMSCs are not permissive to SARS-CoV-2 infection. These results support the safety of MSCs as potential therapy for COVID-19.

PMID:33188579 | DOI:10.1002/sctm.20-0385

Read more:
Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection - DocWire News

The idea of repurposingexisting medicines as a fast approach to containing COVID-19 is still popular, even as vaccines and antibodies designed to combat the disease are starting to gain steam. Scientists at the Cleveland Clinic are among those examining existing compounds as possible treatments for the coronavirus, and now they're suggesting that the popular over-the-counter sleep aid melatonin may be a possible option in treating the disease.

The researchers used an artificial intelligence tool to analyze data from 26,779 individuals in the Cleveland Clinics COVID-19 registry, of whom 8,274 tested positive for SARS-CoV-2, the novel coronavirus that causes COVID-19.

They found that people who were taking melatonin were 28% less likely to test positive for SARS-CoV-2, after adjusting for factors such as age, sex and underlying diseases, according to results published in the journal PLOS Biology.

Start using real-world data to advance your clinical research

Much has been written about the promise of real-world data (RWD) in life sciences, but how does it work in practice? We address this question in a new whitepaper that demonstrates the potential benefits of new RWD technologies with a proof of concept study to show how RWD can be incorporated into clinical research.

The melatonin effect was more pronounced in African Americans, with a reduction of 52%. In White Americans, the number was 23%.

Melatonin is a hormone released by the body that regulates the sleep-wake cycle. As a dietary supplement, its commonly used to help manage insomnia andjet lag.

Besides melatonin, the Cleveland Clinic team also found that the beta-blocker carvedilol, sold under the brand Coreg for high blood pressure and other heart diseases, was associated with a 26% reduction in a persons chance of testing positive for SARS-CoV-2.

RELATED:Melatonin? Stem cells? Researchers step up with unconventional approaches to COVID-19

Some members of the same Cleveland Clinic team previously pinpointed melatonin among a group of drugs they suggested might work for COVID. They showed that melatonin and mercaptopurine might work as a good combo for COVID. Those findings came from a pharmacology-based platform that used a technique called network proximity analysis. It was based on the idea that some proteins involved in other diseases might hold proximity to a virus interaction with the host.

The researchersapplied the same method in the current study to shed a light on clinical manifestations and pathologies common between COVID-19 and 64 other diseases. Closer proximity would mean a higher likelihood of pathological associations between the diseases.

They found that proteins involved in respiratory distress syndrome and sepsis were highly connected with SARS-CoV-2. That wasnt a surprise given that the two disorders can also cause death in patients with severe COVID-19.

This signals to us that a drug already approved to treat these respiratory conditions may have some utility in also treating COVID-19 by acting on those shared biological targets, Feixiong Cheng, Ph.D., the studys senior author, said in a statement.

Overall, they identified close network proximity to SARS-CoV-2 proteins from inflammatory bowel disease, attention deficit hyperactivity disorder, as well as pulmonary diseases such as COPD. Using a computational model, they identified 34 drugs that were significantly proximal to two or more SARS-CoV-2 host protein sets.

RELATED:COVID-19: Bio researchers race to repurpose everything from antiviral to anticancer discoveries

A team at Columbia University has also linked melatonin with increased likelihood of clinical improvement among critically ill COVID-19 patients on intubation or mechanical ventilation.

The sleep-promoting supplement was also reportedly used by President Donald Trump during his COVID-19 infection, though its not clear if he was taking it specifically to treat the disease or as part of his daily nutrition routine.

Despite melatonin emerging as a top pick from the Cleveland Clinic registry, Cheng cautioned that larger, randomized control trials would be needed before the supplement could be widely adopted in the treatment of COVID-19.

Cheng added that AI-based approaches to analyzing COVID-19 patient registries should be embraced in the effort to find effective treatments for the disease.Recent studies suggest that COVID-19 is a systematic disease impacting multiple cell types, tissues and organs, so knowledge of the complex interplays between the virus and other diseases is key to understanding COVID-19-related complications and identifying repurposable drugs, Cheng said. Our study provides a powerful, integrative network medicine strategy to predict disease manifestations associated with COVID-19 and facilitate the search for an effective treatment.

Read more here:
Cleveland Clinic team draws a link between COVID-19 protection and the sleep aid melatonin - FierceBiotech

CLEVELAND University Hospitals announced Thursday its participation in a novel clinical trial testing multiple therapeutics to treat COVID-19 in adults who dont require hospitalization.

University Hospitals said it is adding the ACTIV-2 Trial to its arsenal of investigational treatments. ACTIV-2 is a randomized, blinded, controlled study that tests a variety of new agents against placebo.

This study aims to identify a treatment that can prevent people with COVID-19 from developing advanced disease that requires hospitalization, said Grace McComsey, MD, Vice President of Research and Associate Chief Scientific Officer at UH in a news release. UH is at the forefront of testing experimental treatments for COVID-19, including remdesivir, stem cell therapy and convalescent plasma. Patients suffering from complications of COVID-19 have hope at UH thanks to these options.

This study is one of the few outpatient clinical trials in the Greater Cleveland Area.

There is significant concern nationally as to how hospitals will handle the burden of both influenza and COVID-19 this winter, said Mukesh K. Jain, MD, Chief Academic Officer at UH. Studies focused on helping people recover from COVID-19 at home, without needing hospitalization, are vitally important and we hope our engagement in the ACTIV-2 trial will help us achieve this goal for our community.

The first investigational agent to be evaluated by ACTIV-2 is an experimental monoclonal antibody treatment called LY-CoV555. This antibody was first identified by a blood sample taken from a patient in the U.S. who recovered from COVID-19.

Ones body produces antibodies to fight infections. Monoclonal antibodies are produced in a lab. LY-CoV555 is given as an infusion into a vein in the arm.

To qualify for the study, participants must have tested positive for SARS-CoV-2 infection in the outpatient setting within seven days and started experiencing symptoms within 10 days of enrolling into a study.

For information about enrolling in the trial at University Hospitals:

Call: 1-833-78-TRIALEmail: ClinicalResearch@UHhospitals.orgVisit: uhhospitals.org/researchvolunteer

See complete coverage on our Coronavirus Continuing Coverage page.

Rebound Northeast Ohio News 5's initiative to help people through the financial impact of the coronavirus by offering one place to go for information on everything available to help and how to access it. We're providing resources on:

Getting Back to Work - Learn about the latest job openings, how to file for benefits and succeed in the job market.

Making Ends Meet - Find help on topics from rent to food to new belt-tightening techniques.

Managing the Stress - Feeling isolated or frustrated? Learn ways to connect with people virtually, get counseling or manage your stress.

Doing What's Right - Keep track of the way people are spending your tax dollars and treating your community.

We're Open! Northeast Ohio is place created by News 5 to open us up to new ways of thinking, new ways of gathering and new ways of supporting each other.

Click here for a page with resources including a COVID-19 overview from the CDC, details on cases in Ohio, a timeline of Governor Mike DeWine's orders since the outbreak, coronavirus' impact on Northeast Ohio, and link to more information from the Ohio Department of Health, the Cuyahoga County Board of Health, the CDC and the WHO.

See data visualizations showing the impact of coronavirus in Ohio, including county-by-county maps, charts showing the spread of the disease, and more.

The CDC and the Ohio Department of Health are now recommending the use of cloth face coverings in public to slow the spread of COVID-19.

Read more about the CDC's recommendation here. Here is a step-by-step guide on how to make a face mask from common household materials, without having to know how to sew.

View a global coronavirus tracker with data from Johns Hopkins University.

Originally posted here:
UH announces participation in clinical trial testing antibodies to treat COVID-19 in adults - News 5 Cleveland