May 2020

The Council of Scientific and Industrial Research (CSIR), through its New Millennium Indian Technology Leadership Initiative (NMITLI) program, has approved a project towards development of human monoclonal antibodies (hmAbs) that can neutralize SARS-CoV-2 in patients. This project on generation of neutralizing human monoclonal antibodies as a therapeutic strategy will be implemented by a multi-institutional and multi-disciplinary team.

Monoclonal antibody therapy is a form of immunotherapy designed to produce immunity to a disease or to enhance resistance by the immune system. This new project aims to generate hmAbs to SARS-CoV-2 from gradual recovery phase of COVID-19 patients and select high affinity and neutralizing antibodies. The project also aims to anticipate future adaptation of the virus and generate hmAbs clones that can neutralize the mutated virus so that could be readily used for combating future SARS-CoV infections.

This new project aims to generate hmAbs to SARS-CoV-2 from gradual recovery phase of COVID-19 patients and select high affinity and neutralizing antibodies.

This industry-academia collaboration comprises National Centre for Cell Science (NCCS) Pune; Indian Institute of Technology (IIT), Indore; PredOmix Technologies Ltd, Gurugram; and Bharat Biotech International Ltd (BBIL), Hyderabad. Vaccines and biotherapeutics maker BBIL is leading the project to develop human monoclonal antibodies (hmAbs) for COVID-19 infection. BBIL will be the commercial partner and responsible for subsequent development and commercialization of the hmAbs generated.

DG-CSIR, Dr Shekhar C Mande commented that “As the research into SARS-CoV-2 is in early days and our understanding is evolving each day, it is critical that we deploy all possible strategies to combat the virus. Hence, CSIR is exploring all avenues and we are supporting new ideas which have clear deployment strategy”.

CSIR is leading the fight against COVID-19 using multi-pronged approach and multiple models of engagement. CSIR labs themselves are developing technologies and products and are working with industry and public sector undertakings for deployment. NMITLI is a flagship program of CSIR aimed to support new ideas and projects from academic institutions and industries.

- India Science Wire

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Cipla Limited announced that it has signed a non-exclusive licensing agreement with Gilead Sciences, Inc. for the manufacturing and distribution of the investigational medicine Remdesivir, which has been issued an Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA) to treat COVID-19 patients. This agreement is part of Cipla’s efforts to enhance global access to life-saving treatments for patients affected by the pandemic.

As part of the agreement, Cipla will be permitted to manufacture the API and Finished product, and market it in 127 countries including India and South Africa under Cipla’s own brand name. Cipla will receive the manufacturing know-how from Gilead Sciences, Inc. to manufacture the API and Finished product at a commercial scale. Cipla’s extensive geographical and commercial footprint will help make this therapy accessible to more patients and markets.

According to the World Health Organisation (WHO)’s tracker, the number of reported COVID-19 cases has crossed the four million mark globally.

The EUA will facilitate broader use of Remdesivir to treat hospitalized patients with severe symptoms of COVID-19. The EUA is based on available data from two global clinical trials – US National Institute for Allergy and Infectious Diseases’ placebo-controlled Phase 3 study in patients with moderate to severe symptoms of COVID-19, and Gilead’s global Phase 3 study evaluating Remdesivir in patients with severe disease. Multiple additional clinical trials are ongoing to generate more data on the safety and efficacy of Remdesivir as a potential treatment for COVID-19. Remdesivir continues to be an investigational drug that has not been approved by the FDA.

Commenting on the partnership, Mr. Umang Vohra (MD and Global CEO, Cipla Limited) said, “As the world is faced with the COVID-19 crisis, it is imperative that we collaborate and fight this virus together. We are pleased to partner with Gilead for this cause and take this treatment to patients across countries after the required regulatory approvals. At Cipla, it is our continuous endeavour to ensure that no patient is denied access to life-saving treatments. Our partnership with Gilead represents this unwavering commitment and is a significant step towards saving millions of lives impacted by the pandemic.”

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COVID-19, the disease caused by coronavirus SARS-Cov-2, has infected over 4 million people in 212 countries, of whom at least 272,000 have died. The ongoing economic and social impact of the pandemic is staggering, but despite a daily flood of news on the disease, few laypeople know that paradoxically, COVID-19 mostly kills through an overreaction of the immune system, whose function is precisely to fight infections.

In a new review article - explicitly targeted to non-specialists as well - in Frontiers in Public Health, a team of experts from Zunyi Medical University review the epidemiology, disease pathway, symptoms, diagnosis, and current treatment of severe COVID-19. They stress the key role of a potentially lethal overreaction of the immune system in the progression of the disease.

They explain step-by-step what is known about how the virus infects the airways, multiplies inside cells, and in severe cases causes the immune defenses to overshoot with a "cytokine storm". This storm is an over-activation of white blood cells, which release too-great amounts of cytokines - inflammation-stimulating molecules - into the blood.

"Similar to what happens after infection with SARS and MERS, data show that patients with severe COVID-19 may have a cytokine storm syndrome. The rapidly increased cytokines attract an excess of immune cells such as lymphocytes and neutrophils, resulting in an infiltration of these cells into lung tissue and thus cause lung injury," explains author Professor Daishun Liu from Zunyi Medical University, China.

The cytokine storm ultimately causes high fever, excessive leakiness of blood vessels, blood clotting inside the body, extremely low blood pressure, lack of oxygen and excess acidity of the blood, and build-up of fluids in the lungs ("pleural effusion").

White blood cells are misdirected to attack and inflame even healthy tissue, leading to failure of the lungs, heart, liver, intestines, kidneys, and genitals (Multiple Organ Dysfunction Syndrome, MODS). This may worsen and shutdown the lungs (Acute Respiratory Distress Syndrome, ARDS) due to the formation of a so-called hyaline membrane, composed of debris of proteins and dead cells, lining the lungs, which makes absorption of oxygen difficult. Most deaths due to COVID-19 are therefore due to respiratory failure.

Liu et al. explain how in the absence of a specific antiviral cure for COVID-19, the goal of treatment must be to the fight the symptoms, lowering the mortality rate through intensive maintenance of organ function, for example an artificial liver blood purification system or renal replacement therapy to filtrate the blood through mechanical means.

Especially important are methods to supplement or replace lung function, for example through non-invasive mechanical ventilation through a mask, ventilation through a tube into the windpipe (if possible with the refinement of Positive End Expiratory Pressure, PEEP, where the ventilator delivers extra pressure at the end of each breath of keep the lung vesicles open throughout), the administration of heated and humidified oxygen via a tube in the nose ("transnasal high-flow oxygen"), or a heart-lung bypass.

The authors conclude by stressing the importance of preventing secondary infections: SARS-Cov-2 also invades the intestines, where it causes inflammation and leakiness of the gut lining, allowing the opportunistic entry of other disease-causing microorganisms. They advocate that this should be prevented with nutritional support, for example with probiotics - beneficial bacteria that protect against the establishment of harmful ones - and nutrients and amino acids to improve the immune defenses and function of the intestine.

"Because treatment for now relies on aggressive treatment of symptoms, preventative protection against secondary infections, such as bacteria and fungi, is particularly important to support organ function, especially in the heart, kidneys, and liver, to try and avoid further deterioration of their condition," concludes Liu.

Reference : https://www.frontiersin.org/articles/10.3389/fpubh.2020.00189/full

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For the first time, using a mouse model of Alzheimer's disease, scientists have documented a link between raised levels of calcium in mitochondria and neuronal death in the living brain. This relationship was previously documented in cell culture, but seeing this phenomenon in living mice makes it more likely that this occurs in people also and could point to a new target for Alzheimer's disease.

"We were able to show mitochondrial calcium dysregulation in the neurons of living mice with Alzheimer's-like symptoms using cutting edge live imaging techniques," says the lead author of the paper, Maria Calvo-Rodriguez, PhD. The senior author is Brian J. Bacskai, PhD. They are both from the Department of Neurology at Massachusetts General Hospital.

Their collaborators included researchers from Harvard School of Public Health and the School of Medicine at Instituto de Investigacion Biomedica de Cadiz (INIBICA) in Spain. This study was recently published in Nature Communications.

One of the defining hallmarks of Alzheimer's disease is the deposition of amyloid beta plaques and loss of neurons. The accumulation of amyloid beta has long been thought to be a trigger of the disease, but the exact means by which neurons die in Alzheimer's remain a mystery, and the amyloid beta theory has become controversial because so many drug candidates targeting amyloid beta have failed in clinical trials.

One of the effects of amyloid beta plaques is that they cause high calcium ion (Ca2+) levels in the brain cells. There is also evidence that, at least in cell culture, exposure to amyloid beta can raise Ca2+ levels within mitochondria and lead to neuronal death.

Mitochondria influence Ca2+ signaling inside neurons through the "mitochondrial calcium uniporter" that takes up Ca2+ into mitochondria. The investigation of this mechanism in living mice has been hampered by the lack of technologies sensitive enough to directly assess Ca2+ levels in mitochondria in the living brain.

To explore the relationship between Ca2+, mitochondria and neuronal death, Calvo-Rodriguez and her colleagues combined multiphoton-microscopy with a ratiometric Ca2+ indicator targeted to mitochondria to asses Ca2+ levels. They applied these technologies to examine the neurons of a transgenic mouse model of Alzheimer's disease that develops amyloid plaques similar to those from human patients.

Their studies demonstrate that increased mitochondrial Ca2+ levels are associated with plaque deposition and neuronal death in this model, indicating that abnormal Ca2+ levels in mitochondria could play a role in neuronal cell death in Alzheimer's disease.

Additionally, they observed that when soluble Aβ is applied to the healthy mouse brain Ca2+ concentration in mitochondria increases. That process can be prevented by blockage of the mitochondrial calcium uniporter with a drug. Soluble amyloid beta is a type of amyloid beta similar to that in the human Alzheimer's brain.

"High calcium levels in the mitochondria cause oxidative stress, and the death of neurons via apoptosis," says Calvo-Rodriguez. "We propose that by blocking the neuronal mitochondrial calcium uniporter we can prevent cell death and impact disease progression." Their work suggests targeting calcium entry to the mitochondria could be a promising new therapeutic approach in Alzheimer's disease.

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“The Union Minister of Science and Technology, Earth Sciences, and Health and Family Welfare, Dr. Harsh Vardhan said today that India’s fight against the COVID-19 is moving fast ahead strongly and steadily. He was addressing a digital conference, RE-START – ‘Reboot the Economy through Science, Technology and Research Translations’, organized to celebrate the National Technology Day. The Conference was organized by the Technology Development Board (TDB), a statutory body of the Department of Science and Technology (DST) and the Confederation of Indian Industry (CII).

While applauding the Ministry of Science and Technology’s response to epidemics like COVID in the country, Dr. Harsh Vardhan emphasized that the S&T response reflects the collaborative spirit of the entire S&T ecosystem. “Indian government, academia, scientists, start-ups, entrepreneurs and industry have been working relentlessly to find solutions to combat this pandemic. We must appreciate the efforts of our scientists, our entrepreneurs and our institutions working to find quick and deployable solutions for COVID-19. New discoveries, industry partnerships, and enhanced research initiatives have thus been rapidly developed and adopted”, said the minister.

“Within a short period of time, the nation has been able to mobilize a number of researchers to develop new testing kits, protective equipment, respiratory devices, etc.”, he added.

The minister also apprised the audience about the ‘COVID-19 Task Force’ set up by the Government to map COVID-19-related technology capabilities. “Our Government has vigorously supported the ‘Make in India’ Programme. This has brought in scientific institutions and start-ups to develop the COVID-19 tests, masks, sanitizers, personal protective equipment (PPEs) and ventilators,” he further added.

On the theme for the National Technology Day this year, Dr. Harsh Vardhan pointed out, “We need to mitigate the widespread economic impact and prepare for a stronger recovery using self-reliance as the new mantra. Thus, we look towards new opportunities to galvanize growth in the technological and industrial sector.”

While delivering his special address, Dr. VK Saraswat, Member, NITI Aayog, pointed out the importance of new-age technologies, medical and manufacturing technologies, etc. in boosting the economy as the world adjusts to the new normal.

“ Our Government has vigorously supported the ‘Make in India’ Programme. This has brought in scientific institutions and start-ups to develop the COVID-19 tests, masks, sanitizers, personal protective equipment (PPEs) and ventilators”

Principal Scientific Advisor to the Government of India, Professor K. Vijay Raghavan, pointed out how technology can change the way we live our lives and the way we do things in future, particularly so in the post-COVID era. He pointed out that this is an opportunity to gear up for the future that lies ahead, and a better-equipped R&D workforce and ecosystem will prepare India better for future challenges.

DST has stepped into its 50th year of existence. DST Secretary Professor Ashutosh Sharma, thus, underlined the significance of the National Technology Day in view of the challenges faced during these times of COVID-19. He further emphasized that the COVID-19 crisis had led R&D and technology development to work in various modes. The private-public model has encouraged R&D to greater heights. Plausible translations, prototyping, start-ups, and industry have seen immense growth.

“Rebooting the economy requires new-age technologies, appropriate national missions, programmes and schemes to get into quick action. He added that wherever readymade solutions are not available, research and development needs to be more profound, relevant, speedy, impactful and strongly connected to industry. The lessons learnt now would continue to assist us in addressing the overarching challenges of the future—sustainable development, climate change, industry 4.0, anti-microbial resistance, etc., said Professor Sharma.

Dr. Saumya Swaminathan, Chief Scientist, World Health Organization, highlighted the steps taken internationally to combat the pandemic and the way forward. Dr. Swaminathan appreciated the way India has tackled the COVID-19 challenge. Mr. Chandrajit Banerjee, DG, CII; Mr. Vikram Kirloskar, President, CII, and Dr Neeraj Sharma, Secretary, TDB, were among those who participated in the inaugural session.

During this occasion, Dr. Harsh Vardhan also inaugurated a virtual exposition of companies whose technologies have been supported by TDB. Various organizations and companies showcased their products in the exposition through a digital B2B lounge.

The conference has hence brought together scientists, technocrats, government officials, diplomats, WHO officials, and dignitaries from national and international industry, research institutions and academic institutions on a single platform to share their insights on the role played by S&T to combat this global healthcare crisis and to find solutions for the same.

The conference will have technical sessions on ‘Medicines & Medical Technologies’; ‘Advanced Materials – New Technology Horizons’, ‘Advanced Manufacturing Technologies for Sustainable Future & Global Innovation’ and ‘Technology Alliance for Global Economic Leadership’.

- India Science Wire

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U.S. Food and Drug Administration authorized the first diagnostic test with the option of using home-collected saliva samples for COVID-19 testing. Specifically, the FDA issued an emergency use authorization (EUA) to Rutgers Clinical Genomics Laboratory for their COVID-19 laboratory developed test (LDT), which had been previously added to the high complexity molecular-based LDT “umbrella” EUA, to permit testing of samples self-collected by patients at home using the Spectrum Solutions LLC SDNA-1000 Saliva Collection Device. This announcement builds on last month’s EUA for the first diagnostic test with a home-collection option, which uses a sample collected from the patient’s nose with a nasal swab and saline.

EUA for Rutgers Clinical Genomics Laboratory’s molecular test permits testing of a saliva sample collected from the patient using a designated self-collection kit. Once patients collect their saliva sample, they return it to the Rutgers Clinical Genomics Laboratory in a sealed package for testing.

The Rutgers Clinical Genomics Laboratory test is currently the only authorized COVID-19 diagnostic test that uses saliva samples to test for SARS-CoV-2, the strain of coronavirus that causes COVID-19. The test remains prescription only.

This authorization is limited to testing performed at the Rutgers Clinical Genomics Laboratory using their molecular LDT COVID-19 authorized test for saliva specimens collected using the Spectrum Solutions LLC SDNA-1000 Saliva Collection Device. It is important to note that this is not a general authorization for at-home collection of patient samples using other collection methods, saliva collection devices, or tests, or for tests fully conducted at home.

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U.S. Food and Drug Administration approved Retevmo (selpercatinib) capsules to treat three types of tumors – non-small cell lung cancer, medullary thyroid cancer and other types of thyroid cancers – in patients whose tumors have an alteration (mutation or fusion) in a specific gene (RET or “rearranged during transfection”). Retevmo is the first therapy approved specifically for cancer patients with the RET gene alterations.

Specifically, the cancers that Retevmo is approved to treat include
• Non-small cell lung cancer (NSCLC) that has spread in adults,
• Advanced medullary thyroid cancer (MTC) or MTC that has spread, in patients 12 and older who require systemic therapy (a treatment option that spreads across the entire body, is not targeted), and
• Advanced RET fusion-positive thyroid cancer in those age 12 and older that requires systemic therapy that has stopped responding to radioactive iodine therapy or is not appropriate for radioactive iodine therapy.

Retevmo is a kinase inhibitor, meaning it blocks a type of enzyme (kinase) and helps prevent the cancer cells from growing. Before beginning treatment, the identification of a RET gene alteration must be determined using laboratory testing.

The FDA approved Retevmo on the results of a clinical trial involving patients with each of the three types of tumors. During the clinical trial, patients received 160 mg Retevmo orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR), which reflects the percentage of patients that had a certain amount of tumor shrinkage, and duration of response (DOR). Efficacy for NSCLC was evaluated in 105 adult patients with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy. The ORR for the 105 patients was 64%. For 81% of patients who had a response to the treatment, their response lasted at least six months.

Efficacy was also evaluated in 39 patients with RET fusion-positive NSCLC who had never undergone treatment. The ORR for these patients was 84%. For 58% of patients who had a response to the treatment, their response lasted at least six months.

Efficacy for MTC in adults and pediatric patients was evaluated in those 12 years of age and older with RET-mutant MTC. The study enrolled 143 patients with advanced or metastatic RET- mutant MTC who had been previously treated with cabozantinib, vandetanib or both (types of chemotherapy), and patients with advanced or metastatic RET-mutant MTC who had not received prior treatment with cabozantinib or vandetanib. The ORR for the 55 previously treated patients was 69%. For 76% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in 88 patients who had not been previously treated with an approved therapy for MTC. The ORR for these patients was 73%. For 61% of patients who had a response to the treatment, their response lasted at least six months.

Efficacy for RET fusion-positive thyroid cancer was evaluated in adults and pediatric patients 12 years of age and older. The study enrolled 19 patients with RET fusion-positive thyroid cancer who were radioactive iodine-refractory (RAI, if an appropriate treatment option) and had received another prior systemic treatment, and eight patients with RET fusion-positive thyroid cancer who were RAI-refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79%. For 87% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in eight patients who had not received therapy other than RAI. The ORR for these patients was 100%. For 75% of patients who had a response to the treatment, their response lasted at least six months.

The FDA granted approval of Retevmo to Loxo Oncology, Inc., a subsidiary of Eli Lilly and Company.

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U.S. Food and Drug Administration is providing an update on the agency’s efforts to combat the extremely concerning actions by companies and individuals that are exploiting or taking advantage of widespread fear among consumers during the COVID-19 pandemic. In response to scammers on the internet selling unproven medical products, the FDA has taken – and continues to take – a number of steps to find and stop those selling unapproved products that fraudulently claim to mitigate, prevent, treat, diagnose or cure COVID-19.

To date, the FDA has issued 42 warning letters to companies making bogus COVID-19 claims, including one to a seller of fraudulent chlorine dioxide products, equivalent to industrial bleach, frequently referred to as “Miracle Mineral Solution” or “MMS”, as a treatment for COVID-19. After the seller refused to take corrective action, a federal court issued a preliminary injunction requiring the seller to immediately stop distributing its unproven and potentially dangerous product.

Additionally, as part of the FDA’s Operation Quack Hack, in just a few short weeks, the agency has discovered hundreds of such products including fraudulent drugs, testing kits and personal protective equipment (PPE) sold online with unproven claims. We continue to work with online marketplaces, domain name registrars, payment processors and social media websites to remove from their platforms products that fraudulently claim to mitigate, prevent, treat, diagnose or cure COVID-19 and to keep those products from reappearing under different names. At this time, the FDA has sent hundreds of abuse complaints to domain name registrars and internet marketplaces, who in most instances, have voluntarily removed the identified postings. We will continue to monitor the online ecosystem for fraudulent products peddled by bad actors seeking to profit from this global pandemic.

There are a number of examples of unproven products that the FDA is keeping out of the country. Recently, the agency intercepted and investigated a case of mislabeled COVID-19 “treatment kits” offered for import. As a result, Special Agents with the FDA’s Office of Criminal Investigations, with the help of domestic and international law enforcement counterparts in the United Kingdom, led the Department of Justice to bring a criminal complaint against a British man who sought to profit from this pandemic and jeopardize public health.

Until the curve is flattened, and even after, the FDA will continue to carry out the agency’s mission of protecting the health and safety of American consumers and strive to prevent unlawful FDA-regulated products from entering, or being distributed in, domestic commerce.

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U.S. Food and Drug Administration approved Tabrecta (capmatinib) for the treatment of adult patients with non-small cell lung cancer (NSCLC) that has spread to other parts of the body. Tabrecta is the first FDA-approved therapy to treat NSCLC with specific mutations (those that lead to mesenchymal-epithelial transition or MET exon 14 skipping).

The FDA also approved the FoundationOne CDx assay (F1CDx) as a companion diagnostic for Tabrecta today. Most patients had tumor samples that were tested for mutations that lead to MET exon 14 skipping using local tests and confirmed with the F1CDx, which is a next-generation sequencing based in vitro diagnostic device that is capable of detecting several mutations, including mutations that lead to MET exon 14 skipping.

NSCLC is a disease in which malignant cancer cells form in the tissues of the lung. It is the most common type of lung cancer with up to 90% of all lung carcinomas falling into the non-small cell category. NSCLC occurs when healthy cells become abnormal and grow rapidly. One danger of this form of cancer is that there’s a high likelihood that the cancer cells will spread from the lungs to other organs and body parts. Cancer metastasis consists of a sequential series of events, and MET exon 14 skipping is recognized as a critical event for metastasis of carcinomas. Mutations leading to MET exon 14 skipping are found in 3-4% of patients with lung cancer.

Tabrecta is a kinase inhibitor, meaning it functions by blocking a key enzyme that results in helping to stop the tumor cells from growing. The FDA approved Tabrecta based on the results of a clinical trial involving patients with NSCLC with mutations that lead to MET exon 14 skipping, epidermal growth factor receptor (EGFR) wild-type and anaplastic lymphoma kinase (ALK) negative status, and at least one measurable lesion.

Tabrecta may cause harm to a developing fetus or newborn baby. Health care professionals should advise pregnant women of this risk and should advise both females of reproductive potential and male patients with female partners of reproductive potential to use effective contraception during treatment with Tabrecta and for one week after the last dose.

The FDA granted approval of Tabrecta to Novartis Pharmaceuticals Corporation. The approval of the F1CDx companion diagnostic was granted to Foundation Medicine, Inc.

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