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| 20988 | Antiviral Program for Pandemics | .text-box { background-color: #E3EBED; padding: 20px; } .text-box a { font-weight: normal; } .text-box .action { font-weight: bold; color: #30787D; font-size: 15px; text-decoration-color:#30787D; } NCATS will play a pivotal role in the Antiviral Program for Pandemics (APP), a multi-agency initiative to develop safe and effective oral antivirals. The initial priority for the APP is to develop treatments for SARS-CoV-2 and other coronaviruses, with the program expanding to address other virus families with pandemic potential.Launched in June 2021 with more than $3 billion in funding from the American Rescue Plan, the APP will accelerate the development of a portfolio of promising antivirals that can quickly pivot to combat future pandemics. Having safe and effective oral antiviral candidates ready for deployment in later-stage clinical trials against a newly emergent virus would save lives, reduce serious illness and prevent overwhelming surges in hospitalizations during a viral outbreak or pandemic.Accelerating Antiviral DevelopmentAs part of the APP, NCATS will be a key partner alongside the National Institute of Allergy and Infectious Diseases (NIAID) and the Biomedical Advanced Research and Development Authority (BARDA) to accelerate antiviral development through early discovery and preclinical development. NCATS also will coordinate with partners to take candidates into clinical development.NCATS will apply its proficiency in drug discovery and development and its cutting-edge technologies to fill critical needs of the APP, such as target validation; high-throughput screening (HTS) for drug starting points; medicinal chemistry for lead optimization; and preclinical, investigational new drug (IND)-enabling development.Specific NCATS activities will include:novel assay development for viral targets, including Biosafety Level 2 and Biosafety Level 3 assayscompound testing to characterize activity across virus familiesHTS of diverse collections of chemical compounds to identify drug development starting pointshit-to-lead optimization of promising compounds, from preliminary structure-activity relationship exploration to full-scale medicinal chemistry studiesrigorous evaluation of drug metabolism and pharmacokinetic (DMPK) properties, exploratory toxicology to demonstrate initial safety, and validation of efficacy in relevant in vivo systemspreparation of comprehensive data packages for inclusion in IND applications to the U.S. Food and Drug AdministrationIn addition to SARS-CoV-2, NCATS’ activities will address other viruses within the scope of the APP that represent known threats because of their pandemic potential. The table below shows virus families/orders and examples of viruses that the APP may target.Viral Family/OrderExample Viruses CoronaviridaeSARS-CoV, MERS-CoV, SARS-CoV-2BunyaviralesRift Valley fever, Hantavirus, Crimean-Congo hemorrhagic feverFiloviridaeEbola, MarburgFlaviviridaeYellow fever, Dengue, ZikaParamyxoviridaeHendra, NipahPicornaviridaeEnterovirus D68TogaviridaeChikungunyaOpportunities for Collaboration with NCATSNCATS will partner with extramural scientists and the private sector to advance drug discovery and development programs for oral antiviral candidates. NCATS can collaborate on projects with entry points anywhere along the development pipeline — and with flexible project exit points — to accelerate discovery and overcome the scientific, technical and enterprise barriers to delivering drug candidates ready for Phase 2 clinical trials in future pandemics.To learn more about partnering with NCATS and the Center’s role in the APP, please contact app@ncats.nih.gov.APP News and Resources:APP Form for Developers to Submit Compound CandidatesBiden Administration to Invest $3 Billion from American Rescue Plan as Part of COVID-19 Antiviral Development StrategyNIAID: Antiviral Program for PandemicsReport of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics SummitRead a Director’s Message about NCATS' role in the Antiviral Program for PandemicsNCATS COVID-19 Resources:COVID-19 OpenData PortalA Translational Approach to Addressing COVID‑19National COVID Cohort Collaborative (N3C) | As part of the Antiviral Program for Pandemics, NCATS will accelerate antiviral development through early discovery and preclinical development. | /sites/default/files/Antivirals_900x600.jpg | Antiviral Program for Pandemics | As part of the Antiviral Program for Pandemics, NCATS will accelerate antiviral development through early discovery and preclinical development. | /sites/default/files/Antivirals_900x600_0.jpg | Antiviral Program for Pandemics | ||
| 20943 | Using Abstract Math to Solve Real-World Crises | @media (min-width: 576px) { img.profile-img { float: right; padding: 3px; } } Roland A. Matsouaka, Ph.D. Assistant Professor, Department of Biostatistics and Bioinformatics & Duke Clinical Research Institute, Duke University School of Medicine sites.duke.edu/matsouaka/ scholars.duke.edu/person/roland.matsouaka Personal Testimonial When I was growing up in the Republic of the Congo, HIV/AIDS was ravaging the African continent. During middle and high school, public health educators visited our schools frequently to talk about the virus, what it is, how to protect yourself and what the myths were around it. In my country we chose our academic majors while still in high school, and I chose mathematics. I remember a presentation when someone said, “We need all hands on deck to solve this problem of HIV/AIDS. Not just scientists and doctors, but mathematicians, physicists, people from every field.” That was the first time I realized that I might be able to use the abstract math I had been learning to solve a real-world health crisis. It was not until I came to the United States after college that I learned about biostatistics. Back home, statistics was mainly applied to fields like economics, so it was a revelation to find that it was being used to understand and solve health issues. I earned my Master’s and doctoral degrees in biostatistics from Harvard University, where I studied with Professor Rebecca Betensky (now Chair of the Department of Biostatistics at New York University) and Professor Tianxi Cai. Then, I did a 2-year postdoctoral fellowship on causal inference under the tutelage of Professor Eric Tchetgen Tchetgen (now at The Wharton School of the University of Pennsylvania). Early in my Master’s program, I took many courses on HIV/AIDS, but gradually my research interests shifted toward cardiovascular disease. I have been fortunate to have excellent mentors guiding me, because good mentors make sure your science is great. Professor Betensky treated students like her colleagues, bringing us along to meetings with senior researchers and asking us for our ideas. Sometimes I found myself thinking, “I’m only a student — please tell me what to do!” Now I see that she was preparing me for the environment I would be in after I graduated as a biostatistician immersed in the field of medicine. In my current roles at Duke University, I continue to have wonderful mentors both in the Department of Biostatistics and Bioinformatics and the Duke Clinical Research Institute. Those experiences helped me develop what I consider the most important skill for a translational scientist: to be able to work in a collaborative environment with people from other fields. As a biostatistician, having this skill is not a choice. You have to work with doctors and scientists to solve problems. You must communicate across disciplinary boundaries, earn trust and learn to speak your colleagues’ specialized language. Over time, you discover what is important to your collaborators and understand why they work a certain way. For example, the cardiologists I work with not only have training in medicine but are informed by constant interaction with patients. Their perspective reminds me that my job is not just to write complicated equations — I also need to translate those equations into a common language that people can understand. The support I have received from the Clinical and Translational Science Awards (CTSA) Program has enabled me to continue this translation process and take time to study cardiovascular disease in a different way. Together with my colleagues, I have developed a hierarchal approach to study the multiple outcomes we encounter in cardiovascular disease research. This approach allows us to no longer treat all outcomes or events with the same weight, whether it is hospitalization, stroke, myocardial infarction or death. Instead, we can assess outcomes along a continuum and get a more accurate picture of treatment effectiveness at different stages of care. With CTSA Program support, I have been able to present my work at conferences, meet with people from industry, confer with other biostatisticians using similar methods, and have three papers accepted for publication. It has been very helpful for me personally, and my colleagues and I have been able to contribute a new perspective to the cardiovascular literature. Current Research My methodological research focuses on nonparametric, semiparametric and causal inference methods for comparative effectiveness studies, clinical trials affected by noncompliance, not-so-perfect experiments and observational studies. My goal is to develop statistical methods that make the best use of the data collected to answer scientific questions while applying principled methods to minimize bias and ensure fair assessments. The substantive areas of application of my research include public health and biomedical and social sciences. I collaborate with clinical researchers to better understand and treat cardiovascular diseases. I am actively involved in the analyses of large registry data. I am also a member of the Duke Center for Research to Advance Healthcare Equity (REACH) Equity Measures, Methods, and Analysis Subcore. The overarching goal of the Center is to develop and test interventions that reduce racial and ethnic disparities in health by improving the quality of patient-centered care in the clinical encounter across settings, diagnoses, and stages of illness and throughout the life course. I help to ensure the conduct of rigorous, reproducible, synergistic research related to the Center’s theme and advise clinical investigators on and provide analytic and data management support for research projects conducted by the Center. | CTSA Program Diversity and Re-Entry Supplement Awardee Roland Matsouaka, Ph.D., Assistant Professor, Department of Biostatistics and Bioinformatics & Duke Clinical Research Institute, Duke University | /sites/default/files/Roland_Matsouaka_500x500_0.jpg | Using Abstract Math to Solve Real-World Crises | CTSA Program Diversity and Re-Entry Supplement Awardee Roland Matsouaka, Ph.D., Assistant Professor, Department of Biostatistics and Bioinformatics & Duke Clinical Research Institute, Duke University | /sites/default/files/Roland_Matsouaka_500x500_1.jpg | Using Abstract Math to Solve Real-World Crise | ||
| 20898 | Platform Vector Gene Therapy (PaVe-GT) Pilot Project | section { width: 100%; clear: both; } .row.video { background-color: #30787D; margin: 20px 0; } .video-right{ padding: 4% 3%; } .video-left{ padding:0; } .video-copy p{ color:#fff; font-size:16px; font-weight:400; line-height:1.4; } .video-copy p em{ font-size: 90%; } .embed-responsive { border-top: 1px solid black; } This NIH initiative led by NCATS aims to make gene therapy development and clinical testing more streamlined, more efficient, and potentially more accessible to many people with rare diseases. New technologies — including the use of viruses to deliver genes to cells that need properly functioning genes — are making gene therapy an increasingly attractive treatment option for individuals with rare genetic diseases. Yet, thousands of these disorders are so rare that companies might be reluctant or unable to invest the years of research and the millions of dollars needed to develop, test and bring a gene therapy for a very rare disease to market. To address the unmet need for more efficient gene therapy clinical development, NCATS, along with NIH’s National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, and Eunice Kennedy Shriver National Institute of Child Health and Human Development, launched the Platform Vector Gene Therapy (PaVe-GT) pilot project in February 2019. The goal of this project is to test the impact of using the same gene delivery system and manufacturing methods in multiple rare disease gene therapy clinical trials. Watch this video to meet the investigators behind PaVe-GT. The video aired during Rare Disease Day at NIH, which was held virtually on March 1, 2021. A version of this video with audio description is available. More specifically, PaVe-GT researchers will use a common gene delivery vehicle, adeno-associated virus (AAV), to create gene therapies for four rare genetic diseases. Each disease currently is being studied at the NIH Clinical Center. They include two inherited muscle weakness/neuromuscular junction disorders (Dok7 deficiency and Collagen Q deficiency) and two inherited metabolic diseases (propionic acidemia and isolated methylmalonic acidemia). Researchers plan to use the same manufacturing process and AAV delivery system to carry a therapeutic gene to the right place in the body for all four diseases, but simply switch the cargo — the gene — for each disease. In this many-diseases-at-a-time approach, the PaVe-GT team is working to improve the efficiency of the clinical trial startup process for gene therapy and develop a standardized “blueprint” for similar gene therapy projects focused on rare diseases. To enable others to benefit and learn from the scientific and procedural path taken in PaVe-GT, the PaVe-GT team will make preclinical toxicology and biodistribution data, Investigational New Drug filings, communications with the U.S. Food and Drug Administration (FDA), and other study documents normally considered proprietary by companies available to the public on the PaVe-GT website. Read the original press release on PaVe-GT: Collaborative NIH Effort Aimed at Creating a Gene Therapy Playbook, Making Rare Disease Treatments More Accessible. To hear more about PaVe-GT, watch former NCATS' Office of Rare Diseases Research Director Anne Pariser's I Am Translational Science video. Hear from PaVe-GT scientists about their successful applications for an Orphan Drug Designation and a Rare Pediatric Disease designation from FDA. For more information, please contact P.J. Brooks, Ph.D. | The NCATS-led Platform Vector Gene Therapy (PaVe-GT) pilot project will test the use of the same gene therapy delivery system for rare disease treatments. | /sites/default/files/Double-helix-illustration-Leja_NoMark_900x600.jpg | Gene Therapy Blueprint for Rare Disease Treatments: PaVe-GT | The NCATS-led Platform Vector Gene Therapy (PaVe-GT) pilot project will test the use of the same gene therapy delivery system for rare disease treatments. | /sites/default/files/Double-helix-illustration-Leja_NoMark_900x600_0.jpg | Gene Therapy Blueprint for Rare Disease Treatments: PaVe-GT | ||
| 21000 | Infographics | .shadow { width: 90%; filter: drop-shadow(-5px 5px 10px #0e0e0e); } /* .grid-col-11 a { text-decoration: none; color: #006478; font-size: 18px; font-weight: normal; } */ .grid-row { padding: .9em; margin: 5px 0; } .grid-row:nth-child(odd) { background-color: #f7f7f7; } .grid-row:nth-child(even) { background-color: #e7e7e7; } .grid-row:nth-child(1) { background-color: #662e6b; color: #fff; margin-top: 0; padding: 0; } .h2 .table-header { margin-top: 10px; font-size: 22px; } View, download and share infographics developed by NCATS about translational science and some of the Center’s programs and focus areas.About Translational ScienceSeven Characteristics of a Translational ScientistTranslational Sciences: More Treatments, More QuicklyTranslational Science SpectrumAbout NCATS Programs and Focus AreasA Specialized Platform for Innovative Research Exploration (ASPIRE)Biomedical Data TranslatorCTSA Program Rural Health EffortsTissue Chip for Drug ScreeningNCATS National Pharmaceutical CollectionRare Diseases: Individually Rare, Collectively CommonCopyright and Reuse of GraphicsThe NCATS website uses a mix of copyrighted and copyright-free graphics (including illustrations and photos). If you want to reuse a graphic, please follow these guidelines:Copyrighted graphics will usually be credited to individuals or organizations. Permission to reuse these must be negotiated directly with the creators, and not NCATS.Graphics explicitly credited to NCATS are copyright-free and may be used without our permission. Please credit the National Center for Advancing Translational Sciences as the source.If you are not sure who created a graphic or have other questions about reusing a graphic on the NCATS website, email NCATS at info@ncats.nih.gov. Please include the URL and file name in your email. | View, download and share infographics developed by NCATS about translational science and some of NCATS’ programs and focus areas. | /sites/default/files/TranslationalScienceSpectrumGraphicInteractive_600x600_0.png | Explore the NCATS infographic gallery | View, download and share infographics developed by NCATS about translational science and some of NCATS’ programs and focus areas. | /sites/default/files/TranslationalScienceSpectrumGraphicInteractive_600x600_1.png | Explore the NCATS infographic gallery | ||
| 20253 | Scientists Identify Small-Molecule Cocktail to Improve Stem Cell Use in Research and Disease Treatments | NCATS scientists have devised a small-molecule cocktail called CEPT that helps protect human pluripotent stem cells from potential DNA damage due to the stresses of being grown in a dish. Here, frozen human stem cells were thawed, placed on cell culture plates in the presence of different reagents, and analyzed 12 hours later. In the left and center panels, Caspase 3/7 (green), a marker for dead cells, indicates poor cell survival of stem cells treated with a control (DMSO) and Y-27632. In contrast, the right panel shows that virtually all cells survived in the presence of the CEPT cocktail. (Chen et al., Nature Methods) May 3, 2021 Researchers at the National Institutes of Health have devised a four-part small-molecule cocktail that can protect stem cells called induced pluripotent stem cells (iPSCs) from stress and maintain normal stem cell structure and function. The researchers suggest that the cocktail could enhance the potential therapeutic uses of stem cells, ranging from treating diseases and conditions — such as diabetes, Parkinson’s disease and spinal cord injury — to genome editing. Human pluripotent stem cells are cells that, in theory, can grow forever and serve as an inexhaustible source for specialized cells, such as brain, kidney and heart cells. But stem cells are sensitive, and their potential uses in medicine are hampered by the stress of growing in a cell culture dish, which can damage their DNA and lead to cell death. In a series of experiments, scientists led by Ilyas Singeç, M.D., Ph.D., director of the NCATS Stem Cell Translation Laboratory, used high-throughput screening to systematically test thousands of compounds and drugs to identify a unique combination that greatly improved stem cell survival and reduced cell culture stress. Singeç and his co-investigators described how they developed the cocktail, called CEPT, and its potential applications May 3 in Nature Methods. “The small-molecule cocktail is safeguarding cells and making stem cell use more predictable and efficient. In preventing cellular stress and DNA damage that typically occur, we’re avoiding cell death and improving the quality of surviving cells,” said Singeç. “The cocktail will become a broadly used staple of the stem cell field and boost stem cell applications in both research and the clinic.” iPSCs are derived from reprogrammed skin or blood cells. To improve their survival in culture, Singeç and his team initially tested more than 15,000 U.S. Food and Drug Administration–approved drugs and investigational small-molecule compounds from NCATS’ collections. Among the 20 drugs and compounds that could inhibit the activity of ROCK, a type of kinase enzyme that is involved in stem cell stress, they found that the compound Chroman 1 was more potent than the widely used compound Y 27632 in improving cell survival. To further improve cell survival, Singeç and his colleagues used NCATS’ matrix drug screening capabilities to look for potential synergies between Chroman 1 and other drugs and compounds. Matrix drug screening enables investigators to study the effects of drug combinations and determine possible mechanisms by which these drugs act. The researchers identified an investigational drug, Emricasan, that, when combined with Chroman 1, could provide additional support to improve stem cell viability. According to Singeç, an important effort in stem cell biology is an experimental process called single-cell cloning. Although culturing stem cells in large groups is easier, single-cell cloning — culturing one cell at a time in a tiny well of a cell culture plate — is very stressful to cells and inefficient. The process has critical applications in gene editing and establishing cell lines, which are cell cultures developed from a single cell. In its initial screening work, the team tested the protective effects of drugs and compounds on 500 stem cells at a time in plate wells. To mimic the cell stress seen during single-cell cloning, the researchers then developed a new assay (test) to allow them to examine the effects of more than 7,500 compounds on only 10 cells at a time. This testing led to the identification of a third compound, trans-ISRIB, that enhanced cell survival, even when there were few cells in each plate. Additional experiments showed that a mixture of compounds called polyamines — in combination with Chroman 1, Emricasan and trans-ISRIB — proved best for single-cell cloning. “Cells need to be cultured properly, and they have to be of good quality to go into patients,” said NCATS Acting Director Joni Rutter, Ph.D. “By finding new ways to protect stem cells from damage, these results could eventually have wide-ranging implications for many different diseases, including cancer, Alzheimer’s disease and more.” The team carried out an array of experiments to test the usefulness of the cocktail. The researchers showed, for example, that CEPT improved the biobanking of stem cells, called cryopreservation, which involves freezing the cells and typically is very stressful for them. Cryopreservation is critical to bringing stem cells to the clinic, but significant numbers of cells are lost or damaged during the thawing process. The cocktail dramatically improved the process. In another test, the researchers studied the use of the cocktail on iPSCs that already were differentiated into heart cells, motor neurons and other cell types. They found that these more differentiated cells treated with CEPT also were more viable and showed improved function. Singeç also noted potential uses for the cocktail in tissue engineering and the biomanufacturing of various cell types for regenerative medicine and drug development. “For the last 20 years, we have not been able to culture human stem cells in the most optimal conditions,” Singeç said. “Our approach could improve safety and ensure that the next-generation stem cell lines are cultured at high quality before moving into the clinic.” The research was funded in part by the Regenerative Medicine Program of the NIH Common Fund and in part by the NCATS intramural research program. Media Contact: NCATS Information Officer, ncatsinfo@mail.nih.gov About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov. About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov. NIH…Turning Discovery Into Health® | NCATS researchers devised a four-part small-molecule cocktail, called CEPT to improve stem cell survival. | /sites/default/files/Singec-Nature-Methods_900x600_0.jpg | Systematic Testing Identifies Drug Cocktail to Improve Stem Cell Use | NCATS researchers devised a four-part small-molecule cocktail, called CEPT to improve stem cell survival. | /sites/default/files/Singec-Nature-Methods_900x600_1.jpg | Systematic Testing Identifies Drug Cocktail to Improve Stem Cell Use | ||
| 20079 | Large Clinical Trial to Study Repurposed Drugs to Treat COVID-19 Symptoms | li { color: #000; } .panel { margin-bottom: 10px; } .panel-heading, p > strong, li > strong { color: #333; } .panel-body { padding: 15px; } div > div.panel-heading > div > div.col-xs-9 > div > h3 { font-size: 15px; color: #fff; } .question { margin: 0 15px; } div.panel-body > p:nth-last-child(1) { margin-bottom: 0; } Read the ivermectin 400, ivermectin 600, fluvoxamine 50, fluvoxamine 100, and fluticasone peer-reviewed publication, and the montelukast preprint. Creative rendition of SARS-CoV-2 virus particles. Note: not to scale. (NIAID)April 19, 2021 Using an ACTIV master protocol, the trial will focus on potential interventions for mild-to-moderate illnessThe National Institutes of Health will fund a large, randomized, placebo controlled Phase 3 clinical trial to test several existing prescription and over-the-counter medications for people to self-administer to treat symptoms of COVID-19. Part of the Accelerating COVID 19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership, the ACTIV-6 trial aims to provide evidence-based treatment options for the majority of adult patients with COVID-19 who have mild-to-moderate symptoms and are not sick enough to be hospitalized. NIH will provide an initial investment of $155 million in funding for the trial.“While we’re doing a good job with treating hospitalized patients with severe disease, we don’t currently have an approved medication that can be self-administered to ease symptoms of people suffering from mild disease at home, and reduce the chance of their needing hospitalization,” said NIH Director Francis S. Collins, M.D., Ph.D. “ACTIV-6 will evaluate whether certain drugs showing promise in small trials can pass the rigor of a larger trial.”Several drugs currently are recommended for the treatment of hospitalized patients with moderate to severe COVID-19, including the antiviral drug remdesivir, the anti-inflammatory baricitinib, and corticosteroids. Additionally, the U.S. Food and Drug Administration authorized emergency use of intravenous monoclonal antibodies in non-hospitalized patients with mild to moderate COVID-19 who are at high risk for severe disease. However, medications that can be self-administered at home to reduce COVID-19 symptoms are critically needed.The ACTIV-6 protocol will explore a pool of up to seven drugs approved by FDA for other conditions — an approach called drug repurposing — and test their safety and effectiveness in treating mild to moderate COVID-19. Because the drugs under consideration already have been tested in humans, repurposing could deliver COVID-19 treatment options sooner. Drugs will be administered orally or by inhaler and will be easy for participants to take at home. Participants will be assigned randomly to receive either a placebo or one of the treatments, which will be sent to them by mail.Enrollment is expected to open in a few weeks to up to 13,500 participants who are at least 30 years old, have tested positive for SARS-CoV-2 infection and have experienced two or more mild-to-moderate symptoms of COVID-19 for no more than seven days. Researchers plan to assess changes in patients’ symptoms over a 14-day period, as well as hospitalizations and deaths over a 28-day period. They also will assess long-term COVID-19-related symptoms at 90 days after treatment begins. The list of drugs that will be added to the study arms is still being finalized. All the drugs will have established safety records and early indications from smaller or less controlled studies of effectiveness against COVID-19.The trial will focus on enrollment of people within minority, rural and other communities that are significantly affected by COVID-19 but lack access to major academic medical centers, where large clinical trials usually take place.With funding provided by the American Rescue Plan Act, NIH’s National Center for Advancing Translational Sciences (NCATS) will oversee the trial. The Duke Clinical Research Institute, Durham, North Carolina, an NCATS-funded Clinical and Translational Science Awards (CTSA) Program hub, will serve as the clinical coordinating center, and the Vanderbilt Institute for Clinical and Translational Research CTSA Program hub at Vanderbilt University Medical Center, Nashville, Tennessee, will serve as the trial’s data coordinating center.To expedite enrollment in ACTIV-6, NCATS and its Duke-Vanderbilt Trial Innovation Center will partner with the Patient-Centered Outcomes Research Institute (PCORI), an independent nonprofit research funding organization. PCORnet, the National Patient-Centered Clinical Research Network, which is funded by PCORI, will support the ACTIV-6 governance and operations. In addition, PCORnet sites will enroll participants from a broad range of communities.“Getting approval for a new drug to come to market usually takes years,” said Joni Rutter, Ph.D., NCATS acting director. “By leveraging drug repurposing and existing national clinical trial networks, ACTIV-6 aims to speed the delivery of definitive answers about available drugs that could help people manage COVID-19 symptoms at home.”Media Contact: NCATS Information Officer, ncatsinfo@mail.nih.govQuestions & AnswersHow are drugs selected for this trial?ExpandThe selection process for ACTIV trials is described in detail in “Accelerating Coronavirus Disease 2019 Therapeutic Interventions and Vaccines — Selecting Compounds for Clinical Evaluation in Coronavirus Disease 2019 Clinical Trials.” For ACTIV-6, compounds were selected based on a number of factors, including known safety profiles, route of administration (oral drugs were prioritized for ACTIV-6), early clinical and real-world evidence of effectiveness in treating COVID-19, and level of public and scientific interest. See the article and supplemental content for more details.The first round of ACTIV-6 agent prioritization ended in April 2021. Four agents received high priority rankings and three of these agents — ivermectin, fluvoxamine and fluticasone — currently are being tested in ACTIV-6.A second round to prioritize additional potential treatment candidates for ACTIV-6 was held in October 2021 so that replacement drugs will be available in the event that the ongoing arms are stopped early for safety or futility (e.g., lack of effect). Drug combinations — such as fluvoxamine/fluticasone and ivermectin/fluvoxamine — were considered in the second round of agent prioritization for ACTIV-6.What drugs currently are being studied in ACTIV-6?ExpandEnrollment is open to test the safety and effectiveness of ivermectin, fluvoxamine and fluticasone in treating mild to moderate COVID-19 symptoms at home. Agent prioritization is ongoing, and additional study arms may open. For the latest information on the drugs being studied, visit the ACTIV website.If the drugs to be tested in ACTIV-6 are approved already by the FDA and show some evidence of efficacy in COVID-19, why is a randomized, controlled clinical trial necessary?ExpandAnecdotal evidence and small observational studies are not enough to determine if a treatment is effective at relieving symptoms in mild to moderate COVID-19. Robust data from randomized, placebo-controlled clinical trials like ACTIV-6 are necessary for the FDA to approve the use of one or more of the ACTIV-6 drugs as a COVID-19 treatment and to inform specific, evidence-based guidance on how to effectively use the drugs as a COVID-19 treatment. See the Coronavirus Disease 2019 (COVID-19) Treatment Guidelines for more information about ivermectin (page 125) and fluvoxamine (page 228).Is ivermectin a safe treatment for COVID-19?ExpandNIH’s COVID-19 Treatment Guidelines Panel has determined that data are currently insufficient to recommend either for or against the use of ivermectin for treatment of COVID-19. Results from adequately powered, well-designed and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19. Ivermectin is not authorized or approved by the FDA for prevention or treatment of COVID-19.When will results from ACTIV-6 be available?ExpandEnrollment is underway and results will be available shortly after the trial is completed — approximately 2 years — or possibly sooner, if analysis conducted during the trial indicates that one or more of the drugs is beneficial. When possible, interim results will be shared with other investigators or made public so that access to beneficial drugs can be accelerated.About the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov.About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.NIH…Turning Discovery Into Health® function toggleText(pn) { var elem = document.querySelector(pn); var target = document.querySelector(elem.getAttribute('data-target')); if (elem.textContent === 'Expand') { elem.textContent = 'Collapse'; target.classList.remove('collapse'); } else { elem.textContent = 'Expand'; target.classList.add('collapse'); } } | As part of NIH’s ACTIV partnership, NCATS’ CTSA Program will play a key role in a COVID-19 clinical trial. | /sites/default/files/ACTIV-6_900x600px_0.jpg | NIH Funds Large Clinical Trial to Repurpose Drugs | As part of NIH’s ACTIV partnership, NCATS’ CTSA Program will play a key role in a COVID-19 clinical trial. | /sites/default/files/ACTIV-6_900x600px_1.jpg | NIH Funds Large Clinical Trial to Repurpose Drugs | ||
| 19992 | Drug Testing Approach Uncovers Effective Combination for Treating Small Cell Lung Cancer | Small cell lung carcinoma cells. (Parth Desai, M.D., National Cancer Institute)April 12, 2021 Researchers from the National Institutes of Health have identified and tested a drug combination that exploits a weakness in small cell lung cancer (SCLC), an aggressive, dangerous cancer. The scientists targeted a vulnerability in how the cancer cells reproduce, increasing already high levels of replication stress — a hallmark of out-of-control cell growth in many cancers that can damage DNA and force cancer cells to constantly work to repair themselves. In a small clinical trial, the drug duo shrank the tumors of SCLC patients. The team reported its findings April 12 in Cancer Cell.While many patients with small cell lung cancer initially respond to chemotherapy, they lack an effective follow-up treatment. These patients usually live a matter of weeks after their first treatment stops working and their disease returns. Scientists at NIH’s National Cancer Institute (NCI) and NCATS teamed up to find another option to treat these cancers, which are part of a larger group of similar diseases called small cell neuroendocrine cancers.“We wanted to identify novel drugs and combinations to leverage this vulnerability therapeutically,” said NCI’s Anish Thomas, M.D., who led the study. “We saw potential opportunities because the armamentarium of new chemicals and drugs was rapidly expanding.”The NCI group collaborated with NCATS co-author Craig Thomas, Ph.D., and his team to use NCATS’ matrix screening platform and expertise to explore the potential of nearly 3,000 agents from an oncology-focused library of investigational and approved drugs against SCLC cells in the laboratory.NCATS’ robotics-enabled, high-throughput screening technologies allow scientists to rapidly test thousands of different drugs and drug combinations in a variety of ways. Scientists can examine the most promising drugs and drug combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.The research team found multiple drug combinations involving commonly used chemotherapy drugs that cause DNA damage and drugs designed to block DNA repair. One of the most effective combinations was the U.S. Food and Drug Administration-approved chemotherapy drug topotecan and an investigational drug M6620, or berzosertib, which blocks an enzyme, called ATR, that plays a role in DNA repair.“A lot of exciting advances have led to the clinical availability of ATR inhibitors, including berzosertib,” said NCATS translational scientist Michele Ceribelli, Ph.D., a co-author. “Blocking the ATR enzyme means cancer cells can’t respond to DNA damaging agents properly. This makes chemotherapy even more effective.”The NCI researchers tested the berzosertib-topotecan drug combination in a clinical trial involving SCLC patients who either had relapsed after initial treatment or for whom their therapy had stopped working. They found that the drug combination helped more than one-third of participants (9 of 25) improve in some way. In some cases, the improvement lasted for six months.“There are a lot of unknowns within the translational process,” said Craig Thomas. “Such large combination screening experiments can reveal pharmacologic relationships from an increasingly diverse collection of compounds and drugs. In the best-case scenario, the outcomes of these screens can help clinical teams prioritize their efforts.”When the scientists looked more closely at the tumor samples, they discovered that the patients whose tumors became smaller in response to treatment showed more activity in genes involved in rapid cell growth and DNA repair. The findings suggest that researchers could develop a more personalized approach in treating SCLC patients as well as other types of small cell neuroendocrine cancers.As a next step, NCI is sponsoring a larger clinical trial to compare the effects of berzosertib and topotecan in combination against topotecan alone in SCLC patients.For more information about this clinical trial, visit: https://clinicaltrials.gov/ct2/show/NCT03896503The work was supported by the intramural programs of the Center for Cancer Research, NCI (ZIA BC 011793) and the Division of Preclinical Innovation, NCATS.Media Contact: NCATS Information Officer, ncatsinfo@mail.nih.govAbout the National Center for Advancing Translational Sciences (NCATS): NCATS conducts and supports research on the science and operation of translation — the process by which interventions to improve health are developed and implemented — to allow more treatments to get to more patients more quickly. For more information about how NCATS helps shorten the journey from scientific observation to clinical intervention, visit https://ncats.nih.gov.About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.NIH…Turning Discovery Into Health® | Scientists from NCI and NCATS use a drug testing approach to find a treatment for patients with small cell lung cancer. | Drug Combination Provides Effective Treatment for Small Cell Lung Canc | Scientists from NCI and NCATS use a drug testing approach to find a treatment for patients with small cell lung cancer. | Drug Combination Provides Effective Treatment for Small Cell Lung Canc | ||||
| 19851 | Assay Guidance Workshop for High-Throughput Screening and Lead Discovery Day 2: Nov. 19, 2020 | .video-container { position: relative; padding-bottom: 56.25%; padding-top: 0; height: 0; overflow: hidden; } .video-container iframe, .video-container object, .video-container embed { position: absolute; top: 0; left: 0; width: 100%; height: 100%; } .card { box-shadow: 0 4px 8px 0 rgba(0,0,0,0.2); margin-bottom: 30px; border: solid 1px rgba(0,0,0,0.2); min-height: 500px; } .card-body { padding: 10px; } .card-text { } .hanging-text { padding-left: 10px; text-indent: -10px; margin-top: 0; } .d-flex { margin-bottom:20px; } h3 { margin-top: 0; } h4 { font-size: 16px; } #bh-video.video-container { padding-top: 53.5px; } #chk-video.video-container { padding-top: 35px; } @media screen and (max-width:1200px) { .col-container { padding-right: 0; } #bh-video.video-container, #chk-video.video-container { padding-top: 0 !important; } } /* @media screen and (min-width:992px) { .AD-disclaimer { bottom: 36px; position: absolute; } } @media screen and (min-width:992px) and (max-width:1999px) { .card { min-height: 555px; } } */ This two-day virtual workshop hosted by NCATS Assay Guidance Manual (AGM) covered a broad range of critical concepts underlying assay development and implementation for high-throughput screening and lead discovery projects. The videos from the second day of the workshop are below.Basic Assay Statistics, Data Analysis & Rules of Thumb (ROT)Thomas “TC” D.Y. Chung, Ph.D.Director, Translational Outreach ProgramsSanford Burnham Prebys Medical Discovery InstituteDr. Chung introduces basic statistical concepts for proper HTS data analysis and validation. Dr. Chung then describes the Z-factor (Z’) as a simple parameter that summarizes an assay’s robustness.Reproducibility Assessment of In Vitro Screening ResultsViswanath Devanarayan, Ph.D., FAAPSSenior Statistics DirectorGlaxoSmithKlineDr. Devanarayan introduces minimum significant ratio (MSR) as a metric for evaluating the reproducibility of potency results from dose-response screening assays. He then discusses how MSR is calculated and describes different ways of estimating MSR.Assay Operations: Keeping your Assays Robust and ReproducibleJeffrey R. Weidner, Ph.D.FounderQualSci Consulting, LLCDr. Weidner introduces and defines key statistical concepts for assay robustness and reproducibility. He then introduces the audience to Statistical Process Control (SPC) which applies statistical methods to optimize reproducibility, reliability and quality.Kinetics of Target Binding: Impact on Drug Activity from Bench to BedsideSam Hoare, Ph.D.FounderPharmechanics, LLCDr. Hoare introduces basic concepts and principles in binding kinetics and its impact on drug measurements. Dr. Hoare then describes methodologies for measuring binding kinetics and highlights when to apply kinetics in drug discovery.Why You Want to Use Stem Cells for Drug DiscoveryMarcie Glicksman, Ph.D.Head of BiologyEnClear TherapiesDr. Glicksman emphasizes the importance of using stem cells in drug discovery campaigns and describes different stem cell technologies utilized in drug discovery. Dr. Glicksman also provides examples and case studies where stem cells were used in the drug discovery process as well as for therapy.Toward the Efficient Discovery of Actionable Chemical Matter from DNA-encoded LibrariesTimothy L. Foley, Ph.D.Pharmacology & DEL Selection Biology Lab Head, Primary Pharmacology GroupPfizer Inc.Dr. Foley introduces DNA-encoded chemical libraries (DEL) and describes how they are used for lead discovery. Dr. Foley then addresses several topics including reproducibility in DEL screens, hit selection and conformation, as well as some challenges in these processes.Antibody Binding Sites as Therapeutics: From scFv to VHH and VNARMitchell Ho, Ph.D.Deputy Chief, Laboratory of Molecular BiologyNational Cancer Institute (NCI), NIHDr. Ho describes different approaches for therapeutic antibody discovery. He then introduces the concept of antibody binding site as therapeutics and takes a deep dive into the utility of single-chain variable fragment (scFv) and single domain antibodies in therapeutics.COVID19: The NCATS ExperienceMatthew D. Hall, Ph.D.Director, Early Translation Branch, Division of Preclinical InnovationNational Center for Advancing Translational Sciences (NCATS)Dr. Hall describes activities conducted by NCATS to address COVID-19 including SARS-CoV-2 assay development and screening, as well as the launch of an open data portal to share COVID-19 drug repurposing data in real time.Closing RemarksAnton Simeonov, Ph.D.Scientific Director, Division of Preclinical InnovationNational Center for Advancing Translational Sciences (NCATS)In his closing remarks, Dr. Simeonov describes the AGM as a freely available resource for early discovery and emphasizes that the AGM program is becoming a community of followers, practitioners, and disseminators. Dr. Simeonov highlights the future directions and the upcoming events of the AGM. | Assay Guidance Workshop for High-Throughput Screening and Lead Discovery Day 2: Nov. 19, 2020 | Assay Guidance Workshop for High-Throughput Screening and Lead Discovery Day 2: Nov. 19, 2020 | ||||||
| 19704 | HEAL Target and Compound Library | @media screen and (max-width: 1200px) { .row { margin-left: 0; margin-right: 0; } #top-paragraph { margin-top: 20px; } #logo-col { padding: 0; /* margin-bottom: 20px; */ } #bullet-col { margin-bottom: 0 !important; padding-bottom: 14px !important; } } • With nearly 3,000 small molecules, the HEAL Target and Compound Library is the first to assemble known and potentially novel targets related to addiction, pain and overdose in one collection.• The library provides an integrated platform for data mining, machine learning, structural modeling and virtual screening.• The HEAL Target and Compound Library can be made available for meritorious HEAL-related assays through NCATS DPI in pre-spotted plates. As part of the NIH Helping to End Addiction Long-term® Initiative, or NIH HEAL Initiative®, NCATS is focused on developing novel chemistry, screening and testing methodologies to discover new pharmacological tools and investigational drugs for pain, addiction and overdose. As part of these efforts, the NCATS Early Translation Branch has created a comprehensive, annotated HEAL library of compounds, including drugs, probes and tool compounds for addiction and pain-relevant targets.The modern nature of the HEAL Target and Compound Library incorporates years of valuable sources and lessons learned on high-throughput screening and chemical library design at NCATS. Nearly 3,000 small molecules associated with approximately 60 known and hypothesized HEAL-relevant targets have been assembled, curated and annotated. Physical samples of the compound library have been acquired and plated on 1,536-well and 384-well plate formats, allowing rapid strategic screening for drug repurposing, innovative profiling and hypothesis testing of novel targets and tool compounds. Interested in Accessing the HEAL Library?A plated copy of the HEAL Target and Compound Library along with the plate format and annotated list of compounds can be made available to the research community specifically for meritorious HEAL-related assays through NCATS Division of Preclinical Innovation collaborations. For more information on the HEAL library and how to access it, please contact NCATSHEALPLATE@nih.gov. These graphics are a snapshot of the HEAL Library’s targets and compounds. They are meant to illustrate the diversity of the HEAL Library collection and do not represent the final annotated list of targets and compounds. For more information about the annotated list, please contact NCATSHEALPLATE@nih.gov. (NCATS) | Through the NIH HEAL Initiative, NCATS is developing novel chemistry, screening and testing methodologies to find new pharmacological tools and investigational drugs for pain, addiction and overdose | /sites/default/files/HEAL_logo_1157x579_0.jpg | HEAL Target and Compound Library | Through the NIH HEAL Initiative, NCATS is developing novel chemistry, screening and testing methodologies to find new pharmacological tools and investigational drugs for pain, addiction and overdose | /sites/default/files/HEAL_logo_1157x579_1.jpg | HEAL Target and Compound Library | ||
| 19554 | Assessing a Compound’s Activity, Not Just Its Structure, Could Deepen the Pool of Promising Drug Therapies | This diagram represents the biological activity-based modeling (BABM) process, a new approach aimed at speeding drug discovery. The BABM model uses the biological activity patterns of drugs and compounds in cells across different tests to make predictions about their activity against a new biological target or disease. Researchers then can validate the model’s predictions in experiments. (Huang, R., et al., Nature Biotechnology)View image This diagram represents the biological activity-based modeling (BABM) process, a new approach aimed at speeding drug discovery. The BABM model uses the biological activity patterns of drugs and compounds in cells across different tests to make predictions about their activity against a new biological target or disease. Researchers then can validate the model’s predictions in experiments. (Huang, R., et al., Nature Biotechnology)Close.modal-content-img { background-image:none; } .modal-dialog { width:70%; max-width:1600px; min-width:400px; } .modal-footer p{ text-align:left;} March 3, 2021Assessing a drug compound by its activity, not simply its structure, is a new approach that could speed the search for COVID-19 therapies and reveal more potential therapies for other diseases.This action-based focus — called biological activity-based modeling (BABM) — forms the core of a new approach developed by NCATS researchers and others. Researchers used BABM to look for potential anti-SARS-CoV-2 agents whose actions, not their structures, are similar to those of compounds already shown to be effective.NCATS scientists Ruili Huang, Ph.D., and Wei Zheng, Ph.D., led the research team that created the approach. Their findings were posted online Feb. 23 by the journal Nature Biotechnology.“With this new method, you can find completely new chemical structures based on activity profiles and then develop completely new drugs,” Huang explained. Thus, using information about a compound’s biological activity may expand the pool of promising treatments for a wide range of diseases and conditions.When researchers seek new compounds or look for existing drugs to repurpose against new diseases, they are increasingly using screening tools to predict which drugs might be good candidates. Virtual screening, or VS, allows scientists to use advanced computer analyses to find potentially effective candidates from among millions of compounds in collections.Traditional VS techniques look for compounds with structures similar to those known to be effective against a particular target on a pathogen or cell, for example. Those structural similarities are then assumed to deliver similar biological activities.With BABM, however, researchers don’t need to know a compound’s chemical structure, according to Huang. Instead, they use a profile of a compound’s activity patterns — how it behaves at multiple concentrations against a panel of targets or tests — to predict its potential effectiveness against a new target or in a new drug assay.The now-widespread use of quantitative high-throughput screening (qHTS) allows BABM more accuracy in its predictions. qHTS assesses a compound’s effectiveness at multiple concentrations in thousands of tests over time. That practice provides far more detail about how a compound behaves than does traditional high-throughput screening, which tests only a single concentration of the compound. The information generated by qHTS creates a stronger biological activity profile — also known as a signature — for each one of millions of compounds.In addition to small molecules, this approach can be applied to biologics, antibodies, and other therapies. BABM is for all drug discovery projects.To test the BABM approach, the researchers tapped the vast pool of data generated by hundreds of qHTS analyses run on NCATS’ in-house collection of more than 500,000 compounds and drugs. First, they verified BABM’s ability to use activity profiles to identify compounds already shown to be effective against the Zika and Ebola viruses. BABM also identified new compounds that showed promise against those viruses.The scientists then turned to SARS-CoV-2, the virus that causes COVID-19. They applied BABM, a structure-based model and a combined approach to analyze the NCATS library’s compounds to find potential anti-SARS-CoV-2 agents. BABM predicted that the activity profiles of 311 compounds might indicate promise against the coronavirus.The researchers then had an outside laboratory test those 311 compounds against the live SARS-CoV-2 virus. The result: Nearly one-third of the BABM-backed compounds (99) showed antivirus activity in the test. The BABM-driven prediction hit rate topped that of the structure-based model — and combining the activity-based and structure-based models yielded even better predictive results.A key advantage to BABM is speed. “This method is very fast — you essentially just run a computer algorithm, and you can identify many new drug leads, even with new chemical structures,” Huang noted. In fact, screening the entire NCATS library of half a million compounds for anti-SARS-CoV-2 candidates took only a few minutes.BABM also is a transferable tool — it’s not limited to use in the NCATS compound libraries. “Anyone can use this method by applying any biological activity profile data, including publicly available NCATS data,” Huang emphasized.The NCATS researchers predict their activity-based model’s impact could extend far beyond the search for COVID-19 treatments and small-molecule drug discovery. Given any substance with an available activity profile, scientists can predict its activity against a new target, for a new indication, or against a new disease. “In addition to small molecules, this approach can be applied to biologics, antibodies, and other therapies,” Huang said. “BABM is for all drug discovery projects.” | NCATS researchers created a new approach called biological activity-based modeling to assess a drug compound by its activity. | /sites/default/files/BABM-Nature_1200x6301.jpg | Assessing a Compound’s Activity Could Lead to Promising Drug Therapies | NCATS researchers created a new approach called biological activity-based modeling to assess a drug compound by its activity. | /sites/default/files/BABM-Nature_1200x6301_0.jpg | Assessing a Compound’s Activity Could Lead to Promising Drug Therapies |
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