January 29, 2021
The Honorable Ron Johnson
Chairman, Committee on Homeland Security and Governmental Affairs
United States Senate Washington, DC 20510
Dear Mr. Chairman:
Thank you for your commitment to combatting the COVID-19 pandemic and your interest in the role National Institutes of Health (NIH) research can play in advancing treatment guidelines. NIH has mounted a robust research response against COVID-19 since the beginning of the pandemic as detailed in our strategic plan.1 In this strategic plan for COVID-19 research, NIH shares its framework for funding work across the scientific spectrum to inspire the collective efforts of NIH’s researchers, collaborators, and diverse stakeholders.
NIH has established the COVID-19 Treatment Guidelines Panel to ensure that healthcare providers, patients, and policy experts have the most recent data-driven information regarding the optimal management of COVID-19. The Panel includes representatives of NIH and five other federal agencies along with representatives of ten professional societies, academic experts, treating physicians, including providers from high COVID-19 incidence areas, and community representatives. Each section of the Treatment Guidelines is developed by a working group of Panel members with expertise in the area addressed in the section. Each working group is responsible for identifying relevant information and published scientific literature and for conducting a systematic, comprehensive review of that information and literature. The Panel meets regularly and continuously assesses all possible treatment options for COVID-19 in order to update the Treatment Guidelines as new evidence emerges. It is important to note that the treatment recommendations in these Guidelines should not be considered mandates. The choice of how to treat an individual patient is ultimately a decision between the patient and his or her provider.
The Panel acknowledges the importance of early treatment of COVID-19 in preventing more severe symptoms and indicates in the Treatment Guidelines that outpatients may benefit from receiving monoclonal antibodies against SARS-CoV-2, the virus that causes COVID-19, early in the course of infection. The anti-SARS-CoV-2 monoclonal antibodies bamlanivimab2 and casirivimab plus imdevimab3 are available through U.S. Food and Drug Administration (FDA) Emergency Use Authorizations for outpatients who are at high risk for disease progression. The Panel maintains high standards for incorporating new recommendations and weighs the evidence from many types of studies in crafting the Treatment Guidelines.
During review, the Panel evaluates all aspects of new data including, but not limited to, the source of the data, the type of study (e.g., case series, prospective or retrospective cohorts, randomized controlled trial), the quality and suitability of the methods, the number of participants, and the effect sizes observed. This review encompasses both peer-reviewed published scientific literature and non-peer-reviewed pre-print publications. Data on the use of ivermectin to treat COVID-19 have been evaluated by the Panel on an ongoing basis and were most recently discussed during meetings of the Panel on December 18 and 22, 2020, and on January 6, 2021. These discussions included the papers noted in your letter. The discussion on January 6 included presentations by Dr. Pierre Kory, president of the Frontline COVID-19 Critical Care Alliance, and colleagues. On January 14, 2021, the Panel updated the Treatment Guidelines’ Statement on the Use of Ivermectin for the Treatment of COVID-19 to indicate that data remain insufficient to recommend either for or against its use for the treatment of COVID-19.4 The Panel will continue to assess all available data for ivermectin and other therapies proposed for early treatment of COVID-19 and update the Treatment Guidelines as appropriate.
NIH values data on outcomes from patients treated by their healthcare providers outside of research trials. The National Center for Advancing Translational Sciences (NCATS) National COVID Cohort Collaborative, or N3C, gives researchers access to one of the largest, centralized data repositories of COVID-19 clinical data in the United States.5 Rapidly established and opened early in the fight against COVID-19, the N3C is accessible to the biomedical research community to study, probe, and answer clinically important questions about COVID-19. As of January 22, 2021, the N3C contained electronic health record information from over 2.7 million patients, of whom 516,393 were COVID-19 positive. With the N3C, researchers can analyze information regarding the clinical outcomes of COVID-19 treated patients.
Early in the course of the pandemic, NIH recognized the need for safe, easy to administer, and scalable treatments for outpatients with mild COVID-19. In April 2020, NIH launched the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership to coordinate research strategies for prioritizing and speeding development of the most promising treatments, including for use early in the course of COVID-19. NIH, through the ACTIV partnership, is investigating multiple therapies in studies enrolling adult volunteers with COVID-19 who are not hospitalized. These studies are evaluating monoclonal antibodies, anti-coagulants/anti-thrombo-inflammatory agents, and immune modulators, with plans to include other types of therapeutics such as antivirals. The ACTIV studies evaluate the safety profile of these potential COVID-19 treatments and work to understand whether they can reduce the duration of symptoms in outpatients. For instance, the ACTIV-4 trials, focused on anti-coagulants/anti-thrombo-inflammatory agents, include testing prophylactic versus therapeutic dose heparin in the inpatient setting; assessing aspirin, prophylactic dose apixaban, and therapeutic dose apixaban versus placebo in the pre-hospital setting; or evaluating prophylactic dose versus therapeutic dose apixaban in the post-hospital discharge setting. Data from these and other high-quality studies may lead to additional recommendations for early treatment of COVID-19 by the Panel in the Treatment Guidelines.
NIH is aware that researching whether existing drugs can be repurposed for use against SARS-CoV-2 represents an expeditious and cost-effective strategy for developing COVID-19 treatments. For example, remdesivir, the first antiviral approved by the FDA for the treatment of COVID-19, was previously tested in humans with Ebola virus disease. Additionally, positive data from the RECOVERY trial, a large randomized controlled trial at more than 130 U.K. National Health Service hospitals, led the COVID-19 Treatment Guidelines Panel to recommend the corticosteroid dexamethasone for the treatment of COVID-19 in hospitalized patients with severe disease requiring supplemental oxygen. The NIH-funded ORCHID trial evaluated the malaria drug hydroxychloroquine as a potential therapeutic for hospitalized patients with COVID-19 and found that it did not improve clinical outcomes over placebo after 14 days of treatment. Other trials also demonstrated that hydroxychloroquine is not effective in treating COVID-19 and the Treatment Guidelines recommend against its use in hospitalized patients, and in non-hospitalized patients except in a clinical trial.
NIH scientists have screened a unique collection, called the NCATS Pharmaceutical Collection, of over 10,000 compounds to assess if any of these compounds have activity against the SARS-CoV-2 virus.6 Nearly 3,000 of these compounds were previously approved for clinical use by U.S., European Union, Japanese, Australian and Canadian authorities. Multiple screening efforts and strategies have been conducted since March as our understanding of the virus pathology evolves. Data from these efforts are made publicly available through the OpenData Portal, which was created to rapidly share COVID-19-related drug repurposing data and experiments for all approved drugs.7 Researchers from around the world may access these results and use this preclinical screening data and animal testing data to follow up and conduct additional tests to determine if a given compound has value as a potential drug against SARS-CoV-2.
As part of these screening efforts, NIH scientists have been contacted by, and have collaborated with, physicians, researchers, and biotechnology companies to help pursue ideas for COVID-19/SARS-CoV-2 therapeutics. Data and results are returned directly to those investigators requesting assistance so they can make decisions about advancing potential therapeutics. Examples of potential treatments identified through these efforts include:
Q-Griffithsin: In collaboration with academic partners, NCATS is repurposing the experimental medicine lectin Q-Griffithsin (developed at NCI), currently being tested as a topical HIV microbicide, for use in preventing SARS-CoV-2 infection. Use of this intranasal spray could significantly reduce infection rates in frontline medical settings and other settings with elevated risk for SARS-CoV-2 exposure.
Niclosamide: This FDA-approved antihelminthic drug was identified as active in the NCATS in-house screening program and by several other groups for potential antiviral activity against SARS-CoV-2. However, for its current use, it is minimally absorbed by the body when taken orally. NCATS scientists are currently developing new drug formulations in an animal model of SARS-CoV-2 for potential advancement towards clinical testing.
Emetine: This FDA-approved drug was identified as active in an NCATS in-house screening program and has been demonstrated by NCATS scientists over the past decade to be active against a broad range of viruses. NCATS has partnered with Acer Therapeutics (a Massachusetts-based biotech) to develop emetine towards clinical trials for COVID-19.
GS-441524: This Gilead-developed compound is currently being evaluated independently by NCATS as an orally available antiviral candidate and was identified as active in NCATS in-house screening program.
NIH is conducting and supporting additional studies, including the ACTIV-5/Big Effect Trial (BET), to test whether therapeutics initially developed for other purposes can treat COVID-19. This trial is designed to determine whether certain approved therapies or investigational drugs in late-stage clinical development may have a large treatment effect against COVID-19. The first therapeutics being evaluated in this trial are risankizumab, a monoclonal antibody developed by Boehringer Ingelheim and AbbVie and approved by the FDA for the treatment of severe plaque psoriasis, and lenzilumab, an investigational immunomodulatory monoclonal antibody developed by Humanigen. ACTIV-5/BET will include as many as 40 U.S. sites with the goal of identifying promising treatments for further study in large-scale trials and rapidly eliminating from consideration those that are not as promising.
The ACTIV-1 IM/Randomized Master Protocol for Immune Modulators for Treating COVID-19 trial is testing promising immune modulators, a class of drugs that could help minimize the deleterious effects of an overactive immune response that develops in some individuals with SARS-CoV-2 infection. This Phase 3 trial is enrolling hospitalized adults with moderate to severe COVID-19 disease. It will evaluate the safety and efficacy of three immune modulators, two of which are approved for other uses, when given as an add-on therapy to the standard of care in use at trial sites, which may include remdesivir. The initial agents are infliximab (REMICADE), developed by Janssen Research & Development, LLC.; abatacept (ORENCIA), developed by Bristol Myers Squibb; and Cenicriviroc (CVC), an investigational late-stage agent developed by AbbVie. The different treatments will be assessed with respect to illness severity, recovery speed, mortality, and hospital resource utilization. Additional immune modulators may be tested in the future.
NIH recognizes therapeutic development is a costly, complex, and time-consuming process. The average length of time from target discovery to approval of a new drug is about 14 years. When COVID-19 emerged, NCATS rapidly adapted the New Therapeutic Uses Program (NTU) to address the pandemic through funding opportunities. NTU facilitates research partnerships between researchers and industry to test and repurpose existing therapeutics that already have undergone significant research and development by the pharmaceutical industry. Cooperative agreement awards issued include:
Fenofibrate: An award to Penn State University involves a clinical trial testing the potential therapeutic benefit of fenofibrate, a widely available, FDA-approved generic medicine, for treatment of COVID-19.
Eflornithine and Suldinac: An award to the University of Arizona involves initial testing of two FDA-approved drugs (eflornithine and suldinac) individually and in combination in vitro and in an animal model of COVID-19.
I hope that this information is helpful to you. Please be assured that NIH is committed to addressing the urgent public health threat of COVID-19 through the support of a wide range of research, including efforts to identify safe and effective treatments for COVID-19 early in the course of the disease. We will continue to follow the scientific evidence as we work with our partners in the public and private sectors to develop medical countermeasures against COVID-19.
Thank you for your interest in the Administration’s COVID-19 response. We look forward to working with you on this important issue. An identical response also has been sent to Senator Rand Paul, the co-signer of your letter. In addition, a response to your January 22, 2021 letter is forthcoming.
1 NIH-Wide Strategic Plan for COVID-19 Research: https://www.nih.gov/sites/default/files/research- training/initiatives/covid-19-strategic-plan/coronavirus-strategic-plan-20200713.pdf
2 The COVID-19 Treatment Guidelines Panel’s Statement on the Emergency Use Authorization of Bamlanivimab for the Treatment of COVID-19: https://www.covid19treatmentguidelines.nih.gov/statement-on-bamlanivimab-eua/
3 The COVID-19 Treatment Guidelines Panel’s Statement on the Emergency Use Authorization of the Casirivimab Plus Imdevimab Combination for the Treatment of COVID-19: https://www.covid19treatmentguidelines.nih.gov/statement-on-casirivimab-plus-imdevimab-eua/
4 The COVID-19 Treatment Guidelines Panel’s Statement on the Use of Ivermectin for the Treatment of COVID-19: https://www.covid19treatmentguidelines.nih.gov/statement-on-ivermectin/
6 The NCATS Pharmaceutical Collection is a comprehensive, publicly accessible collection of approved molecular entities for high-throughput screening that provides a valuable resource for both validating new models of disease and better understanding the molecular basis of diseases and interventions: https://ncats.nih.gov/expertise/preclinical/npc