Big Effect Trial
Posted on by Dr. Francis Collins
Right now, many U.S. hospitals are stretched to the limit trying to help people battling serious cases of COVID-19. But as traumatic as this experience still is for patients and their loved ones, the chances of surviving COVID-19 have in fact significantly improved in the year since the start of the pandemic.
This improvement stems from several factors, including the FDA’s emergency use authorization (EUA) of a number of therapies found to be safe and effective for COVID-19. These include drugs that you may have heard about on the news: remdesivir (an antiviral), dexamethasone (a steroid), and monoclonal antibodies from the companies Eli Lilly and Regeneron.
Yet the quest to save more lives from COVID-19 isn’t even close to being finished, and researchers continue to work intensively to develop new and better treatments. A leader in this critical effort is NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, a public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies.
ACTIV was founded last April to accelerate drug research that typically requires more than a decade of clinical ups and downs to develop a safe, effective therapy. And ACTIV has indeed moved at unprecedented speed since its launch. Cutting through the usual red tape and working with an intense sense of purpose, the partnership took a mere matter of weeks to set up its first four clinical trials. Beyond the agents mentioned above that have already been granted an EUA, ACTIV is testing 15 additional potential agents, with several of these already demonstrating promising results.
Here’s how ACTIV works. The program relies on four expert “working groups” with specific charges:
Preclinical Working Group: Shares standardized preclinical evaluation resources and accelerate testing of candidate therapies and vaccines for clinical trials.
Therapeutics Clinical Working Group: Prioritizes therapeutic agents for testing within an adaptive master protocol strategy for clinical research.
Clinical Trial Capacity Working Group: Has developed and organized an inventory of clinical trial capacity that can serve as potential settings in which to implement effective COVID-19 clinical trials.
Vaccines Working Group: Accelerates the evaluation of vaccine candidates.
To give you just one example of how much these expert bodies have accomplished in record time, the Therapeutics Clinical Working Group got to work immediately evaluating some 400 candidate therapeutics using multiple publicly available information sources. These candidates included antivirals, host-targeted immune modulators, monoclonal antibodies (mAb), and symptomatic/supportive agents including anticoagulants. To follow up on even more new leads, the working group launched a COVID-19 Clinical & Preclinical Candidate Compound Portal, which remains open for submissions of therapeutic ideas and data.
All the candidate agents have been prioritized using rigorous scoring and assessment criteria. What’s more, the working group simultaneously developed master protocols appropriate for each of the drug classes selected and patient populations: outpatient, inpatient, or convalescent.
Through the coordinated efforts of all the working groups, here’s where we stand with the ACTIV trials:
ACTIV-1: A large-scale Phase 3 trial is enrolling hospitalized adults to test the safety and effectiveness of three medicines (cenicriviroc, abatacept, and infliximab). They are called immune modulators because they help to minimize the effects of an overactive immune response in some COVID-19 patients. This response, called a “cytokine storm,” can lead to acute respiratory distress syndrome, multiple organ failure, and other life-threatening complications.
ACTIV-2: A Phase 2/3 trial is enrolling adults with COVID-19 who are not hospitalized to evaluate the safety of multiple monoclonal antibodies (Lilly’s LY-CoV555, Brii Biosciences’s BRII-196 and BRII-198, and AstraZeneca’s AZD7442) used to block or neutralize the SARS-CoV-2 virus. The Lilly monoclonal antibody LY-CoV555 received an EUA for high risk non-hospitalized patients on November 9, 2020 and ACTIV-2 continued to test the agent in an open label study to further determine safety and efficacy in outpatients. Another arm of this trial has just started, testing inhaled, easy-to-administer interferon beta-1a treatment in adults with mild-to-moderate COVID-19 who are not hospitalized. An additional arm will test the drug camostat mesilate, a protease inhibitor that can block the TMPRSS2 host protein that is necessary for viral entry into human cells.
ACTIV-3: This Phase 3 trial is enrolling hospitalized adults with COVID-19. This study primarily aims to evaluate safety and to understand if monoclonal antibodies (AstraZeneca’s AZD7442, BRII-196 and BRII-198, and the VIR-7831 from GSK/Vir Biotechnology) and potentially other types of therapeutics can reduce time to recovery. It also aims to understand a treatment’s effect on extrapulmonary complications and respiratory dysfunction. Lilly’s monoclonal antibody LY-CoV555 was one of the first agents to be tested in this clinical trial and it was determined to not show the same benefits seen in outpatients. [Update: NIH-Sponsored ACTIV-3 Clinical Trial Closes Enrollment into Two Sub-Studies, March 4, 2021]
ACTIV-4: This trial aims to determine if various types of blood thinners, including apixaban, aspirin, and both unfractionated (UF) and low molecular weight (LMW) heparin, can treat adults diagnosed with COVID-19 and prevent life-threatening blood clots from forming. There are actually three Phase 3 trials included in ACTIV-4. One is enrolling people diagnosed with COVID-19 but who are not hospitalized; a second is enrolling patients who are hospitalized; and a third is enrolling people who are recovering from COVID-19. ACTIV-4 has already shown that full doses of heparin blood thinners are safe and effective for moderately ill hospitalized patients.
ACTIV-5: This is a Phase 2 trial testing newly identified agents that might have a major benefit to hospitalized patients with COVID-19, but that need further “proof of concept” testing before they move into a registrational Phase 3 trial. (In fact, another name for this trial is the “Big Effect Trial”.) It is testing medicines previously developed for other conditions that might be beneficial in treatment of COVID-19. The first two agents being tested are risankizumab (the result of a collaboration between Boehringer-Ingelheim), which is already FDA-approved to treat plaque psoriasis, and lenzilumab, which is under development by Humanigen to treat patients experiencing cytokine storm as part of cancer therapy.
In addition to trials conducted under the ACTIV partnership, NIH has prioritized and tested additional therapeutics in “ACTIV-associated trials.” These are NIH-funded, randomized, placebo-controlled clinical trials with one or more industry partners. Here’s a table with a comprehensive list.
Looking a bit further down the road, we also seek to develop orally administered drugs that would potentially block the replication ability of SARS-CoV-2, the coronavirus that causes COVID-19, in the earliest stages of infection. One goal would be to develop an antiviral medication for SARS-CoV-2 that acts similarly to oseltamivir phosphate (Tamiflu®), a drug used to shorten the course of the flu in people who’ve had symptoms for less than two days and to prevent the flu in asymptomatic people who may have been exposed to the influenza virus. Yet another major long-term effort of NIH and its partners will be to develop safe and effective antiviral medications that work against all coronaviruses, even those with variant genomes. (And, yes, such drugs might even cure the common cold!)
So, while our ACTIV partners and many other researchers around the globe continue to harness the power of science to end the devastating COVID-19 pandemic as soon as possible, we must also consider the lessons learned this past year, in order to prepare ourselves to respond more swiftly to future outbreaks of coronaviruses and other infectious disease threats. Our work is clearly a marathon, not a sprint.
COVID-19 Research (NIH)
Combat COVID (U.S. Department of Health and Human Services, Washington, D.C.)
Pull Up a Chair with Dr. Freire: The COVID Conversations (Foundation for the National Institutes of Health, Bethesda, MD)
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Posted In: News
Tags: Accelerating COVID-19 Therapeutic Interventions and Vaccines, ACTIV, antiviral, apixaban, aspirin, AstraZeneca, AZD7442, Big Effect Trial, blood clots, blood thinner, Boehringer-Ingelheim, Brii Bioscience, BRII-196, BRII-198, camostat mesilate, clinical trials, coronavirus, COVID-19, COVID-19 Clinical & Preclinical Candidate Compound Portal, COVID-19 treatment, COVID-19 vaccine, dexamethasone, drug development, Eli Lilly and Company, EUA, GSK/Vir Biotechnology, heparin, host-targeted immune modulator, Humanigen, immune modulator, lenzilumab, LY-CoV555, monoclonal antibody, novel coronavirus, oseltamivir phosphate, pandemic, public-private partnership, Regeneron, remdesivir, risankizumab, SARS-CoV-2, Tamiflu, therapeutics, TMPRSS2, treatments, VIR-7831