The ACTIV-3 clinical trial, funded by the National Institute of Allergy and Infectious Diseases (NIAID) and a large group of collaborators, has been paused due to possible safety issues observed by the independent data safety monitoring board (DSMB). This federally funded study, launched in August, investigates the combination of Gilead’s Remdesivir and Lilly’s LY-CoV-555 (bamlanivimab), a monoclonal antibody produced in partnership with University of British Columbia spinoff, AbCellera, and NIAID’s Vaccine Center. Last Tuesday, the DSMB initiated the recommendation after the group observed “an overall difference in the clinical status between the group receiving LY-CoV555 and the group receiving saline placebo.” TrialSite notes that pauses of this type are not uncommon and indicate the DSMB is doing its job.
Lots of Moving Parts
Lilly recently applied to the U.S. Food and Drug Administration for an Emergency Use Authorization (EUA) for its monotherapy LY-CoV555 (bamlanivimab), which could possibly be impacted by this recent event, depending on the outcome of the findings.
TrialSite noted that Lilly appeared to have sufficient data from its existing studies involving LY-CoV555 to file for EUA, but in the case of the ACTIV-3 study, some form of safety anomaly has been observed—however, the details aren’t disclosed as of yet.
This study also involves the use of Remdesivir as an inherent part of the “study drug.” Remdesivir is approved via EUA via an unorthodox process of swapping final endpoint measures, as reported by TrialSite News.
The ACTIV-3 clinical trial investigates the safety and effectiveness of different drugs in treating COVID-19 in people who have been hospitalized with the SARS-CoV-2 infection. Participants are treated with either the study drug plus the current standard of care or with placebo with the current standard of care.
The study drug in the case of ACTIV-3 receives the standard of care (Remdesivir) plus the study drug (LY-CoV555) while the placebo group receives remdesivir—unless for some reason they cannot take Remdesivir.
In a master protocol study, the sponsor (federal government) seeks to test multiple investigational agents to modify the host immune response to SARS-CoV-2 infection or directly enhance viral control to limit disease progression. The study is based on the premise that antivirals (e.g., Remdesivir) are not sufficient. Hence the bundling of advanced monoclonal antibodies in these complex, highly expensive industry and taxpayer-funded investigational efforts.
As reported by Peter Loftus and Joseph Walker for the Wall Street Journal (WSJ) on Saturday, October 17, this particular study had enrolled 326 patients prior to the study pause. NIAID reported that the DMSB recommended the pause after it observed the differences between two groups after a scheduled analysis for the first 300 patients.
What Differentiates This Study From others
In a press release, Lilly reported that the ACTIV-3 study is the only ongoing study investigating the efficacy of Lilly’s neutralizing antibody in hospitalized patients, the most advanced stage of the disease. The dose of bamlanivimab (LY-CoV555) under investigation equals 700 mg. Lilly reminds us that those participants in this study have been infected with COVID-19 for a longer period of time. In many cases, they will have more severe symptoms and receive different treatments than those infected at the earlier stages. In this study, Remdesivir is used on every patient.
Lilly suggests in their press release that hospitalized patients may have less benefit from neutralizing antibodies, again a supplement to the patients’ own immune system, as they have developed their own endogenous antibody response and are possibly in the phase of the disease characterized by inflammatory responses to the virus. Hence the use of immunosuppressive treatments is both widespread and still investigated in hospitalized patients.
Lilly Monoclonal Antibody Program—Other Trials Not Affected
Lilly is conducting a number of studies involving their monoclonal antibody investigational products as potential therapeutics for COVID-19 across two different patient populations, including:
BLAZE-1, an ongoing Phase 2 study in people recently diagnosed with COVID-19 in the ambulatory setting (NCT04427501). This trial is testing bamlanivimab both alone and in combination with a second antibody licensed by a Chinese company (etesevimab, LY-CoVV016).
BLAZE-2, a Phase 3 study of bamlanivimab for the prevention (prophylaxis) of COVID-19 in residents and staff at long-term care facilities (NCT04497987).
Bamlanivimab is also being tested in the NIH-led ACTIV-2 study in recently diagnosed mild to moderate COVID-19 patients.
Lilly reported that these trials associated with the program above were not affected by the enrollment pause in the NIH-sponsored trial of hospitalized patients.
Existing Lilly Data
In their press release, Lilly reported that they have some data already analyzed based on recently diagnosed mild to moderate COVID-19 illness in high-risk patients. In this population, they have a large safety database inclusive of over 480 drug-treated patients across a broad range and have reported a potential benefit in clinical outcomes with a reduction in viral load and rates of symptoms and hospitalizations.
Additionally, in the BLAZE-1 trial, rates and types of adverse events were similar between bamlanivimab and placebo, with the majority being mild to moderate in severity with no drug-related serious adverse events reported thus far. In other bamlanivimab studies, Lilly reports some isolated drug-related infusion reactions or hypersensitivity that were generally mild (two reported as serious reactions; however, both patients recovered).
Call to Action: Multiple media reports that the DSMB will meet on October 26 to discuss the ACTIV-3 clinical trial’s next steps. TrialSite will provide updates. Sign up for the daily newsletter.