By Daniel R. Lucey M.D., MPH, FIDSA
Rapidly evolving events regarding studies of monoclonal antibodies reemphasize the call first made here Oct. 19 that the U.S. Food and Drug Administration convene an outside expert advisory committee ASAP to advise on requests for Emergency Use Authorization for monoclonal antibodies against SARS-CoV-2.
On Oct. 7 Lilly announced filing with FDA for EUA for its (single) monoclonal antibody for non-hospitalized patients with mild-to-moderate COVID-19 disease.
On Oct. 14 Lilly announced in a statement on “the NIAID Decision to pause enrollment in ACTIV-3 clinical trial” involving hospitalized patients receiving their mononoclonal “bamlanivimab” (“LYCoV555)” due to a recommendation by the independent data safety monitoring board.
On Oct. 26, Lilly announced “The ACTIV-3 clinical trial is being run by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and is the only study evaluating the efficacy of bamlanivimab in hospitalized COVID-19 patients. Based on an updated dataset from the trial reviewed on October 26, no additional COVID-19 patients in this hospitalized setting will receive bamlanivimab. This recommendation was based on trial data suggesting that bamlanivimab is unlikely to help hospitalized COVID-19 patients recover from this advanced stage of their disease.”
Today the New England Journal of Medicine published a paper by Chen et al. including multiple Lilly scientists as co-authors regarding a planned interim analysis of their Phase 2 study (termed “BLAZE-1”) titled: “SARS-CoV-2 Neutralizing antibody LY-CoV555 in Outpatients with Covid-19.
The conclusion summary is: “In this interim analysis of a phase 2 trial, one of three doses of neutralizing antibody LY-CoV555 appeared to accelerate the natural decline in viral load over time, whereas the other doses had not by day 11”.
Of note, neither the 700 mg dose (p=.038), nor the 7000 mg dose (p=0.70) led to a reduction in viral load at day 11 (the primary outcome of the study). Only the middle dose of 2,800 mg showed a statistically significant decrease in viral load at day 11 (p-0.02). The authors stated (p. 2 of 9 in pdf) that “The doses evaluated in this trial were based on pharmacological modeling that predicted that the 700-mg dose would be efficacious.”
Also today Lilly issued an announcement stating: “an initial agreement with the U.S. government to supply 300,000 vials of bamlanivimab (LY-CoV555) 700 mg, an investigational neutralizing antibody, for $375 million. The U.S. government will accept the vials of bamlanivimab if it is granted an Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA). Lilly submitted a request for an EUA for bamlanivimab for the treatment of mild to moderate COVID-19 in high-risk patients to the FDA in early October. The initial agreement is for delivery over the two months following an EUA and also provides the option for the U.S. government to purchase up to an additional 650,000 vials through June 30, 2021…”
“Lilly anticipates manufacturing up to one million doses of bamlanivimab 700 mg by the end of 2020 – with 100,000 doses ready to ship within days of authorization – for use around the world.”
Given the confluence of preliminary scientific data from an interim analysis of Phase 2 study in outpatients published today, especially noting the lack of viral load reduction at day 11 with the 700 mg dose, and the stopping of the only study of hospitalized patients due to lack of benefit, a question arises. In the context of the U.S. government purchase of this monoclonal antibody and potential international availability, shouldn’t the FDA convene an independent expert advisory committee as soon as possible to advise on requests for Emergency Use Authorization for this and other monoclonal antibodies against SARS-CoV-2.
Daniel Lucey, M.D. MPH, FIDSA, FACP, is an infectious diseases physician and adjunct professor of infectious diseases at Georgetown University Medical Center, a senior scholar at the Georgetown University O’Neil Institute, Anthropology Research Associate, Smithsonian Museum of Natural History and a member of the Infectious Diseases Society of America Global Health Committee.He has served as a volunteer medical responder to outbreaks that included the West Africa Ebola crisis. He has collected information on outbreaks starting in 2001 with cases of anthrax in 2001, and including smallpox vaccination 2002, SARS 2003, H5N1 Flu 2004, MERS in 2013, and Ebola in April, 2014, He has gathered, and updated information on the spread of the coronavirus here since Jan. 6.