Results of a futility analysis prompted Regeneron Pharmaceuticals Inc. to continue the phase III study of its virus-neutralizing monoclonal antibodies, a REGN-10933 and REGN-10987 cocktail for treating hospitalized COVID-19 patients who are seronegative and need low-flow oxygen.
Data from the analysis, taken from patients randomized in Regeneron’s phase I and II study of the antibodies, showed the casirivimab and imdevimab cocktail injection, REGN-COV2, was efficacious in reducing the incidence of death or the need for mechanical ventilation by half starting one week post treatment.
The analysis focused on seronegative COVID-19 patients, those without antibodies, at baseline. The results passed the futility analysis (p<0.3 one-sided).
The treatment reduced the time-weighted average daily viral load through day seven by -0.54 log10 copies/mL and through day 11 by -0.63 log10 copies/mL, producing a nominal p=0.002 for combined doses. At day five, the relative reduction compared to placebo was -1.1 log10 copies/mL, producing a nominal p=0.002 for combined doses.
Regeneron’s ongoing phase I/II/III study of the monoclonal antibody cocktail, an adaptive trial design, allows patients to be enrolled in more than one phase at a time. While the phase III is up and running, patients are still being enrolled in the phase II and III. The design allows for maximum flexibility and to gather data as quickly as possible during the pandemic, Hannah Kwagh, Regeneron senior communication manager, told BioWorld.
The randomized, double-blinded, the ongoing experiment is designed to measure the effect of adding REGN-COV2 to standard-of-care treatment compared to adding placebo.
The company said the cocktail, which has the FDA’s emergency use authorization for non-hospitalized yet high-risk COVID-19 patents, is the first antibody therapy demonstrating an antiviral effect in hospitalized COVID-19 patients.
While the data spurred Regeneron to continue its study, the company also sounded a cautionary note.
“It is important to remember that while the virology results from this analysis of hospitalized patients were robust, the clinical efficacy data are based on a small data set of events and cannot be viewed as conclusive at this stage,” according to George Yancopoulos, Regeneron’s president and chief scientific officer.
The much larger and U.K.-based Recovery trial, Yancopoulos added, should provide data to characterize the effect.
Investors and a few analysts shrugged at the new data. The typically resilient company stock (NASDAQ:REGN) dropped 1.22% to close at $478.30 per share on Dec. 30 though the year has seen a solid 28% uptick in the price.
Baird Equity Research analyst Brian Skomey wrote Dec. 30 that he is “profoundly skeptical” that monoclonal antibodies are the future of treating hospitalized COVID-19 patients. Like Yancopoulos, the small number of patients whose data was included in the analysis gave him pause but Skomey also expressed concern about patient safety, citing Eli Lilly and Co.’s monoclonal antibody bamlanivimab (LY-CoV555), whose NIH-sponsored phase III trial, ACTIV-3, testing bamlanivimab and Veklury in hospitalized COVID-19 patients was paused and then halted after data showed it was unlikely to help advanced patients.
Baird remains “deeply concerned about the safety risks persistent with the COVID-19 mAb class, particularly in hospitalized disease,” Skomey wrote.
Lilly and Vancouver-based Abcellera Biologics Inc. said on Dec. 22 that they plan to begin a new study of bamlanivimab in high-risk patients with COVID-19 to gather real-world evidence on the neutralizing antibody. It is currently authorized in the U.S. and Canada for treating mild to moderate COVID-19 patients who are at high risk for progressing to severe disease and/or hospitalization.
While the new analysis provided positive data, SVB Leerink analyst Geoffrey Porges wrote Dec. 30 that “it still leaves physicians with very little guidance about how and when to use the product. Even in hospitalized COVID patients on low flow oxygen, antibody titers and/or viral load titers are not widely available, and obtaining such titers seems to be a pre-condition for receiving any benefit from the treatment.”
Regeneron and their academic collaborators have failed to establish reliable clinical correlates for these biomarkers that separate responders and non-responders, Porges added.
“Given these obstacles, we believe revenue from the antibody cocktail will continue to fall short of supply, at least until the necessary biomarker assays are widely available,” he wrote.