Missing the primary endpoint along with key secondary endpoints in a phase III trial of Kevzara (sarilumab), an interleukin-6 (IL-6) receptor antibody, for treating COVID-19 patients who need mechanical ventilation caused Regeneron Pharmaceuticals Inc. and Sanofi SA to halt the study.
Tarrytown, N.Y.-based Regeneron then followed the closing by initiating two late-stage studies, a phase III and a phase II/III, to evaluate REGN-CoV2, a double antibody cocktail for treating and preventing COVID-19.
The stumble produced a good day for Tiziana Life Sciences plc (NASDAQ:TLSA), whose stock rose 9.6% July 6, closing at $7.19 a share. London-based Tiziana is developing its own anti-IL-6 receptor monoclonal antibody, TZLS-501, to be delivered directly into the lungs of a COVID-19 patient using an inhaler or nebulizer. In April, the company filed a patent application to support the treatment.
H.C. Wainwright and Co. analyst Raghuram Selvaraju wrote Monday morning that he believes “TZLS-501 may prove successful where Kevzara failed.” He also noted that TZLS-501 may also demonstrate superior efficacy to Actemra (tocilizumab) from Roche Holding AG, which is in late-stage development for treating coronavirus patients and is also being tested in combination with Gilead Sciences Inc.’s remdesivir.
“TZLS-501, a unique and best-in-class anti-IL-6R mAb, follows a dual mechanism by not only blocking downstream signaling pathways from membrane-bound and soluble IL-6 receptors but also rapidly depleting bloodstream (i.e., systemic) levels” of IL-6, Selvaraju added.
The study of Kevzara, a drug usually prescribed for treating rheumatoid arthritis, had problems before this halt. The study was amended in late April after an independent data monitoring committee reviewed all the available phase II and phase III data and found that, compared to placebo, the treatment “had no notable benefit on clinical outcomes” in patients with severe or critical respiratory illness caused by COVID-19. The study was tweaked immediately afterward so that only critically ill COVID-19 patients would be enrolled to receive Kevzara or placebo.
In the amended study results, there were some minor positive trends noted in the primary prespecified analysis group, which were critical patients receiving Kevzara 400 mg and were mechanically ventilated at baseline, that failed to reach statistical significance. However, negative trends in the subgroup of critical patients not mechanically ventilated at baseline countered the positive ones.
The trial’s primary analysis group included 194 patients who were critically ill with COVID-19 and receiving mechanical ventilation at the time they were enrolled. The primary endpoint was an assessment of patients achieving at least a one-point change, on a seven-point scale, from baseline. The scale included death; those hospitalized requiring invasive mechanical ventilation or extracorporeal membrane oxygenation; those hospitalized, requiring non-invasive ventilation or high-flow oxygen devices; those hospitalized requiring supplemental oxygen, not requiring supplemental oxygen but requiring ongoing medical care (COVID-19 related or otherwise); those hospitalized and not requiring supplemental oxygen and no longer requiring ongoing medical care; and those discharged from hospital.
Eighty percent of Kevzara patients had an adverse event with the treatment, as did 77% of the placebo group. Serious adverse events occurred in at least 3% of patients, and more frequently among the Kevzara patients were multi-organ dysfunction syndrome (6% Kevzara, 5% placebo) and hypotension (4% Kevzara, 3% placebo).
The trial’s halt included a second, only partially recruited patient cohort receiving an 800-mg dose of Kevzara or placebo.
The trial was designed after a small, single-arm study in China among mostly severe COVID-19 patients found elevated IL-6 levels and suggested that inhibiting the pathway with a different IL-6 inhibitor, Actemra, led to rapidly reduced fever and improved oxygenation, allowing for successful hospital discharge.
Regeneron gets back in the COVID-19 race with REGN-CoV2 in two studies. A phase III trial of REGN-CoV2 is designed to evaluate its ability to prevent infection among uninfected people who have had close exposure to a COVID-19 patient. The late-stage trial is being run with the National Institute of Allergy and Infectious Diseases, which is part of the U.S. NIH.
REGN-CoV2 has shifted into the phase II/III portion of two adaptive phase I/II/III trials testing the cocktail's ability to treat hospitalized and non-hospitalized COVID-19 patients. The shift follows a positive review from an independent data monitoring committee of REGN-CoV2 phase I safety results in an initial cohort of 30 hospitalized and non-hospitalized COVID-19 patients.
The REGN-CoV2 cocktail is composed of two antibodies taken from genetically modified mice and humans who recovered from COVID-19. The treatment is designed to bind to the virus’ spike protein.