Preliminary data from the first part of a phase II/III trial testing the interleukin-6 (IL-6) receptor antibody Kevzara (sarilumab, Regeneron Pharmaceuticals Inc. and Sanofi SA) in patients with severe or critical respiratory illness caused by COVID-19 found that, relative to a placebo, the medicine "had no notable benefit on clinical outcomes" among that combined group. In some cases in the phase II part of the trial, patients treated with Kevzara did even worse than those on placebo on some exploratory measures.
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 (tocilizumab, Roche Holding AG), led to rapidly reduced fever and improved oxygenation, allowing for successful hospital discharge.
Following a review of the study by its independent data monitoring committee of all available phase II and phase III data, the trial will be immediately amended so that only critical patients continue to be enrolled to receive Kevzara 400 mg or placebo. The ongoing portion of the phase III trial, which is continuing to enroll, currently includes more than 600 patients in the critical group – those who require mechanical ventilation, high-flow oxygenation, or required treatment in an intensive care unit. Regeneron and Sanofi remain blinded to the ongoing portion of the study and expect to report results by June, they said.
Though having earlier characterized Actemra to have "remarkable benefits and effects" against COVID-19, Regeneron President and Chief Scientific Officer George Yancopoulos struck a more moderate tone evaluating the current state of affairs.
"Emerging evidence with Kevzara and other repurposed drugs in the COVID-19 crisis highlight the challenges of making decisions about existing medicines for new viral threats using small, uncontrolled studies," he said. "We await results of the ongoing phase III trial to learn more about COVID-19, and better understand whether some patients may benefit from Kevzara treatment."
Furthermore, Yancopoulos said, "there is an acute need for tailored approaches that specifically target this virus." To that end, Regeneron is advancing development of a targeted anti-SARS-CoV-2 antibody cocktail that it plans to begin trials of in June. In late March, the company said it had identified hundreds of virus-neutralizing antibodies and expected to begin initial trials by early summer.
"Although this might come as a relative disappointment to some – especially given the heightened sensitivities around COVID-19 – we believe REGN may have a better shot treating this pandemic with its antibody cocktail," said J.P. Morgan analyst Cory Kasimov.
On Monday, Regeneron shares (NASDAQ:REGN) fell $18.69, or 3.3% to $547.52, while Sanofi shares (NASDAQ:SNY) rose 78 cents, or 1.6%, to $50.63.
Regeneron and Sanofi co-developed Kevzara and, beginning with its May 2017 FDA approval, co-commercialized the fully human monoclonal antibody. By binding to the IL-6 receptor, it inhibits IL-6-mediated signaling – a feature that has proved beneficial in its approved indication, rheumatoid arthritis, where IL-6 is a signaling protein produced in increased quantities and has been associated with disease activity, joint destruction and other systemic problems.
In the phase II/III study, baseline levels of IL-6 were elevated across all treatment arms, and higher levels were observed in "critical" patients compared to "severe" patients.
It's not yet clear whether other IL-6 antibodies will see similar outcomes to what Regeneron and Sanofi have seen with Kevzara. In late March, Roche started its own randomized, double-blind, placebo-controlled test of Actemra. The phase III trial is testing the drug on top of standard of care in hospitalized adults with severe COVID-19 pneumonia vs. placebo plus standard of care. Results are expected in early summer.
Other IL-6 candidates in development for COVID-19 include Hemel Hempstead, U.K.-based Eusa Pharma Inc.’s siltuximab and London-based Tiziana Life Sciences plc’s TZLS-501.
At the beginning of April, Eusa said that preliminary results of a trial testing its FDA- and EMA-approved IL-6 antibody, siltuximab, in COVID-19 patients found the drug helped one-third of patients in an observational trial improve, with a reduced need for oxygen support, while 43% (n=9) saw their condition stabilize. A worsening of the disease was seen in 15% of patients, while one patient died, and one experienced a cerebrovascular event.
Tiziana said Monday that it has filed a provisional patent application on its combination of nanoparticle-actinomycin D with an anti-IL-6 receptor monoclonal antibody as a potential therapy for management of COVID-19 disease. The underlying invention concepts are based on the hypothesis that a combination of an antiviral drug controlling proliferation of COVID-19 with an anti-inflammatory agent suppressing a possible cytokine storm may provide immediate relief to severe cases of COVID-19 patients, the company said. Safety and tolerability of the combination remain to be evaluated in healthy volunteers prior to clinical studies.