Sanofi and Regeneron Pharmaceuticals said Monday that preliminary results from the Phase II portion of an ongoing study showed that the IL-6 receptor antibody Kevzara (sarilumab) had "no notable benefit" on clinical outcomes versus placebo in hospitalised patients with severe or critical respiratory illness caused by COVID-19. Meanwhile, French researchers conducting a separate trial of Roche's Actemra (tocilizumab), an IL-6 receptor antagonist, reported that the drug significantly improved clinical outcomes in patients suffering from moderate-to-severe COVID-19 pneumonia.
George Yancopoulos, chief scientific officer at Regeneron, remarked "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." In the meantime, Sanofi and Regeneron said that following a review of all available data by an independent data monitoring committee (IDMC), the study will be immediately amended so that only critical patients continue to be enrolled, with more than 600 already registered, and these will receive either the higher dose of Kevzara that was being tested or placebo.
In the trial, which was conducted in the US, 457 hospitalised patients with COVID-19 were randomised to receive Kevzara, administered intravenously at doses of 200 mg or 400 mg, or placebo. Sanofi and Regeneron noted that 28% of patients had severe illness, meaning they required oxygen supplementation without mechanical or high-flow oxygenation, while 49% were deemed critical, which meant they needed mechanical ventilation or high-flow oxygenation, or required treatment in an intensive care unit. Another 23% of patients in the study had multi-system organ dysfunction. The companies noted that baseline levels of IL-6 were elevated across all treatment arms, with higher levels observed in critical patients than severe patients.
The primary goal was reduction in C-reactive protein (CRP), while exploratory endpoints in the critical group included death, being on a ventilator, clinical improvement, being off a ventilator and hospital discharge. Analysis of clinical outcomes in the Phase II portion of the trial was focused on the severe and critical groups. Sanofi and Regeneron said that there were "negative trends" for most outcomes in the severe group, while "positive trends" were seen for all outcomes in the critical group. The companies added that following the IDMC review, their own analysis of the discontinued severe group that revealed the negative trends in the Phase II portion were not reproduced in Phase III, with clinical outcomes balanced across all treatment arms.
Specifically for the primary endpoint, the companies reported that CRP levels fell by 77% and 79% in the 200-mg and 400-mg Kevzara dose groups, versus a decline of 21% for placebo. Meanwhile, in the critical group, rates of patients who either died or were required to be on a ventilator were 46% for the 200-mg Kevzara group, 32% for the higher-dose arm, and 55% for placebo. Clinical improvement, as measured by a two-point improvement on a seven-point scale, was seen in 51% and 59% of patients in the low- and high-dose Kevzara groups, versus 41% for placebo. Further, 43% of patients in the low-dose arm were off oxygenation, compared with 58% for the 400-mg group and 41% in the placebo arm, while discharge rates were 39%, 53% and 41%, respectively.
"There's still hope it might help, but more modest than people hoped," Yancopoulos said, adding that Kevzara "doesn't look like the magic panacea that everyone would've wanted for the pandemic." Results from the Phase III portion of the US trial, which has already enrolled more than 600 patients in the critical group, are expected by June. A second late-stage trial of Kevzara outside the US in approximately 400 patients hospitalised with COVID-19 infection is currently enrolling in Italy, Spain, Germany, France, Canada, Russia, Israel and Japan, with preliminary results slated for the third-quarter. The companies noted that similar amendments to the trial outside the US will be considered.
Meanwhile, researchers in France reported early results from the CORIMUNO-TOCI trial testing Actemra in 129 patients with COVID-19 pneumonia. Participants, who were hospitalised for COVID-19-related moderate-or-severe pneumonia not requiring intensive care upon admission, were randomised to receive standard-of-care, either with or without Actemra. The primary composite outcome was the need for either non-invasive or mechanical ventilation or death at the 14-day mark.
Investigators stated that a significantly lower proportion of patients reached the primary outcome in the Actemra arm than in the comparator group. They noted that results of the study will be submitted for publication in a peer-reviewed journal, but that they should be confirmed independently by additional trials. Last month, the FDA allowed the so-called COVACTA trial of Actemra to move ahead, testing Roche's drug plus standard care in adults hospitalised with severe COVID-19 pneumonia.
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