Feature

Sarilumab enters clinical trial for COVID-19, spotlighting 'key role' for IL-6

Cassandra Calabrese

The rheumatoid arthritis drug sarilumab is set to enter a clinical trial program for patients hospitalized with severe COVID-19 infection, according to a joint statement released by Regeneron Pharmaceuticals and Sanofi.

Sarilumab (Kevzara) — jointly developed Regeneron and Sanofi — is a fully human, monoclonal antibody that inhibits the interleukin-6 (IL-6) pathway by binding and blocking the IL-6 receptor. According to the pharmaceutical companies’ joint statement, IL-6 may play a role in driving the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19.

In an email, Cassandra Calabrese, DO, of the Cleveland Clinic, and Leonard Calabrese, DO, RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, and chief medical editor of Healio Rheumatology, wrote there is a growing body of reports showing the benefit of targeting the IL-6 pathway in patients with COVID-19, most notably in recent single-arm study in China.

“It appears that IL-6 may play a key role in driving the inflammatory response that leads to morbidity and mortality and patients with COVID-19 who develop acute respiratory distress syndrome,” they told Healio Rheumatology. “While we await evidence-based data, there have been reports of increasing experience using tocilizumab, another IL-6 inhibitor, to treat these patients with severe COVID-19 infection, including a non-peer-reviewed retrospective Chinese experience describing 21 COVID-19 positive patients with severe illness who received tocilizumab. They observed improvement in oxygenation and other clinical outcomes.”

 
The RA drug sarilumab is set to enter a clinical trial program for patients hospitalized with severe COVID-19 infection, according to a joint statement.
Source: Adobe

In that Chinese study, conducted by Xiaolong Xu, MD, of the First Affiliated Hospital of the University of Science and Technology of China, and colleagues, tocilizumab (Actemra, Genentech) was given to 21 patients with severe COVID-19, in addition to routine therapy, between Feb. 5 and Feb. 14. According to the researchers, fevers returned to normal and all other symptoms “improved remarkably” within a few days. Additionally, 75% of patients had lowered their oxygen intake and one patient no longer needed oxygen therapy. There were no obvious adverse reactions.

Nineteen patients were discharged after an average of 13.5 days following treatment, with the remainder “recovering well” as of the time of the study’s release, the researchers wrote.

Leonard Calabrese, DO
Leonard Calabrese

According to Cassandra Calabrese and Leonard Calabrese, the role of IL-6 in the integrated host defense is complex. A review article published in June 2017 in Nature Reviews Rheumatology, and co-authored by Calabrese, found that IL-6 has a role in both the innate and adaptive immune responses that protect the host from a variety of infections. Clinical studies of IL-6 inhibitors, specifically tocilizumab, reveal that their use is associated with an increased rate of both serious and opportunistic infections generally in the range observed with other non-IL-6 directed biologic therapies, the researchers wrote.

They added that targeting IL-6 has several other important clinical implications related to diagnosis, management and prevention of infectious diseases.

“Although the role of IL-6 clearly important in the integrated host defense against a variety of pathogens, extrapolation from genetic knockout models is problematic and not consistent with partial neutralization during periods of overproduction,” Cassandra Calabrese and Leonard Calabrese said. “The pathogenesis of progressive COVID-19 disease is still being investigated, but it appears that advanced disease states with hypoxemic pneumonia is associated with a marked pro-inflammatory state or ‘cytokine storm’ phenotype.”

“Given that in at least one other ‘cytokine storm clinical setting,’ such as the associated CAR T-cell therapy, IL-6 targeting was approved for use in 2017,” they added. “Based on this model and the preliminary observations from Chinese investigators, we believe this supports aggressive investigation of IL-6 targeting in those with advanced COVID-19 disease and a defined inflammatory phenotype. We applaud this aggressive strategy and eagerly look forward to seeing the data.”

According to Regeneron and Sanofi, the U.S.-based sarilumab trial will begin in New York and will assess the safety and efficacy of adding the drug to usual supportive care, compared with supportive care plus placebo.

The multicenter, double-blind, phase 2/3 trial will come in two parts. In part one, patients with severe COVID-19 recruited from 16 centers will be evaluated for fever and need for supplemental oxygen. The second, larger part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and hospitalization. The researchers anticipate enrolling up to 400 participants.

In addition to the sarilumab program, Regeneron is also advancing a novel antibody cocktail for the prevention and treatment of COVID-19, which the company hopes to have available for human testing this summer, according to the release.

“To initiate this trial quickly, so that the results may inform evidence-based treatment of this ongoing pandemic, Regeneron and Sanofi have worked closely with the U.S. FDA and the Biomedical Advanced Research and Development Authority, also known as BARDA,” George D. Yancopoulos, MD, PhD, co-founder, president and chief scientific officer of Regeneron, said in the press release.

“Data from China suggest that the IL-6 pathway may play an important role in the overactive inflammatory response in the lungs of patients with COVID-19,” he added. “Despite this encouraging finding, it’s imperative to conduct a properly designed, randomized trial to understand the true impact. Our trial is the first controlled trial in the United States to evaluate the effect of IL-6 inhibition prospectively in COVID-19 patients.” – by Jason Laday

Disclosures: Leonard Calabrese reports consulting relationships with AbbVie, Centecor Biopharmaceutical, Crescendo Bioscience, GlaxoSmithKline, Horizon Pharma, Janssen Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals and UCB. Cassandra Calabrese reports no relevant financial disclosures.

Cassandra Calabrese

The rheumatoid arthritis drug sarilumab is set to enter a clinical trial program for patients hospitalized with severe COVID-19 infection, according to a joint statement released by Regeneron Pharmaceuticals and Sanofi.

Sarilumab (Kevzara) — jointly developed Regeneron and Sanofi — is a fully human, monoclonal antibody that inhibits the interleukin-6 (IL-6) pathway by binding and blocking the IL-6 receptor. According to the pharmaceutical companies’ joint statement, IL-6 may play a role in driving the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19.

In an email, Cassandra Calabrese, DO, of the Cleveland Clinic, and Leonard Calabrese, DO, RJ Fasenmyer chair of clinical immunology at the Cleveland Clinic, and chief medical editor of Healio Rheumatology, wrote there is a growing body of reports showing the benefit of targeting the IL-6 pathway in patients with COVID-19, most notably in recent single-arm study in China.

“It appears that IL-6 may play a key role in driving the inflammatory response that leads to morbidity and mortality and patients with COVID-19 who develop acute respiratory distress syndrome,” they told Healio Rheumatology. “While we await evidence-based data, there have been reports of increasing experience using tocilizumab, another IL-6 inhibitor, to treat these patients with severe COVID-19 infection, including a non-peer-reviewed retrospective Chinese experience describing 21 COVID-19 positive patients with severe illness who received tocilizumab. They observed improvement in oxygenation and other clinical outcomes.”

 
The RA drug sarilumab is set to enter a clinical trial program for patients hospitalized with severe COVID-19 infection, according to a joint statement.
Source: Adobe

In that Chinese study, conducted by Xiaolong Xu, MD, of the First Affiliated Hospital of the University of Science and Technology of China, and colleagues, tocilizumab (Actemra, Genentech) was given to 21 patients with severe COVID-19, in addition to routine therapy, between Feb. 5 and Feb. 14. According to the researchers, fevers returned to normal and all other symptoms “improved remarkably” within a few days. Additionally, 75% of patients had lowered their oxygen intake and one patient no longer needed oxygen therapy. There were no obvious adverse reactions.

Nineteen patients were discharged after an average of 13.5 days following treatment, with the remainder “recovering well” as of the time of the study’s release, the researchers wrote.

Leonard Calabrese, DO
Leonard Calabrese

According to Cassandra Calabrese and Leonard Calabrese, the role of IL-6 in the integrated host defense is complex. A review article published in June 2017 in Nature Reviews Rheumatology, and co-authored by Calabrese, found that IL-6 has a role in both the innate and adaptive immune responses that protect the host from a variety of infections. Clinical studies of IL-6 inhibitors, specifically tocilizumab, reveal that their use is associated with an increased rate of both serious and opportunistic infections generally in the range observed with other non-IL-6 directed biologic therapies, the researchers wrote.

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They added that targeting IL-6 has several other important clinical implications related to diagnosis, management and prevention of infectious diseases.

“Although the role of IL-6 clearly important in the integrated host defense against a variety of pathogens, extrapolation from genetic knockout models is problematic and not consistent with partial neutralization during periods of overproduction,” Cassandra Calabrese and Leonard Calabrese said. “The pathogenesis of progressive COVID-19 disease is still being investigated, but it appears that advanced disease states with hypoxemic pneumonia is associated with a marked pro-inflammatory state or ‘cytokine storm’ phenotype.”

“Given that in at least one other ‘cytokine storm clinical setting,’ such as the associated CAR T-cell therapy, IL-6 targeting was approved for use in 2017,” they added. “Based on this model and the preliminary observations from Chinese investigators, we believe this supports aggressive investigation of IL-6 targeting in those with advanced COVID-19 disease and a defined inflammatory phenotype. We applaud this aggressive strategy and eagerly look forward to seeing the data.”

According to Regeneron and Sanofi, the U.S.-based sarilumab trial will begin in New York and will assess the safety and efficacy of adding the drug to usual supportive care, compared with supportive care plus placebo.

The multicenter, double-blind, phase 2/3 trial will come in two parts. In part one, patients with severe COVID-19 recruited from 16 centers will be evaluated for fever and need for supplemental oxygen. The second, larger part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and hospitalization. The researchers anticipate enrolling up to 400 participants.

In addition to the sarilumab program, Regeneron is also advancing a novel antibody cocktail for the prevention and treatment of COVID-19, which the company hopes to have available for human testing this summer, according to the release.

“To initiate this trial quickly, so that the results may inform evidence-based treatment of this ongoing pandemic, Regeneron and Sanofi have worked closely with the U.S. FDA and the Biomedical Advanced Research and Development Authority, also known as BARDA,” George D. Yancopoulos, MD, PhD, co-founder, president and chief scientific officer of Regeneron, said in the press release.

“Data from China suggest that the IL-6 pathway may play an important role in the overactive inflammatory response in the lungs of patients with COVID-19,” he added. “Despite this encouraging finding, it’s imperative to conduct a properly designed, randomized trial to understand the true impact. Our trial is the first controlled trial in the United States to evaluate the effect of IL-6 inhibition prospectively in COVID-19 patients.” – by Jason Laday

Disclosures: Leonard Calabrese reports consulting relationships with AbbVie, Centecor Biopharmaceutical, Crescendo Bioscience, GlaxoSmithKline, Horizon Pharma, Janssen Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals and UCB. Cassandra Calabrese reports no relevant financial disclosures.

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