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Novartis’s anti-inflammatory drug canakinumab has failed to cut deaths in a trial involving critically ill COVID-19 patients with pneumonia and cytokine release syndrome (CRS).

The CAN-COVID study involved 454 patients at multiple centers across the US, Russia and Europe who were hypoxic but not requiring intubation or invasive mechanical ventilation. The trial was designed with the aim of ensuring patients' condition did not deteriorate further and lead to deaths, but failed to show an impact on survival.

An interim analysis of the randomized, double-blind, placebo-controlled trial found the drug failed to meet its primary endpoint of improving survival for patients without the need for invasive mechanical ventilation, compared with placebo plus standard of care (SoC) up to day 29.

Neither did it meet its key secondary endpoint of reducing the COVID-19-related death rate during the four-week period after treatment. A follow-up period up to day 127 after treatment is ongoing, with full results expected in early 2021, but is not expected to change the overall conclusion of the study.

Canakinumab is already licensed under the brand name Ilaris as a treatment of systemic juvenile idiopathic arthritis and active Still's disease. The monoclonal antibody blocks interleukin-1 beta, excessive production of which plays a role in some inflammatory diseases and immune responses.

The results represent another disappointment among existing drugs which have been repurposed to treat the most critically ill COVID-19 patients, and follows failures from numerous other anti-inflammatory drugs. These include most notably the IL-6 inhibitor class, where Roche’s Actemra (tocilizumab) and Regeneron/Sanofi’s Kevzara (sarilumab) have also failed to show clear benefits for these patients.

Roche did register its first trial success with Actemra in September, though the results were far from clear cut. (Also see "First COVID-19 Trial Success For Roche’s Actemra, But No Sign It Saves Lives" - Scrip, 18 Sep, 2020.)

While there have been no pharma industry-led breakthroughs for these patients, the UK’s academic-led RECOVERY trial showed earlier this year that the corticosteroid dexamethasone can help save lives. The study showed the drug can cut deaths by a third in COVID-19 patients who are ventilated and by one fifth in those receiving oxygen. While RECOVERY did not specifically target patients with pneumonia and CRS, it is believed that the corticosteroid improves tissue injury associated with the uncontrolled release of proinflammatory cytokines seen in CRS.

John Tsai Novartis

JOHN TSAI Novartis

John Tsai, head of global drug development for Novartis, said the CAN-COVID results were disappointing but added to the scientific understanding of COVID-19.

Tsai added that the company would continue to apply its “best scientific minds in support of the global pandemic response.” This includes a Phase III trial of ruxolitinib, its JAK-1/JAK-2 inhibitor, which is already marketed as Jakavi for myelofibrosis. (Also see "Coronavirus Update: Novartis Joins Antiviral Therapies Search With Novel DARPin Alliance" - Scrip, 28 Oct, 2020.)

In the CAN-COVID trial, the primary endpoint of survival without the need for mechanical ventilation was 88.8% for canakinumab plus SoC vs 85.7% for placebo plus SoC (P=0.29). The key secondary endpoint of COVID-19-related mortality up to four weeks was 4.9% for canakinumab plus SoC vs 7.2% for placebo plus SoC (P=0.33). Both the primary and key secondary endpoints trended in favor of canakinumab but did not reach statistical significance. No new safety signals were identified.

Novartis said that the interim analysis will be submitted to a peer-reviewed journal in the coming weeks. The company is looking to expand the drug’s use and said the CAN-COVID results do not affect any other ongoing trials for canakinumab, including investigations for the treatment of non-small cell lung cancer.

Many more companies are conducting trials to develop new therapies or repurpose existing drugs for hospitalized COVID-19 patients, with a variety of anti-inflammatory mechanisms being investigated. These include Alexion., which is conducting a Phase III trial of  Ultomiris (ravulizumab), a C5 complement inhibitor, in hospitalized patients with severe pneumonia or acute respiratory distress syndrome, with interim results expected in early 2021.

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