DUBLIN – Canakinumab, an interleukin-1 beta (IL-1beta) inhibitor, has joined a growing list of immunomodulatory therapies that have failed to demonstrate efficacy in COVID-19. Novartis AG said that an interim analysis showed the drug did not meet the primary endpoint of clinical response, defined as survival without the need for mechanical ventilation up to day 29 in the placebo-controlled phase III CAN-COVID trial (NCT04362813). The drug also failed on a key secondary endpoint, reduction in COVID-19-related death within four weeks after the treatment period. The study, which was conducted in the U.S., Europe and Russia, recruited 454 COVID-19 patients with cytokine release syndrome as a consequence of pneumonia.

The topline data, which Basel, Switzerland-based Novartis released on Nov. 6, trended in favor of canakinumab, but they were not statistically significant. The rate of survival without the need for mechanical ventilation was 88.8% for those in the drug treatment arm, vs. 85.7% for those in the placebo arm (p=0.29). The four-week COVID-19-related mortality rate was 4.9% for those on drug plus standard of care (SOC) vs. 7.2% for those on placebo plus SOC (p=0.33).

The study recruited patients who were hospitalized and had low blood oxygen levels but who were not in immediate need of intubation. The study recruited a heterogeneous patient population – 30% of the participants were Hispanic, 16% were African American and 4% were Asian. The eligibility criteria included confirmed SARS-CoV-2 infection, low oxygen saturation and evidence of inflammation as measured by C-reactive protein or ferritin levels.

Canakinumab has, in the correct settings, powerful anti-inflammatory effects. It has been approved for over a decade for treating cyropyrin-associated periodic syndromes (Caps), a set of inherited auto-inflammatory conditions arising from mutations in cryopyrin. The protein is now better known as the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), the key component of the NLRP3 inflammasome, an intracellular pro-inflammatory complex, which undergoes assembly and activation in response to danger signals from pathogens, environmental toxins or endogenous sources. When activated, it triggers the maturation of IL-1b and another pro-inflammatory cytokine, IL-18, and it also drives pyroptosis, an inflammatory cell death program.

More recently, Novartis has shown that canakinumab has effects on cardiovascular disease and it is currently investigating its potential in non-small cell lung cancer. In both of these settings, canakinumab is acting on chronic inflammation. But the importance of IL-1beta in the acute pathology of COVID-19 has not been definitively established. An influential study conducted at the Icahn School of Medicine at Mount Sinai, New York, identified high baseline levels of IL-6 and tumor necrosis factor alpha (TNF-alpha) as being most strongly predictive of a poor prognosis in a study involving 1,484 patients. IL-1beta levels were, the study authors reported, “mostly low or at the limit of detection” of the assay they employed.

In the CAN-COVID study, baseline cytokine profiles were not measured, which means that any potential efficacy signal may have been missed. It’s a common feature of studies of cytokine-directed therapies in COVID-19. There has been no stratification of patients on the basis of their inflammatory signatures, but there is evidence that cytokine release syndrome, which a critical driver of COVID-19 pathology and mortality, varies considerably from patient to patient.

Novartis is following patients up to day 127, and the final dataset is expected early next year, but Novartis plans to submit the current data for publication in a peer-reviewed journal. Olatec Therapies LLC, of New York, is also focused on blocking IL-1beta in COVID-19, but it is taking a broader approach by testing an oral, small-molecule NLRP3 inflammasome inhibitor, dapansutrile. It recently opened enrolment onto a phase II trial in 80 ambulatory patients with moderate disease who have not been hospitalized but who exhibit early signs of cytokine release syndrome. The participants will receive a daily dose of drug over 14 days. In the CAN-COVID trial, in contrast, participants only received a single infusion of canakinumab.