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 top-line 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, which is marketed as Ilaris, has, in the correct settings, powerful anti-inflammatory effects. It has been approved for over a decade for treating cryopyrin-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 – although it failed to gain approval in this indication – 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 is less clear. At the outset of the pandemic, there was some evidence that IL-1beta was elevated in some patients with pneumonia and cytokine release syndrome, a Novartis spokesperson told BioWorld. “Due to the seriousness of the pandemic and the many unknowns about COVID-19, we believed conducting a large-scale confirmatory trial was extremely important.”

Subsequently, 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. That information was not known when Novartis initiated the study. It now states that the current results “are consistent with the latest evidence suggesting that targeting interleukins (such as IL-1) is not likely to be beneficial in patients with severe COVID-19,” the spokesperson said.

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. The subgroup analyses Novartis did conduct did not focus on immunological biomarkers. “In terms of sub-group analyses, these were conducted based on demography, baseline disease characteristics and use of concomitant therapies,” the Novartis spokesperson said. “There is no evidence to conclude potential benefit of canakinumab in the sub-groups investigated so far.”

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. It will not undertake any further development of the drug in COVID-19, however.

A broader approach to blocking IL-1beta

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 enrollment 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.

Whether a subtly different mechanism and a longer duration of treatment will work in a patient population with early stage disease is an open question for now.

Novartis, meanwhile, has several other COVID-19 drug development programs underway. It recently entered an alliance with Zurich, Switzerland-based Molecular Partners AG to develop two trispecific darpin molecules against SARS-CoV-2 targets. The first of these, MP-0420, which binds three different epitopes on the receptor binding domain, is due to enter a phase I trial this month. A phase III trial of the Janus kinase (Jak) inhibitor ruxolitinib, which it is conducting in partnership with Wilmington, Del.-based Incyte Corp., is ongoing.