DUBLIN – Kancera AB is the latest contender to reposition a clinical-stage small molecule with an immunomodulatory mechanism as a drug candidate for COVID-19. The Stockholm-based firm is planning a phase II trial of its fractalkine receptor inhibitor, KAND-567, to prevent hyperinflammation in COVID-19 patients before they develop full-blown acute respiratory distress syndrome (ARDS). “The goal is to prevent an escalation of the immune response and prevent progression to ventilation support and ICU,” Kancera CEO Thomas Olin told BioWorld.
As with so many other drug developers, the company has some clinical evidence suggestive of safety and target engagement, preclinical evidence that the molecule works in certain models of inflammation and autoimmune disease, and circumstantial evidence – which requires confirmation – that fractalkine could potentially play a role in COVID-19.
The company is operating on the basis that KAND-567 could prevent damaging infiltration of immune cells – particularly monocytes – into the lung tissue, which is a key driver of the COVID-19 pathology in patients who fail to clear the initial viral infection. “What we have to lean on is studies showing inhibition can reduce the infiltration into the vasculature of monocytes carrying the receptor. We have shown this in different disease models,” Olin said.
In non-COVID-19 clinical settings, elevated fractalkine levels have been observed in ARDS and sepsis, both of which are life-threatening consequences of hyperinflammation. “High fractalkine levels are markers of poor prognosis,” Olin said. Circulating monocytes are the likely culprit. Those express high levels of fractalkine receptor and are attracted to sites of inflammation by the release of soluble fractalkine ligand, a chemokine also known as CX3CL1. The latter also exists in membrane-bound form, and that assists the extravasation of monocytes across the endothelial barrier and into the alveoli, where they differentiate into macrophages and further fuel the immune cascade.
That, at least, is the presumed pathological mechanism that Kancera aims to disrupt. The upcoming trial will be conducted in just one clinical center, Capio St. Görans Hospital AB in Stockholm, under the leadership of clinical investigators Mantas Okas and Mats Wistrand. The center is highly experienced in managing COVID-19, having treated 4,000 patients so far. Petter Brodin, at the Science for Life Laboratory and Karolinska Institute, will provide scientific support by analyzing patients’ genetic and immunological profiles during the study. “We will have a very detailed mapping of the response to the drug and the disease,” Olin said.
The study is still waiting on regulatory approval from the Sweden’s Medical Products Agency, although it usually turns around applications quickly. “We are more or less ready to start, as soon as we get approval,” Olin said. The trial will randomize 40 patients, in a 1-to-1 ratio, to receive either oral KAND-567 plus best supportive care or best supportive care only. The study has an open-label design because of the absence of an available placebo that would visually resemble the experimental drug. “From an ethical perspective, there is no reason to wait another three months to produce the placebo,” Olin said. What’s more, the study will evaluate numerous objective measures of lung function and oxygenation and will follow more than 50 biomarkers.
The study will recruit COVID-19 patients with hypoxia who have failed to clear the initial infection and are in the early stages of or at risk of developing a hyperinflammatory response. “You can define them by CRP [C-reactive protein] level, for example, and you can define them by oxygen saturation,” said Olin. Patients with <94% oxygen saturation or who need 1 liter to 6 liters of supplemental oxygen per minute to maintain oxygen saturation levels between 93% and 96% will be eligible to participate. Data are expected later this year.
COVID-19 now represents the fourth lead indication for KAND-567. It was originally conceived by Cambridge, U.K.-based Astrazeneca plc as a multiple sclerosis drug. Kancera took on the asset when it was still preclinical and planned initially to move it into immuno-oncology. However, a study with clinical collaborators in the U.K. suggested a key role for fractalkine in the hyperinflammation that can arise after percutaneous coronary intervention (coronary angioplasty) treatment following myocardial infarction. Kancera still plans to undertake a study in that indication, but that has now been pushed back to next year.
Tokyo-based Eisai Co. Ltd. is developing an antibody-based fractalkine inhibitor that acts on the ligand rather than the receptor. E-6011 has completed phase II trials in Crohn’s disease and rheumatoid arthritis, and has induced remission in Crohn’s patients, Olin said.