DUBLIN – The most solid conclusion that can be drawn from Immunic Inc.’s phase II trial of IMU-838 in hospitalized COVID-19 patients is that a reduction in the need for invasive ventilation is no longer a useful endpoint for studies of COVID-19 drugs.

The study randomized 233 hospitalized patients with moderate disease to receive either a twice daily dose of IMU-838 (vidofludimus calcium), an oral dihydroorotate dehydrogenase (DHOD) inhibitor, or placebo, over a 14-day treatment period. The primary endpoint was the proportion of patients without any need for invasive ventilation at any point throughout the 28-day study.

The efficacy of the drug on this measure was not evaluable, however, due to the trial’s extraordinarily low event rate. Of 204 participants analyzed, less than 1% of those enrolled required ventilation during the study, which, trial sponsors Immunic Inc., noted, was in marked contrast to the relatively high rates of ventilation reported in the first COVID-19 wave in early 2020. The outcome was consistent with other recent third-party trials, the company added.

At the outset of the Immunic trial, the main fears were the looming global shortage of ventilators and ICU capacity.

Andreas Muehler, chief medical officer, Immunic

“We all had this mindset where our resources would never be enough to deal with this situation,” Immunic chief medical officer Andreas Muehler told BioWorld.

Much has changed in the interim, however. The trial protocol allowed for physician’s choice of standard of care therapy. That, combined with the clinical experience developed in managing patients over the past 12 months, was the study’s undoing in terms of establishing efficacy on the main endpoints. Any therapy with an emergency use authorization, apart from hydroxychloroquine, was permitted. About 20% of study participants received antiviral therapies, Muehler said, while about two-thirds received dexamethasone or other corticosteroids.

The study, which was conducted in 20 centers in the U.S. and Europe, also failed to demonstrate any difference between IMU-838 and placebo on two key secondary endpoints, 28-day survival and the need for ICU care. Immunic again attributed these outcomes to very low event rates. The 28-day mortality rate on the trial was less than 2%, while less than 4.5% of trial participants were admitted to ICU.

A way forward?

Immunic, of New York, nevertheless, claimed that the study uncovered signs of efficacy based on additional clinical, biochemical and virological parameters.

Daniel Vitt, CEO, Immunic

“Yes, we clearly see a way forward,” CEO Daniel Vitt told BioWorld. “The majority of the signals are going in the same direction.” IMU-838 has both antiviral and anti-inflammatory effect. It disrupts replication of actively dividing cells – or viruses, by starving them of pyrimidine.

Those on IMU-838 were more likely to achieve clinical recovery within 28 days – 71.3% of those on the drug (n=57) achieved this endpoint, as compared with 66.7% of those in the control arm (n=58). The proportion of patients reaching clinical improvement at 28 days was 90.9% for those on drug (n=90), as compared with 87.4% for those on placebo (n=90). It also reported that, for high-risk patients, the 75% probability of reaching clinical improvement was accelerated by 3.8 days for those on drug as compared to those on placebo. Elderly patients (>65 years) on drug also attained clinical improvement more rapidly than those on placebo.

A post-hoc analysis indicated a possible effect on post-viral fatigue, one of the key effects of ‘Long Covid.’ This was conducted in a small sub-group – just 36 patients – but it found that 80% of those in the placebo group reported that problem, as did 50% of those on active treatment. There were no new or significant safety concerns – the drug “was found to be safe and well-tolerated” in the study population, Immunic said.

Whether these effects represent any clinically meaningful addition to the currently available therapies is moot. “It’s important to get feedback from regulators to my mind,” Muehler said.

Some investors weren’t inclined to wait. The stock (NASDAQ:IMUX) was off by about 20% during trading on Feb. 17. A final analysis of the full dataset involving 223 patients is expected in the second quarter.

IMU-838 has the same immunomodulatory mechanism as Aubagio (teriflunomide), an oral drug marketed by Paris-based Sanofi SA, which has attained blockbuster status in multiple sclerosis. Both target DHOD, a mitochondrial enzyme involved in pyrimidine biosynthesis. The two molecules mediate their anti-inflammatory effects by selectively hitting rapidly dividing cells, such as immune effector cells during inflammation, leading to reductions in interleukin 17 (IL-17) and interferon-gamma production. Immunic claims IMU-838 offers a superior safety profile than Aubagio, which can cause liver toxicity in a small number of patients. It plans to start a phase III trial of IMU-383 in MS by the third or fourth quarter.