DUBLIN – Top-line data from a placebo-controlled phase II trial of Vicore Pharma Holding AB’s angiotensin II type two receptor (AT2R) agonist, C21, provide preliminary evidence that the oral drug may provide benefit to patients with severe COVID-19 disease on top of steroid therapy.

The study recruited 106 hospitalized patients who were not in need of mechanical invasive or non-invasive ventilation at randomization. The primary endpoint was a change from baseline in levels of C-reactive protein (CRP) after seven days of therapy.

The Gothenburg, Sweden-based company reported Dec. 8 that 14 of 51 patients (27%) on a twice-daily dose of the drug (n=51) plus standard of care required oxygen therapy at the end of the treatment period vs. 22 of 55 patients (45%) in the control arm. That corresponds to a 40% relative risk reduction, an effect, the company said, that was “statistically significant (p=0.057) at the 10% level as predefined in the statistical analysis plan.”

Carl-Johan Dalsgaard, CEO, Vicore

Although that falls below the probability threshold generally required for drug approval, it is, CEO Carl-Johan Dalsgaard told a conference call audience, standard for a phase II trial with low patient numbers and highly variable disease to designate a “p” value <0.1 as being statistically significant. “This is something we had pre-planned for,” he said. It provides the company with sufficient confidence to progress to a phase II/III pivotal trial next year.

Vicore also observed numerical trends in favor of the drug in two other key clinical outcomes. Just one of the patients in the active treatment arm required mechanical ventilation whereas four in the control group did. There was one death in the active treatment arm (the same patient who also required ventilation) as compared with three in the control group. Neither result was statistically significant, however, given the low numbers involved. “These data all point in the same direction,” Dalsgaard said.

C21 had no effect on CRP levels, the primary endpoint of the study. Nor were there any differences between the two study arms in levels of interleukin-6 or tumor necrosis factor-alpha, two inflammatory cytokines that are associated with severe disease. The company attributed those findings to the use of immunosuppressive corticosteroid therapy in the vast majority (>100/106) of patients. Steroid use had become standard of care after the company finalized its study design, but it decided to continue the trial rather than delay it by amending the protocol.

The seven-day treatment period, followed by a seven- to 10-day follow-up, appears relatively short compared to trials of other COVID-19 drugs, particularly given the disease course, which can take much longer than two weeks. The study was intended to be “lean and mean,” Dalsgaard said, to minimize disruption to the treating centers, given the war zone conditions in which doctors were operating.

Vicore will conduct a follow-up analysis of lung scan data at 24 weeks to analyze whether C21 had any effect on the development of lung fibrosis. “It’s another shot on goal for the study we have completed,” Dalsgaard said.

It is also working on a phase II/III protocol, which it hopes to finalize within the first half of next year. That study will involve two weeks of treatment followed by weeks of follow-up. Dalsgaard dismissed any suggestions that the imminent rollout of vaccines will render it futile. “I see the pandemic going on for the next year definitely – hopefully not increasing at the pace at which it has progressed in the last few weeks,” he said. The pivotal trial, which will include U.S. clinical centers, will employ changes to the eight-point ordinal scale for clinical improvement as the primary endpoint.

Restoring Ras balance

The scientific rationale for the study is directly linked to the biology of COVID-19. The SARS-CoV-2 virus enters lung epithelial cells – and cells in other tissues – by binding angiotensin converting enzyme 2 (ACE2), which is part of the “type 1 receptor rescue system” in the renin-angiotensin system (Ras). That, according to Vicore, impedes ACE2 activity, which results in overstimulation of the type 1 system and to damaging inflammatory effects that can lead to cytokine storm. C21, a first-in-class drug, may act by stimulating the other arm of the Ras system, the “protective type 2 system,” and restoring the overall balance of the Ras system, which is responsible for controlling blood pressure and fluid and electrolyte balance.

The same compound (also called VP-01) is undergoing phase II studies in patients with idiopathic pulmonary fibrosis and in patients with Raynaud’s syndrome secondary to systemic sclerosis.

Shares in Vicore (Stockholm:VICO) closed Dec. 8 at SEK25 (US$2.95), a gain of 22.5% on the stock’s previous close.