DUBLIN – Apeiron Biologics AG reported March 12 that APN-01, recombinant angiotensin converting enzyme 2 (ACE2; alunacedase alfa) failed to attain the primary endpoint of lowering all-cause death or the need for invasive mechanical ventilation in hospitalized patients with severe COVID-19.

Although there was a numerical difference between the two study arms – nine (10%) of those on APN-01 (n=88) vs. 12 (13%) of those on placebo (n=90) experienced one or both of those two events – it was not deemed to be statistically significant. At the same time, the Vienna-based company still maintains that it has an active drug on its hands, and it is seeking more funding to take the program forward. “The vaccines have got hundreds of millions in support. The therapeutics have got tens of millions,” Apeiron CEO Peter Llewellyn-Davies told BioWorld.

The molecule did attain statistical significance on a number of secondary endpoints, reduction in the number of ventilation-free days during the 28-day study period and a reduction in viral load at day three and day five of the seven-day treatment period. Patients on the drug also tended to recover more quickly than those on placebo, as measured retrospectively by the WHO’s 11-point disease severity scale. The ordinal scale was not in place at the outset of the study, so it was not possible to include this measure prospectively.

Peter Llewellyn-Davies, CEO, Apeiron

“These are very promising data,” Llewellyn-Davies said. The company will consult with key opinion leaders and regulators before deciding on its next steps, while completing the data analysis.

The present trial followed an investigator-initiated study in China and a case report published on Nov. 1, 2020, in The Lancet Respiratory Medicine. In the latter, the study investigators noted that the virus disappeared rapidly from the serum following administration of therapy, although it was cleared more slowly from the nasal cavity and the lungs. Apeiron is also developing an alternative formulation of APN-01 for inhalation, which might have a faster onset of action. “We’re working on that in parallel,” Llewellyn-Davies said. “We’re ready to go.”

The trial illustrates the difficulties many drug developers have faced in their efforts to uncover efficacy signals for investigational drugs when background therapy and management are changing rapidly. When the company was developing the phase II protocol last March, death and mechanical ventilation were the two biggest issues facing clinicians grappling with the first wave of the disease, Llewellyn-Davies said, but standard of care evolved rapidly in the interim. The U.K. Recovery trial and subsequent studies established a strong evidence base to support the use of corticosteroids to reduce death and speed recovery, which has lowered the event rate in other trials examining those endpoints.

The rationale for testing APN-01 in COVID-19 had several dimensions. Given that ACE2 is the key receptor by which SARS-CoV-2 achieves cellular entry, through binding of its spike protein, a circulating form of the protein could conceivably act as a decoy receptor and prevent at least some virus from entering some airway epithelial cells. But its effects on the renin angiotensin system (RAS), which controls blood pressure and fluid balance, may be more relevant. ACE2 catalyzes the conversion of the vasoconstrictive hormone angiotensin II to angiotensin, and Apeiron’s scientific founder, Josef Penninger, of the University of British Columbia, Vancouver, previously reported during the original SARS outbreak that ACE2 protected mice against lung failure. It also has anti-inflammatory effects.

But whether those effects add up to a clinically meaningful signal is still in question. The drug, which was previously licensed to London-based Glaxosmithkline plc, failed to demonstrate efficacy in patients with acute lung injury or acute respiratory distress syndrome.

Gothenburg, Sweden-based Vicore Pharma Holding AB is also accessing the RAS system, but through the angiotensin II receptor type 2 (AT2) rather than ACE2, which also has protective effects in the lung. It reported last year that its oral AT2 receptor agonist C21 reduced the need for oxygen therapy in hospitalized patients who were not in need of ventilation at baseline. It is now planning a phase III trial.

Meanwhile, Boehringer Ingelheim GmbH has terminated development in COVID-19 of BI-764198, a first-in-class inhibitor of transient receptor potential canonical type 6 (TRPC6), following an interim analysis of phase II data, which showed “a clear lack of benefit” in hospitalized patients in need of oxygen support. The trial was assessing the drug’s impact on acute respiratory distress syndrome. The study recruited patients 50 and older who had a score of either 5 (hospitalized, receiving oxygen by mask or nasal prongs) or 6 (hospitalized, receiving oxygen by non-invasive ventilation or high-flow therapy) on the WHO classification scale.