Development of a novel, pan-variant aerosol intervention for COVID-19

Abstract

To develop a universal strategy to block SARS-CoV-2 cellular entry and infection represents a central aim for effective COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here we show that intranasal administration of APN01 in a mouse model of SARS-CoV-2 infection dramatically reduced weight loss and prevented animal death. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers can now be initiated, with subsequent Phase II testing in individuals with SARS-CoV-2 infection. This strategy could be used to develop a viable and rapidly actionable therapy to prevent and treat COVID-19, against all current and future SARS-CoV-2 variants.

Clinical grade ACE2 as a universal agent to block SARS‐CoV ‐2 variants

“…These results support the notion that this therapeutic is inherently resistant to escape mutations that constitute a major problem for both vaccines and antibody‐based therapeutics. Data provided in this study and in (preprint: Shoemaker et al , 2021 ) as well as clinical data already generated for APN01 set the stage for the development of universal and pan‐variant SARS‐CoV‐2 prevention and therapy.…”

“…APN01 has now undergone phase 2 testing in severe (WHO scores 4, 5, and 6) COVID‐19 patients using intravenous infusions. Additionally, a new formulation of APN01 that can be inhaled as an aerosol to directly interfere with the earliest steps of viral infection and prevent lung damage and spreading to other organ systems has been developed (preprint: Shoemaker et al , 2021 ). Moreover, the preclinical efficacy of APN01 lung administration in a mouse‐adapted severe COVID‐19 model has been demonstrated, providing proof of concept for phase 1 clinical inhalation trials in humans that are currently ongoing.…”