A PHASE 1B STUDY OF ZOTATIFIN FOR THE TREATMENT OF MILD TO MODERATE COVID (PROpel)

ABSTRACT

Background: Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic initiation factor 4A (eIF4A), a host RNA helicase required for SARS-CoV-2 replication. In vitro, zotatifin demonstrates broad spectrum antiviral activity against all human coronaviruses tested. Zotatifin has physicochemical and pharmacokinetic (PK) properties suitable for convenient, single subcutaneous (sc) injection. This study assessed the safety, antiviral activity, and PK of zotatifin in non-hospitalized patients (pts) with mild/moderate COVID. Method(s) PROPEL is a randomized, placebo-controlled, double-blind study in non-hospitalized pts with mild/moderate COVID. At randomization, pts must have had a SARS-CoV-2 positive test within 7 days and at least 1 COVID symptom. Pts were randomized (31) to zotatifin or placebo sc in 3 cohorts of 12 pts each. Cohort 1, 2 and 3 received a single dose (SD) of zotatifin of 0.01. 0.02 and 0.035 mg/kg or matching placebo. Safety (adverse event (AE) and laboratory tests), antiviral activity (mid-turbinate nasal swabs and saliva), and plasma PK were collected over 30 days. The primary endpoint was safety;key secondary endpoints included SARS-CoV-2 viral load (VL) and PK. The study was not powered for statistical inferential testing. Result(s) 36 pts were enrolled across all three cohorts and completed a 30-day follow up. Data is currently available for pts in cohorts 1 and 2, 18 and 6 of whom received zotatifin and placebo, respectively. Baseline characteristics were comparable between groups. The most common AE was erythema at injection site in cohort 1 (44%) and cohort 2 (89%), vs. 0% in the zotatifin and pooled placebo groups, respectively. Other AE frequencies were comparable between zotatifin and placebo and no serious AEs were reported. The concentrationtime profile of zotatifin from cohorts 1 and 2 following sc administration was similar to that reported previously following IV administration, demonstrated a terminal elimination half-life (t1/2) of ~ 4 days, high steady-state volume of distribution (Vss) of 31 L/kg, and low plasma clearance (Cl) of 3.9 mL/min/kg. A faster time to viral RNA undetectability was observed with zotatifin vs. placebo (see Fig 1. Not statistically significant). Conclusion(s) Zotatifin was safe, well tolerated and demonstrated a trend in clinical antiviral activity in patients with mild to moderate COVID which supports further clinical development. Zotatifin sc route of administration supports a point of care treatment for COVID.