eFFECTOR Therapeutics, Inc. announced top-line results from its Phase 1b clinical trial of zotatifin for the treatment of COVID demonstrating favorable safety results as well as positive trends in several measures of antiviral activity. eFFECTOR also presented preclinical data that demonstrated the breadth of zotatifin's activity against RNA viruses. These results were presented at the 30th Conference on Retroviruses and Opportunistic Infections on February 20, 2023.

The primary objective of the trial was to evaluate safety of zotatifin in subjects with mild-to-moderate COVID. Zotatifin was generally well tolerated at all doses, with injection site reactions from the sub-cutaneous route (all Grade 1 or 2) being the only adverse event showing a potential relationship to zotatifin dose. Secondary and exploratory objectives included evaluation of antiviral activity in nasal and saliva samples and pharmacokinetics (PK).

Trends in antiviral activity favoring zotatifin over placebo were seen by several assessments. In particular, in saliva, which was sampled more frequently than nasal cavity, virus level undetectability (VLU) was achieved approximately twice as fast in the zotatifin-treated subjects compared to placebo, with a median time to VLU of 3 days for zotatifin vs 7 days for placebo. The Hazard Ratio (HR) for achieving VLU in saliva was 2.83 (95% confidence intervals 0.64, 12.5; p=0.13) in favor of zotatifin.

Zotatifin administered by the sub-cutaneous route showed very similar PK parameters compared to IV administration in other trials, supporting continued development of zotatifin by the sub-cutaneous route. The half-life of zotatifin was measured to be approximately 4 days (across all dosing groups), supporting further development of zotatifin as a single administration to treat COVID. In the randomized, double-blind, placebo-controlled dose escalation trial, 27 subjects received zotatifin at doses ranging from 0.01 to 0.035 mg/kg and 9 subjects received placebo.

At the outset of the trial, one patient received zotatifin and one patient received placebo by intravenous administration. All other subjects (n=34) received study drug by sub-cutaneous injection. Enrolled subjects had mild or moderate COVID and were positive for SARS-CoV-2 RNA or antigen within 7 days of randomization.

The trial was conducted in collaboration with the Quantitative Biosciences Institute (QBI) at the University of California, San Francisco (UCSF), which holds a $5 million cooperative agreement sponsored by the Defense Advanced Research Projects Agency. eFFECTOR also presented results from preclinical studies in which zotatifin was active against numerous COVID isolates and other coronaviruses and was 10-100 times more potent than several agents authorized by the FDA for treatment of COVID, based on concentrations required to achieve comparable reductions in virus yield and protection from virus-induced cytopathic effects in cell-based assays. Zotatifin is a potent and sequence-selective small molecule inhibitor of eIF4A, a host protein required to unwind the complex secondary structures within the 5'- untranslated region of the genome of SARS-CoV-2 and other RNA viruses.

As an investigational host-directed antiviral, zotatifin is intended to act on a human protein that the SARS-CoV-2 virus hijacks to synthesize new viruses. Inhibiting the activity of eIF4A prevents the translation of the viral polyprotein needed for replication of the virus. The Company believes zotatifin's administration for COVID as a single sub-cutaneous injection fits well with the Test to Treat initiative and provides a convenient way to ensure compliance with a full course of therapy.

Zotatifin reduced SARS-CoV-2 viral infectivity in a study conducted by the international research consortium QBI Coronavirus Research Group (QCRG), led by Nevan Krogan, and previously published in Nature.