Zotatifin treatment of adults with mild to moderate COVID-19

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

This project is a clinical trial that has completed enrollment and collection of data from all patients. No additional patients will be enrolled or studied, but analysis of the full set of collected clinical and laboratory data is ongoing. An abstract of the interim analysis was submitted and presented in February 2023 and is included below at the end of this Summary before the references (that include as Ref #4 the presented abstract). Specifically this was a multisite (3 sites including the NIH Clinical Center), Phase 1b dose-escalation safety clinical trial of intravenous or subcutaneous administerd zotatifin (eFT226) in adults with mild to moderate severity coronavirus disease 2019 (COVID-19). Zotatifin is a small molecule inhibitor of elF4A,(Reference #1) an RNA helicase regulator of protein synthesis through RNA translation essential for infection and replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).(Reference #2) Zotatifin demonstrates in vitro inhibition of SARS-CoV-2 replication with a 90% effective concentration (EC90) of 37 nM. (Reference #3) Zotatifin has been administered to humans in a dose-escalation oncology clinical trial for patients with KRAS mutant and RTK driven tumors administered as a 1-hour infusion weekly over an extended period of time (See ClinicalTrials.gov reference number NCT04092673 for the oncology study). In that study, zotatifin was well tolerated at up to 0.070 mg/kg/wk for many weeks of treatment, which is a dose that is two-times above the highest dose planned for this current study; is for a much more prolonged period of treatment than the two doses planned for this study; and demonstrated plasma half-life of 107 hours which is why a single dose is likely to provide antivirus activity for at least 5 days. In this COVID-19 treatment protocol, the study population are adult patients who have a postive PCR test for SARS-CoV-2 and present with signs and symptoms plus demographics and medical history criteria that define a participant population likely to have lower risk of disease progression to severe COVID-19. Participants must present with at least 2 symptoms or signs of COVID-19, but starting no more than 7 days before randomization and treatment with zotatifin. Participants must have a positive quantitative real-time polymerase chain reaction assay for SARS-CoV-2 infection within 48 hours of randomization and study infusion. This protocol assesses 3 dose levels of zotatifin (0.010 mg/kg/wk, 0.020 mg/kg/wk, and 0.035 mg/kg/wk) administered as a single IV infusion over 1 hour or subcutaneously, with 12 participants enrolled at each dose level. Participants are assessed at frequent intervals over 15 days following infusion/injection, with telephone evaluations at Day 22 and at 30 days after the last infusion/injection to complete the study. Each dosing cohort consists of 12 patients randomized 3:1 zotatifin 9 patients : placebo 3 patients. At study completion of the three dose levels the study will have accrued 9 patients treated with zotatifin at each dose level (27 patients receiving zotatifin) and 9 patients treated with placebo. The primary objective was to assess safety and tolerability of zotatifin treatment. The primary endpoint is incidence of classes of AEs and changes in clinical status from baseline (Day 1). Secondary objectives are to assess antivirus activity, which includes assessments of time to virus load undetectability, proportion of participants becoming virus-negative, and time to clinical resolution (0 on the World Health Organization 9-point ordinal scale), and to assess plasma pharmacokinetics for zotatifin. Exploratory objectives assess virus sampling procedures, virus resistance, circulating inflammatory or coagulopathy markers, and other indicators of disease worsening. The Sponsor of this 3 site, multicenter trial is eFFECTOR Therapeutics, Inc who have listed the main trial at ClinicalTrials.gov Identifier: NCT04632381 "Intravenous Zotatifin in Adults With Mild or Moderate COVID-19 (PROPEL)". The NIH site is conducting this trial under NIH Protocol #000134-I entitled, "A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial of Intravenous Zotatifin in Adults with Mild or Moderate Coronavirus Disease 2019 (COVID-19)", where the NIH site PI is Harry L. Malech, MD. Initial screening of subjects for enrollment at the NIH site into NIH protocol 000134 may be preceded by evaluation medical screening of these potential candidates under the general screening NIH Protocol 05-I-0213 designed to study patients with infections or immune deficiencies. INTERIM ANALYSIS RESULTS OF CLINICAL TRIAL: 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 concentration-time 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 was observed as a trend but did not reach statistical significance. Conclusions: 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. Scientific References 1. Ernst JT, Thompson PA, Nilewski C, et al. Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase. J Med Chem. 2020;63(11):5879-5955. 2. Mller C, Obermann W, Schulte FW, et al. Comparison of broad-spectrum antiviral activities of the synthetic rocaglate CR-31-B (-) and the eIF4A-inhibitor Silvestrol. Antiviral Res. 2020;175:104706. 3. Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459-468. 4. (ABSTRACT PRESENTATION) Harry Malech, Almena Free, Enola Okonkwo, Patricia Littel, Nicole Rooths, Priscilla Quackenbush, Martha Marquesen, Michael Hodges, Amy Patick, Sam Sperry, Bin Yao, Nawaid Rana, Doug Warner. A PHASE 1B STUDY OF ZOTATIFIN FOR THE TREATMENT OF MILD TO MODERATE COVID (PROpel). Conference on Retroviruses and Opportunistic Infections. February 19-22, 2023 Seattle, Washington. Abstract #545. https://www.croiconference.org/abstract/a-phase-1b-study-of-zotatifin-for-the-treatment-of-mild-to-moderate-covid-propel/