Adintrevimab for COVID-19

Abstract Background ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses with pandemic potential. Our objective was to develop a PPK model that describes the serum ADI concentration-time profile following intravenous (IV) and intramuscular (IM) administration. Methods The ADI PPK model was developed on PK data from a Phase 1 single-ascending dose study (24 adults, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE; 659 adults, IM) and treatment (STAMP; 189 adults, IM) studies. 1,486 PK samples were included in the analysis. The impact of covariates (e.g. body weight, age, and baseline viral load) on ADI serum disposition were evaluated. Prediction-corrected visual predictive check (PC-VPC) plots were used to qualify the PPK model. Participant-specific ADI exposure estimates were generated using individual post hoc PK parameters. Results The PPK model is comprised of 2 systemic compartments, zero-order infusion for IV administration and first-order absorption for IM administration and provided a robust fit to the data based on the PC-VPC plots and goodness-of-fit plots (data not shown). Body weight influenced clearance, intercompartmental clearance, and central and peripheral volume compartments. The relationship between body weight and clearance was not suggestive of the need for dose adjustment over the population weight range studied (38.6 to 178.7 kg). There was no apparent impact of baseline viral load or age on ADI clearance. The median [range] half-lives in days by study; Phase 1 (α1.71 [1.18-2.46]; β 125 [117-149]), Phase 2/3 prevention (α 1.86 [0.640-3.13]; β 136 [105-209]), and Phase 2/3 treatment (α 1.89 [0.631-3.01]; β 136 [108-206]). The population mean IM bioavailability estimate was 90.5%. The figure shows the PPK model median (90% confidence interval) concentration-time profile following a single 300 mg IM ADI dose by study. Conclusion The PPK model provided a precise and unbiased fit to the observed ADI concentration-time data and will be useful for future PK-pharmacodynamic analyses. Moreover, ADI demonstrated high IM bioavailability and a median terminal elimination half-life of 125 to 136 days. Disclosures Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals:..

Abstract Background Safe and effective treatments are needed to prevent severe outcomes in individuals with COVID-19. We report results from STAMP, a phase 2/3, multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended half-life monoclonal antibody, for treatment of high-risk ambulatory patients with mild to moderate COVID-19. Methods Non-hospitalized, unvaccinated participants aged ≥12 years with mild to moderate COVID-19 and ≥1 risk factor for disease progression were randomized to receive a single intramuscular injection of 300 mg adintrevimab or placebo. Enrollment was paused due to the global emergence of the Omicron BA.1/BA1.1 variants, against which adintrevimab showed reduced activity in vitro. The primary efficacy endpoint was COVID-19-related hospitalization or all-cause death through day 29 in participants with COVID-19 due to laboratory-confirmed or suspected non-Omicron SARS-CoV-2 variants. Results Between August 8, 2021, and January 11, 2022, 399 participants were randomized to receive adintrevimab (n=198) or placebo (n=201), including 336 with COVID-19 due to non-Omicron variants. COVID-19-related hospitalization or all-cause death through day 29 occurred in 8/169 (4.7%) participants in the adintrevimab group and 23/167 (13.8%) in the placebo group, a 66% relative risk reduction in favor of adintrevimab (standardized risk difference, -8.7% [95% CI, -14.71 to -2.67; P=.0047]). Incidence of treatment-emergent adverse events (TEAEs) was similar between treatment groups (33.9% for adintrevimab and 39.5% for placebo). No adintrevimab-related serious TEAEs were reported. Conclusion Treatment with a single intramuscular injection of adintrevimab provided protection against severe outcomes in high-risk ambulatory participants with COVID-19 due to susceptible variants, without safety concerns. Clinical Trial Registration. NCT04805671