P-1232. Dose selection of obeldesivir for clinical evaluation in treatment of adult participants with respiratory syncytial virus infection

TL;DR

This paper outlines the process of selecting the optimal dose of obeldesivir for treating adults with respiratory syncytial virus infection, based on pharmacokinetic and safety data from prior trials.

Contribution

The study introduces a data-driven approach to dose selection for obeldesivir in RSV treatment, integrating preclinical and clinical findings.

Findings

A 700 mg BID on Day 1 and 350 mg BID on Days 2-5 regimen is predicted to meet efficacy targets and maintain safety.

Pharmacokinetic models were used to estimate exposures and potential treatment-emergent laboratory abnormalities.

Renal function and pre-existing conditions were considered in dose prediction and safety evaluation.

Abstract

Obeldesivir (ODV) is an oral prodrug of the parent nucleoside, GS-441524, which is then converted intracellularly to the active metabolite. ODV is efficacious against respiratory syncytial virus (RSV), SARS-CoV-2, and filoviruses in nonhuman primates (NHP). The pharmacokinetics (PK) and safety of ODV were evaluated in a robust clinical development program (5 Phase 1 trials in healthy participants; 2 Phase 3 trials in patients with COVID-19). Here we describe ODV dose selection for a Phase 2 study in nonhospitalized adults with acute RSV infection, leveraging PK, safety, and efficacy data.

The optimal RSV ODV dose was chosen to ensure safe and efficacious GS-441524 exposures. The RSV clinical PK efficacy target was based on NHP PK and efficacy studies, wherein administration of ODV 30 and 90 mg/kg/day for 6 days, respectively, had RSV antiviral efficacy. The target plasma GS-441524 maximum concentration and overall exposures associated with NHP efficacious regimens were estimated by extrapolating single-dose PK to multiple-dose PK via nonparametric superposition. Clinical data were used to develop a GS-441524 population PK model characterizing patient subpopulation PK. A logistic regression PK/pharmacodynamic (PD) model characterized the relationship between ODV PK and Grade ≥3 creatinine clearance (CrCL) treatment-emergent laboratory abnormalities (TELAs); however, these TELAs may have been confounded by COVID-19 or pre-existing renal impairment (RI), RI increasing ODV PK, and the low incidence of Grade ≥3 CrCL TELAs. Assuming RSV disease increases GS-441524 exposures by 25% compared to healthy participants, PK and PK/PD were used to predict exposures and rates of CrCL TELAs associated with various dosing regimens.

Based on predicted exposures and CrCL TELAs for those aged >16 years with normal renal function (eGFR ≥90 mL/min/1.73 m2) or mild RI (eGFR 60-89 mL/min/1.73 m2), an ODV regimen of 700 mg BID on Day 1 and 350 mg BID on Days 2-5 is anticipated to exceed the NHP PK efficacy target GS-441524 exposure and result in an acceptable rate of CrCL TELAs.

To provide an optimal benefit-risk profile, an ODV regimen was selected for the Phase 2 RSV adult study based on the totality of clinical and preclinical data and model-predicted PK and CrCL TELAs.

Elham Amini, PharmD, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Eric Salgado, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Vincent Chang, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Santosh Davies, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Darius Babusis, BA, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) John P. Bilello, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Olivia Fu, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Luzelena Caro, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)