Vincent Chang1, Eric Salgado1, Elham Amini1, Luzelena Caro1, Xiaoning Wang1
1Gilead Sciences, Inc.
Introduction/Objectives Obeldesivir (ODV, GS-5245) is an oral prodrug of GS-441524 with broad-spectrum antiviral activity against COVID-19 and other emerging viruses.¹ ² ³ Five Phase 1 trials in healthy participants and two Phase 3 trials in participants with COVID-19 were conducted. We are currently evaluating additional indications for ODV and leveraging all clinical data from the ODV program to assess the safety and tolerability of ODV, which will inform its future development. Thus, the objective of this analysis was to assess the clinical data from Phase 1 healthy participants and Phase 3 COVID-19 participants to characterize the relationship between ODV plasma exposure and various safety endpoints. Methods Subject-level PK metrics (including AUC and Cmax) of GS-441524 were extracted from a previously developed population PK model. Logistic regression, data manipulation, and visualization were performed in R v4.2.1.4 Logistic regression models correlated PK metrics to the incidence of safety endpoints and asymptomatic treatment-emergent lab abnormalities (TELAs) of interest. A logistic regression model was considered appropriate given the limited sampling time points during treatment of COVID-19 participants. Available data from up to 1521 participants administered ODV and up to 1236 participants administered placebo were evaluated in this safety analysis. We considered the following GS-441524 PK metrics: Day 1 and Day 5 Cmax, Day 1 and Day 5 AUCtau, and total cumulative exposure (AUCtotal) to determine whether early exposure, steady-state exposure, or overall exposure relates to the incidence of safety endpoints. Safety endpoints considered included diarrhea, Grade 2+ CrCL TELAs, Grade 3+ CrCL TELAs, Grade 1+ serum creatinine (SCr) TELAs, and Grade 3+ SCr TELAs. Results Of all PK metrics considered, the most statistically significant relationship identified was between AUCtotal and incidence of Grade 3+ CrCL TELAs (Odds Ratio 1.30 for every 100 µM*h increase, 95% CI 1.14 – 1.48). No other safety endpoints were found to have statistically significant relationships with any of the PK metrics. However, some limitations must be considered. There may be a confounding effect of ODV treatment, COVID-19 infection, and renal impairment on CrCL TELAs that is difficult to discern with the currently available dataset. Additionally, it is unclear if ODV has any time-dependent or first dose effects where the AUCtotal relationship would not capture and therefore would underestimate the exposure-safety relationship. Conclusions Clinical and pharmacokinetic data, as well as modeling and simulation, were leveraged to perform a subject-level meta-analysis of ODV exposure relative to safety. Statistically significant PK/PD relationships were found only for Grade 3+ CrCL TELAs. However, ODV is primarily renally eliminated, so renal impairment can lead to higher ODV exposure and is associated with CrCL fluctuations. Additionally, COVID-19 infection is known to potentially impact renal function.5 6 Thus, the relative contributions of ODV treatment, COVID-19 infection, and renal impairment to asymptomatic CrCL TELAs remain unclear.
[1] Mackman R et al., “Discovery of GS-5245 (obeldesivir), an oral prodrug of nucleoside GS-441524 that exhibits antiviral activity in SARS-CoV-2-infected African green monkeys,” J. Med. Chem., vol. 66, pp. 11701-11717, 2023, doi: 10.1021/acs.jmedchem.3c00750. [2] Cross R et al., “Oral obeldesivir provides postexposure protection against Marburg virus in nonhuman primates,” Nat Med (2025), doi: https://doi.org/10.1038/s41591-025-03496-y. [3] Pitts J et al., “Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys,” bioRxiv, 2025, doi: https://doi.org/10.1101/2025.02.24.639976. [4] R Core Team, “R: A language and environment for statistical computing.” Accessed: Mar. 1, 2024. [Online]. Available: https://www.r-project.org/ [5] Dellepiane S, et al. Acute Kidney Injury in Patients Hospitalized With COVID-19 in New York City: Temporal Trends From March 2020 to April 2021. Kidney Med. 2021 Sep-Oct;3(5):877-879. doi: 10.1016/j.xkme.2021.06.008. Epub 2021 Jul 31. PMID: 34368666; PMCID: PMC8325375. [6] Fisher M, et al. AKI in Hospitalized Patients with and without COVID-19: A Comparison Study. J Am Soc Nephrol. 2020 Sep;31(9):2145-2157. doi: 10.1681/ASN.2020040509. Epub 2020 Jul 15. PMID: 32669322; PMCID: PMC7461660.
Reference: PAGE 33 (2025) Abstr 11366 [www.page-meeting.org/?abstract=11366]
Poster: Drug/Disease Modelling - Other Topics