Obeldesivir (ODV), an orally bioavailable prodrug of the GS-441524 nucleoside analog, is under evaluation for treatment of RSV in nonhospitalized patients. Here, we report the antiviral activity of GS-441524 and ODV against RSV L polymerase substitutions that emerged during in vitro resistance selections in the presence of ODV, GS-441524, or ALS-8112 (parent nucleoside of lumicitabine) using an optimized RSV minigenome phenotypic assay and a recombinant infectious virus system. In the optimized minigenome assay, plasmids encoding L, N, P, and M2-1 proteins were reverse-transfected with a firefly luciferase reporter into HEK293T cells, with luciferase activity measured at 48 hours. Phenotypic testing in an infectious virus system used HEp-2 cells with a cellomics-based immunofluorescent readout measured at 72 hours. The L polymerase substitutions C319R, I777L, and L1453W identified during in vitro resistance selection with GS-441524 or ODV and the QUAD substitutions (M628L + A789V + L795I + I796V), both alone and in combination, that emerged during in vitro selection with ALS-8112 were tested in both systems. GS-441524 and ODV half-maximal effective concentration (EC50) values were determined using variable slope non-linear regression. L polymerase substitutions C319R, A789V, L795I, I796V, L1453W, and QUAD had similar susceptibility to GS-441524 and ODV as the wild type reference in the minigenome system (< 1.09- and < 1.20-fold change in EC50, respectively) and the infectious virus system (< 1.79- and < 2.00-fold change in EC50, respectively). The I777L substitution was associated with low-level reduced susceptibility to GS-441524 and ODV in both the minigenome system (2.06- and 2.07-fold change in EC50, respectively) and the infectious virus system (3.31- and 3.83-fold change in EC50, respectively). The M628L mutant could not be tested due to poor replication. Overall, GS-441524 and ODV EC50 fold changes were concordant in both phenotypic systems. These data support the use of the optimized RSV minigenome system to evaluate the susceptibility of RSV L polymerase substitutions against GS-441524 and ODV and indicate that these drugs have a high barrier to resistance development. Jasmine Moshiri, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) J. Lizbeth Reyes Zamora, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Dong Han, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Josolyn Chan, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Nadine Peinovich, MPH, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Christopher Richards, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Stacey Eng, BS, 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) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

Prolonged shedding of SARS-CoV-2 has been documented in viral dynamics studies of immunocompromised patients. Remdesivir (RDV) is a nucleotide analog prodrug approved to treat COVID-19 in hospitalized and nonhospitalized patients. Here we present SARS-CoV-2 viral load (VL) analyses in participants with solid organ transplantation (SOT) from the Phase 3 REDPINE study. REDPINE was a double-blind, placebo-controlled trial in participants hospitalized for COVID-19 with severely reduced kidney function who were randomized 2:1 to receive RDV or placebo (PBO) for 5 days. Out of 243 participants enrolled and treated in the study, forty-two participants had SOT and received immunosuppressive drugs prior to and during the study. Nasopharyngeal swab samples were collected on days 1 (baseline), 3, 5, 7, 14, 21, and/or 29. The change from baseline in SARS-CoV-2 RNA VL was compared in an ad hoc analysis between the RDV and PBO groups and between participants with and without SOT in the RDV group using a mixed model repeated measures (MMRM) approach. Overall, RDV treatment led to significantly greater reductions from baseline in VL on Day 5 (least-squares mean [LSM] difference, −0.48 log10 copies/mL; P = 0.0332) and Day 7 (−0.57 log10 copies/mL; P = 0.0335) compared to PBO. In the RDV-treated group, changes from baseline in VL (log10 copies/mL) for participants with and without SOT, respectively, were as follows: Day 5, –0.69 and –1.45; Day 7, –0.85 and –2.02; Day 14, –1.06 and –2.40. Participants with SOT showed slower VL reductions from baseline on Days 5, 7, and 14 compared to participants without SOT (P ≤0.0191). In RDV-treated participants without SOT, 14/20 (70%) reached the lower limit of quantification (LLOQ) of the RT-qPCR VL assay (3.35 log10 copies/mL) at Day 14, whereas 3/11 (27%) participants with SOT reached the LLOQ at Day 14. In the REDPINE study, RDV treatment resulted in reduced SARS-CoV-2 VL compared to PBO. In RDV-treated participants with SOT, VL reductions were slower compared to participants without SOT, potentially due to diminished immune system support to clear the virus. These findings suggest that extending the duration of RDV treatment beyond 5 days may be beneficial in this patient population to mitigate prolonged viral shedding. Lauren Rodriguez, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Shuguang Chen, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Yu Hu, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jasmine Moshiri, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Ross Martin, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Yiannis Koullias, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

With the ongoing emergence of SARS-CoV-2 variants, continued surveillance of antiviral susceptibility remains critical for detecting resistance that could compromise treatment efficacy. This study evaluated the activity of 2 SARS-CoV-2 RNA-dependent RNA polymerase (Nsp12) inhibitors against emerging Omicron variants: remdesivir (RDV), an approved antiviral for the treatment of COVID-19, and obeldesivir (ODV), an oral prodrug that shares the same parent nucleoside as RDV. Both RDV and ODV were shown to retain antiviral activity against the Omicron subvariants BA.2.86.1, JN.1.7, KP.2, KP.3.1.1, KP.3.3, LP.8.1, NB.1.8.1, XBB.2, XEC, and XFG compared with wild-type reference strains. Only 1 new lineage-defining Nsp12 substitution, D284Y (detected in NB.1.8.1), was observed. Phenotypic analysis demonstrated that a replicon containing this substitution remained susceptible to both RDV and ODV. These findings are consistent with previous studies showing that RDV and ODV retain potent activity against previously identified Omicron variants, support the continued clinical use of RDV against circulating SARS-CoV-2 variants, and reinforce the potential of ODV as an oral antiviral therapeutic.

BACKGROUND:Obeldesivir is an oral nucleoside analog prodrug inhibitor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS:Nonhospitalized adults with risk factors for developing severe coronavirus disease 2019 (COVID-19) were enrolled ≤5 days from COVID-19 symptom onset and randomized 1:1 to receive obeldesivir 350 mg or placebo twice daily for 5 days. The primary end point was COVID-19-related hospitalization or all-cause death by day 29. Other end points included time to symptom alleviation by day 15, change in SARS-CoV-2 viral RNA copy number and infectious viral titer, and incidence of adverse events and laboratory abnormalities. RESULTS:Four hundred and sixty five participants were randomized and received ≥1 dose of study drug. Baseline characteristics were generally balanced between groups. Overall, 58% had received ≥1 COVID-19 vaccination, and 92% were seropositive for SARS-CoV-2 antibodies. COVID-19-related hospitalization or all-cause death by day 29 was reported in 0 of 211 (0%) participants with obeldesivir and 1 of 207 (0.5%) participants with placebo (log-rank P = .32). Time to COVID-19 symptom alleviation was numerically shorter with obeldesivir versus placebo. Obeldesivir reduced viral RNA copy number at day 5 and infectious titer at days 3 and 5 versus placebo. The safety profile was generally comparable across arms. CONCLUSIONS:Although underpowered in the context of a changing COVID-19 landscape, obeldesivir in nonhospitalized adults with targeted risk factors did not improve COVID-19-related hospitalization or all-cause death. Obeldesivir reduced viral RNA copy number and infectious titer, demonstrating its ability to inhibit SARS-CoV-2 replication, and resulted in numerically faster symptom alleviation. CLINICAL TRIALS REGISTRATION:NCT05603143; EudraCT 2022-002741-18.

Remdesivir inhibits the SARS-CoV-2 RNA-dependent polymerase (Nsp12). Here, we present virology analyses from the Phase 3 REDPINE trial in participants with impaired kidney function hospitalized for COVID-19 and treated with remdesivir or placebo for 5 days. Out of 243 participants enrolled and treated in the study, 42 participants had solid organ transplantation (SOT) and received immunosuppressive medication prior to and during the study. Nasopharyngeal swabs were collected at baseline and through Day 29. Virology assessments were performed using SARS-CoV-2 RT-qPCR, next-generation sequencing, and site-directed mutagenesis in a SARS-CoV-2 replicon system. Remdesivir treatment demonstrated significantly greater reductions from baseline in viral load on Day 5 and Day 7 compared with placebo (P ≤ 0.034). In the remdesivir treatment group, participants with SOT showed significantly smaller viral load reductions from baseline on Days 5, 7, and 14 compared with participants without SOT (all P < 0.05). Mathematical modeling of viral load kinetics in participants with kidney transplants predicted a >13-day faster time to viral load decline by extending the remdesivir treatment duration from 5 days to 10 days. In four participants treated with remdesivir, emergent substitutions in Nsp12 (E136V, M794I, and C799F) with low-level reduced in vitro susceptibility to remdesivir (≤3.4 fold change in half-maximal effective concentration) were observed 9 days after cessation of remdesivir treatment. Three of the four participants had undergone SOT. Overall, remdesivir demonstrated antiviral activity in participants with impaired kidney function, with delayed viral clearance in SOT recipients and rare posttreatment emergence of Nsp12 substitutions that confer low-level reduced susceptibility to remdesivir.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04745351; EudraCT registration no. 2020-005416-22.

Obeldesivir is an oral nucleoside analog prodrug that targets and inhibits the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. This study evaluated the development of obeldesivir resistance in participants from the Phase 3, multicenter, double-blind BIRCH study. High-risk, nonhospitalized adults with COVID-19 were randomized to receive obeldesivir or placebo twice daily for 5 days. Mid-turbinate nasal swab samples were collected on Days 1 (baseline), 3, 5, 10, and 15. Amino acid substitutions were identified using deep sequencing and phenotyped using a replicon system. Of the 465 participants randomized and treated, 252 (obeldesivir, 190; placebo, 62) met the sequencing analysis criteria and had sequencing data at baseline. Phenotypic analysis of the 5 Nsp12 substitutions observed at baseline resulted in half-maximal effective concentration (EC50) fold changes ≤1.8 relative to the wildtype reference, indicating no change in susceptibility to obeldesivir. Among participants with baseline and postbaseline sequencing data, 12/73 (16.4 %) and 5/54 (9.3 %) participants in the obeldesivir and placebo groups, respectively, had emergent Nsp12 substitutions. Nine emergent Nsp12 substitutions were detected in the obeldesivir group postbaseline that were not observed in the placebo group. Of these, only 1 substitution (V792I) observed in 1 participant from the obeldesivir group demonstrated a low-level reduction in susceptibility to obeldesivir (EC50 fold change, 4.01). This substitution was first detected on Day 15, and the participant was never hospitalized. The low-to-no change in obeldesivir susceptibility among the treatment-emergent Nsp12 substitutions indicates a high barrier to the development of obeldesivir resistance in high-risk, nonhospitalized patients with COVID-19.Clinicaltrials.gov identifier: NCT05603143.

BACKGROUND:Obeldesivir is an oral nucleoside analogue prodrug antiviral that inhibits SARS-CoV-2 replication. We aimed to assess the efficacy, safety, and tolerability of obeldesivir for the treatment of COVID-19 in non-hospitalised individuals at low risk of progression to severe disease. METHODS:OAKTREE was a phase 3, randomised, double-blind, placebo-controlled trial in 107 centres (including research centres, primary care centres, and hospitals) in Japan and the USA. Low-risk, non-hospitalised adults and adolescents with mild-to-moderate COVID-19 were enrolled within 3 days of symptom onset. Eligible participants were randomly assigned 1:1 using permuted block randomisation (block size of four), stratified by historical completion of a primary COVID-19 vaccination series, to receive either oral obeldesivir 350 mg or matched placebo twice daily for 5 days. The primary efficacy endpoint was time to COVID-19 symptom alleviation by day 29, which was assessed in all randomly assigned participants who received one or more doses of study drug, had positive SARS-CoV-2 RT-PCR (per central laboratory testing) at baseline, and had COVID-19 symptom data (full analysis positive set). The primary safety endpoint was the incidence of adverse events and laboratory abnormalities and was assessed in all randomly assigned participants who received one or more doses of study drug. As a secondary endpoint we assessed change from baseline in nasal swab viral RNA copy number at day 5 in all randomly assigned participants who received one or more doses of study drug and had a quantifiable baseline value. This trial is registered with ClinicalTrials.gov, NCT05715528, and is complete. FINDINGS:Between Feb 13, 2023 and Oct 31, 2023, 1955 participants (1155 female and 800 male; 1698 White, 207 Black, 42 Asian, and eight Other) were randomly assigned and received at least one dose of either obeldesivir (n=979) or placebo (n=976). Overall, 1368 (70·0%) participants had completed a primary COVID-19 vaccination series and 1938 (99·6%) were seropositive for SARS-CoV-2 antibodies. There were 884 participants in each group in the full analysis positive set. Among those in the full analysis positive set who completed the symptom questionnaire (ie, who had COVID-19 symptom data; 879 obeldesivir, 882 placebo), median time to COVID-19 symptom alleviation was 5·9 days (95% CI 5·4-6·1) in the obeldesivir group and 6·0 days (5·8-6·3) in the placebo group (hazard ratio 1·099 [95% CI 0·997-1·211], p=0·068). The least-squares mean change from baseline in viral RNA copy number at day 5 was -2·13 log10 copies per mL (SE 0·04) and -1·95 log10 copies per mL (0·04) for the obeldesivir group (n=637) and placebo group (n=622), respectively, with a least-squares mean difference of -0·18 (95% CI -0·30 to -0·06) log10 copies per mL (p=0·0037). The safety profile was comparable between groups. 53 (5·4%) of 979 participants in the obeldesivir group and 56 (5·7%) of 976 participants in the placebo group had one or more treatment-emergent adverse events. 753 (77·5%) participants in the obeldesivir group and 757 (78·5%) participants in the placebo group had one or more graded laboratory abnormalities, most of which were grade 1 or 2. INTERPRETATION:Obeldesivir was generally safe and well tolerated, with greater reduction of SARS-CoV-2 viral RNA copy number versus placebo at day 5. However, obeldesivir did not significantly reduce time to symptom alleviation, possibly reflecting the challenges of assessing efficacy in this population in an era of high rates of vaccine-induced and natural immunity. FUNDING:Gilead Sciences.

Abstract Background COVID-19 remains a serious condition, as the risk of severe outcomes increases with age and comorbid conditions. Early antiviral therapy has been shown to prevent disease progression. Obeldesivir (ODV) is an oral, broad spectrum, nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase. Methods BIRCH was a Phase 3, double-blind, placebo-controlled study in adults with risk factors for developing severe COVID-19 who were randomized 1:1 to ODV 350 mg or placebo twice daily for 5 days. The primary endpoint was COVID-19-related hospitalization or all-cause death through Day 29. Other endpoints included time to symptom alleviation and change in viral load and infectious titer. Safety assessments included adverse events (AEs) and laboratory abnormalities. Results Study enrollment was stopped early, reflecting the evolving COVID-19 landscape with low rates of clinical events. Overall, 465 participants were randomized and received ≥1 dose. 56% were female, 4% were Black, 9% were American Indian or Alaska native, and 12% were Asian. Median age was 56 years; 29% were ≥65 years of age. 76% were randomized within 3 days of symptom onset, 42% had never been vaccinated, and 92% were SARS-CoV-2 seropositive. 90% were SARS-CoV-2 positive by nucleic acid amplification test at baseline for efficacy analyses. COVID-19-related hospitalization or all-cause death through Day 29 was reported in 0% for ODV (0/211 participants) and 0.5% for placebo (1/207 participants; P = 0.3161). Among the 162 participants who completed a symptom questionnaire, ODV showed a 2-day improvement in median time to symptom alleviation by Day 15 (ODV: 7.3 days; placebo: 9.3 days; P = 0.0859). ODV demonstrated greater reductions in viral load from baseline to Day 5 (–0.58 log10 copies/mL; P < 0.0001), and a greater proportion with negative infectious titer at Day 5 (ODV: 68/68 [100%]; placebo: 56/69 [81%]; P = 0.0001). The safety profiles of ODV and placebo were comparable, with similar rates of AEs, serious AEs, and AEs leading to discontinuation of study drug. Conclusion ODV treatment resulted in greater decreases in viral load and infectious titer, and a trend in faster time to symptom alleviation. In this population of participants with risk factors for severe COVID-19, ODV was generally safe and well tolerated. Disclosures Anca Streinu-Cercel, MD PhD Prof. Infectious Diseases, Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria Antonella Castagna, MD, Bristol-Myers Squibb: Advisor/Consultant|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck Sharp & Dohme: Advisor/Consultant|Merck Sharp & Dohme: Grant/Research Support|Merck Sharp & Dohme: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria Yiannis Koullias, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Afsaneh Mozaffarian, MS, 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) Rita Humeniuk, PhD, Gilead Sciences, Inc.: Former Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Luzelena Caro, 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) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Shuguang Chen, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Kim Etchevers, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Nicole Behenna-Renton, BSc Hons, Gilead Science Europe Ltd: Employee|Gilead Science Europe Ltd: Stocks/Bonds (Public Company) Joe Llewellyn, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anu Osinusi, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Frank Duff, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jesus Abraham Simón Campos, MD, AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|Lilly: Advisor/Consultant|Lilly: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Roche: Advisor/Consultant|Roche: Honoraria

Abstract Background Remdesivir (RDV) is a nucleotide analog prodrug approved for treatment of COVID-19. Here we present comprehensive SARS-CoV-2 resistance analyses from all cohorts of the Phase 2/3 CARAVAN study, which demonstrated the safety of RDV for treatment of COVID-19 in pediatric participants from birth to < 18 years of age. Methods CARAVAN was a single-arm, open-label study wherein pediatric participants received IV RDV for ≤10 days. Full-genome deep sequencing of SARS-CoV-2 was performed on respiratory samples collected on Days 1 (baseline), 3, 5, 7, and/or 10. In vitro antiviral activity of RDV against substitutions observed in the SARS-CoV-2 RNA replication complex was evaluated using a subgenomic replicon system. Substitutions were phenotyped if they met any of the criteria: 1) baseline Nsp12 substitutions detected in ≥3 participants; 2) baseline replication complex substitutions detected in ≥2 participants with viral RNA increase postbaseline; 3) treatment-emergent postbaseline replication complex substitutions. Results Of 58 participants enrolled and treated, baseline sequencing data were obtained from 37 participants. Six baseline amino acid polymorphisms met criteria for phenotyping, none of which impacted RDV susceptibility (EC50 fold change ≤1.55). Baseline and postbaseline sequencing data were obtained from 28 participants. Five treatment-emergent substitutions in Nsp12 were identified in 3 participants as mixtures with wildtype. Of these, only Nsp12 V792I alone and in combination with V166L showed low-level reduced susceptibility to RDV (Table 1). The participant in whom V166L and V792I were observed achieved clinical recovery and was released from the hospital on Day 13. Structural modeling suggests V166L and V792I are located on or adjacent to motif D of the viral RNA-dependent RNA polymerase and may alter the dynamics of nucleoside triphosphate incorporation. Six treatment-emergent substitutions in Nsp9, Nsp10, and Nsp13 were identified in 3 participants; none impacted RDV susceptibility (fold change ≤0.74). Conclusion The results of resistance analyses from the CARAVAN study support a high barrier to clinically meaningful resistance to RDV in pediatric patients with COVID-19. Disclosures Jasmine Moshiri, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jiani Li, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Lauren Rodriguez, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Dong Han, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Simin Xu, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Pui Yan Ho, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Nadine Peinovich, MPH, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Clarissa Martinez, MPH, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Silvia Chang, Masters, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Kathryn Kersey, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jason K. Perry, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Danielle P. Porter, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

Remdesivir inhibits the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp; Nsp12). Here, we conducted viral resistance analyses from the Phase 3 PINETREE trial of remdesivir in nonhospitalized participants at risk of severe COVID-19. Nasopharyngeal swabs (collected at baseline [Day 1], Days 2, 3, 7, and 14) were eligible for analysis if their viral load was above the lower limit of quantification for the RT-qPCR assay (2228 copies/mL). The SARS-CoV-2 genome was sequenced for all remdesivir participants and 50% of placebo participants (baseline, Days 3, 7, and 14) and for participants who progressed to COVID-19-related hospitalization or all-cause death (all time points). Emergent substitutions in Nsp12 and other replication complex proteins were phenotyped using site-directed mutagenesis in a SARS-CoV-2 subgenomic replicon system. Overall, emergent Nsp12 substitutions were detected in 8/115 (7.0%) remdesivir participants and 7/129 (5.4%) placebo participants (1 substitution overlap between groups). Based on a structural analysis, none of the emergent Nsp12 substitutions were in direct contact with the incoming nucleoside triphosphate substrate, the RNA, or the RNA template 5 ' overhang. One substitution (A376V) showed reduced susceptibility to remdesivir (12.6-fold change in remdesivir half-maximal concentration [EC50]); it also showed reduced fitness when introduced in the SARS-CoV-2 replicon and virus in vitro. Other substitutions had <1.1-fold change in remdesivir EC50. None of the emergent substitutions in Nsp8, Nsp10, Nsp13, or Nsp14 (remdesivir, 10/115 [8.7%]; placebo, 10/129 [7.8%]) showed reduced remdesivir susceptibility. In conclusion, emergent substitutions in the SARS-CoV-2 RdRp complex with reduced remdesivir susceptibility were uncommon, indicating a high barrier to remdesivir resistance.

As new SARS-CoV-2 variants continue to emerge, it is important to evaluate the potency of antiviral drugs to support their continued use. Remdesivir (RDV; VEKLURY®) an approved antiviral treatment for COVID-19, and obeldesivir (ODV) are inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. Here we show these two compounds retain antiviral activity against the Omicron variants BA.2.86, BF.7, BQ.1, CH.1.1, EG.1.2, EG.5.1, EG.5.1.4, FL.22, HK.3, HV.1, JN.1, JN.1.7, JN.1.18, KP.2, KP.3, LB.1, XBB.1.5, XBB.1.5.72, XBB.1.16, XBB.2.3.2, XBC.1.6, and XBF when compared with reference strains. Genomic analysis identified 29 Nsp12 polymorphisms in these and previous Omicron variants. Phenotypic analysis of these polymorphisms confirmed no impact on the antiviral activity of RDV or ODV and suggests Omicron variants containing these Nsp12 polymorphisms remain susceptible to both compounds. These data support the continued use of RDV in the context of circulating SARS-CoV-2 variants and the development of ODV as an antiviral therapeutic.

Abstract Background COVID-19 continues to cause morbidity. Obeldesivir (ODV) is an oral, broad spectrum, nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase. Methods OAKTREE was a Phase 3, randomized, double-blind, placebo (PBO)-controlled study in adults and adolescents without risk factors for progression to severe COVID-19. Participants were enrolled within 3 days of COVID-19 symptom onset and randomized 1:1 to receive 350 mg of ODV or PBO twice a day for 5 days. Primary endpoints were time to symptom alleviation (9 symptoms; first of 48 consecutive hours) by Day 29 and incidence of adverse events (AEs) and laboratory abnormalities. Secondary endpoints included symptom resolution and viral kinetics. Results 1955 participants were enrolled (Feb 13-Oct 31, 2023), randomized, and received ≥1 dose of study drug (98% completed study drug and the study). Baseline characteristics were similar between groups (overall mean age 41 years, 59% female, 93% Hispanic or Latino, 87% White, 11% Black, and 2% Asian). Seropositivity was >99% for SARS-CoV-2 (anti-S or anti-N) antibodies, 73% were vaccinated, and mean baseline SARS-CoV-2 viral load was 5.09 log10 copies/mL. The efficacy analysis set consisted of 1768 participants with PCR-confirmed SARS-CoV-2 at baseline. The Kaplan-Meier estimate of median time to symptom alleviation was 5.9 days (95% CI, 5.4-6.1) with ODV and 6.0 days (95% CI, 5.8-6.3) with PBO (P = 0.068). Times to symptom resolution were similar (ODV: 9.2 days [95% CI 8.9-10.0]; PBO: 9.3 days [95% CI 8.9-10.1]; P = 0.56). ODV reduced viral load at Days 3 and 5, with least squares mean treatment differences of -0.31 (P < 0.0001) and -0.18 (P = 0.0037) log10 copies/mL, respectively. The safety profile of ODV was similar to PBO, with similar rates of AEs, treatment-related AEs, serious AEs, and AEs leading to study drug discontinuation. No deaths or hospitalizations were reported by Day 29. Conclusion ODV was generally safe and well tolerated but did not significantly reduce time to symptom alleviation or resolution in a standard risk population with >99% SARS-CoV-2 seropositivity. ODV reduced SARS-CoV-2 viral load at Days 3 and 5 compared to PBO. Symptom duration was markedly shorter than in prior trials, consistent with milder disease in a population with high rates of hybrid immunity. Disclosures Onyema Ogbuagu, MD, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|GSK/ViiV: Advisor/Consultant|GSK/ViiV: Honoraria|Janssen: Advisor/Consultant|Moderna: Advisor/Consultant|Moderna: Honoraria Jason D. Goldman, MD, MPH, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Speaker|Helix: Grant/Research Support Robert L. Gottlieb, MD, AbbVie: Advisor/Consultant|AbCellera: Stocks/Bonds (Public Company)|AstraZeneca: Advisor/Consultant|Eli Lilly: Advisor/Consultant|Gilead Sciences Inc.: Advisor/Consultant|Gilead Sciences Inc.: Honoraria|Gilead Sciences Inc.: travel support, gift-in-kind to his institution to facilitate an unrelated academic-sponsored clinical trial NCT03383419|GSK Pharmaceuticals: Advisor/Consultant|Johnson & Johnson: Advisor/Consultant|Pfizer: Honoraria|Regeneron: Grants or contracts to institution|Roche: Advisor/Consultant|Roivant Sciences (Kinevant Sciences): Grants or contracts to institution Upinder Singh, MD, FIDSA, Gilead Sciences, Inc.: Advisor/Consultant|Pfizer: Grant/Research Support|Regeneron: Advisor/Consultant Masaharu Shinkai, MD, PhD, AstraZeneca: Grant/Research Support|AstraZeneca: Lecture fees|Fujifilm: Grant/Research Support|Genova Inc: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|GSK: Grant/Research Support|GSK: Lecture fees|Kyorin Pharmaceutical: Lecture fees|Pfizer: Grant/Research Support|Sanofi: Grant/Research Support|Sanofi: Lecture fees|Shionogi: Grant/Research Support Dahlene Fusco, MD, PhD, AICURIS: Site PI|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Site PI|Metro Biotech: Site PI|Regeneron: Site PI|The Biomedical Advanced Research and Development Authority (BARDA) and the National Institute of Allergy and Infectious Diseases (NIAID): Site PI Erika Gonzalez, MD, AstraZeneca: Clinical research PI; Business relationship|DBV: Clinical research PI; Business relationship|Genentech: Clinical research PI; Business relationship|Novartis: Clinical research PI; Business relationship|Regeneron: Clinical research PI; Business relationship Princy N. Kumar, MD, Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Board Member|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Medical writing support provided by Aspire Scientific (Bollington, UK)|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)|Johnson & Johnson: Stocks/Bonds (Public Company)|Merck: Advisor/Consultant|Merck: Board Member|Merck: Grant/Research Support|Merck: Stocks/Bonds (Public Company)|Moderna: Stocks/Bonds (Public Company)|Pfizer: Stocks/Bonds (Public Company)|Theratechnologies: Grant/Research Support|ViiV/GSK: Advisor/Consultant|ViiV/GSK: Board Member|ViiV/GSK: Grant/Research Support|ViiV/GSK: Stocks/Bonds (Public Company) Annie Luetkemeyer, MD, Cepheid: Grant/Research Support|Gilead Sciences, Inc.: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|ViiV: Grant/Research Support|Vir: Advisor/Consultant Amos Lichtman, MPH, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Afsaneh Mozaffarian, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Yiannis Koullias, 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) Joe Llewellyn, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anu Osinusi, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Frank Duff, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Rita Humeniuk, PhD, Gilead Sciences, Inc.: Former Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Luzelena Caro, 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) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Shuguang Chen, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Kim Etchevers, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Priyanka Nadig, MPH, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anita Kohli, MD, Eli Lilly: Received clinical trial revenue|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Received clinical trial revenue|Vir: Received clinical trial revenue

Abstract Background Remdesivir (RDV), a nucleotide analog prodrug that targets the viral RNA-dependent RNA polymerase, Nsp12, is approved to treat COVID-19 in hospitalized and nonhospitalized patients. Obeldesivir (ODV), an oral mono-5’-isobutyryl ester prodrug, is metabolized into the same active triphosphate as RDV. The antiviral activity of RDV and ODV against previous Omicron subvariants (BA.1 to XBF) was maintained with respect to the ancestral WA1 strain. Here, RDV and ODV antiviral activity data against recent Omicron subvariants (XBB.2.3.2, EG.5.1, EG.1.2, BA.2.86, XBC.1.6, HK.3, and JN.1) are reported using clinical isolates and site directed mutants (SDMs) in replicons bearing Nsp12 substitutions observed in these subvariants. Methods The prevalence of Nsp12 substitutions in Omicron subvariants was assessed using Global Initiative on Sharing Avian Influenza Data (GISAID) EpiCoV database sequences. Structures of identified substitutions were analyzed using a previously established cryo-electron microscopy-based model of the replication-transcription complex. Antiviral activity (half-maximal effective concentration [EC50]) of RDV and ODV against subvariant clinical isolates was assessed by nucleoprotein ELISA in A549-hACE2-TMPRSS2 cells and by SDMs in a replicon system. Results Genomic analysis of >2.5 million Omicron subvariant sequences revealed unique substitutions in Nsp12 vs WA1. Two new defining mutations (≥75% of sequences; D63N [HK.3] and G823insD [XBC.1.6]) were found compared with earlier Omicron subvariants. Less prevalent substitutions (1.0% to 15.9%; T26I, D40G, T85I, I171V, Y175H, I223M, T225I, D258N, Y289H, D303N, T394M, P461S, V476A, M666I, T803I, and V848I) were also observed; none had direct interaction with the incoming nucleotide triphosphate or the viral RNA. Phenotyping of individual substitutions using SDMs showed no loss of RDV or ODV susceptibility (≤1.60-fold change). Phenotyping of clinical isolates of XBB.2.3.2, EG.5.1, EG.1.2, BA.2.86, XBC.1.6, HK.3, and JN.1 indicated no change of RDV or ODV in vitro antiviral activity (< 1.05-fold change). Conclusion RDV and ODV retained potent in vitro antiviral activity against all tested Omicron subvariants and Nsp12 substitutions with potencies comparable to reference strains. Disclosures Lauren Rodriguez, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) J. Lizbeth Reyes Zamora, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Dong Han, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Nadine Peinovich, MPH, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Clarissa Martinez, MPH, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Pui Yan Ho, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Jiani Li, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Thomas Aeschbacher, PhD, 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) Jason K. Perry, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identify a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated ~24 hours post-infection significantly reduces log10 viral RNA copies/mL × day area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

Abstract Background COVID-19 remains a serious condition, especially for those with certain risk factors. Obeldesivir (ODV) is an oral, broad spectrum, nucleoside analog prodrug inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase. Methods BIRCH was a Phase 3, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of a 5-day ODV treatment in adults with risk factors for developing severe COVID-19. Nasal swab samples were collected on Days 1, 3, 5, 10, and 15. For participants with baseline viral load (VL) ≥106 copies/mL, samples were evaluated for SARS-CoV-2 infectious titers. In participants with baseline infectious titer ≥200 plaque forming units (PFU)/mL, Day 3 or 5, and, if available, Day 10 samples were assessed. Infectious titer assays were performed by inoculating Vero E6 cells with nasal swab sample serial dilutions, incubating for 96 hours with a carboxymethylcellulose overlay, and quantifying PFU following staining of the cell monolayer. The proportion of participants with undetectable infectious titers was compared between the ODV and placebo (PBO) groups using Fisher’s exact test. Additionally, change from baseline in infectious titer was compared between the ODV and PBO groups using a mixed model repeated measures approach. Results The proportion of participants with positive infectious titers at baseline (≥200 PFU/mL) was similar between the ODV (74/137 [54%]) and PBO (72/129 [56%]) groups. ODV treatment reduced VL at Day 5 versus PBO (–0.58 log10 copies/mL; P < 0.0001) and led to significantly greater reductions from baseline in infectious titers on Day 3 (−0.54 log10 PFU/mL; P = 0.0003) and Day 5 (−0.17 log10 PFU/mL; P = 0.0014) compared to PBO. At Day 3, 35/44 participants (80%) in the ODV group and 18/37 participants (49%) in the PBO group were negative for infectious virus (P = 0.0049). At Day 5, 68/68 participants (100%) in the ODV group and 56/69 participants (81%) in the PBO group were negative for infectious virus (P = 0.0001). At Day 10, the proportions of participants negative for infectious virus were similar between the groups (ODV: 47/49 [96%]; PBO: 40/41 [98%]: P = 1.000). Conclusion In BIRCH, ODV reduced SARS-CoV-2 infectious titers and VL, demonstrating inhibition of SARS-CoV-2 replication in adults with risk factors for developing severe COVID-19. Disclosures Lauren Rodriguez, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Anca Streinu-Cercel, MD PhD Prof. Infectious Diseases, Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria Yiannis Koullias, MD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Afsaneh Mozaffarian, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Kim Etchevers, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Shuguang Chen, PhD, 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) Joe Llewellyn, PharmD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Romas Geleziunas, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Antonella Castagna, MD, Bristol-Myers Squibb: Advisor/Consultant|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Grant/Research Support|Gilead Sciences, Inc.: Honoraria|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Janssen: Honoraria|Merck Sharp & Dohme: Advisor/Consultant|Merck Sharp & Dohme: Grant/Research Support|Merck Sharp & Dohme: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria Charlotte Hedskog, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company)

OBJECTIVES:Remdesivir decreases the risk of SARS-CoV-2 infection progressing to severe disease in adults. This study evaluated remdesivir safety and pharmacokinetics in infants and children. METHODS:This was a phase 2/3, open-label trial in children aged 28 days to 17 years hospitalized for polymerase chain reaction-confirmed SARS-CoV-2 infection. Participants received for ≤10 days once-daily intravenous remdesivir doses defined using physiologically based pharmacokinetic modeling (for ≥40 kg, 200 mg day 1, then 100 mg/day; for age ≥28 days and ≥3 to <40 kg, 5 mg/kg day 1, then 2.5 mg/kg/day). Sparse pharmacokinetic samples were analyzed using population-pharmacokinetic approaches for remdesivir and metabolites GS-704277 and GS-441524. RESULTS:Among 53 participants, at enrollment the median (Q1, Q3) number of days of COVID-19 symptoms was 5 (3, 7) and hospitalization was 1 (1, 3). Underlying conditions included obesity in 19 (37%), asthma in 11 (21%), and cardiac disorders in 11 (21%). Median duration of remdesivir treatment was 5 days (range, 1-10). Remdesivir treatment had no new apparent safety trends. Two participants discontinued treatment because of adverse events including elevated transaminases; both had elevated transaminases at baseline. Three deaths occurred during treatment (and 1 after). When compared with phase 3 adult data, estimated mean pediatric parameters (area under the concentration-time curve over 1 dosing interval, AUCτ, Cmax, and Cτ) were largely overlapping but modestly increased (remdesivir, 33%-129%; GS-704277, 37%-124%; GS-441524, 0%-60%). Recovery occurred for 62% of participants on day 10 and 83% at last assessment. CONCLUSIONS:In infants and children with COVID-19, the doses of remdesivir evaluated provided drug exposure similar to adult dosing. In this study with a small sample size, no new safety concerns were observed.

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.

OBJECTIVES: Remdesivir decreases the risk of SARS-CoV-2 infection progressing to severe disease in adults. This study evaluated remdesivir safety and pharmacokinetics in infants and children. METHODS: This was a phase 2/3, open-label trial in children aged 28 days to 17 years hospitalized for polymerase chain reaction-confirmed SARS-CoV-2 infection. Participants received for <= 10 days once-daily intravenous remdesivir doses defined using physiologically based pharmacokinetic modeling (for >= 40 kg, 200 mg day 1, then 100 mg/day; for age >= 28 days and >= 3 to <40 kg, 5 mg/kg day 1, then 2.5 mg/kg/day). Sparse pharmacokinetic samples were analyzed using population-pharmacokinetic approaches for remdesivir and metabolites GS-704277 and GS-441524. RESULTS: Among 53 participants, at enrollment the median (Q1, Q3) number of days of COVID-19 symptoms was 5 (3, 7) and hospitalization was 1 (1, 3). Underlying conditions included obesity in 19 (37%), asthma in 11 (21%), and cardiac disorders in 11 (21%). Median duration of remdesivir treatment was 5 days (range, 1-10). Remdesivir treatment had no new apparent safety trends. Two participants discontinued treatment because of adverse events including elevated transaminases; both had elevated transaminases at baseline. Three deaths occurred during treatment (and 1 after). When compared with phase 3 adult data, estimated mean pediatric parameters (area under the concentration-time curve over 1 dosing interval, AUC tau, Cmax, and C tau) were largely overlapping but modestly increased (remdesivir, 33%-129%; GS-704277, 37%-124%; GS-441524, 0%-60%). Recovery occurred for 62% of participants on day 10 and 83% at last assessment. CONCLUSIONS: In infants and children with COVID-19, the doses of remdesivir evaluated provided drug exposure similar to adult dosing. In this study with a small sample size, no new safety concerns were observed.

Ebola virus (EBOV) causes severe disease in humans, with mortality as high as 90%. The small-molecule antiviral drug remdesivir (RDV) has demonstrated a survival benefit in EBOV-exposed rhesus macaques. Here, we characterize the efficacy of multiple intravenous RDV dosing regimens on survival of rhesus macaques 42 days after intramuscular EBOV exposure. Thirty rhesus macaques underwent surgical implantation of telemetry devices for the fine-scale monitoring of body temperature and activity, as well as central venous catheters, to enable treatment administration and blood collection. Treatment, consisting of a loading dose of RDV followed by once-daily maintenance doses for 11 days, was initiated 4 days after virus exposure when all animals were exhibiting disease signs consistent with incipient EBOV disease as well as quantifiable levels of EBOV RNA in plasma. In the RDV treatment groups receiving loading/maintenance doses of 5/2.5 mg/kg, 10/5 mg/kg, and 20/10 mg/kg, a total of 6 of 8 (75%), 7 of 8 (87.5%), and 5 of 7 (71.4%) animals survived, respectively. In the vehicle control group, one of seven animals (14.3%) survived. The improved survival rate compared to the control group was statistically significant only for the 10/5 mg/kg RDV treatment group. This treatment regimen also resulted in a significantly lower systemic viral load compared to the vehicle control after a single RDV treatment. All three RDV regimens produced a significantly lower systemic viral load after two treatments. For most animals, RDV treatment, regardless of dose, resulted in the amelioration of many of the clinical–pathological changes associated with EBOV disease in this model.