Veklury

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals, ATC code: J05AB16 Mechanism of action Remdesivir is an adenosine nucleotide prodrug that is metabolized within host cells to form the pharmacologically active nucleoside triphosphate metabolite.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Remdesivir triphosphate acts as an analog of adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into nascent RNA chains by the SARS-CoV‑2 RNA-dependent RNA polymerase, which results in delayed chain termination during replication of the viral RNA. As an additional mechanism, remdesivir triphosphate can also inhibit viral RNA synthesis following its incorporation into the template viral RNA as a result of read-through by the viral polymerase that may occur in the presence of higher nucleotide concentrations. When remdesivir nucleotide is present in the viral RNA template, the efficiency of incorporation of the complementary natural nucleotide is compromised, thereby inhibiting viral RNA synthesis. Antiviral activity Remdesivir exhibited in vitro activity against a clinical isolate of SARS-CoV-2 in primary human airway epithelial cells with a 50% effective concentration (EC 50 ) of 9.9 nM after 48 hours of treatment. Remdesivir inhibited the replication of SARS-CoV-2 in the continuous human lung epithelial cell lines Calu-3 and A549-hACE2 with EC 50 values of 280 nM after 72 hours of treatment and 115 nM after 48 hours of treatment, respectively. The EC 50 values of remdesivir against SARS-CoV-2 in Vero cells were 137 nM at 24 hours and 750 nM at 48 hours post-treatment. The antiviral activity of remdesivir was antagonised by chloroquine phosphate in a dose-dependent manner when the two drugs were co-incubated at clinically relevant concentrations in HEp-2 cells infected with respiratory syncytial virus (RSV). Higher remdesivir EC 50 values were observed with increasing concentrations of chloroquine phosphate. Increasing concentrations of chloroquine phosphate reduced formation of remdesivir triphosphate in A549-hACE2, HEp-2 and normal human bronchial epithelial cells. Based on in vitro testing, remdesivir retained similar antiviral activity (EC50 fold change values below the in vitro susceptibility change cutoff of 2.8-fold) against clinical isolates of SARS-CoV-2 variants compared to an earlier lineage SARS-CoV-2 (lineage A) isolate, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Epsilon (B.1.429), Zeta (P.2), Iota (B.1.526), Kappa (B.1.617.1), Lambda (C.37) and Omicron variants (including B.1.1.529/BA.1, BA.2, BA.2.12.1, BA.2.75, BA.2.86, BA.4, BA.4.6, BA.5, BF.5, BF.7, BQ.1, BQ.1.1, CH.1.1, EG.1.2, EG.5.1, EG.5.1.4, FL.22, HK.3, HV.1, JN.1, XBB, XBB.1.5, XBB.1.5.72, XBB.1.16, XBB.2.3.2, XBC.1.6, and XBF). For these variants, the EC50 fold change values ranged between 0.2 to 2.3 compared to an earlier lineage SARS-CoV-2 (lineage A) isolate. Using the SARS-CoV-2 replicon system, remdesivir retained similar antiviral activity (EC50 fold change values below the in vitro susceptibility change cutoff of 2.5-fold) against Omicron subvariants JN.1.7, JN.1.18, KP.2, KP.3, LB.1 and XBB.1.9.2 compared to the wildtype reference replicon (lineage B). Resistance In Cell Culture SARS-CoV-2 isolates with reduced susceptibility to remdesivir have been selected in cell culture. In one selection with GS-441524, the parent nucleoside of remdesivir, virus pools emerged expressing combinations of amino acid substitutions at V166A, N198S, S759A, V792I, C799F, and C799R in the viral RNA-dependent RNA polymerase, conferring EC50 fold-changes of 2.7 up to 10.4. When individually introduced into a wild-type recombinant virus by site-directed mutagenesis, 1.7- to 3.5-fold reduced susceptibility to remdesivir was observed. In a second selection with remdesivir using a SARS-CoV-2 isolate containing the P323L substitution in the viral polymerase, a single amino acid substitution at V166L emerged. Recombinant viruses with substitutions at P323L alone or P323L+V166L in combination exhibited 1.3- and 1.5-fold changes in remdesivir susceptibility, respectively. Cell culture resistance profiling of remdesivir using the rodent CoV murine hepatitis virus identified two substitutions (F476L and V553L) in the viral RNA-dependent RNA polymerase at residues conserved across CoVs that conferred 5.6‑fold reduced susceptibility to remdesivir. Introduction of the corresponding substitutions (F480L and V557L) into SARS-CoV resulted in 6‑fold reduced susceptibility to remdesivir in cell culture and attenuated SARS-CoV pathogenesis in a mouse model. When individually introduced into a SARS-CoV-2 recombinant virus, the corresponding substitutions at F480L and V557L each conferred 2-fold reduced susceptibility to remdesivir. In Clinical Trials In NIAID ACTT-1 Study (CO-US-540-5776), among 61 patients with baseline and post-baseline sequencing data available, the rate of emerging substitutions in the viral RNA-dependent RNA polymerase was similar in patients treated with remdesivir compared to placebo. In 2 patients treated with remdesivir, substitutions in the RNA-dependent RNA polymerase previously identified in resistance selection experiments (V792I or C799F) and associated with low fold change in remdesivir susceptibility (≤3.4-fold) were observed. No other RNA-dependent RNA polymerase substitutions observed in patients treated with remdesivir were associated with resistance to remdesivir. In Study GS-US-540-5773, among 19 patients treated with remdesivir who had baseline and post-baseline sequencing data available, substitutions in the viral RNA-dependent RNA polymerase (nsp12) were observed in 4 patients. The substitutions T76I, A526V, A554V and C697F were not associated with resistance to remdesivir (≤ 1.45-fold change in susceptibility). The effect of substitution E665K on susceptibility to remdesivir could not be determined due to lack of replication. In GS-US-540-9012 Study, among 244 patients with baseline and post-baseline sequencing data available, the rate of emerging substitutions in the viral RNA-dependent RNA polymerase was similar in patients treated with remdesivir compared to placebo. In one patient treated with remdesivir, one substitution in the RNA-dependent RNA polymerase (A376V) emerged and was associated with a decrease in remdesivir susceptibility in vitro (12.6-fold). No other substitutions in the RNA-dependent RNA polymerase or other proteins of the replication-transcription complex observed in patients treated with remdesivir were associated with resistance to remdesivir. In Study GS-US-540-5912, among 60 patients with baseline and post-baseline sequencing data available, substitutions in the viral RNA-dependent RNA polymerase emerged in 8 patients treated with remdesivir. In 4 patients treated with remdesivir, substitutions in the RNA-dependent RNA polymerase (M794I, C799F, or E136V) emerged and were associated with reduced susceptibility to remdesivir in vitro (≤3.5-fold). No other substitutions in the RNA-dependent RNA polymerase detected in patients treated with remdesivir were associated with resistance to remdesivir. In Study GS-US-540-5823, among patients with baseline and post-baseline sequencing data available, substitutions in the viral RNA-dependent RNA polymerase (A656P and G670V) were observed in one of 23 patients treated with remdesivir. The substitutions observed have not been associated with resistance to remdesivir. Clinical efficacy and safety Clinical trials in patients with COVID‑19 NIAID ACTT-1 Study (CO-US-540-5776) A randomised, double-blind, placebo-controlled clinical trial evaluated remdesivir 200 mg once daily for 1 day followed by remdesivir 100 mg once daily for up to 9 days (for a total of up to 10 days of intravenously administered therapy) in hospitalised adult patients with COVID-19 with evidence of lower respiratory tract involvement. The trial enrolled 1,062 hospitalised patients: 159 (15%) patients with mild/moderate disease (15% in both treatment groups) and 903 (85%) patients with severe disease (85% in both treatment groups). Mild/moderate disease was defined as SpO2 > 94% and respiratory rate < 24 breaths/minute without supplemental oxygen; severe disease was defined as SpO2 ≤ 94% on room air, a respiratory rate ≥ 24 breaths/min, and an oxygen requirement, or a requirement for mechanical ventilation. A total of 285 patients (26.8%) (n=131 received remdesivir) were on mechanical ventilation/Extracorporeal Membrane Oxygenation (ECMO). Patients were randomised 1:1, stratified by disease severity at enrolment, to receive remdesivir (n=541) or placebo (n=521), plus standard of care. The baseline mean age was 59 years and 36% of patients were aged 65 or older. Sixty-four percent were male, 53% were White, 21% were Black, 13% were Asian. The most common comorbidities were hypertension (51%), obesity (45%) and type 2 diabetes mellitus (31%); the distribution of comorbidities was similar between the two treatment groups. Approximately 38.4% (208/541) of the patients received a 10‑day treatment course with remdesivir. The primary clinical endpoint was time to recovery within 29 days after randomisation, defined as either discharged from hospital (with or without limitations of activity and with or without home oxygen requirements) or hospitalised but not requiring supplemental oxygen and no longer requiring ongoing medical care. The median time to recovery was 10 days in the remdesivir group compared to 15 days in the placebo group (recovery rate ratio 1.29; [95% CI 1.12 to 1.49], p < 0.001). No difference in time to recovery was seen in the stratum of patients with mild-moderate disease at enrolment (n=159). The median time to recovery was 5 days in the remdesivir and 7 days in the placebo groups (recovery rate ratio 1.10; [95% CI 0.8 to 1.53]); the odds of improvement in the ordinal scale in the remdesivir group at Day 15 when compared to the placebo group were as follows: odds ratio, 1.2; [95% CI 0.7 to 2.2, p = 0.562]. Among patients with severe disease at enrolment (n=903), the median time to recovery was 12 days in the remdesivir group compared to 19 days in the placebo group (recovery rate ratio, 1.34; [95% CI 1.14 to 1.58]; p < 0.001); the odds of improvement in the ordinal scale in the remdesivir group at Day 15 when compared to the placebo group were as follows: odds ratio, 1.6; [95% CI 1.3 to 2.0]. Overall, the odds of improvement in the ordinal scale were higher in the remdesivir group at Day 15 when compared to the placebo group (odds ratio, 1.6; [95% CI 1.3 to 1.9], p < 0.001). The 29-day mortality in the overall population was 11.6% for the remdesivir group vs 15.4% for the placebo group (hazard ratio, 0.73; [95% CI 0.52 to 1.03]; p=0.07). A post-hoc analysis of 29-day mortality by ordinal scale is reported in Table 8. Table 8: 29-Day mortality outcomes by ordinal scale a at baseline—NIAID ACTT-1 trial Ordinal Score at Baseline 5 6 Requiring low-flow oxygen Requiring high-flow oxygen or non-invasive mechanical ventilation Remdesivir (N=232) Placebo (N=203) Remdesivir (N=95) Placebo (N=98) 29-day mortality 4.1 12.8 21.8 20.6 Hazard ratio b (95% CI) 0.30 (0.14, 0.64) 1.02 (0.54, 1.91) a Not a pre-specified analysis. b Hazard ratios for baseline ordinal score subgroups are from unstratified Cox proportional hazards models. Study GS-US-540-5773 in Patients with Severe COVID-19 A randomised, open-label multi-centre clinical trial (Study 5773) of patients at least 12 years of age with confirmed SARS-CoV-2 infection, oxygen saturation of ≤ 94% on room air, and radiological evidence of pneumonia compared 200 patients who received remdesivir for 5 days with 197 patients who received remdesivir for 10 days. All patients received 200 mg of remdesivir on Day 1 and 100 mg once daily on subsequent days, plus standard of care. The primary endpoint was clinical status on Day 14 assessed on a 7-point ordinal scale ranging from hospital discharge to increasing levels of oxygen and ventilatory support to death. The odds of improvement at Day 14 for patients randomized to a 10-day course of remdesivir compared with those randomized to a 5-day course was 0.67 (odds ratio); [95% CI 0.46 to 0.98]. Statistically significant imbalances in baseline clinical status were observed in this study. After adjusting for between-group differences at baseline, the odds of improvement at Day 14 was 0.75 (odds ratio); [95% CI 0.51 to 1.12]. In addition, there were no statistically significant differences in recovery rates or mortality rates in the 5-day and 10-day groups once adjusted for between group differences at baseline. All-cause 28-day mortality was 12% vs 14% in the 5- and 10-day treatment groups, respectively. Study GS-US-540-9012 in patients with confirmed COVID-19 at increased risk for disease progression A randomised, double-blind, placebo-controlled, multi-centre clinical trial to evaluate treatment with remdesivir in an outpatient setting in 562 patients including 8 adolescents (12 years of age and older and weighing at least 40 kg) with confirmed COVID-19 and at least one risk factor for disease progression to hospitalisation. Risk factors for disease progression were: aged ≥ 60 years, chronic lung disease, hypertension, cardiovascular or cerebrovascular disease, diabetes mellitus, obesity, immunocompromised state, chronic mild or moderate kidney disease, chronic liver disease, current cancer, or sickle cell disease. Vaccinated patients were excluded from the study. Patients treated with remdesivir received 200 mg on Day 1 and 100 mg once daily on subsequent days for a total of 3 days of intravenously administered therapy. Patients were randomized in a 1:1 manner, stratified by residence in a skilled nursing facility (yes/no), age (< 60 vs ≥ 60 years), and region (US vs ex-US) to receive remdesivir (n=279) or placebo (n=283), plus standard of care. At baseline, mean age was 50 years (with 30% of patients aged 60 or older); 52% were male, 80% were White, 8% were Black, 2% were Asian, 44% were Hispanic or Latino; median body mass index was 30.7 kg/m 2 . The most common comorbidities were diabetes mellitus (62%), obesity (56%), and hypertension (48%). Median (Q1, Q3) duration of symptoms prior to treatment was 5 (3,6) days; median viral load was 6.3 log 10 copies/mL at baseline. The baseline demographics and disease characteristics were balanced across the remdesivir and placebo treatment groups. Post-hoc exploratory analysis of optional biomarker samples showed 14.8% of patients were serological positive at baseline and 37.7% were serological negative (47.5% did not consent to optional biomarker collection). The primary endpoint was the proportion of patients with COVID-19 related hospitalisation (defined as at least 24 hours of acute care) or all-cause 28-day mortality. Events (COVID-19-related hospitalisation or all-cause 28-day mortality) occurred in 2 (0.7%) patients treated with remdesivir compared to 15 (5.3%) patients concurrently randomized to placebo, demonstrating an 87% reduction in COVID-19-related hospitalisation or all-cause mortality compared to placebo (hazard ratio, 0.134 [95% CI, 0.031 to 0.586]; p=0.0076). The absolute risk reduction was 4.6% (95% CI, 1.8% to 7.5%). No deaths were observed at Day 28. Six of the 17 hospitalisation events occurred in participants with known baseline serostatus (serological positive: n=0 in remdesivir group and n=2 in placebo group; serological negative: n=2 in remdesivir group and n=2 in placebo group). Eleven of the 17 hospitalisation events occurred in participants with unknown baseline serostatus in placebo group and none in the remdesivir group. No conclusion can be made on efficacy in the subgroups stratified by serostatus due to the small number of patients with known serostatus and overall low event rates. Study GS-US-540-5912 in patients with COVID-19 and renal impairment A randomised, double-blind, placebo-controlled clinical study (Study GS-US-540-5912) evaluated remdesivir 200 mg once daily for 1 day followed by remdesivir 100 mg once daily for 4 days (for a total of up to 5 days of intravenously administered therapy) in 243 hospitalised adult patients with confirmed COVID-19 and renal impairment. The trial included 90 patients (37%) with AKI (defined as a 50% increase in serum creatinine within a 48-hour period that was sustained for ≥6 hours despite supportive care), 64 patients (26%) with CKD (eGFR <30 mL/minute), and 89 patients (37%) with ESRD (eGFR <15 mL/minute) requiring haemodialysis. Patients were randomised in a 2:1 manner, stratified by ESRD, high-flow oxygen requirement, and region (US vs ex-US) to receive remdesivir (n=163) or placebo (n=80), plus standard of care. At baseline, mean age was 69 years (with 62% of patients aged 65 or older); 57% of patients were male, 67% were White, 26% were Black, and 3% were Asian. The most common baseline risk factors were hypertension (89%), diabetes mellitus (79%), and cardiovascular or cerebrovascular disease (51%); the distribution of risk factors was similar between the two treatment groups. A total of 45 patients (19%) were on high-flow oxygen, 144 (59%) were on low-flow oxygen, and 54 (22%) were on room air at baseline; no patients were on invasive mechanical ventilation (IMV). A total of 182 patients (75%) were not on renal replacement therapy, and 31 patients (13%) had received a COVID-19 vaccine. The study closed prematurely due to feasibility issues and was underpowered to assess primary (all-cause death or IMV by Day 29) and secondary efficacy endpoints because of lower than expected enrolment. QT In a thorough QT/QTc trial that dosed 60 healthy subjects with 600 mg of remdesivir as a single treatment, no effect was seen on the QTc interval. Paediatric population Study GS-US-540-5823 is a single-arm, open-label study where the pharmacokinetics and safety of remdesivir in paediatric patients at least 28 days of age and weighing at least 3 kg with COVID-19 (n=53) was assessed. Efficacy endpoints were secondary and descriptively analysed and therefore these should be interpreted with caution. The study is ongoing. Patients weighing ≥ 40 kg received 200 mg of remdesivir on Day 1 followed by remdesivir 100 mg once daily on subsequent days (i.e., the adult dose); patients weighing ≥ 3 kg to < 40 kg received remdesivir 5 mg/kg on Day 1 followed by remdesivir 2.5 mg/kg once daily on subsequent days. Median (range) exposure to remdesivir was 5 (1, 10) days. At baseline, median age was 7 years (range: 0.1 to 17 years); 57% were female; median weight was 24.6 kg (range: 4 kg to 192 kg). A total of 19 patients (37%) were obese (BMI-for-age ≥ 95 th percentile); 7 (58%), 2 (17%), 3 (27%), 3 (27%), and 4 (80%) patients in Cohorts 1, 2, 3, 4 and 8 respectively. A total of 12 patients (23%) were on invasive mechanical ventilation (score of 2 in a 7-point ordinal scale), 18 (34%) were on non-invasive ventilation or high-flow oxygen (score of 3); 10 (19%) were on low‑flow oxygen (score of 4); and 13 (25%) were on room air (score of 5), at baseline. The overall median (Q1, Q3) duration of symptoms and hospitalisation prior to first dose of remdesivir was 5 (3, 7) days and 1 (1, 3) day, respectively. In the overall population of the study, the median (Q1, Q3) change from baseline in clinical status (assessed on a 7-point ordinal scale ranging from death [score of 1] to hospital discharge [score of 7]) was +2.0 (1.0, 4.0) points on Day 10. Among those with an ordinal score of ≤ 5 points at baseline, the proportion who had a ≥ 2-point improvement in clinical status on Day 10 was 75.0% (39/52); median (Q1, Q3) time to recovery was 7 (5, 16) days. Overall, 60% of patients were discharged by Day 10. Most patients 92% (49/53) received at least 1 concomitant medication other than remdesivir for the treatment of COVID-19 including immune modulator and anti-inflammatory agents. Three patients died during the study.