Vemlidy

The efficacy and safety of VEMLIDY were evaluated in the trials summarized in Table 11.

The efficacy and safety of VEMLIDY in the treatment of adults with chronic hepatitis B virus infection with compensated liver disease are based on 48-week data from two randomized, double-blind, active-controlled trials, Trial 108 (N=425) and Trial 110 (N=873). In both trials, besides trial treatment, subjects were not allowed to receive other nucleosides, nucleotides, or interferon.

In Trial 108, HBeAg-negative treatment-naïve and treatment-experienced subjects with compensated liver disease (no evidence of ascites, hepatic encephalopathy, variceal bleeding, INR <1.5× ULN, total bilirubin <2.5× ULN, and albumin >3.0 mg/dL) were randomized in a 2:1 ratio to receive VEMLIDY 25 mg (N=285) once daily or TDF 300 mg (N=140) once daily for 48 weeks. The mean age was 46 years, 61% were male, 72% were Asian, 25% were White, 2% were Black, and 1% were other races. 24%, 38%, and 31% had HBV genotype B, C, and D, respectively. 21% were treatment experienced [previous treatment with oral antivirals, including entecavir (N=41), lamivudine (N=42), TDF (N=21), or other (N=18)]. At baseline, mean plasma HBV DNA was 5.8 log₁₀IU/mL, mean serum ALT was 94 U/L, and 9% of subjects had a history of cirrhosis.

In Trial 110, HBeAg-positive treatment-naïve and treatment-experienced subjects with compensated liver disease were randomized in a 2:1 ratio to receive VEMLIDY 25 mg (N=581) once daily or TDF 300 mg (N=292) once daily for 48 weeks. The mean age was 38 years, 64% were male, 82% were Asian, 17% were White, and 1% were Black or other races. 17%, 52%, and 23% had HBV genotype B, C, and D, respectively. 26% were treatment experienced [previous treatment with oral antivirals, including adefovir (N=42), entecavir (N=117), lamivudine (N=84), telbivudine (N=25), TDF (N=70), or other (n=17)]. At baseline, mean plasma HBV DNA was 7.6 log₁₀IU/mL, mean serum ALT was 120 U/L, and 7% of subjects had a history of cirrhosis.

In both trials, randomization was stratified on prior treatment history (nucleoside naïve or experienced) and baseline HBV DNA (<7, ≥7 to <8, and ≥8 log₁₀IU/mL in Trial 108; and <8 and ≥8 log₁₀IU/mL in Trial 110). The efficacy endpoint in both trials was the proportion of subjects with plasma HBV DNA levels below 29 IU/mL at Week 48. Additional efficacy endpoints include the proportion of subjects with ALT normalization, HBsAg loss and seroconversion, and HBeAg loss and seroconversion in Trial 110.

Treatment outcomes of Trials 108 and 110 at Week 48 are presented in Table 12 and Table 13.

In Trial 108, the proportion of subjects with cirrhosis who achieved HBV DNA <29 IU/mL at Week 48 was 92% (22/24) in the VEMLIDY group and 93% (13/14) in the TDF group. The corresponding proportions in Trial 110 were 63% (26/41) and 67% (16/24) in the VEMLIDY and TDF groups, respectively.

The efficacy and safety of switching from TDF to VEMLIDY in virologically suppressed adults with chronic hepatitis B virus infection is based on 48-week data from a randomized, double-blind, active-controlled trial, Trial 4018 (N=488). Subjects must have been taking TDF 300 mg once daily for at least 12 months, with HBV DNA less than the Lower Limit of Quantitation by local laboratory assessment for at least 12 weeks prior to screening and HBV DNA <20 IU/mL at screening. Subjects were stratified by HBeAg status (HBeAg-positive or HBeAg-negative) and age (≥50 or <50 years) and randomized in a 1:1 ratio to either switch to VEMLIDY 25 mg once daily (N=243) or stay on TDF 300 mg once daily (N=245). The mean age was 51 years (22% were ≥60 years), 71% were male, 82% were Asian, 14% were White, and 68% were HBeAg-negative. At baseline, median duration of prior TDF treatment was 220 and 224 weeks in the VEMLIDY and TDF groups, respectively. At baseline, mean serum ALT was 27 U/L, and 16% of subjects had a history of cirrhosis.

The primary efficacy endpoint was the proportion of subjects with plasma HBV DNA levels ≥20 IU/mL at Week 48. Additional efficacy endpoints in Trial 4018 included the proportion of subjects with HBV DNA <20 IU/mL, ALT normal and normalization, HBsAg loss and seroconversion, and HBeAg loss and seroconversion.

Treatment outcomes of Trial 4018 at Week 48 are presented in Table 14 and Table 15.

In Trial 4035, Part A, the efficacy and safety of switching from TDF and/or other antivirals to VEMLIDY were evaluated in an open-label clinical trial of virologically suppressed chronic hepatitis B infected adults with moderate to severe renal impairment (estimated creatinine clearance between 15 and 59 mL per minute by Cockcroft-Gault method) (Cohort 1, N=78) or ESRD (estimated creatinine clearance below 15 mL per minute by Cockcroft-Gault method) on hemodialysis (Cohort 2, N=15). At baseline, 98% of subjects in Part A had baseline HBV DNA <20 IU/mL. Median age was 65 years, 74% were male, 77% were Asian, 16% were White, and 83% were HBeAg-negative. Previous treatment with oral antivirals included TDF (Cohort 1, N=57; Cohort 2, N=1), lamivudine (N=46), adefovir dipivoxil (N=46), and entecavir (N=43). At baseline, 97% and 95% of subjects had ALT ≤ULN based on central laboratory criteria and 2018 AASLD criteria, respectively; median estimated creatinine clearance by Cockcroft-Gault was 43 mL per minute (45 mL per minute in Cohort 1 and 7 mL per minute in Cohort 2); and 34% of subjects had a history of cirrhosis.

Overall, 98% of subjects achieved HBV DNA <20 IU/mL at Week 24 (Cohort 1, 97%; Cohort 2, 100%). Two subjects in Cohort 1 discontinued treatment early (due to subject decision); last available HBV DNA for both of these subjects was <20 IU/mL. The overall mean (SD) change from baseline in ALT values was +1 (11.3) U/L (Cohort 1, +1 [11.9] U/L; Cohort 2, +3 [7.9] U/L) at Week 24. No subject had HBeAg or HBsAg loss at Week 24. The mean (SD) changes in HBsAg level from baseline were -0.05 (0.122) log₁₀IU/mL (-0.05 [0.124] log₁₀IU/mL for Cohort 1 and -0.07 [0.115] log₁₀IU/mL for Cohort 2) at Week 24.

In Trial 1092, the efficacy and safety of VEMLIDY in chronic HBV-infected subjects were evaluated in a randomized, double-blind, placebo-controlled clinical trial of treatment-naïve and treatment-experienced subjects between the ages of 12 to less than 18 years weighing at least 35 kg (Cohort 1; N=70) and 6 to less than 12 years weighing at least 25 kg (Cohort 2, Group 1; N=18). Subjects were randomized to receive VEMLIDY (N=59) or placebo (N=29) once daily. Baseline demographics and HBV disease characteristics were comparable between the VEMLIDY treatment arm and the placebo arm: in the VEMLIDY group, 58% were male, 63% were Asian, and 27% were White; 9%, 24%, 22%, and 44% had HBV genotype A, B, C, and D, respectively; 98% percent were HBeAg positive. At baseline, overall median HBV DNA was 8.1 log₁₀IU/mL, mean ALT was 107 U/L, median HBsAg was 4.5 log₁₀IU/mL. Previous treatment included oral antivirals (N=20 [23%]), including entecavir (N=10 [11%]), lamivudine (N=10 [11%]), and TDF (N=2 [2%]), and/or interferons (N=13 [15%]).

The results for each treatment group and cohort for HBV DNA < 20 IU/mL at Weeks 24, 48 and 96 are presented in Table 16 below.

At Week 96, the overall mean (SD) change from baseline in HBV DNA for VEMLIDY-treated subjects and subjects who switched from placebo to VEMLIDY, respectively, was -6.18 (1.495) log₁₀IU/mL and -5.92 (1.775) log₁₀IU/mL. The overall median change from baseline in ALT values for the VEMLIDY and placebo-VEMLIDY treatment groups, respectively, was -39.5 U/L and -46.5 U/L at Week 96. ALT normalization (AASLD criteria) was achieved for 54% of VEMLIDY-treated subjects and 57% of subjects who switched from placebo to VEMLIDY.

At Week 96, 14/58 (24%) VEMLIDY-treated subjects and 5/29 (17%) subjects who switched from placebo to VEMLIDY experienced HBeAg loss with anti-HBe seroconversion. One of 47 (2%) subjects in the Cohort 1 VEMLIDY group achieved HBsAg loss at Week 96.