Mavyret (Glecaprevir And Pibrentasvir)

Serum HCV RNA values were measured during the clinical trials using the Roche COBAS AmpliPrep/COBAS TaqMan HCV test (version 2.0) with a lower limit of quantification (LLOQ) of 15 IU/mL (except for SURVEYOR-2 which used the Roche COBAS TaqMan real-time reverse transcriptase-PCR (RT-PCR) assay v. 2.0 with an LLOQ of 25 IU/mL). The primary endpoint across all clinical trials was sustained virologic response (SVR12), defined as HCV RNA less than LLOQ at 12 weeks after the end of treatment. Relapse was defined as HCV RNA ≥ LLOQ after end-of-treatment response among subjects who completed treatment. Subjects with missing HCV RNA data, such as those who discontinued due to an adverse event, subject withdrawal or were lost to follow-up, were counted as SVR12 failures.

Of the 2,152 subjects without cirrhosis or with compensated cirrhosis who were treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir (PRS), treated in the registrational studies excluding EXPEDITION-4 and MAGELLAN-1, the median age was 54 years (range: 19 to 88); 73% were treatment-naïve, 27% were PRS treatment-experienced; 39% had HCV genotype 1; 21% had HCV genotype 2; 29% had HCV genotype 3; 7% had HCV genotype 4; 4% had HCV genotype 5, or 6; 13% were ≥65 years; 54% were male; 5% were Black; 12% had cirrhosis; 20% had a body mass index of at least 30 kg per m²; and median baseline HCV RNA level was 6.2 log₁₀IU/mL.

The efficacy of MAVYRET in subjects who were treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir (PRS) with genotype 1, 2, 4, 5, or 6 chronic HCV infection without cirrhosis was studied in three trials using an 8-week duration: ENDURANCE-1, ENDURANCE-5,6, and SURVEYOR-2 [(Part 2 and Part 4)].

ENDURANCE-1 was a randomized (1:1), open-label, multi-national trial comparing the efficacy of 8 weeks of treatment with MAVYRET versus 12 weeks of treatment in subjects without cirrhosis with genotype 1 infection with or without HIV-1 co-infection (n=33 co-infected).

The SVR12 data from the open-label trials SURVEYOR-2 (Parts 2 and 4) and ENDURANCE-5,6 are pooled by genotype, where appropriate, in

The efficacy of MAVYRET in treatment-naïve subjects with genotype 1, 2, 3, 4, 5 or 6 chronic HCV infection and compensated cirrhosis (Child-Pugh A) was studied in EXPEDITION-8, a single-arm, open-label trial in 343 subjects who received MAVYRET for 8 weeks.

The efficacy of MAVYRET in treatment-naive or PRS treatment-experienced subjects with genotype 1, 2, 4, 5 or 6 chronic HCV infection with compensated cirrhosis (Child-Pugh A) was studied in EXPEDITION-1 a single-arm, open-label trial, which included 146 subjects (TN N=110, TE-PRS N=36) treated with MAVYRET for 12 weeks, and in ENDURANCE-5, 6, an open-label trial in 84 subjects (TN N= 76, TE-PRS N=8) with genotype 5 or 6 chronic HCV infection, 9 of whom had compensated cirrhosis (GT5 N=3, GT6 N=6) and received MAVYRET for 12 weeks.

The efficacy of MAVYRET in subjects who were treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin and/or sofosbuvir (PRS) with genotype 3 chronic HCV infection without cirrhosis or with compensated cirrhosis was studied in ENDURANCE-3, EXPEDITION-8 and in SURVEYOR-2 Part 3. Subjects with genotype 3 HCV infection were also included in two Asian regional studies, VOYAGE-1 and VOYAGE-2.

ENDURANCE-3 was a partially-randomized, open-label, active-controlled trial in treatment-naïve subjects without cirrhosis. Subjects were randomized (2:1) to either MAVYRET for 12 weeks or to the combination of sofosbuvir and daclatasvir for 12 weeks; subsequently the trial included a third non-randomized arm with MAVYRET for 8 weeks. The SVR12 data are summarized in

The efficacy of MAVYRET in subjects who were treatment-naïve with genotype 3 chronic HCV infection and compensated cirrhosis was studied in EXPEDITION-8. The SVR12 rate of the treatment-naïve subjects with genotype 3 and compensated cirrhosis was 95% (60/63) and one subject experienced virologic relapse

SURVEYOR-2 Part 3 was an open-label trial randomizing PRS treatment-experienced subjects with genotype 3 infection without cirrhosis to 16-weeks of treatment. In addition, the trial evaluated the efficacy of MAVYRET in PRS treatment-experienced genotype 3-infected subjects with compensated cirrhosis for a 16-week duration. Among PRS treatment-experienced subjects treated with MAVYRET for 16 weeks, 49% (34/69) had failed a previous regimen containing sofosbuvir.

The efficacy of MAVYRET in subjects with HCV subtype 3b infection was evaluated in the VOYAGE-1 and VOYAGE-2 trials. Genotype 3b is a subtype that is uncommon in the U.S. (<1% of HCV GT3 infections) but has been reported in China, India and other countries in South and Southeast Asia. VOYAGE-1 and VOYAGE-2 were conducted in China, Singapore, and South Korea in HCV genotype 1, 2, 3, 4 or 6 infected subjects without cirrhosis (VOYAGE-1) or with compensated cirrhosis (VOYAGE-2) who were treatment-naive or PRS-treatment-experienced. All subjects without cirrhosis or with compensated cirrhosis received 8 or 12 weeks of MAVYRET, respectively, except genotype 3 PRS-treatment-experienced subjects who received 16 weeks of MAVYRET.

Across both trials, subjects with HCV genotype 3b infection had a numerically lower SVR12 rate of 70% (14/20) [58% (7/12) for non-cirrhotic subjects and 88% (7/8) for subjects with compensated cirrhosis] compared to subjects infected with genotype 3a or other HCV genotypes. All six genotype 3b subjects without SVR12 experienced virologic failure (2 on-treatment virologic failure, 4 relapse). SVR12 results in subjects with genotype 3a or other HCV genotypes were comparable with other trials.

EXPEDITION-4 was an open-label, single-arm, multicenter trial to evaluate safety and efficacy in subjects with severe renal impairment (CKD Stages 4 and 5) with compensated liver disease (with and without Child-Pugh A cirrhosis). There were 104 subjects enrolled, 82% were on hemodialysis, and 53%, 15%, 11%, 19%, 1% and 1% were infected with HCV genotypes 1, 2, 3, 4, 5 and 6, respectively. Overall, 19% of subjects had compensated cirrhosis and 81% of subjects were non-cirrhotic; 58% and 42% of subjects were treatment-naïve and PRS treatment-experienced, respectively. The overall SVR12 rate was 98% and no subjects experienced virologic failure. The presence of renal impairment did not affect efficacy; no dose-adjustments were required during the trial.

MAGELLAN-1 was a randomized, multipart, open-label trial in 141 genotype 1- or 4-infected subjects who failed a previous regimen containing an NS5A inhibitor and/or NS3/4A PI. Part 1 (n=50) was a randomized trial exploring 12 weeks of glecaprevir 200 mg and pibrentasvir 80 mg, glecaprevir 300 mg and pibrentasvir 120 mg, with and without ribavirin (only data from glecaprevir 300 mg plus pibrentasvir 120 mg without ribavirin are included in these analyses). Part 2 (n=91) randomized genotype 1- or 4-infected subjects without cirrhosis or with compensated cirrhosis to 12- or 16-weeks of treatment with MAVYRET.

Of the 42 genotype 1-infected subjects treated in Parts 1 and 2, who were either NS5A inhibitor-experienced only (and treated for 16 weeks), or NS3/4A PI-experienced only (and treated for 12 weeks), the median age was 58 years (range: 34 to 70); 40% of the subjects were NS5A-treatment experienced only and 60% were PI experienced only; 24% had cirrhosis; 19% were ≥65 years, 69% were male; 26% were Black; 43% had a body mass index ≥ 30 kg/m²; 67% had baseline HCV RNA levels of at least 1,000,000 IU per mL; 79% had subtype 1a infection, 17% had subtype 1b infection and 5% had non-1a/1b infection.

Due to higher rates of virologic failure and treatment-emergent drug resistance, the data do not support labeling for treatment of HCV genotype 1-infected patients who are both NS3/4A PI and NS5A inhibitor-experienced.

EXPEDITION-2 was an open-label study in 153 HCV/HIV-1-coinfected subjects. Subjects without cirrhosis received MAVYRET for 8 weeks and subjects with compensated cirrhosis received MAVYRET for 12 weeks. The study included subjects who were HCV treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin, and/or sofosbuvir, with the exception of genotype 3-infected subjects who were all treatment naïve.

Of the 153 subjects treated, the median age was 45 years (range: 23 to 74); 63% had HCV genotype 1, 7% had HCV genotype 2, 17% had HCV genotype 3, 11% had HCV genotype 4, 2% had HCV genotype 6; 11% had cirrhosis; 84% were male; and 16% were Black.

In EXPEDITION-2, the SVR12 rate in HCV/HIV-1 co-infected subjects was 98% (150/153). One subject experienced on-treatment virologic failure and no subjects relapsed.

MAGELLAN-2 was a single-arm, open-label study in 100 post-liver or -kidney transplant HCV genotype 1, 2, 3, 4, or 6 infected subjects without cirrhosis who received MAVYRET for 12 weeks. The study included subjects who were HCV treatment-naïve or treatment-experienced to combinations of (peg)interferon, ribavirin, and/or sofosbuvir, with the exception of genotype 3-infected subjects who were all treatment-naïve.

Of the 100 subjects treated, the median age was 60 years (range: 39 to 78); 57% had HCV genotype 1, 13% had HCV genotype 2, 24% had HCV genotype 3, 4% had HCV genotype 4, 2% had HCV genotype 6; 75% were male; 8% were Black; 80% of subjects were post-liver transplant and 20% were post-kidney transplant. Immunosuppressants allowed for co-administration were cyclosporine ≤100 mg, tacrolimus, sirolimus, everolimus, azathioprine, mycophenolic acid, prednisone, and prednisolone.

The overall SVR12 rate in post-transplant subjects was 98% (98/100). There was one relapse and no on-treatment virologic failures.

Among 4,655 chronic HCV genotype 1-6-infected adolescents and adults in Phase 2 and 3 trials who received MAVYRET and specified whether or not they had a history of injection drug use, 1,373 subjects were identified as PWID based on self-reported history of injection drug use at trial enrollment and 3,282 subjects did not report injection drug use (non-PWID). Of the PWID population, 62 subjects were considered current/recent PWID (defined as self-reported injection drug use within the last 12 months prior to starting MAVYRET), 959 subjects were considered former PWID (defined as self-reported injection drug use more than 12 months prior to starting MAVYRET), and 352 subjects did not specify current/recent PWID versus former PWID and were not included in the analysis. Compared to former/non-PWID subjects (n=4,241), the current/recent PWID subjects were more frequently male (79%), White (73%), younger (median age [range]: 40 years [19 to 64]), treatment-naïve (94%), and had higher proportions of HCV genotype 3 infection (44%) and HIV co-infection (24%). Similar to the former/non-PWID subjects, the majority of current/recent PWID subjects were non-cirrhotic (73%). The overall SVR12 rate was 98% in former/non-PWID subjects and 89% in current/recent PWID subjects; the difference between the two groups was primarily due to missing data at the time of the SVR12 measurement window in the current/recent PWID group. Virologic failure rates, however, were similar in both groups: 2% in the current/recent PWID subjects and 1% in former/non-PWID subjects.

Among 4,655 chronic HCV genotype 1-6-infected adolescents and adults in Phase 2 and 3 trials who received MAVYRET and specified whether or not they had a history of injection drug use, 225 subjects reported concomitant use of MAT for opioid use disorder and 4,098 subjects reported no use of MAT (332 subjects were not included in the analysis due to missing assessment of MAT). Compared to those not on MAT, subjects on MAT were more frequently male (70%), White (92%), younger (median age [range]: 47 years [23 to 76]), treatment-naïve (89%), and had a higher proportion of HCV genotype 3 infection (50%). Of subjects on MAT, 74% were non-cirrhotic, and 7% were co-infected with HIV, similar to those not on MAT. The SVR12 rates were similar between subjects on MAT (96%) and those not on MAT (98%), with low rates of virologic failure in both groups (<1% and 1%, respectively).

The efficacy of MAVYRET was evaluated in an open-label study (DORA [Part 1 and Part 2]) that evaluated pediatric subjects 3 years to less than 18 years without cirrhosis who received MAVYRET for 8, 12, or 16 weeks. Treatment duration was chosen to match approved adult durations based on HCV genotype and prior treatment experience.

Forty-seven subjects were enrolled in DORA (Part 1) and received the adult dose of MAVYRET tablets. The median age was 14 years (range: 12 years to 17 years); the mean weight was 59 kg (range: 32 kg to 109 kg); 55% were female; 74% were White; 13% were Asian, and 9% were Black; 79% had HCV genotype 1, 6% had HCV genotype 2, 9% had HCV genotype 3, and 6% had HCV genotype 4; 77% were HCV TN; 23% were treatment-experienced to interferon; 4% had HIV-coinfection; none had cirrhosis. The overall SVR12 rate was 100% (47/47).

Eighty subjects aged 3 years to less than 12 years were enrolled in DORA (Part 2) and received weight-based dosing of MAVYRET oral pellets for 8, 12, or 16 weeks. The median age was 7 years (range: 3 years to 11 years); the mean weight was 26 kg (range: 13 kg to 44 kg); 55% were female; 69% were White, 18% were Asian, and 4% were Black; 73% had HCV genotype 1, 3% had HCV genotype 2, 23% had HCV genotype 3, and 3% had HCV genotype 4; 97.5% were HCV TN; 2.5% were treatment-experienced to interferon; 1% had HIV-coinfection; none had cirrhosis.

Sixty-two subjects received the weight-based recommended dosage. Eighteen subjects received doses lower than the recommended weight-based dosage and were not included in the efficacy assessment. The overall SVR12 rate for the subjects who received the recommended dosage was 98.4% (61/62); the subject who did not achieve SVR12 discontinued treatment due to an adverse reaction

The efficacy of MAVYRET in subjects with documented acute HCV infection was evaluated in M20-350, a single-arm, open-label study of 286 adults who were treatment-naïve for the current infection and received MAVYRET for 8 weeks.

Diagnosis of acute HCV infection at screening was based on physician diagnosis, quantifiable HCV RNA, and one or more of the following: negative anti-HCV antibody, recent conversion of negative to positive results in anti-HCV antibody, HCV RNA or HCV core antigen testing, liver disease signs associated with acute HCV infection, and recent risk behaviors for HCV infection. Eighty-four percent of enrolled subjects had evidence of clinical hepatitis at screening in the absence of other causes of liver disease and with recent risk behavior for HCV transmission. At baseline, 96% of subjects had quantifiable HCV RNA, of whom 39% had a documented result of negative HCV antibody or unquantifiable HCV RNA within the previous year, and 4% of subjects had unquantifiable HCV RNA possibly reflecting spontaneous clearance of the HCV infection during the pre-treatment period.

The median age was 43 years (range: 20 to 78); 18% had a history of a prior HCV infection; 58% had HCV genotype 1, 4% had HCV genotype 2, 12% had HCV genotype 3, 17% had HCV genotype 4; 6% were ≥65 years; 89% were male; 11% were Black; 2% had cirrhosis; 50% had HIV co-infection; 14% were current/recent PWID; 7% reported ongoing use of MAT for opioid use disorder, 9% had a body mass index of at least 30 kg per m²; and median baseline HCV RNA level was 5.4 log₁₀IU/mL.

The overall SVR12 rate was 96% (275/286); no subjects experienced virologic failure. Two subjects who did not achieve SVR12 likely were reinfected with HCV based on having different HCV genotypes or subtype clades between the baseline and follow-up periods.