MAVYRET Labeling Revisions

MAVYRET Label Revisions: (1) study results HCV genotype 3b infection and (2) information in people who inject drugs (PWID) and those on medication-assisted treatment (MAT) for opioid use disorder

The MAVYRET (glecaprevir and pibrentasvir) product labeling was updated to include the efficacy results from VOYAGE-1 and VOYAGE-2 clinical trials conducted in subjects with chronic hepatitis C virus genotype 3b infection. In addition, information in people who inject drugs (PWID) and those on medication-assisted treatment (MAT) for opioid use disorder was added. A summary of the revisions to the label are as follows:

Section 6: ADVERSE REACTION was updated with the following data:

Adverse Reactions in People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

The safety of MAVYRET in PWID with HCV GT 1, 2, 3, 4, 5, or 6 infection is based on data from Phase 2 and 3 trials in which 62 subjects identified as current/recent PWID (defined as self-reported injection drug use within the last 12 months prior to starting MAVYRET) and 3,282 subjects reported no injection drug use (non-PWID).

Among current/recent PWID, adverse reactions observed in greater than or equal to 5% of subjects were fatigue (16%), headache (13%), diarrhea (6%), and nausea (6%). Among non-PWID subjects, adverse reactions observed in greater than or equal to 5% were headache (7%) and fatigue (6%). Serious adverse reactions and/or adverse reactions leading to treatment discontinuation occurred in one current/recent PWID subject (2%) compared to less than 1% in non-PWID subjects.

Among 225 subjects reporting concomitant use of MAT for opioid use disorder, adverse reactions observed in greater than or equal to 5% were headache (15%), fatigue (12%), nausea (11%), and diarrhea (6%). Among 4,098 subjects who were not on MAT, adverse reactions observed in greater than or equal to 5% were headache (9%), fatigue (8%), and nausea (5%).  Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among subjects on MAT and were experienced by less than 1% of subjects not on MAT.

Section 8 USE IN SPECIFIC POPULATIONS was updated to include the following new subsection:

8.8 People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

No dosage adjustment of MAVYRET is required in PWID or those who are on MAT for opioid use disorder. In clinical trials of MAVYRET, the safety and efficacy were similar between subjects who self-identified as current/recent PWID, those who were former PWID, and those who did not report history of injection drug use. The safety and efficacy of MAVYRET were also similar between subjects who reported concomitant MAT for opioid use disorder and those who did not report concomitant MAT.

Section 12.4 was updated with the following data:

In a genotype 3b replicon, the presence of naturally occurring polymorphisms K30 and M31 in NS5A reduced susceptibility to pibrentasvir by 24-fold relative to the activity of pibrentasvir in a genotype 3a replicon. Introduction of an NS5A Y93H substitution into a genotype 3b replicon further reduced susceptibility to pibrentasvir by 6336-fold.

Genotype 3: In registrational trials, HCV subtype 3a was the predominant genotype 3 subtype overall and was detected in >99% of U.S. genotype 3-infected subjects.

In the VOYAGE-1 and VOYAGE-2 trials conducted in China, Singapore, and South Korea, 50% (20/40) of genotype 3-infected subjects had subtype 3b, of whom 14 (70%) achieved SVR12 with MAVYRET durations of 8, 12 or 16 weeks. The naturally occurring NS5A K30 and M31 polymorphisms were detected in 95% (19/20) and 100% (20/20) of genotype 3b-infected subjects.

Section 14 CLINICAL STUDIES was updated to include the following data:

Subjects with Genotype 3b Infection in VOYAGE-1 and VOYAGE-2

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 12="" 16="" 1="" 2="" 3="" 4="" 6="" 8="" all="" and="" asia.="" been="" but="" china="" cirrhosis="" compensated="" conducted="" countries="" div="" except="" genotype="" gt3="" has="" hcv="" in="" india="" infected="" infections="" korea="" mavyret.="" mavyret="" of="" or="" other="" prs-treatment-experienced.="" prs-treatment-experienced="" received="" reported="" respectively="" singapore="" south="" southeast="" subjects="" treatment-naive="" voyage-1="" voyage-2="" weeks="" were="" who="" with="" without="">

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.

14.9 People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder

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 1="" and="" div="" respectively="">

The updated label will soon be available at Drugs@FDA or DailyMed. Kimberly Struble Division of Antivirals Food and Drug Administration