Mavyret Drug Information
Generic name: GLECAPREVIR AND PIBRENTASVIR
Hepatitis C Virus NS3/4A Protease Inhibitor [EPC] Hepatitis C Virus NS5A Inhibitor [EPC]
Uses of Mavyret
is indicated for the treatment of adult and pediatric patients 3 years and older with acute or chronic hepatitis C virus (HCV) genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is indicated for the treatment of adult and pediatric patients 3 years and older with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor (PI), but not both. MAVYRET is a fixed-dose combination of glecaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, and is indicated for the treatment of adult and pediatric patients 3 years and older with acute or chronic HCV genotype (GT) 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is indicated for the treatment of adult and pediatric patients 3 years and older with HCV genotype 1 infection, who previously have been treated with a regimen containing an HCV NS5A inhibitor or an NS3/4A protease inhibitor, but not both.
Dosage & Administration of Mavyret
| 1, 2, 3, 4, 5, or 6 | 8 weeks |
|---|
Side Effects of Mavyret
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of MAVYRET cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Overall Adverse Reactions in Subjects with Chronic HCV Infection without Cirrhosis or with Compensated Cirrhosis (Child-Pugh A) The adverse reactions data for MAVYRET in subjects without cirrhosis or with compensated cirrhosis (Child-Pugh A) were derived from nine registrational Phase 2 and 3 trials which evaluated approximately 2,300 adults infected with genotype 1, 2, 3, 4, 5, or 6 HCV who received MAVYRET for 8, 12 or 16 weeks . The overall proportion of subjects who permanently discontinued treatment due to adverse reactions was 0.1% for subjects who received MAVYRET for 8, 12 or 16 weeks. The most common adverse reactions, all grades, observed in greater than or equal to 5% of subjects receiving 8, 12, or 16 weeks of treatment with MAVYRET were headache (13%), fatigue (11%), and nausea (8%). In subjects receiving MAVYRET who experienced adverse reactions, 80% had an adverse reaction of mild severity (Grade 1). One subject experienced a serious adverse reaction.
Adverse reactions (type and severity) were similar for subjects receiving MAVYRET for 8, 12 or 16 weeks. The type and severity of adverse reactions in subjects with compensated cirrhosis (Child-Pugh A) were similar to those seen in subjects without cirrhosis. Adverse Reactions in Subjects with Chronic HCV Infection without Cirrhosis ENDURANCE-2 Among 302 treatment-naïve or PRS treatment-experienced, HCV genotype 2-infected adults without cirrhosis enrolled in ENDURANCE-2, adverse reactions (all intensity) occurring in at least 5% of subjects treated with MAVYRET for 12 weeks are presented in Table 4. In subjects treated with MAVYRET for 12 weeks, 32% reported an adverse reaction, of which 98% had adverse reactions of mild or moderate severity.
No subjects treated with MAVYRET or placebo in ENDURANCE-2 permanently discontinued treatment due to an adverse drug reaction. Table 4. Adverse Reactions Reported in ≥5% of Treatment-Naïve and PRS-Experienced Adults without Cirrhosis Receiving MAVYRET for 12 Weeks in ENDURANCE-2 Adverse Reaction MAVYRET 12 Weeks (N = 202) % Placebo 12 Weeks (N = 100) % Headache 9 6 Nausea 6 2 Diarrhea 5 2 ENDURANCE-3 Among 505 treatment-naïve, HCV genotype 3-infected adults without cirrhosis enrolled in ENDURANCE-3, adverse reactions (all intensity) occurring in at least 5% of subjects treated with MAVYRET for 8 or 12 weeks are presented in Table 5. In subjects treated with MAVYRET, 45% reported an adverse reaction, of which 99% had adverse reactions of mild or moderate severity. The proportion of subjects who permanently discontinued treatment due to adverse reactions was 0%, < 1% and 1% for the MAVYRET 8-week arm, MAVYRET 12 week arm and DCV + SOF arm, respectively.
Table 5. Adverse Reactions Reported in ≥5% of Treatment-Naïve Adults without Cirrhosis Receiving MAVYRET for 8 Weeks or 12 Weeks in ENDURANCE-3 Adverse Reaction MAVYRET* 8 Weeks (N = 157) % MAVYRET 12 Weeks (N = 233) % DCV 1 + SOF 2 12 Weeks (N = 115) % Headache 16 17 15 Fatigue 11 14 12 Nausea 9 12 12 Diarrhea 7 3 3 1 DCV=daclatasvir 2 SOF=sofosbuvir * The 8-week arm was a non-randomized treatment arm. Adverse Reactions in Subjects with Chronic HCV Infection with Compensated Cirrhosis (Child-Pugh A) The safety of MAVYRET in HCV GT 1, 2, 3, 4, 5, or 6 subjects with compensated cirrhosis is based on data from 288 adults from the Phase 2/3 registrational trials treated with MAVYRET for 12 or more weeks and 343 adults from EXPEDITION-8 treated with MAVYRET for 8 weeks. The adverse reactions observed were generally consistent with those observed in clinical studies of MAVYRET in non-cirrhotic subjects . In the Phase 2/3 registrational trials, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=288) treated across all durations of MAVYRET were fatigue (15%), headache (14%), nausea (8%), diarrhea (6%), and pruritus (6%). In EXPEDITION-8, the adverse reactions reported in greater than or equal to 5% of compensated cirrhotic subjects (n=343) were fatigue (8%), pruritus (7%), and headache (6%). No subjects with compensated cirrhosis in the Phase 2/3 registrational trials (without severe renal impairment) or in EXPEDITION-8 discontinued treatment with MAVYRET due to an adverse reaction.
Adverse Reactions in Subjects with Chronic HCV Infection with Severe Renal Impairment Including Those on Dialysis The safety of MAVYRET in subjects with chronic kidney disease (Stage 4 or Stage 5 including subjects on dialysis) with genotypes 1, 2, 3, 4, 5 or 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) was assessed in 104 adults (EXPEDITION-4) who received MAVYRET for 12 weeks. The most common adverse reactions observed in greater than or equal to 5% of subjects receiving 12 weeks of treatment with MAVYRET were pruritus (17%), fatigue (12%), nausea (9%), asthenia (7%), and headache (6%). In subjects treated with MAVYRET who reported an adverse reaction, 90% had adverse reactions of mild or moderate severity (Grade 1 or 2). The proportion of subjects who permanently discontinued treatment due to adverse reactions was 2%. Adverse Reactions in Subjects with Chronic HCV Infection Co- I nfected with HIV-1 The safety of MAVYRET in subjects with HIV-1 co-infection with genotypes 1, 2, 3, 4 or 6 chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) was assessed in 153 adults (EXPEDITION-2) who received MAVYRET for 8 or 12 weeks. Thirty-three subjects with HIV-1 coinfection also received 8 or 12 weeks of therapy in ENDURANCE-1. The overall safety profile in HCV/HIV-1 co-infected subjects (ENDURANCE-1 and EXPEDITION-2) was similar to that observed in HCV mono-infected subjects.
Adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET in EXPEDITION-2 for 8 or 12 weeks were fatigue (10%), nausea (8%), and headache (5%). Adverse Reactions in Subjects with Chronic HCV Infection with Liver or Kidney Transplant The safety of MAVYRET was assessed in 100 adult post-liver or -kidney transplant recipients with genotypes 1, 2, 3, 4, or 6 chronic HCV infection without cirrhosis (MAGELLAN-2). The overall safety profile in transplant recipients was similar to that observed in subjects in the Phase 2 and 3 studies, without a history of transplantation. Adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET for 12 weeks were headache (17%), fatigue (16%), nausea (8%) and pruritus (7%). In subjects treated with MAVYRET who reported an adverse reaction, 81% had adverse reactions of mild severity. Two percent of subjects experienced a serious adverse reaction, and no subjects permanently discontinued treatment due to adverse reactions.
Adverse Reactions in People Who Inject Drugs (PWID) and those on Medication-Assisted Treatment (MAT) for Opioid Use Disorder with Chronic HCV Infection PWID The safety of MAVYRET in PWID with chronic HCV GT 1, 2, 3, 4, 5, or 6 infection is based on data from adults and adolescents in 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. MAT The safety of MAVYRET in subjects with chronic HCV GT 1, 2, 3, 4, 5, or 6 infection reporting concomitant use of MAT for opioid use disorder is based on data from adults and adolescents in Phase 2 and 3 trials in which 225 subjects reported concomitant use of MAT and 4,098 subjects reported no concomitant use of MAT. Among subjects on MAT, adverse reactions observed in greater than or equal to 5% were headache (15%), fatigue (12%), nausea (11%), and diarrhea (6%). Among 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. Adverse Reactions in Subjects with Acute HCV Infection The safety of MAVYRET in subjects with acute HCV GT 1, 2, 3, or 4 infection was assessed in 286 adults who received MAVYRET for 8 weeks. Among these subjects, 142 had HIV-1 co-infection, 41 identified as current/recent PWID, and 21 reported concomitant use of MAT. At baseline, 49% of subjects had ALT elevations greater than 3 x upper limit of normal (ULN), 13% had ALT elevations greater than 10 x ULN, and 12% had total bilirubin elevations greater than ULN. The overall safety profile in these subjects was similar to that observed in subjects with chronic HCV infection.
Serious adverse reactions and/or adverse reactions leading to treatment discontinuation were not observed among subjects with acute HCV infection. The most commonly reported adverse reactions were fatigue (3%), asthenia (2%), headache (2%) and diarrhea (2%) . Adverse Reactions in Pediatric Subjects 3 Y ears and Older with Chronic HCV Infection The safety of MAVYRET in HCV GT 1, 2, 3, or 4 infected adolescents is based on data from a Phase 2/3 open-label trial in 47 subjects aged 12 years to less than 18 years without cirrhosis treated with MAVYRET for 8 or 16 weeks (DORA-Part 1). The adverse reactions observed in subjects 12 years to less than 18 years of age were consistent with those observed in clinical trials of MAVYRET in adults. The only adverse reaction observed in greater than or equal to 5% of subjects receiving MAVYRET in DORA Part 1 was fatigue (6%). No subjects discontinued or interrupted treatment with MAVYRET due to an adverse reaction.
The safety of MAVYRET in HCV GT 1, 2, 3, or 4 infected pediatric subjects aged 3 years to less than 12 years is based on data from a Phase 2/3 open-label trial in 80 subjects aged 3 to less than 12 years without cirrhosis treated with weight-based MAVYRET oral pellets in packets for 8, 12 or 16 weeks (DORA-Part 2). The adverse reactions observed in subjects 3 years to less than 12 years of age were consistent with those observed in clinical trials of MAVYRET in adults with the exception of vomiting (occurring at 8%), rash, and abdominal pain upper (each occurring at 4%) which were observed more frequently in pediatric subjects less than 12 years of age compared to adults. Other adverse reactions observed in greater than or equal to 5% of subjects receiving MAVYRET in DORA-Part 2 include fatigue and headache, each occurring at 8%. One subject discontinued treatment due to an adverse reaction of erythematous rash (Grade 3). All other adverse reactions were Grade 1 or 2 and no subjects interrupted treatment due to an adverse reaction . Laboratory Abnormalities Serum bilirubin elevations in su bjects wit h chronic HCV infection Elevations of total bilirubin at least 2 times the ULN occurred in 3.5% of adult subjects treated with MAVYRET versus 0% in placebo; these elevations were observed in 1.2% of adult subjects across the Phase 2 and 3 trials. In adult subjects with compensated cirrhosis (Child-Pugh A), 17% experienced early, transient post-baseline elevations of bilirubin above the ULN. These bilirubin elevations were typically less than 2 × ULN, generally occurred within the first 2 weeks of treatment and resolved with continued treatment.
The subjects with compensated cirrhosis and bilirubin elevations did not have concurrent increases in ALT or AST, or signs of liver decompensation or failure, and these laboratory events did not lead to treatment discontinuation. MAVYRET inhibits OATP1B1/3 and is a weak inhibitor of UGT1A1 and may have the potential to impact bilirubin transport and metabolism, including direct and indirect bilirubin. Few subjects experienced jaundice or ocular icterus and total bilirubin levels decreased after completing MAVYRET. Liver tests in subjects with acute HCV infection Elevations of total bilirubin at least 2 times ULN occurred in 2.8% of subjects treated with MAVYRET. Subjects with total bilirubin elevations did not have concurrent increases in ALT or AST, or signs of liver decompensation or failure, and these laboratory events did not lead to treatment discontinuation.
All subjects with baseline ALT > 3 × ULN improved from baseline by the final treatment visit.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of MAVYRET. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders : Angioedema Hepatobiliary Disorders: Hepatic decompensation, hepatic failure .
Warnings & Cautions for Mavyret
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with
HCV and HBV Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic evidence of resolved HBV infection (i.e., HBsAg negative and anti-HBc positive). HBV reactivation has also been reported in patients receiving certain immunosuppressant or chemotherapeutic agents; the risk of HBV reactivation associated with treatment with HCV direct-acting antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level. In patients with resolved HBV infection reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis, i.e., increase in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can occur.
Test all patients for evidence of current or prior HBV infection by measuring HBsAg and anti- HBc before initiating HCV treatment with MAVYRET. In patients with serologic evidence of HBV infection, monitor for clinical and laboratory signs of hepatitis flare or HBV reactivation during HCV treatment with MAVYRET and during post-treatment follow-up. Initiate appropriate patient management for HBV infection as clinically indicated.
Risk of Hepatic Decompensation/Failure in Patients with Evidence of Advanced Liver Disease
Postmarketing cases of hepatic decompensation/failure, including those with fatal outcomes, have been reported in patients treated with HCV NS3/4A protease inhibitor-containing regimens, including MAVYRET. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The majority of patients with severe outcomes had evidence of advanced liver disease with moderate or severe hepatic impairment (Child-Pugh B or C) prior to initiating therapy with MAVYRET, including some patients reported as having compensated cirrhosis with mild liver impairment (Child-Pugh A) at baseline but with a prior decompensation event (i.e., prior history of ascites, variceal bleeding, encephalopathy). Rare cases of hepatic decompensation/failure were reported in patients without cirrhosis or with compensated cirrhosis (Child-Pugh A); many of these patients had evidence of portal hypertension. Events also occurred in patients taking a concomitant medication not recommended for coadministration, or in patients with confounding factors such as serious liver-related medical or surgical comorbidities.
Cases typically occurred within the first 4 weeks of treatment (median of 27 days). In patients with compensated cirrhosis (Child-Pugh A) or evidence of advanced liver disease such as portal hypertension, perform hepatic laboratory testing as clinically indicated; and monitor for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage. Discontinue MAVYRET in patients who develop evidence of hepatic decompensation/failure. MAVYRET is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation .
Risk of Reduced Therapeutic Effect Due to
Concomitant Use of MAVYRET with Carbamazepine, Efavirenz Containing Regimens, or St. John’s Wort Carbamazepine, efavirenz, and St. John’s wort may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of MAVYRET. The use of these agents with MAVYRET is not recommended.
Drug Interactions with Mavyret
Mechanisms for the Potential Effect of
MAVYRET on Other Drugs Glecaprevir and pibrentasvir are inhibitors of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP) 1B1/3. Coadministration with MAVYRET may increase plasma concentration of drugs that are substrates of P-gp, BCRP, OATP1B1 or OATP1B3. Glecaprevir and pibrentasvir are weak inhibitors of cytochrome P450 (CYP) 3A, CYP1A2, and uridine glucuronosyltransferase (UGT) 1A1.
Mechanisms for the Potential Effect of Other Drugs on
MAVYRET Glecaprevir and pibrentasvir are substrates of P-gp and/or BCRP. Glecaprevir is a substrate of OATP1B1/3. Coadministration of MAVYRET with drugs that inhibit hepatic P-gp, BCRP, or OATP1B1/3 may increase the plasma concentrations of glecaprevir and/or pibrentasvir. Coadministration of MAVYRET with drugs that induce P-gp/CYP3A may decrease glecaprevir and pibrentasvir plasma concentrations. Carbamazepine, phenytoin, efavirenz, and St.
John’s wort may significantly decrease plasma concentrations of glecaprevir and pibrentasvir, leading to reduced therapeutic effect of MAVYRET. The use of these agents with MAVYRET is not recommended .
Established and Other Potential Drug Interactions Clearance of
HCV infection with direct-acting antivirals may lead to changes in hepatic function, which may impact the safe and effective use of concomitant medications. For example, altered blood glucose control resulting in serious symptomatic hypoglycemia has been reported in diabetic patients in postmarketing case reports and published epidemiological studies. Management of hypoglycemia in these cases required either discontinuation or dose modification of concomitant medications used for diabetes treatment.
Frequent monitoring of relevant laboratory parameters (e.g. International Normalized Ratio in patients taking warfarin, blood glucose levels in diabetic patients) or drug concentrations of concomitant medications such as CYP P450 substrates with a narrow therapeutic index (e.g. certain immunosuppressants) is recommended to ensure safe and effective use. Dose adjustments of concomitant medications may be necessary.
Table 6 provides the effect of MAVYRET on concentrations of coadministered drugs and the effect of coadministered drugs on glecaprevir and pibrentasvir . All interaction studies were performed in adults. Table 6. Potentially Significant Drug Interactions Identified in Drug Interaction Studies Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comments Antiarrhythmics: Digoxin ↑ digoxin Measure serum digoxin concentrations before initiating MAVYRET. Reduce digoxin concentrations by decreasing the dose by approximately 50% or by modifying the dosing frequency and continue monitoring. Anticoagulants: Dabigatran etexilate ↑ dabigatran If MAVYRET and dabigatran etexilate are coadministered, refer to the dabigatran etexilate prescribing information for dabigatran etexilate dose modifications in combination with P-gp inhibitors in the setting of renal impairment.
Anticonvulsants: Carbamazepine ↓ glecaprevir ↓ pibrentasvir Coadministration may lead to reduced therapeutic effect of MAVYRET and is not recommended. Antimycobacterials: Rifampin ↓ glecaprevir ↓ pibrentasvir Coadministration is contraindicated because of potential loss of therapeutic effect . Ethinyl Estradiol-Containing Products: Ethinyl estradiol-containing medications such as combined oral contraceptives ↔ glecaprevir ↔ pibrentasvir MAVYRET may be used with products containing 20 mcg or less of ethinyl estradiol. Coadministration of MAVYRET with products containing more than 20 mcg of ethinyl estradiol may increase the risk of ALT elevations and is not recommended.
Herbal Products: St. John’s wort ( hypericum perforatum ) ↓ glecaprevir ↓ pibrentasvir Coadministration may lead to reduced therapeutic effect of MAVYRET and is not recommended. HIV-Antiviral Agents: Atazanavir ↑ glecaprevir ↑ pibrentasvir Coadministration is contraindicated due to increased risk of ALT elevations . Darunavir Lopinavir Ritonavir ↑ glecaprevir ↑ pibrentasvir Coadministration is not recommended.
Efavirenz ↓ glecaprevir ↓ pibrentasvir Coadministration may lead to reduced therapeutic effect of MAVYRET and is not recommended. HMG-CoA Reductase Inhibitors: Atorvastatin Lovastatin Simvastatin ↑ atorvastatin ↑ lovastatin ↑ simvastatin Coadministration may increase the concentration of atorvastatin, lovastatin, and simvastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis.
Coadministration with these statins is not recommended. Pravastatin ↑ pravastatin Coadministration may increase the concentration of pravastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis.
Reduce pravastatin dose by 50% when coadministered with MAVYRET. Rosuvastatin ↑ rosuvastatin Coadministration may significantly increase the concentration of rosuvastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Rosuvastatin may be administered with MAVYRET at a dose that does not exceed 10 mg.
Fluvastatin Pitavastatin ↑ fluvastatin ↑ pitavastatin Coadministration may increase the concentrations of fluvastatin and pitavastatin. Increased statin concentrations may increase the risk of myopathy, including rhabdomyolysis. Use the lowest approved dose of fluvastatin or pitavastatin.
If higher doses are needed, use the lowest necessary statin dose based on a risk/benefit assessment. Immunosuppressants: Cyclosporine ↑ glecaprevir ↑ pibrentasvir MAVYRET is not recommended for use in patients requiring stable cyclosporine doses > 100 mg per day. See Clinical Pharmacology, Tables 10 and 11. ↑= increase; ↓= decrease; ↔ = no effect
Medication-Assisted Treatment (MAT) for Opioid Use Disorder No buprenorphine/naloxone or methadone dosage
adjustment is required when used concomitantly with MAVYRET. There is insufficient information to make a recommendation regarding the concomitant use of naltrexone with MAVYRET.
Drugs with No Observed Clinically Significant Interactions with
MAVYRET No dose adjustment is required when MAVYRET is coadministered with the following medications: abacavir, amlodipine, caffeine, dextromethorphan, dolutegravir, elvitegravir/ cobicistat, emtricitabine, ethinyl estradiol of 20 mcg or less, felodipine, lamivudine, lamotrigine, losartan, midazolam, norethindrone or other progestin-only contraceptives, omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan.
Pregnancy Safety for Mavyret
Pregnancy Risk Summary No adequate human data are available to establish whether or not MAVYRET poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when the components of MAVYRET were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) the human exposures at the recommended dose of MAVYRET (see Data ). No definitive conclusions regarding potential developmental effects of glecaprevir could be made in rabbits, since the highest achieved glecaprevir exposure in this species was only 7% (0.07 times) of the human exposure at the recommended dose. There were no effects with either compound in rodent pre/post-natal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times, respectively, the exposure in humans at the recommended dose (see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Glecaprevir Glecaprevir was administered orally to pregnant rats (up to 120 mg/kg/day) and rabbits (up to 60 mg/kg/day) during the period of organogenesis (gestation days (GD) 6 to 18, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed in rats at dose levels up to 120 mg/kg/day (53 times the exposures in humans at the recommended human dose (RHD)). In rabbits, the highest glecaprevir exposure achieved was 7% (0.07 times) of the exposure in humans at RHD. As such, data in rabbits during organogenesis are not available for glecaprevir systemic exposures at or above the exposures in humans at the RHD. In the pre/post-natal developmental study in rats, glecaprevir was administered orally (up to 120 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures 47 times the exposures in humans at the RHD. Pibrentasvir Pibrentasvir was administered orally to pregnant mice and rabbits (up to 100 mg/kg/day) during the period of organogenesis (GD 6 to 15, and GD 7 to 19, respectively). No adverse embryo-fetal effects were observed at any studied dose level in either species. The systemic exposures at the highest doses were 51 times (mice) and 1.5 times (rabbits) the exposures in humans at the RHD. In the pre/post-natal developmental study in mice, pibrentasvir was administered orally (up to 100 mg/kg/day) from GD 6 to lactation day 20. No effects were observed at maternal exposures approximately 74 times the exposures in humans at the RHD.
Pediatric Use of Mavyret
Pediatric Use No dosage adjustment of MAVYRET is required in pediatric patients 12 years and older or weighing at least 45 kg. The recommended dosage of MAVYRET in pediatric patients 3 to less than 12 years of age is based on weight . The safety, efficacy, and pharmacokinetics of MAVYRET in HCV GT1, 2, 3, or 4 infected pediatric patients 3 years and older is based on data from an open-label trial in 127 subjects with chronic HCV infection, without cirrhosis, and aged 3 years to less than 18 years who were either treatment-naïve (n=114) or treatment-experienced (n=13) and received MAVYRET for 8, 12 or 16 weeks (DORA-Part 1 and Part 2). The adverse reactions observed in subjects 3 years to less than 18 years of age were consistent with those observed in clinical trials of MAVYRET in adults with chronic HCV infection with the exception of vomiting, rash and abdominal pain upper which were observed more frequently in pediatric subjects less than 12 years of age compared to adults . The efficacy results observed in this trial were consistent with those observed in clinical trials of MAVYRET in adults . Use of MAVYRET in pediatric patients with acute HCV infection is supported by extrapolation of safety and efficacy data from adult patients with acute HCV infection and adult and pediatric patients with chronic HCV infection. It is expected that adult and pediatric patients with acute HCV infection have similar disease response to treatment.
No clinically meaningful differences in MAVYRET exposures are expected among pediatric patients with acute HCV infection and pediatric patients with chronic HCV infection. In pediatric patients with cirrhosis, history of a kidney and/or liver transplant, or HCV GT5 or 6 infection, the safety and efficacy of MAVYRET are supported by the comparable glecaprevir and pibrentasvir exposures observed between pediatric subjects and adults . The safety and effectiveness of MAVYRET in children less than 3 years of age have not been studied.
Contraindications for Mavyret
is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation . MAVYRET is contraindicated with atazanavir or rifampin . Patients with moderate or severe hepatic impairment (Child-Pugh B or C) or those with any history of prior hepatic decompensation. Coadministration with atazanavir or rifampin.
Overdosage Information for Mavyret
In case of overdose, the patient should be monitored for any signs and symptoms of toxicities. Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removed by hemodialysis.
Clinical Studies of Mavyret
Description of Clinical Trials Table 12 summarizes the clinical trials conducted to
support the effectiveness of MAVYRET in subjects with HCV genotype 1, 2, 3, 4, 5 or 6 infection and compensated liver disease (including Child-Pugh A cirrhosis) according to treatment history and cirrhosis status. Table 12. Clinical Trials Conducted with MAVYRET in Subjects with HCV Genotype 1, 2, 3, 4, 5 or 6 Infection and Compensated Liver Disease Genotype (GT) Clinical Trial (NCT Number) Treatment Duration* Clinical Trials of Chronic HCV Infection TN and PRS-TE Subjects without Cirrhosis GT1** ENDURANCE-1 (NCT02604017) MAVYRET for 8 (n=351) or 12 weeks (n=352) GT2 SURVEYOR-2 (NCT02243293) MAVYRET for 8 weeks (n=197) GT3 ENDURANCE-3 (NCT02640157) MAVYRET for 8 (n=157) or 12 weeks (n=233) sofosbuvir + daclatasvir for 12 weeks (n=115) SURVEYOR-2 MAVYRET for 16 (PRS-TE only) weeks (n=22) GT4, 5, 6 ENDURANCE-5,6 (NCT02966795) MAVYRET for 8 weeks (GT5 n=20; GT6 n=55) SURVEYOR-2 MAVYRET for 8 weeks (GT4 n=46; GT5 n=2; GT6 n=10) GT1, 2, 3, 6 VOYAGE-1 (NCT03222583) MAVYRET for 8 (n=356) or 16 weeks (n=6; GT3 PRS-TE only) TN and PRS-TE Subjects with Compensated Cirrhosis GT1, 2, 4, 5, 6 EXPEDITION-1 (NCT02642432) MAVYRET for 12 weeks (n=146) GT1, 2, 3, 4, 5, 6 EXPEDITION-8 (NCT03089944) MAVYRET for 8 weeks (n=343) (TN only) GT3 SURVEYOR-2 MAVYRET for 16 weeks (PRS-TE only) (n=47) GT5, 6 ENDURANCE-5,6 MAVYRET for 12 weeks (GT 5 n=3; GT 6 n=6) GT1, 2, 3, 4, 6 VOYAGE-2 (NCT03235349) MAVYRET for 12 (n=157) or 16 weeks (n=3; GT3 PRS-TE only) Subjects with CKD Stage 4 and 5 without Cirrhosis or with Compensated Cirrhosis GT1-6 EXPEDITION-4 (NCT02651194) MAVYRET for 12 weeks (n=104) NS5A Inhibitor or PI-Experienced Subjects without Cirrhosis or with Compensated Cirrhosis GT1 MAGELLAN-1 (NCT02446717) MAVYRET for 12 (n=25) or 16 weeks (n=17) HCV/HIV-1 Co-Infected Subjects without Cirrhosis or with Compensated Cirrhosis GT1, 2, 3, 4, 6 EXPEDITION-2 (NCT02738138) MAVYRET for 8 (n=137) or 12 weeks (n=16) Liver or Kidney Transplant Recipients without Cirrhosis GT1, 2, 3, 4, 6 MAGELLAN-2 (NCT02692703) MAVYRET for 12 weeks (n=100) Adolescent Subjects (12 to less than 18 years) GT1, 2, 3, 4** DORA (Part 1) (NCT03067129) MAVYRET for 8 (n=44) or 16 weeks (n=3) Pediatric Subjects (3 to less than 12 years) GT1, 2, 3, 4** DORA (Part 2) (NCT03067129) MAVYRET for 8 (n=78), 12 (n=1), or 16 weeks (n=1) Clinical Trial of Acute HCV Infection GT1, 2, 3, 4** M20-350 (NCT04903626) MAVYRET for 8 weeks (n=286) TN=treatment naïve; PI=protease inhibitor; CKD=chronic kidney disease PRS-TE= defined as prior treatment experience with regimens containing (peg)interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor. * Treatment durations for some trial arms shown in this table do not reflect recommended dosing for the respective genotypes, prior treatment history, and/or cirrhosis status. For recommended dosing in adults and pediatric patients 3 years and older . ** ENDURANCE-1 included 33 subjects co-infected with HIV-1. DORA included 3 subjects co-infected with HIV-1. M20-350 included 142 subjects co-infected with HIV-1. 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. Demographics and Baseline Characteristics of Clinical Trials in Adults with Chronic HCV Infection Who Were Treatment-Naïve or Treatment-Experienced to (peg)Interferon, Ribavirin and/or Sofosbuvir (PRS) without Cirrhosis or with Compensated Cirrhosis (Child-Pugh A) 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 m 2 ; and median baseline HCV RNA level was 6.2 log 10 IU/mL.
Treatment-Naïve or
PRS Treatment-Experienced Adults with Chronic HCV Genotype 1, 2, 4, 5, or 6 Infection without Cirrhosis 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. 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). Table 13 presents SVR12 in MAVYRET-treated genotype 1-infected subjects for the 8-week treatment arm. Due to numerically similar efficacy, MAVYRET is recommended for 8 weeks for treatment-naïve and PRS treatment-experienced genotype 1 subjects without cirrhosis, rather than 12 weeks . Table 13. ENDURANCE-1: Efficacy in Treatment-Naïve and PRS Treatment-Experienced Adults with Chronic HCV Genotype 1 Infection without Cirrhosis MAVYRET 8 Weeks GT1 N=351 SVR12 99% (348/351) Outcome for Subjects without SVR12 On-treatment VF <1% (1/351) Relapse 0/349 Other* <1% (2/351) VF= virologic failure * Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. 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 Table 14 for ease of display.
Table 14. SURVEYOR-2 (Part 2 and Part 4) and ENDURANCE-5, 6: Efficacy in Treatment-Naïve and PRS Treatment-Experienced Adults with Chronic HCV Genotypes 2, 4, 5 or 6 Infection without Cirrhosis MAVYRET 8 Weeks GT2 N=197 GT4 N=46 GT5 N=22 GT6 N=65 SVR 12 98% (193/197) 93% (43/46) 95% (21/22) 100% (65/65) Outcome for Subjects without SVR12 On Treatment VF 0/197 0/46 0/22 0/65 Relapse 1% (2/195) 0/45 5% (1/22) 0/65 Other* 1% (2/197) 7% (3/46) 0/22 0/65 GT=genotype; VF= virologic failure * Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.
Treatment-Naïve Adults with Chronic
HCV Genotype 1-6 Infection with Compensated Cirrhosis or PRS Treatment-Experienced Adults with Chronic HCV Genotype 1, 2, 4, 5, or 6 Infection with Compensated Cirrhosis 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. Table 15. EXPEDITION-8: Efficacy in Treatment-Naïve Adults with Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection with Compensated Cirrhosis MAVYRET 8 Weeks (N=343) Total (all GTs) (N=343) GT1 (N=231) GT2 (N=26) GT3 (N=63) GT4 (N=13) GT5 (N=1) GT6 (N=9) SVR12 98% (335/343) 98% (226/231) 100% (26/26) 95% (60/63) 100% (13/13) 100% (1/1) 100% (9/9) Outcome for Subjects without SVR12 On-treatment VF 0/343 0/231 0/26 0/63 0/13 0/1 0/9 Relapse <1% (1/336) 0/225 0/26 2% (1/62) 0/13 0/1 0/9 Other * 2% (7/343) 2% (5/231) 0/26 3% (2/63) 0/13 0/1 0/9 GT = genotype; VF = virologic failure * Includes subjects who discontinued due to lost to follow-up or subject withdrawal. 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.
Table 16. EXPEDITION-1 and ENDURANCE-5, 6: Efficacy in Treatment-Naïve and PRS Treatment-Experienced Adults with Chronic HCV Genotype 1, 2, 4, 5 or 6 Infection with Compensated Cirrhosis MAVYRET 12 Weeks Total (all GTs) (N=155) GT1 (N=90) GT2 (N=31) GT4 (N=16) GT5 (N=5) GT6 (N=13) SVR12 99% (153/155) 99% (89/90) 100% (31/31) 100% (16/16) 100% (5/5) 92% (12/13) Outcome for Subjects without SVR12 On-treatment VF <1% (1/155) 0/90 0/31 0/16 0/5 8% (1/13) Relapse <1% (1/152) 1% (1/88) 0/31 0/16 0/5 0/12 GT = genotype; VF = virologic failure
Treatment-Naïve or
PRS Treatment-Experienced Adults with Chronic HCV Genotype 3 Infection without Cirrhosis or with Compensated Cirrhosis 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 Table 17. Due to numerically similar efficacy, MAVYRET is recommended for 8 weeks for treatment-naïve genotype 3 subjects without cirrhosis, rather than 12 weeks . Table 17. ENDURANCE-3: Efficacy in Treatment-Naïve, Chronic HCV Genotype 3-Infected Adults without Cirrhosis MAVYRET 1 8 Weeks (N=157) MAVYRET 12 Weeks* (N=233) DCV+SOF 12 Weeks (N=115) SVR12 95% (149/157) 95% (222/233)* 97% (111/115) Outcome for Subjects without SVR12 On-treatment VF 1% (1/157) <1% (1/233) 0/115 Relapse 3% (5/150) 1% (3/222) 1% (1/114) Other 2 1% (2/157) 3% (7/233) 3% (3/115) VF=virologic failure 1 MAVYRET 8 weeks was a non-randomized treatment arm. 2 Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. * Data for MAVYRET 12-week treatment is displayed to reflect the original randomized study design.
The treatment difference (95% confidence interval) was -1.2% (-5.6, 3.1) between the randomized arms of MAVYRET 12 weeks and DCV + SOF 12 weeks. 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. Table 18. SURVEYOR-2 Part 3: Efficacy in PRS Treatment-Experienced, Chronic HCV Genotype 3-Infected Adults without Cirrhosis or with Compensated Cirrhosis PRS Treatment-Experienced without Cirrhosis or With Compensated Cirrhosis MAVYRET 16 Weeks (N=69) SVR12 96% (66/69) Outcome for Subjects without SVR12 On-treatment VF 1% (1/69) Relapse 3% (2/68) Other* 0/69 SVR12 by Cirrhosis Status Without Cirrhosis 95% (21/22) With Compensated Cirrhosis 96% (45/47) VF=virologic failure * Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal. 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% 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) 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.
Treatment-Naïve and
PRS Treatment-Experienced Adults with CKD Stage 4 and 5 and Chronic HCV Infection without Cirrhosis or with Compensated Cirrhosis 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.
Adults with Chronic
HCV Infection w ho are NS5A Inhibitor or NS3/4A-Protease Inhibitor (PI)-Experienced, without Cirrhosis or with Compensated Cirrhosis 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/m 2 ; 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. Table 19. MAGELLAN-1: Efficacy in HCV Genotype 1-Infected Adults with Chronic HCV Infection Who Are NS3/4A PI-Experienced or NS5A Inhibitor-Experienced, without Cirrhosis or with Compensated Cirrhosis PI-Experienced 1 (NS5A Inhibitor- naïve) NS5A Inhibitor- Experienced 2 (PI-naïve) MAVYRET 12 Weeks (N=25) MAVYRET 16 Weeks (N=17) SVR12 92% (23/25) 94% (16/17) Outcome for Subjects without SVR On-treatment Virologic Failure 0/25 6% (1/17) Relapse 0/25 0/16 Other 3 8% (2/25) 0/17 PI= protease inhibitor 1 Includes subjects who were treated with a regimen containing an NS3/4A PI (simeprevir with sofosbuvir, or simeprevir, boceprevir, or telaprevir with (peg)interferon and ribavirin) and without prior treatment with an NS5A inhibitor. 2 Includes subjects who were treated with a regimen containing an NS5A inhibitor (ledipasvir with sofosbuvir or daclatasvir with (peg)interferon and ribavirin) and without prior treatment with an NS3/4A PI. 3 Includes subjects who discontinued due to adverse event, lost to follow-up, or subject withdrawal.
Treatment-Naïve or
PRS Treatment-Experienced Adults with Chronic HCV/HIV-1 Coinfection without Cirrhosis or with Compensated Cirrhosis 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.
Treatment-Naïve or
PRS Treatment-Experienced Adults with Chronic HCV Infection with Liver or Kidney Transplant without Cirrhosis 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.
People Who Inject Drugs (PWID) and those on Medication - Assisted Treatment
(MAT) for Opioid Use Disorder with Chronic HCV Infection PWID 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 : 40 years ), 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.
MAT 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 : 47 years ), 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). 14. 10 Clinical Trial in Pediatric Subjects 3 Years and Older with Chronic HCV Infection The efficacy of MAVYRET was evaluated in an open-label study (DORA ) 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. DORA Part 1 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). DORA Part 2 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 . 14. 11 Adults with Acute HCV Infection 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 m 2 ; and median baseline HCV RNA level was 5.4 log 10 IU/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.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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