Friday, August 4, 2017

FDA Hepatitis Updates - MAVYRET Treatment Duration, Overall Adverse Reactions, Drug Interactions


On August 3, 2017, FDA approved MAVYRET. MAVYRET is a fixed-dose combination of glecaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor.

MAVYRET is indicated for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5 or 6 infection without cirrhosis or with compensated cirrhosis (Child-Pugh A). MAVYRET is also indicated for the treatment of adult patients 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

The safety and efficacy of MAVYRET were evaluated during clinical trials enrolling approximately 2,300 adults with genotype 1, 2, 3, 4, 5 or 6 HCV infection without cirrhosis or with mild cirrhosis. Results of the trials demonstrated that 92-100 percent of patients who received MAVYRET for 8, 12 or 16 weeks duration had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.  Highlights from the label are summarized below.

DOSAGE AND ADMINISTRATION

Testing Prior to the Initiation of Therapy
Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with MAVYRET.

Recommended Dosage in Adults
MAVYRET is a fixed-dose combination product containing glecaprevir 100 mg and pibrentasvir 40 mg in each tablet.

The recommended oral dosage of MAVYRET is three tablets (total daily dose: glecaprevir 300 mg and pibrentasvir 120 mg) taken once daily with food.

Tables 1 and 2 provide the recommended MAVYRET treatment duration based on the patient population in HCV mono-infected and HCV/HIV-1 co-infected patients with compensated liver disease (with or without cirrhosis) and with or without renal impairment including patients receiving dialysis.

Table 1. Recommended Duration for Treatment-Naïve Patients


HCV
Genotype
Treatment Duration
No Cirrhosis
Compensated Cirrhosis
(Child-Pugh A)
1, 2, 3, 4, 5, or 6
8 weeks
12 weeks

Table 2.  Recommended Duration for Treatment-Experienced Patients

Treatment Duration
HCV
Genotype
Patients Previously Treated With a Regimen Containing:
No Cirrhosis
Compensated Cirrhosis
(Child-Pugh A)
1An NS5A inhibitor1 without prior treatment with an NS3/4A protease inhibitor
16 weeks
16 weeks
An NS3/4A PI2 without prior treatment
with an NS5A inhibitor
12 weeks
12 weeks
1, 2, 4, 5, or 6PRS3
8 weeks
12 weeks
3PRS3
16 weeks
16 weeks
1 In clinical trials, subjects were treated with prior regimens containing ledipasvir and sofosbuvir or daclatasvir with pegylated interferon and ribavirin.
2 In clinical trials, subjects were treated with prior regimens containing simeprevir and sofosbuvir, or simeprevir, boceprevir, or telaprevir with pegylated interferon and ribavirin.
3 PRS=Prior treatment experience with regimens containing interferon, pegylated interferon, ribavirin, and/or sofosbuvir, but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor.

Hepatic Impairment

MAVYRET is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C)

CONTRAINDICATIONS

MAVYRET is contraindicated in patients with severe hepatic impairment (Child-Pugh C)

MAVYRET is contraindicated with atazanavir or rifampin

WARNINGS AND PRECAUTIONS

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 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

ADVERSE REACTIONS

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 HCV-Infected Adults 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 Phase 2 and 3 trials which evaluated approximately 2,300 subjects 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 comparable to those seen in subjects without cirrhosis.

Adverse Reactions in HCV-Infected Adults treated with MAVYRET in Controlled Trials

ENDURANCE-2
Among 302 treatment-naïve or PRS treatment-experienced, HCV genotype 2 infected adults 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 3.  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 3.  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 4. 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 4.  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)
%
DCV1 + SOF2
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 HCV-Infected Adults with Severe Renal Impairment Including Subjects 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 subjects (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%.

Laboratory Abnormalities
Serum bilirubin elevations
Elevations of total bilirubin at least 2 times the upper limit of normal occurred in 3.5% of subjects treated with MAVYRET versus 0% in placebo; these elevations were observed in 1.2% of subjects across the Phase 2 and 3 trials. 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. No subjects experienced jaundice and total bilirubin levels decreased after completing MAVYRET.

Drug Interactions
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, 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

Table 5 provides the effect of MAVYRET on concentrations of coadministered drugs and the effect of coadministered drugs on glecaprevir and pibrentasvir

Table 5.  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 ↑ dabigatranIf 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 ↓ pibrentasvirCoadministration is contraindicated because of potential loss of therapeutic effect [see Contraindications (4)].
Ethinyl Estradiol-Containing Products:
Ethinyl estradiol-containing medications such as combined oral contraceptives ↔ glecaprevir ↔ pibrentasvir Coadministration of MAVYRET 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 ↑ pibrentasvirCoadministration is contraindicated due to increased risk of ALT elevations [see Contraindications (4)].
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↑ pravastatinCoadministration 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↑ rosuvastatinCoadministration 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 ↑ pitavastatinCoadministration 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 8 and 9. ↑= increase; ↓= decrease; ↔ = no effect


Drugs with No Observed Clinically Significant Interactions with MAVYRET
No dose adjustment is required when MAVYRET is coadministered with the following medications: abacavir, amlodipine, buprenorphine, caffeine, dextromethorphan, dolutegravir, elvitegravir/cobicistat, emtricitabine, felodipine, lamivudine, lamotrigine, losartan, methadone, midazolam, naloxone, norethindrone or other progestin-only contraceptives, omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan.

CLINICAL STUDIES

Description of Clinical Trials

Table 10 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 10. Clinical Trials Conducted with MAVYRET in Adults With HCV Genotype 1, 2, 3, 4, 5 or 6 Infection and Compensated Liver Disease

Genotype (GT)Clinical TrialTreatment Duration*
TN and PRS-TE Subjects Without Cirrhosis
GT1ENDURANCE-1MAVYRET for 8 (n=351) or 12 weeks (n=352)
GT2SURVEYOR-2 MAVYRET for 8 weeks (n=197)
GT3ENDURANCE-3MAVYRET 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, 6ENDURANCE-4MAVYRET for 12 weeks (n=26, GT5; n=19, GT6)
SURVEYOR-1MAVYRET for 12 weeks (n=1, GT5; n=11, GT6)
SURVEYOR-2MAVYRET for 8 weeks (n=46, GT4; n=2, GT5; n=10 GT6)
TN and PRS-TE Subjects With Compensated Cirrhosis
GT1, 2, 4, 5, 6EXPEDITION-1MAVYRET for 12 weeks (n=146)
GT3SURVEYOR-2MAVYRET for 12 weeks (TN only) (n=40) or 16 weeks (PRS-TE only) (n=47)
Subjects With CKD Stage 4 and 5 Without Cirrhosis or With Compensated Cirrhosis
GT1-6EXPEDITION-4MAVYRET for 12 weeks (n=104)
NS5A Inhibitor or PI-Experienced Subjects Without Cirrhosis or With Compensated Cirrhosis
GT1MAGELLAN-1MAVYRET for 12 (n=25) or 16 weeks (n=17)
TN=treatment naïve; PI=protease inhibitor; CKD=chronic kidney disease
PRS-TE= defined as prior treatment experience with regimens containing interferon, pegylated 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.

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-1 and 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 Treatment-Naïve or Treatment-Experienced Adults to PegInterferon, Ribavirin and/or Sofosbuvir (PRS) Without Cirrhosis or With Compensated Cirrhosis (Child-Pugh A)

Of the 2,152 treated subjects without cirrhosis  or with compensated cirrhosis who were treatment-naïve or treatment-experienced to a combination of interferon, peginterferon, ribavirin and/or sofosbuvir (PRS), 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% were HCV genotype 1; 21% were HCV genotype 2; 29% were HCV genotype 3; 7% were HCV genotype 4; 4% were HCV genotype 5-6; 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 log10 IU/mL.

Treatment-Naïve or PRS Treatment-Experienced Adults With 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 peginterferon, ribavirin and/or sofosbuvir (PRS) with genotype 1, 2, 4, 5 or 6 chronic HCV infection without cirrhosis was studied in four trials using 8- or 12-week durations: ENDURANCE-1, ENDURANCE-4, SURVEYOR-1 (Part 2), 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). Table 11 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 11.  ENDURANCE-1: Efficacy in Treatment-Naïve and PRS Treatment-Experienced With HCV Genotype 1 Infection and Without Cirrhosis


Genotype 1
MAVYRET
8 Weeks
(N=351)
SVR1299% (348/351)
Outcome for Subjects without SVR12
On-treatment VF<1% (1/351)
Relapse0/349
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), ENDURANCE-4 and SURVEYOR-1 (Part 2) are pooled by genotype, where appropriate, in Table 12 for ease of display.

Table 12.  SURVEYOR-2 (Part 2 and Part 4), ENDURANCE-4 and SURVEYOR-1 (Part 2): Efficacy in Treatment-Naïve and PRS Treatment-Experienced Adults With HCV Genotypes 2, 4, 5 or 6 Infection Without Cirrhosis



SURVEYOR-2
MAVYRET
8 Weeks
ENDURANCE-4 and SURVEYOR-1
MAVYRET
12 Weeks
GT2
N=197
GT4
N=46
GT5
N=2
GT6
N=10
GT5
N=27
GT6
N=30
SVR 12
98% (193/197)
93%
(43/46)
100% (2/2)
100% (10/10)
100% (27/27)
100% (30/30)
Outcome for Subjects Without SVR12
  On Treatment 
  VF
0/197
0/46
0/2
0/10
0/27
0/30
  Relapse
1%
(2/195)
0/45
0/2
0/10
0/26
0/29
  Other*
1%
(2/197)
7%
(3/46)
0/2
0/10
0/27
0/30
GT=genotype; VF= virologic failure
* Includes subjects who discontinued due to adverse event, lost to follow-up, or subject
   withdrawal.

Treatment-Naïve or PRS Treatment-Experienced Adults with HCV Genotype 1, 2, 4, 5, or 6 Infection With Compensated Cirrhosis
The efficacy of MAVYRET in subjects who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir (PRS) with genotype 1, 2, 4, 5 or 6 chronic hepatitis C virus infection with compensated cirrhosis (Child-Pugh A) was studied in the single-arm, open-label EXPEDITION-1 trial, which included 146 subjects treated with MAVYRET for 12 weeks.

Table 13. EXPEDITION-1: Efficacy in Treatment-Naïve and PRS Treatment-Experienced Adults With HCV Genotype 1, 2, 4, 5 or 6 Infection With Compensated Cirrhosis



MAVYRET 12 Weeks
(N=146)
Total
(all GTs) (N=146)
GT1
(N=90)
GT2 (N=31)
GT4 (N=16)
GT5
(N=2)
GT6
(N=7)

SVR12
99% (145/146)
99%
(89/90)
100%
(31/31)
100%
(16/16)
100%
(2/2)
100%
(7/7)
Outcome for Subjects Without SVR12
    On-treatment VF
0/146
0/90
0/31
0/16
0/2
0/7
    Relapse
<1%
(1/144)
1%
(1/88)
0/31
0/16
0/2
0/7
GT = genotype; VF = virologic failure
















Treatment-Naïve or PRS Treatment-Experienced Adults With HCV Genotype 3 Infection Without Cirrhosis or With Compensated Cirrhosis
The efficacy of MAVYRET in subjects without cirrhosis or with compensated cirrhosis who were treatment-naïve or treatment-experienced to combinations of peginterferon, ribavirin and/or sofosbuvir (PRS) with genotype 3 chronic HCV infection was studied in ENDURANCE-3 and in SURVEYOR-2 Part 3.

ENDURANCE-3 was a partially-randomized, open-label, active-controlled trial in treatment-naïve subjects. 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 14. Due to numerically similar efficacy MAVYRET is recommended for 8 weeks for treatment-naïve genotype 3 subjects without cirrhosis, rather than 12 weeks.

Table 14. ENDURANCE-3: Efficacy in Treatment-Naïve, HCV Genotype 3-Infected Subjects Without Cirrhosis


MAVYRET1 8 Weeks (N=157)
MAVYRET 12 Weeks* (N=233)
DCV+SOF 12 Weeks (N=115)
SVR12
94.9% (149/157)
95.3% (222/233)*
96.5% (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)
Other2
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. 

SURVEYOR-2 Part 3 was an open-label trial randomizing PRS treatment-experienced subjects with genotype 3 infection without cirrhosis to 12- or 16-weeks of treatment. In addition, the trial evaluated the efficacy of MAVYRET in genotype 3 infected subjects with compensated cirrhosis in two dedicated treatment arms using 12-week (treatment-naïve only) and 16-week (PRS treatment-experienced only) durations. Among PRS treatment-experienced subjects treated with MAVYRET for 16 weeks, 49% (34/69) had failed a previous regimen containing sofosbuvir.

Table 15. SURVEYOR-2 Part 3: Efficacy in Treatment-Naïve or PRS Treatment-Experienced, HCV Genotype 3-Infected Adults Without Cirrhosis or With Compensated Cirrhosis


Treatment-Naïve With Compensated Cirrhosis
PRS Treatment-Experienced Without Cirrhosis or With Compensated Cirrhosis
MAVYRET 12 Weeks (N=40)
MAVYRET 16 Weeks (N=69)
SVR12
98% (39/40)
96% (66/69)
Outcome for Subjects Without SVR12
    On-treatment VF
0/40
1% (1/69)
    Relapse
0/39
3% (2/68)
    Other*
3% (1/40)
0/69
SVR12 by Cirrhosis Status
    Without Cirrhosis
NA
95% (21/22)
    With Compensated  Cirrhosis
98% (39/40)
96% (45/47)
VF=virologic failure
* Includes subjects who discontinued due to adverse event, lost to follow-up, or subject  
   withdrawal.

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 Who 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/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.

Table 16.  MAGELLAN-1: Efficacy in HCV Genotype 1-Infected Adults Who Are NS3/4A PI-Experienced or NS5A Inhibitor-Experienced, Without Cirrhosis or With Compensated Cirrhosis


PI-Experienced(NS5A Inhibitor- naïve)
NS5A Inhibitor-Experienced2
(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
Other3
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 pegylated 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 pegylated 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.

The updated labels will soon be available drugs@fda or DailyMed
Steve MorinOffice of Health and Constituent Affairs
Food and Drug Administration
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
For more information about the Hepatitis Liaison Program visit the FDA Patient Network

Thursday, August 3, 2017

AbbVie Receives U.S. FDA Approval of MAVYRET™ (glecaprevir/pibrentasvir)

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FDA Press Release
FDA approves Mavyret for Hepatitis C
The U.S. Food and Drug Administration today approved Mavyret (glecaprevir and pibrentasvir) to treat adults with chronic hepatitis C virus (HCV) genotypes 1-6 without cirrhosis (liver disease) or with mild cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis. Mavyret is also approved for adult patients with HCV genotype 1 infection who have been previously treated with a regimen either containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both.

Mavyret is the first treatment of eight weeks duration approved for all HCV genotypes 1-6 in adult patients without cirrhosis who have not been previously treated. Standard treatment length was previously 12 weeks or more.

“This approval provides a shorter treatment duration for many patients, and also a treatment option for certain patients with genotype 1 infection, the most common HCV genotype in the United States, who were not successfully treated with other direct-acting antiviral treatments in the past,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the United States have chronic HCV. Some patients who suffer from chronic HCV infection over many years may have jaundice (yellowish eyes or skin) and complications, such as bleeding, fluid accumulation in the abdomen, infections, liver cancer and death.

There are at least six distinct HCV genotypes, or strains, which are genetically distinct groups of the virus. Knowing the strain of the virus can help inform treatment recommendations. Approximately 75 percent of Americans with HCV have genotype 1; 20-25 percent have genotypes 2 or 3; and a small number of patients are infected with genotypes 4, 5 or 6.

The safety and efficacy of Mavyret were evaluated during clinical trials enrolling approximately 2,300 adults with genotype 1, 2, 3, 4, 5 or 6 HCV infection without cirrhosis or with mild cirrhosis. Results of the trials demonstrated that 92-100 percent of patients who received Mavyret for eight, 12 or 16 weeks duration had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured.

Treatment duration with Mavyret differs depending on treatment history, viral genotype, and cirrhosis status.

The most common adverse reactions in patients taking Mavyret were headache, fatigue and nausea.

Mavyret is not recommended in patients with moderate cirrhosis and contraindicated in patients with severe cirrhosis. It is also contraindicated in patients taking the drugs atazanavir and rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Mavyret.

The FDA granted this application Priority Review and Breakthrough Therapy designations.
The FDA granted approval of Mavyret to AbbVie Inc.

AbbVie Receives U.S. FDA Approval of MAVYRET™ (glecaprevir/pibrentasvir) for the Treatment of Chronic Hepatitis C in All Major Genotypes (GT 1-6) in as Short as 8 Weeks

MAVYRET is a new 8-week, pan-genotypic treatment for hepatitis C patients without cirrhosis and who are new to treatment

- FDA approval is supported by an overall 98 percent cure rate (rates ranged between 92-100 percent) in patients who received the recommended duration of treatment
- MAVYRET is a pan-genotypic treatment approved for use in patients across all stages of chronic kidney disease
- MAVYRET may be used in up to 95 percent of HCV patients, depending on stage of liver disease and prior treatment history*

NORTH CHICAGO, Ill., Aug. 3, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) approved MAVYRET™ (glecaprevir/pibrentasvir), a once-daily, ribavirin-free treatment for adults with chronic hepatitis C virus (HCV) infection across all major genotypes (GT1-6). MAVYRET is an 8-week, pan-genotypic treatment for patients without cirrhosis and who are new to treatment. Up to 95 percent of HCV patients in the U.S. may be eligible for treatment with MAVYRET, including patients with compensated cirrhosis or without cirrhosis and those with limited treatment options, such as patients with chronic kidney disease (CKD).*

"With MAVYRET, physicians and patients now have a treatment option that is highly effective and has the potential to cure the majority of HCV patients in as short as 8 weeks, regardless of genotype," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "The approval of MAVYRET demonstrates AbbVie's commitment to advancing science to help address unmet needs by delivering a new cure for patients who historically had limited treatment options, including those with genotype 3 HCV, individuals with CKD and certain DAA failure patients."

Approximately 3.4 million Americans are chronically infected with HCV.1 Additionally, HCV is common among people with severe CKD, with an estimated more than 500,000ⱡ people having both chronic HCV and CKD.2 MAVYRET was designed to deliver a cure** across all major genotypes and specific treatment challenges, such as patients with severe CKD, and GT1 patients not cured by a NS5A inhibitor or a NS3/4A protease inhibitor (PI) direct-acting antiviral (DAA) treatment, but not both. MAVYRET combines two new DAAs that target and inhibit proteins essential for the replication of the hepatitis C virus.

"The clinical trial program for MAVYRET resulted in high cure rates across a range of patient populations, from those who have never been treated and who do not have cirrhosis, all the way to patients with compensated cirrhosis," said Fred Poordad, M.D., vice president, academic and clinical affairs, Texas Liver Institute and professor of medicine, University of Texas Health, San Antonio. "This approval helps achieve physicians' goals of delivering effective options for a broad range of patients."

The approval of MAVYRET is supported by data from nine registrational studies in AbbVie's clinical development program, which evaluated more than 2,300 patients in 27 countries across all major HCV genotypes (GT1-6) and special populations.

Approval of MAVYRET follows an FDA-granted Breakthrough Therapy Designation for the treatment of GT1 HCV patients who were not cured with prior DAA therapy, as well as Priority Review. According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of therapies for serious or life-threatening conditions, which may offer substantial improvement over available therapies.

AbbVie's pan-genotypic regimen was also recently granted marketing authorization by the European Commission. AbbVie's treatment is now licensed for use in all 28 member states of the European Union, as well as Iceland, Liechtenstein and Norway.

*Ipsos Healthcare HCV Monitor, 2017. New York, NY: Ipsos in North America. ©Ipsos 2017, all rights reserved.
**Patients who achieve a sustained virologic response at 12 weeks post treatment (SVR12) are considered cured of hepatitis C.
ⱡBased on IMS Dx (Oct. 2016) distribution of 15.7% Renal patients in diagnosed population applied to ~3.4M HCV prevalence population of all major HCV genotypes.

About MAVYRET™ (glecaprevir/pibrentasvir)
MAVYRET™ is approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis C virus (HCV) infection in adults across all major genotypes (GT1-6). MAVYRET is a pan-genotypic, once-daily, ribavirin-free treatment that combines glecaprevir (100mg), an NS3/4A protease inhibitor, and pibrentasvir (40mg), an NS5A inhibitor, dosed once-daily as three oral tablets, taken with food.

MAVYRET is an 8-week, pan-genotypic option for patients without cirrhosis and who are new to treatment, who comprise the majority of people living with HCV. MAVYRET is also approved as a treatment for patients with specific treatment challenges, including those (GT1) not cured by prior treatment experience to either a protease inhibitor or NS5A inhibitor (but not both), and in patients with limited treatment options, such as those with severe chronic kidney disease (CKD) or those with genotype 3 chronic HCV. MAVYRET is a pan-genotypic treatment approved for use in patients across all stages of CKD.

Glecaprevir (GLE) was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors.

Full prescribing information can be found here.

Use and Important Safety Information

USE
MAVYRET™ (glecaprevir and pibrentasvir) tablets are a prescription medicine used to treat adults with chronic (lasting a long time) hepatitis C virus (hep C) genotypes 1, 2, 3, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.

IMPORTANT SAFETY INFORMATION
What is the most important information to know about MAVYRET?

Hepatitis B virus reactivation: Before starting treatment with MAVYRET, a doctor will do blood tests to check for hepatitis B virus infection. If people have ever had hepatitis B virus infection, the hepatitis B virus could become active again during or after treatment of hepatitis C virus with MAVYRET. Hepatitis B virus becoming active again (called reactivation) may cause serious liver problems including liver failure and death. A doctor will monitor people if they are at risk for hepatitis B virus reactivation during treatment and after they stop taking MAVYRET.

MAVYRET must not be taken if people:
Have certain liver problems
Are taking the medicines:
atazanavir (Evotaz®, Reyataz®)
rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®)

What should people tell a doctor before taking MAVYRET?
If they have ever had hepatitis B virus infection, liver problems other than hep C infection, or any other medical conditions.
If they are pregnant or plan to become pregnant, or if they are breastfeeding or plan to breastfeed. It is not known if MAVYRET will harm a person's unborn baby or pass into breast milk. A doctor should be consulted about the best way to feed a baby if taking MAVYRET.

About all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. MAVYRET and other medicines may affect each other. This can cause people to have too much or not enough MAVYRET or other medicines in their body. This may affect the way MAVYRET or other medicines work, or may cause side effects.
− A new medicine must not be started without telling a doctor. A doctor will provide instruction on whether it is safe to take MAVYRET with other medicines.

What are the common side effects of MAVYRET?
The most common side effects of MAVYRET are headache and tiredness.

These are not all of the possible side effects of MAVYRET. A doctor should be notified if there is any side effect that is bothersome or that does not go away.

This is the most important information to know about MAVYRET. For more information, people should talk to a doctor or healthcare provider.

People are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see full Prescribing Information, including the Patient Information.

If people cannot afford their medication, they should contact www.pparx.org for assistance.

About AbbVie
AbbVie is a global, research-driven biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook or LinkedIn.

Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2015 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.

1 Messina JP, Humphreys I., Flaxman A., et.al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015;61(1): 77-87 (and supplementary appendix).
2 IMS Health. IMS Dx/LRx. December 2016. (©IMS Health Inc., all rights reserved).

Some liver cancers linked to missing ‘guardian gene’

Some liver cancers linked to missing ‘guardian gene’

A clinician scientist-led research team from the National Cancer Centre Singapore (NCCS) and their US partner from the Cleveland Clinic has led to an important discovery that the GATA4 gene, which contributes to normal liver development, is commonly deleted in liver cancer.

Continue reading....

Is the 25-year hepatitis C marathon coming to an end to declare victory?

World J Hepatol. Jul 28, 2017; 9(21): 921-929
Published online Jul 28, 2017. doi: 10.4254/wjh.v9.i21.921

Minireviews
Is the 25-year hepatitis C marathon coming to an end to declare victory?
Khulood T Ahmed, Ashraf A Almashhrawi, Jamal A Ibdah, Veysel Tahan


It has been less than three decades since the discovery of hepatitis C virus (HCV) in 1989 by Choo et al[1]. The process of discovering the virus was very daunting as described in Dr. Houghton’s paper[2]. Recognized as the reason behind non-A non-B hepatitis, the big picture of the health and financial burden this virus would have caused became clear. With the high sustained virologic responses (SVRs) reported recently with the use of direct acting, soon will be forgotten the miserable quality of life patients of hepatitis C have had to endure with the not as effective and with unpleasant side effects interferon-based treatments. Not until five years ago when direct acting agents, protease inhibitors telaprevir (Incivec, Vertex) and boceprevir (Victrelis, Merck) were approved by the Food and Drug Administration, had we started seeing SVR rates above 70%. Since then, many direct acting agents have been approved with SVR rates above 90%. While very promising, challenges for treatment, such as access to medications and healthcare management, remain widely spread.

Continue reading....