AbbVie’s pangenotypic combination of glecaprevir and pibrentasvir cured almost all of the hardest-to-treat genotype 3 patients – those with cirrhosis and/or previous treatment experience – in a phase II trial, and looks suitable for use as an 8-week regimen in genotypes 2, 4,5 and 6, according to results of studies presented at the 2016 AASLD Liver Meeting this week in Boston.
AbbVie is developing the combination of glecepravir and pibrentasvir (G/P) as a pangenotypic regimen for hepatitis C treatment, to be dosed as a once-daily pill without ribavirin. AbbVie will seek licensing approval for the combination in the United States and European Union within the next few months.
Glecaprevir (ABT-493) is a hepatitis C virus (HCV) NS3/4A protease inhibitor active against all genotypes of hepatitis C. Pibrentasvir (ABT-530) is an NS5A inhibitor also active against all genotypes of HCV. Both agents are active against common variants that confer resistance to first-generation agents of their classes. ABT-493 is more potent against genotype 3 than other HCV protease inhibitors, including products being developed by Merck (grazoprevir) and Gilead (GS-9451), and ABT-530 has demonstrated higher potency than most other NS5A inhibitors across all genotypes.
Results of two phase II studies, in most-difficult-to-treat people with genotype 3 and of an 8-week treatment course, were presented at Sunday sessions of The Liver Meeting. Further data from phase III registrational studies are also being presented at the meeting and are reported separately.
Glecaprevir and pibrentasvir in the hardest-to-treat patients
People with genotype 3 hepatitis C are at higher risk of developing advanced liver fibrosis and hepatocellular carcinoma than people infected with other genotypes, and people with prior treatment experience have fewer interferon-free treatment options than those infected with other genotypes.
Part 3 of the SURVEYOR-II study investigated the efficacy of a 12 or 16-week regimen of glecaprevir and pibrentasvir in people with genotype 3 with prior treatment experience and/or cirrhosis. Treatment-experienced people without cirrhosis (n = 44) were randomised 1:1 to receive a 12-week or 16-week course of treatment. Previously untreated people with cirrhosis (n = 40) received a 12-week course of treatment, while treatment-experienced people with cirrhosis (n = 47) received a 16-week course of treatment.
Treatment-experienced people with exposure to direct-acting antivirals other than sofosbuvir were excluded from the study, as were people with HIV or hepatitis B virus co-infection. People with a previous history of hepatic decompensation were excluded from the study.
In the non-cirrhotic study arms 64% of participants were male, 77% and 91% were male in the 12- and 16-week arms, 35% and 41% respectively had been exposed to sofosbuvir, 50% and 68% respectively had F0 or F1 fibrosis, and 32% and 23% respectively had F3 fibrosis. A high proportion in each arm (41% and 32% respectively) had a high viral load at baseline (> 6 million IU/ml).
In the cirrhotic study arms patient characteristics were broadly similar. Sixty per cent of the previously untreated and 77% of the treatment-experienced arms were male, 93% and 89% respectively were white, 10% and 23% had a high viral load at baseline, and 53% of the treatment-experienced group had previous exposure to sofosbuvir.
Intent-to-treat analysis showed that the regimen was highly effective. In treatment-experienced people without cirrhosis the 16-week regimen was more effective than the 12-week regimen, with 96% achieving SVR12 in the 16-week arm compared to 91% in the 12-week arm. In the cirrhotic arms 98% of previously untreated and 96% of treatment-experienced participants achieved SVR12.
Five virologic failures occurred in the study – four cases of viral relapse and one viral breakthrough on treatment – all of them in people with very high baseline viral loads (range 2.84 million – 18.9 million IU/ml). All failures occurred in treatment-experienced people (2 with cirrhosis).
Six serious adverse events were reported in the study population but none were considered to be related to the study drugs. Fatigue and headache were the most commonly reported adverse events (fatigue 13-34% by study arm, headache 13-25% by study arm). Three Grade 3 liver enzyme and one Grade 3 total bilirubin elevations were observed.
In conclusion, said David Wyles of Denver Medical Center presenting the findings, G/P proved highly effective and well tolerated in perhaps the hardest-to-treat patient populations, treatment-experienced people and people with cirrhosis with genotype 3 infection who until now have had very limited options for achieving a hepatitis C cure.
Eight weeks of glecaprevir and pibrentasvir cures 97% in genotype 2, 4, 5 and 6
Part 4 of the SURVEYOR-II study examined the virological efficacy of an 8-week course of treatment with glecaprevir and pibrentasvir in people with genotypes 2, 4, 5 or 6. The study recruited 200 participants, of which 71% had genotype 2 infection, 22% had genotype 4 infection, 1% genotype 5 and 5% genotype 6. The study population was evenly split between men and women, 76% of participants were white and the vast majority of participants had less advanced fibrosis (F0 or F1 stage) (84%). Eighty-seven per cent were previously untreated.
Overall, 97% of study participants achieved SVR12. In 145 genotype 2 participants, 98% achieved SVR12; in 46 genotype 4 participants 93% achieved SVR12; both genotype 5 participants and nine out of the ten genotype 6 participants achieved SVR12. Two viral relapses occurred, in the genotype 2 group. Two treatment discontinuations due to non-compliance and loss to follow-up, and three cases of missing SVR12 data accounted for the remaining cases of treatment failure. In the cases of missing SVR12 data, one had achieved SVR4 and two had achieved SVR8. When non-virologic failures were excluded, a modified intent-to-treat analysis showed efficacy of 99% for an 8-week regimen.
No adverse events led to discontinuation of study drugs. Two serious adverse events were not considered to be related to study drugs and the most common adverse events were headache, fatigue and nausea, reported by 11-16% of participants.
In genotype 2 the 8-week regimen was found to be non-inferior to the historical 95% SVR rate achieved with a 12-week course of sofosbuvir/ribavirin, the currently-recommended regimen in most settings.
References
Wyles DL et al. SURVEYOR-II, Part 3: efficacy and safety of ABT-493/ABT-530 in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or cirrhosis. Hepatology Special Issue, The 67th Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, abstract 113, Boston, 2016.
Hassanein T et al. Glecaprevir/pibrentasvir demonstrates high SVR rates in patients with HCV genotype 2, 4, 5, or 6 infection without cirrhosis following an 8-week treatment duration (SURVEYOR-II, Part 4). Hepatology Special Issue, The 67th Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting, abstract LB-15, Boston, 2016.