AASLD 2016: AbbVie Pangenotypic Combination Cures Hard-to-Treat People with HCV Genotype 3

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AbbVie’s pangenotypic combination of glecaprevir and pibrentasvir cured almost all of the hardest-to-treat genotype 3 hepatitis C patients -- those with cirrhosis or previous treatment experience -- in a Phase 2 trial, and looks suitable for use as an 8-week regimen for HCV genotypes 2, 4,5 and 6, according to results of studies presented at the AASLD Liver Meeting last week in Boston.

[Produced in collaboration with infohep.org]

AbbVie is developing the combination of glecaprevir 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 HCV genotypes. 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 from Merck (grazoprevir) and Gilead (voxilaprevir), and ABT-530 has demonstrated higher potency than most other NS5A inhibitors across all genotypes.

Results from a pair of Phase 2 studies of glecaprevir/pibrentasvir for the most-difficult-to-treat people with HCV genotype 3 and of an 8-week treatment course were presented at The Liver Meeting. Further data from Phase 3 registrational studies were also presented at the meeting and are reported separately.

Glecaprevir/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 with other HCV 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 for people with HCV genotype 3 with prior treatment experience and/or cirrhosis. Treatment-experienced people without cirrhosis (n=44) were randomized 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 coinfection. People with a previous history of hepatic decompensation were also excluded from the study.

In the non-cirrhotic study arms, 64% of participants were male, 77% and 91% were white in the 12- and 16-week arms, 35% and 41%, respectively, had been exposed to sofosbuvir, 50% and 68%, respectively, had stage F0 or F1 (absent or mild) liver fibrosis, and 32% and 23%, respectively, had F3 (advanced) 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. 60% 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 sustained virological response at 12 weeks post-treatment (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.

There were 5 virological failures occurred in the study -- 4 cases of viral relapse and 1 viral breakthrough on treatment -- all of them in people with very high baseline viral loads (range 2.84-18.9 million IU/mL). All failures occurred in treatment-experienced people (2 with cirrhosis).

Investigators reported 6 serious adverse events 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). They observed 3 grade 3 liver enzyme elevations and 1 grade 3 total bilirubin elevation.

In conclusion, David Wyles of Denver Medical Center, who presented the findings, said that 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 HCV who until now have had very limited options for achieving a hepatitis C cure.

Genotypes 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 for people with HCV genotypes 2, 4, 5, or 6. The study recruited 200 participants, of whom 71% had genotype 2, 22% had genotype 4, 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 had less advanced fibrosis at stage F0 or F1 (84%). 87% 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 a sustained response. Both genotype 5 participants and 9 out of the 10 genotype 6 participants achieved SVR12. There were 2 viral relapses in the genotype 2 group.

There were 2 treatment discontinuations due to non-compliance and loss to follow-up, and 3 cases of missing SVR12 data, which accounted for the remaining cases of treatment failure. In the cases of missing SVR12 data, 1 patient had achieved SVR4 and 2 had achieved SVR8. When non-virological failures were excluded, a modified intent-to-treat analysis showed efficacy of 99% for the 8-week regimen.

No adverse events led to discontinuation of study drugs. There were 2 serious adverse events not considered to be related to study drugs. The most common adverse events were headache, fatigue, and nausea, reported by 11%-16% of participants.

For 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 for this genotype in most settings.

11/17/16

Sources

DL Wyles, F Poordad, S Wang, 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. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 113.

T Hassanein, DL Wyles, S Wang, 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). AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract LB-15.