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AASLD 2016: AbbVie Pangenotypic Combination Cures 98% or More Across HCV Genotypes

AbbVie’s combination of glecaprevir and pibrentasvir cured at least 98% of people with hepatitis C in 3 large clinical trials covering 5 out of 6 genotypes of the virus, and it is likely to receive marketing approval in the United States and European Union as the first ribavirin-free pangenotypic direct-acting antiviral combination next year, according to a report at the AASLD Liver Meeting last week in Boston.

[Produced in collaboration with infohep.org]

In another clinical trial the combination cured almost all genotype 3 patients who were treatment-experienced and/or had cirrhosis, the hardest groups of patients to cure of hepatitis C.

AbbVie is developing the combination of glecaprevir (ABT-493) and pibrentasvir (ABT-530), referred to as "G/P" by the company, as a pangenotypic regimen for hepatitis C treatment. The combination is dosed once-daily, without ribavirin.

Glecaprevir is an HCV NS3/4A protease inhibitor active against all genotypes of hepatitis C virus. Pibrentasvir 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. Glecaprevir is more potent against genotype 3 than other HCV protease inhibitors, including products from Merck (grazoprevir) and Gilead (voxilaprevir)). Pibrentasvir has demonstrated higher potency than most other NS5A inhibitors across all genotypes.

Results from a trio of Phase 3 studies of the combination were presented at The Liver Meeting, including a comparison of 8- and 12-week treatment regimens for people with genotype 1 infection. The studies are code-named ENDURANCE.

Genotype 1

ENDURANCE-1 tested the combination in previously untreated or treatment-experienced people with genotype 1 HCV. The study excluded people with cirrhosis but included people with HIV and HCV coinfection. The study recruited treatment-experienced people exposed to previous interferon-based regimens or to sofosbuvir and ribavirin. People with prior exposure to any other direct-acting antivirals were excluded.

Participants were randomized to receive glecaprevir and pibrentasvir (300 mg/120 mg) once-daily for 8 or 12 weeks. The study recruited 703 people, of which 43% had HCV genotype 1a. The study population had less advanced liver damage: 85% had stage F0 or F1 (absent or mild) fibrosis, whereas only 9% in the 8-week and 8% in the 12-week arm had progressed to stage F3 (advanced) fibrosis. The study population was predominantly white (82%-86%) and evenly split between men and women. The median body mass index was 25. 38% of study participants were treatment-experienced, almost all through exposure to interferon-based treatment. 5% had HIV/HCV coinfection and were predominantly receiving treatment with integrase inhibitor-based antiretroviral regimens.

In the 12-week arm 99.7% of 332 participants achieved sustained virological response (SVR12) in an intent-to-treat analysis which excluded people with HIV coinfection and sofosbuvir-experienced patients. All of the 332 participants in the 8-week arm achieved SVR12 in a per-protocol analysis which excluded people who discontinued treatment prematurely or experienced virological failure prior to week 8.

In the 12-week arm 1 participant has not yet attended for a 12-week post-treatment visit but is not lost to follow-up. In the 8-week arm 1 participant experienced on-treatment virological failure at day 29, but for reasons unexplained in the presentation, the study protocol did not count this evident failure of treatment as a failure when comparing the efficacy of the 8-week and 12-week regimens. This exclusion did not affect the overall conclusion, that the 8-week regimen was non-inferior to the 12-week regimen.

Unusually, the full intent-to-treat analysis was reported as a secondary efficacy endpoint. In this analysis 99.0% of the 8-week and 99.7% of the 12-week study arm achieved SVR 12, with 1 on-treatment virological failure, probably due to suboptimal treatment adherence, 1 discontinuation at day 2 due to non-compliance with the study protocol, and 2 people with missing SVR12 data.

None of the participants discontinued treatment as a result of study drug-related adverse events. The most common adverse events were headache (19%) and fatigue (9% in the 8-week group and 12% in the 12-week group); 2 people in the 8-week group and 1 participant in the 12-week group experienced a grade 3 bilirubin elevation (3-10 x ULN).

Genotype 2

ENDURANCE-2 tested the combination in previously untreated or treatment-experienced people with HCV genotype 2.

Participants were randomized to receive glecaprevir and pibrentasvir (300 mg/120 mg) once-daily for 12 weeks, or placebo. Those who received the placebo for 12 weeks went on to receive open-label treatment with glecaprevir and pibrentasvir for 12 weeks. Efficacy was compared to a historical control treatment of sofosbuvir and ribavirin.

The study recruited 302 people, of which 29% were treatment-experienced. The study population was 49% male in the active drug arm and 45% male in the placebo arm, 60% white in both study arms, and 34% Asian. The median age of participants was 58 years.

Study participants had less advanced liver disease: 76% in the active drug arm had stage F0 or F1 fibrosis, 9% had stage F2 (moderate) fibrosis, and 15% had stage F3 fibrosis.

The sustained virological response rate was 99% by intent-to-treat analysis. No virological failures occurred in this study. One participant who achieved SVR 4 was lost to follow-up before a 12-week post-treatment evaluation. There were no treatment discontinuations due to adverse events.

The most common adverse events were headache (12%) and fatigue (11%). Serious adverse events were judged to be unrelated to study drugs. There were two people in the active study drug arm who experienced grade 3 AST elevations and 1 experienced a grade 3 ALT elevation. In addition, 1 experienced a grade 3 bilirubin elevation which subsequently declined as treatment proceeded.

Genotypes 4, 5, and 6

ENDURANCE-4 tested the combination in previously untreated or treatment-experienced people with genotypes 4, 5, or 6, without cirrhosis. The study recruited treatment-experienced people previously exposed to either pegylated interferon plus ribavirin or to sofosbuvir with or without ribavirin. The study excluded people with hepatitis B or HIV coinfection.

All participants received glecaprevir and pibrentasvir (300 mg/120 mg) once-daily for 12 weeks.

The study recruited 121 people, 76 with genotype 4, 26 with genotype 5, and 19 with genotype 6. The overall study population was 64% male, 71% white, 8% black, with an average age of 54 years. The median body mass index was 24.8.

As in other ENDURANCE studies, the vast majority of participants had less advanced liver disease (86% stage F0-F1), with 7% having stage F2 and 7% having stage F3 fibrosis. Approximately two-thirds (68%) were previously untreated and all treatment-experienced participants had previous exposure only to interferon-based treatment.

In the overall study population intent-to-treat analysis showed that 99% achieved SVR12. No cases of virological breakthrough or rebound occurred in the study population.

One person in the genotype 4 arm discontinued treatment on day 12 due to a transient ischemic attack, while 2 other participants discontinued treatment before the end of the treatment period due to anxiety and to heartburn, respectively. Both achieved SVR12. The most common adverse events were headache (21%) and fatigue (17%). No grade 3 laboratory adverse events were observed.

11/17/16

Sources

S Zeuzem, J Feld, S Wang, et al. ENDURANCE-1: Efficacy and Safety of 8- versus 12-week Treatment with ABT-493/ABT-530 in Patients with Chronic HCV Genotype 1 Infection. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 253.

KV Kowdley, M Colombo, N Zadeikis, et al. ENDURANCE-2: Safety and Efficacy of ABT-493/ABT-530 in HepatitisC Virus Genotype 2-infected Patients without Cirrhosis, a Randomized, Double-Blind, Placebo-Controlled Study. AASLD Liver Meeting. Boston, November 11-15, 2016.Abstract 73.

T Asselah, C Hezode, N Zadeikis, et al. ENDURANCE-4: Efficacy and Safety of ABT-493/ABT-530 Treatment in Patients with Chronic HCV Genotype 4, 5, or 6 Infection. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 114.