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AASLD 2015: New AbbVie Hepatitis C Combination Cures Up to 97% with Genotype 3

A combination of 2 experimental direct-acting antivirals developed by AbbVie cured 83%-97% of people with genotype 3 hepatitis C after a 12-week course of treatment, Paul Kwo from Indiana University School of Medicine reported at the 2015 AASLD Liver Meeting this week in San Francisco.

[Produced in collaboration with Aidsmap.com]

Genotype 3 hepatitis C virus is associated with an increased risk of fibrosis progression and hepatocellular carcinoma (liver cancer) compared to other genotypes, making affordable and effective treatment options for this group of patients an important unmet need. Almost 30% of worldwide hepatitis C infections are estimated to be genotype 3, with a particular concentration in the Indian sub-continent and among populations of Indian origin living elsewhere. Genotype 3 is also widespread in the Russian Federation, Scandinavia, Thailand, Brazil and Australia.

Genotype 3 hepatitis C is more difficult to cure with interferon-free therapy than other genotypes, requiring a longer course of treatment with most direct-acting antiviral regimens. The only currently approved 12-week interferon-free regimen for treatment of genotype 3 consists of daclatasvir (Daklinza) and sofosbuvir (Sovaldi).

The SURVEYOR-2 study assessed the effectiveness and safety of 2 experimental next-generation direct-acting antivirals, with or without ribavirin, at different doses. ABT-493 is an HCV NS3/4A protease inhibitor active against all genotypes of HCV. ABT-530 is a 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 (vedroprevir), and ABT-530 has demonstrated higher potency than most other NS5A inhibitors across all genotypes.

The SURVEYOR-2 study recruited 120 people with genotype 3 HCV, who were randomized to 1 of 4 different 12-week regimens, all dosed once-daily:

• ABT-493 (300 mg) and ABT-530 (120 mg);
• ABT-493 (200 mg) and ABT-530 (120mmg);
• ABT-493 (200 mg) and ABT-530 (120 mg) and ribavirin;
• ABT-493 (200 mg) and ABT-530 (40 mg).

The study recruited previously untreated people or previous null responders to pegylated interferon and ribavirin, with no evidence of cirrhosis. There was some variation across study arms in demographic characteristics, notably in the proportion of men (48%-63%) and F3 fibrosis (10%-23%). The mean HCV viral load ranged from 6.3-6.7 log/IU/mL across the 4 study arms.

At 12 weeks after the completion of treatment, rates of sustained virological response (SVR12) ranged from 83% in the ABT-493 (200 mg) and ABT-530 (40 mg) arm, to 93% in the 2 remaining ribavirin-sparing arms and 94% in the ribavirin-containing arm. In a per-protocol analysis which excluded non-virological failures, sustained response rates were highest (97%) in the ABT-493 (300 mg) and ABT-530 (120 mg) arms and in the ribavirin-containing arm.

A single on-treatment viral breakthrough occurred in both the ribavirin arm and the ABT-493 (200 mg) and ABT-530 (40 mg) arm, leading researchers to conclude that ABT-493 at a dose of 300 mg and ABT-530 at a dose of 120 mg were most likely to prevent viral breakthrough. These doses will now be taken forward in further studies in patients with cirrhosis and as a shorter, 8-week treatment course in patients without cirrhosis.

The number of treatment-experienced participants in the study was very low due to the exclusion of people who had taken direct-acting antivirals in addition to pegylated interferon and ribavirin, so it is difficult to draw meaningful conclusions.

There were 2 severe drug-related adverse events reported: 1 case of decreased hemoglobin in the ribavirin-containing arm and 1 increase in creatine phosphokinase (CPK) in the ABT-493 (300 mg) and ABT-530 (120 mg) arm. Commonly reported side effects were fatigue, headache, and nausea, and most adverse events were mild or moderate. Laboratory abnormalities were most frequently reported in the ribavirin group (3 cases of grade 2 hemoglobin decrease).

Genotype 2: No Virological Failures with ABT-493 and ABT-530

The SURVEYOR-2 study also included a 2 population with HCV genotype 2 in which a 12-week treatment course was tested at three different doses:

• ABT-493 (300 mg) and ABT-530 (120 mg);
• ABT-493 (200 mg) and ABT-530 (120 mg);
• ABT-493 (200 mg) and ABT-530 (120 mg) and ribavirin.

This study recruited 75 participants, randomized equally between the 3 arms. Eligibility criteria were the same as for the genotype 3 population.

SVR12 were very high: 96% in the 300 mg/120 mg arm, and 100% in the remaining arms, with the less-than-total virological response rate explained by the loss of 1 participant to follow-up at week 2.

In this group 2 participants experienced severe adverse events of headache, which may have been study drug-related in the opinion of investigators, but in 1 case the headaches resolved within 2 days and in the other case, migraine headaches in a chronic sufferer became less severe and subsided more quickly after ribavirin dose reduction.

A combination of ABT-493 (300 mg) and ABT-530 (120 mg) will now be taken forward for further studies in genotype 2 populations, including patients with cirrhosis and those who have failed sofosbuvir and ribavirin, and an 8-week treatment course will be tested.

11/18/15

Reference

PY Kwo, M Bennett, S Wang, et al. High SVR4 Rates Achieved With the Next Generation NS3/4A Protease Inhibitor ABT-493 and NS5A Inhibitor ABT-530 in Non-Cirrhotic Treatment-Naive and Treatment-Experienced Patients With HCV Genotype 3 Infection (SURVEYOR-2). AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract 248.

DL Wyles, MS Sulkowski, S Wang, et al. High SVR4 Rates Achieved With the Next Generation NS3/4A Protease Inhibitor ABT-493 and NS5A Inhibitor ABT-530 in Non-Cirrhotic Treatment-Naive and Treatment-Experienced Patients With HCV Genotype 2 Infection (SURVEYOR-2). AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract 250.

Other Source

AbbVie. AbbVie Announces High Sustained Virologic Response Rates in Phase 2 Studies with Pan-Genotypic, Investigational Regimen in Patients with Chronic Hepatitis C.Press release. November 16, 2015.