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EASL 2016: ABT-493 + ABT-530 Works Well for Patients Who Did Not Respond to Prior DAAs

An experimental combination of direct acting antivirals (DAAs) from AbbVie is effective and safe in patients with hepatitis C virus (HCV) genotype 1 who did not respond to previous DAA therapy, according to research presented at the European Association for the Study of the Liver's International Liver Congress (EASL 2016) last month in Barcelona. Between 86% and 100% of patients achieved sustained virological response and the combination worked well in the context of pre-existing resistance mutations.

[Produced in collaboration with infohep.org]

The development of oral DAAs has revolutionized the treatment of HCV infection. Response rates of 90% or more have been observed in both clinical trials and real-world settings. The failure of DAA treatment is often associated with the presence of drug-resistant strains of virus. The majority of resistance-associated variants (RAVs) can persist for more than 2 years after treatment with agents in the NS5A class of DAAs.

ABT-493 and ABT-530 are investigational next generation DAAs. ABT-493 is an HCV NS3/4A protease inhibitor active against all HCV genotypes. ABT-530 is an NS5A inhibitor also active against all genotypes. Both agents are active against common variants that confer resistance to first-generation agents of their classes. Laboratory studies showed they have a high barrier to resistance and are potent in the presence of common NS3A and NS5A RAVs. The combination also has the advantage of once-daily oral dosing.

Investigators designed the Phase 2 MAGELLAN-1 study to explore the efficacy and safety of ABT-493 plus ABT-530 for the treatment of non-cirrhotic genotype 1 chronic hepatitis C patients who were not cured with previous DAAs.

The study involved 50 participants without cirrhosis who had not achieved a sustained virological response at 12 weeks after the completion of therapy (SVR12) with previous DAA-containing therapy.

Most of the patients were male, approximately a third were black, and over half were aged between 39 and 70 years. Baseline HCV viral load was between 6.1-6.7 log IU/mL. The majority of patients had genotype 1a infection and had fibrosis stage F0-F1 (absent to mild).

Half the patients had experience using NS5A-containing therapy and 84% had previously taken an HCV protease inhibitor. At baseline NS3 or NS5A resistance mutations were was detected in 77%-86% of patients.

The study was open-label. Patients were randomized to receive 1 of 3 doses:

• ABT-493/ABT-530 200/80 mg (6 patients);
• ABT-493/ABT-530 300/120 mg with ribavirin 800 mg (22 patients);
• ABT-493/ABT-530 300/120 mg (22 patients).

However, recruitment to the low-dose arm was halted on the basis of dose-finding studies, and patients already recruited to this arm were randomized to one of the remaining study groups.

Analysis including all 50 randomized patients (intent-to-treat analysis) showed that SVR12 was achieved by all 6 patients initially in the low dose arm, 91% of patients treated with ABT-493/ABT-530 300/120 mg and ribavirin, and by 86% of patients in the ABT-493/ABT-530 300/120 mg without ribavirin arm.

There was 1 case of viral breakthrough (300/120 mg without ribavirin arm) and 1 patient relapsed (ABT-493/ABT-530 300/120 mg plus ribavirin arm); 3 patients were lost to follow-up.

Exclusion of the patients lost to follow-up (modified intent-to-treat analysis) showed SVR12 rates of 95% in both ABT-493/ABT-530 300/120 mg study arms.

Therapy worked well in the context of common NS3 and NS5A resistance mutations.

Side effects were reported by 77% and 86% of patients, and 83% of these adverse events were mild in severity. There were no serious laboratory abnormalities, but 3 patients in the ribavirin-containing arm experienced a mild elevation in bilirubin.

The researchers concluded that this investigational therapy was associated with high SVR12 rates with only 2 virological failures. Baseline resistance did not appear to impact on the efficacy of therapy and the addition of ribavirin did not significantly increase SVR12 rates.

5/3/16

Reference

F Poordad, SC Gordon, A Asatryan, et al. High efficacy of ABT-493 and ABT-530 in HCV genotype 1 infected patients who have failed direct-acting antiviral-containing regimens: the MAGELLAN-I study. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract GS11.

Other Source

AbbVie. AbbVie's Investigational, Pan-Genotypic Regimen of ABT-493 and ABT-530 Shows High SVR Rates in Genotype 1 Hepatitis C Patients Who Failed Previous Therapy with Direct-Acting Antivirals. Press release. April 15, 2016.