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Previous non-responders & relapsers

Investigational combination ABT-493 and ABT-530 works well in patients who did not achieve SVR12 with previous DAA therapy

Michael Carter
Published:
26 April 2016
Fred Poordad presenting at ILC 2016. Photo by Liz Highleyman, hivandhepatitis.com

An experimental combination of direct acting antivirals (DAAs) is effective and safe in HCV-genotype-1-infected patients who did not respond to previous DAA therapy, according to research presented to the recent International Liver Congress in Barcelona.

The study involved 50 adult patients without cirrhosis who did not achieve a sustained virological response (SVR) with previous DAA-containing therapy. They were randomised to receive one of three doses of ABT-493 (NS3/4A protease inhibitor) and ABT-530 (NS5A inhibitor). Most of the patients had pre-existing resistance to drugs in these classes. Between 86 and 100% of patients had a SVR 12 weeks after the completion of therapy (SVR12) and there were only two virologic failures. The combination worked well in the context of pre-existing resistance mutations. There were no serious side effects or laboratory abnormalities.

The development of oral DAAs has revolutionised 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 two years after treatment with agents in the NS5A class of DAAs.

Glossary

intent to treat analysis

All participants in a clinical trial are included in the final analysis, in the groups they were originally assigned to, whether or not they actually completed their course of treatment. Provides a better estimate of the real world effect of a treatment than an ‘on treatment analysis’.

more from the glossary

ABT-493 and ABT-530 are investigational next generation DAAs. ABT-493 is an HCV NS3/4A protease inhibitor active against all genotypes of hepatitis C. 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. Laboratory studies show 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 a phase 2 study (Magellan-1) to explore the efficacy and safety of ABT-493 and ABT-530 in combination for the treatment of non-cirrhotic HCV genotype-1 infected patients who did not had a sustained virologic response to previous DAA therapy.

The study was open label. Patients were randomised to receive one of three doses:

  • ABT-493/ABT-530 200/80mg (six patients)
  • ABT-493/ABT-530 300/120mg with ribavirin 800mg (22 patients)
  • ABT-493/ABT-530 300/120mg (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 randomised to the remaining study groups.

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 log10 IU/ml. The majority of patients had genotype-1a infection and had fibrosis stage F0-F1.

Half the patients had experience of NS5A-containing therapy and 84% had previously taken a HCV protease inhibitor.

A baseline NS3 or NS5A resistance mutation was detected in between 77 and 86% of patients.

Analysis including all 50 randomised patients (intent to treat analysis) showed that SVR12 was achieved by all six patients in the low dose arm, by 91% of patients treated with ABT-493/ABT-530 300/120mg and ribavirin, and by 86% of patients in the ABT-493/ABT-530 300/120mg arm.

There was one case of viral breakthrough (ABT-493/ABT-530 300/120mg arm) and one patient relapsed (ABT-493/ABT-530 300/120mg ribavirin arm). Three patients were lost to follow-up.

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

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

Side-effects were reported by between 77 and 86% of patients, and 83% of these adverse events were mild in severity. There were no serious laboratory abnormalities, but three patients in the ABT-493/ABT-530 300/120mg ribavirin arm experienced a mild elevation in bilirubin.

The investigators conclude that the investigational therapy was associated with high SVR12 rates with only two virologic failures. Baseline resistance did not appear to impact on the efficacy of therapy and the addition of ribavirin did not increase SVR12 rates.

Reference

Poordad F 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-1 Study. International Liver Congress, Barcelona, 2016.