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AbbVie’s Combination Drug for Hepatitis C has Elicited Mixed Expert Opinions

Biopharmaceutical Report II

Issue8_November 2015

• Success in vitro foreshadows pan-genotypic success

• Six HCV genotypes have unique viral dynamics

• Drug should be bearable for patients even with mild side effects

AbbVie’s (NYSE:ABBV) ABT-493/ABT-530 combination drug for hepatitis C has elicited mixed expert opinions on whether earlier positive Phase IIb data in genotypes 1-3 can translate to genotypes 4-6.

Good genotype 3 cohort data and positive pan-genotypic in vitro experiments foreshadow positive data for the remaining genotypes, some experts said. However, others said it is difficult to extrapolate results from one set of genotype to another with each having different clinical manifestations.

The drug’s safety profile also appears positive with earlier genotype 1-3 results only reporting one adverse event, they said.

A Phase IIb study of ABT-493/ABT-530 against genotypes 1, 4, 5 and 6 with or without ribavirin (SURVEYOR-I) is due for completion in March 2016 (NCT02243280), states. Genotype 1 results are from the SURVEYOR-I trial, whereas the genotype 2 and 3 results are from the SURVEYOR-II trial (NCT02243293), recently released abstracts state.

ABT-493 is an HCV NS3/4A inhibitor and ABT-530 is an NS5A inhibitor, the company website states. NS3/4A is a protease that helps in viral polyprotein maturation and evasion of the host’s innate antiviral immunity, while NS5A assists in RNA replication.

AbbVie did not respond to request for comment.

Strong uptake prospects in postautologous transplant, high-risk patients

Genotype 4 to 6 results could mirror genotype 1 to 3 results

Positive efficacy results against HCV genotypes 4-6 could be drawn based on positive genotype 1-3 trial results, said Dr Brian Conway, medical director, Vancouver Infectious Disease Centre, Canada.

AbbVie recently released three abstracts covering the ABT combo drug efficacy/safety against genotypes 1-3 in this month’s Journal of the American Association of the Study of Liver Diseases ahead of the Liver Meeting in San Francisco in November. The abstracts showed 98-100% of 79 patients in the genotype 1 cohort had no detectable HCV after four weeks (SVR4). Between 96-100% of the genotype 2 cohort (75 patients) and 93-96% of the genotype 3 cohort (120 patients) also had SVR4.

The ABT combo drug is envisaged as a once daily treatment without ribavirin to be taken in less than 12 weeks, the company website states.

Genotype 3 is currently considered as the HCV treatment “weak spot”, meaning current drugs are not as effective against this genotype compared to others, Conway said. So, with high SVR4 demonstrated in genotype 3, SV4 results in genotypes 4-6 would likely be even better because they are less complicated to treat, he said.

Genotype 3 is the toughest genotype to beat because patients have faster rates of fibrosis progression, steatosis and hepatocellular carcinoma and these patients are generally treated for longer, explained Michael Smith, assistant professor of clinical pharmacy at the University of the Sciences, Philadelphia, Pennsylvania.

In the genotype 3 cohort, there was also only one patient with virologic failure, which is a medical advance considering much higher failure rates are usually observed with this genotype, Conway said. However, more data is needed to see the context of this result, he added.

Based on some data coming out of Egypt-based clinical studies, genotype 4 SVR rates could be tantamount to genotype 1 data, agreed Dr Geoffrey Dusheiko, medicine emeritus professor University College London and Royal Free Hospital in London, England and Abdel-Rahamn Zekri, molecular virology professor, Cairo University, Egypt.

Another reason for optimism would be positive in vitro efficacy results of ABT-493 and ABT530, Conway added. Posters presented at the Retroviruses and Opportunistic Infections Conference on March 2014 showed the ABT drugs have potent and similar activity against genotypes 1-6, with ABT-493 showing substantially improved in vitro birological profile compared to earlier generation NS3/4A protease inhibitors.

Hepatitis C virus

However, Smith argued there are insufficient studies to show results from one genotype can be used to predict results in another genotype. For example, genotype 4 has relatively little data because it is mostly seen in sub-Saharan Africa and Egypt, while most trials are staged in the US and Europe, where genotype 1 is mostly investigated, he said. When the genomes of all six HCV genotypes were mapped by academics, it was discovered they are distant from each other after different evolutions, Dusheiko noted. This means that the six HCV genotypes have unique viral dynamics, treatment response rates and disease progression, he said.

All six genotypes may cause liver cirrhosis, but as all six have different clinical manifestations and in the past required different treatment regimens, Dusheiko said. Dr Jose Debes, gastroenterologist Veterans Affairs Medical Centre, Minneapolis, Minnesota, agreed that extrapolating data from one genotype to another is unfounded because each is unique.

Targeted population small, usually does not receive treatment

Safety appears positive

The ABT combo drug’s safety profile against genotypes 4-6 appears positive, experts agreed, with only one recorded adverse event (AE) in the trials covering genotypes 1-3. One patient in the genotype 3 cohort had to discontinue with the treatment because of abdominal pain and heat sensation, one of the abstracts states.

This specific AE seems ABT-related because this issue has never been reported with ribavirin before, Smith said. However, one patient discontinuing is not really a concern as patients have varying levels of tolerance, he said. It would be worrisome if at least 10% of patients complained or discontinued the drug, he said.

Sometimes abdominal pain and heat sensation can be felt even in placebo drugs, said Debes. Considering the positive response rates, and as long as the AEs are not life-threatening, the drug should be bearable for most patients, he added. Considering the drug is only used for three months to eliminate HCV, patients wouldn’t mind some minimal discomfort for long-term benefit, he said.

Most direct-acting antivirals (DAAs) (like the ABT combo drug) are much improved in terms of safety compared with previously used drugs against HCV, Smith said. Ribavirin, for example, which is sometimes used alongside DAAs to improve patient response rates, can cause anaemia, Debes said. Patients only receiving DAAs get generalised nonspecific side effects that vary from drug to drug, he added.

There was one treatment-naïve genotype 1 patient who had post-treatment relapse at week 4, one of the recently released abstracts states. Relapses and virologic failure are usually due to a patient’s noncompliance, Smith and Eric Gowans, senior research fellow University of Adelaide, Australia, agreed.

A relapse caused by HCV mutation is unlikely because mutations only happen in treated patients, Gowans said. Because the ABT combo is potent, it also makes mutations the less likely reason for the relapse, Smith added.

AbbVie has a market cap of USD 93bn.

Reynald Castaneda

Reporter, London

Before moving to London, Reynald was a journalist for healthcare newspaper New Zealand Doctor, covering primary care health politics and medical research. He has a BSc in Biological Sciences from the University of Auckland and a postgraduate diploma in journalism from AUT University. Prior to venturing into journalism, Reynald worked as a laboratory technician for Massey University’s Institute of Molecular Biosciences.

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