New Hep C Combo Cures Most Patients with Cirrhosis

Glecaprevir/pibrentasvir highly effective against most hepatitis C genotypes

By Liz Highleyman,

Contributing Writer,

MedPage Today

April 20, 2017

AMSTERDAM — An investigational combination of two antiviral agents taken for three months cured almost all patients with compensated liver cirrhosis and hepatitis C virus (HCV) genotypes 1, 2, 4, 5, or 6, a researcher reported here.

The glecaprevir/pibrentasvir combination cleared HCV in 99% of participants in the EXPEDITION-I trial, according to Xavier Forns, MD, from IDIBAPS in Barcelona, speaking at the opening session of the International Liver Congress, the annual meeting of the European Association for the Study of Liver Diseases (EASL).

Direct-acting antiviral drugs used in interferon-free regimens can now cure most people with hepatitis C, but there is still room for better options for hard-to-treat patients, as well as medications that are active against all types of HCV.

Glecaprevir is an HCV protease inhibitor and pibrentasvir is an NS5A inhibitor. Both drugs are pangenotypic, or active against all HCV genotypes. They are coformulated into a combination pill; patients take three tablets together once daily with food.

The Phase III EXPEDITION-I study enrolled 146 chronic hepatitis C patients with compensated cirrhosis at 40 sites in North America, Europe, and South Africa. People with decompensated cirrhosis were excluded, as were those with hepatitis B or HIV coinfection. About 60% were men and the median age was 60 years.

A quarter had previously been treated for hepatitis C, mostly using pegylated interferon and ribavirin, although a small number had used sofosbuvir (Sovaldi). About one in four had pre-existing viral variants associated with drug resistance. A majority had HCV genotype 1a (33%) or 1b (27%), while 23% had genotype 2 and 11% had genotype 4; few had genotypes 5 or 6, Forns reported.

“These were impressive results and treatment was very well tolerated,” EASL Secretary General Laurent Castera, MD, told MedPage Today. “But the study didn’t include genotype 3, which is now the hardest to treat.”

Another trial to be presented later in the conference will look at the effectiveness of glecaprevir/pibrentasvir for patients with genotype 3.

All participants in the open-label EXPEDITION-I study received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks.

The primary study endpoint was the proportion of people with sustained virological response, or HCV RNA below the lower limit of quantification at 12 weeks after the end of treatment (SVR12).

Treatment was highly effective, with an SVR12 rate of 99%. A single patient with HCV genotype 1a experienced viral relapse eight weeks after finishing treatment, Forns said. That individual had new NS5A resistance mutations at the time of treatment failure.

Glecaprevir/pibrentasvir was generally safe and well tolerated. The most common adverse events reported by at least 10% of patients were fatigue, headache, and itching. A majority of adverse events were mild.

Serious adverse events were rare, according to Forns. Eleven people experienced such events, but none were considered related to the study drugs, he said. No one stopped treatment early due to adverse events. One patient died after treatment due to cerebral hemorrhage and one person developed liver cancer.

EXPEDITION-I demonstrated that once-daily, ribavirin-free treatment with glecaprevir/pibrentasvir produced a 99% SVR12 rate in cirrhotic patients with HCV genotypes 1, 2, 4 5, or 6, regardless of baseline patient or viral characteristics, Forns concluded.

Given that this regimen is so effective, “the only remaining question is what to do with patients who fail,” he said. “They will probably need [to be retreated using] a different drug class.”

EXPEDITION-1 is part of series of pivotal trials submitted for marketing approval of glecaprevir/pibrentasvir. The EXPEDITION-4 trial, presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting last November, showed that the combination cured 98% of patients with severe kidney disease, another hard-to-treat population.

Drugmaker AbbVie submitted a New Drug Application for glecaprevir/pibrentasvir to the FDA in December and a decision is expected this fall. The combination is also undergoing accelerated review by the European Medicines Agency.

This study was funded by AbbVie.

Primary Source:

EASL 2017

Source Reference: Forns X, et al “EXPEDITION-I: efficacy and safety of glecaprevir/pibrentasvir in adults with chronic hepatitis C virus genotype 1, 2, 4, 5 or 6 infection and compensated cirrhosis” EASL 2017; abstract GS-006.