New Protease Inhibitor TMC435 Cures Most HCV Patients

Daniel M. Keller, PhD

April 24, 2012

April 24, 2012 (Barcelona, Spain) — In patients infected with hepatitis C virus (HCV) genotype 1 for whom previous treatment with pegylated interferon plus ribavirin (PR) failed to eliminate the virus, treatment with TMC435 plus PR was significantly more effective than PR plus placebo. TMC435 is a once-daily oral therapy that inhibits HCV NS3/4A protease.

Stefan Zeuzem, MD, professor of medicine and chief of the Department of Medicine I at the J.W. Goethe University Hospital in Frankfurt, Germany, presented the results of the international, double-blind, placebo-controlled phase 2b ASPIRE clinical trial here at The International Liver Congress 2012.

The 462 patients in this trial were assigned to 48 weeks of active therapy with 1 of 4 treatment regimens: TMC435 + PR for 12 weeks, followed by PR + placebo weeks for 36 weeks; TMC435 + PR for 24 weeks, followed by PR + placebo for 24 weeks; TMC435 + PR for 48 weeks; or PR + placebo for 48 weeks (control group).

In patients receiving TMC435, the dose was 100 or 150 mg daily. All patients were followed for 24 weeks after the 48-week treatment period.

Eligible men and women were 18 to 70 years of age, had a body weight of 40 to 125 kg, were chronically infected with HCV genotype 1 HCV, and had plasma HCV RNA greater than 10,000 IU/mL. They had to have received at least 1 previous course of PR for at least 12 consecutive weeks.

Patients were ineligible for the trial if they had decompensated liver disease or liver disease from any cause other than HCV; if they had hepatocellular carcinoma; if they were infected with HIV, hepatitis B virus, or any HCV that was not genotype 1; or if they had any laboratory or hematologic abnormalities.

At baseline, about two thirds of the patients were men, median age was about 50 years, body weight ranged from 80.0 to 84.8 kg, and 83% to 89% had HCV RNA greater than 800,000 IU/mL. Previously in each group, about 40% had relapsed, 35% had partially responded, and 25% had not responded.

In the 3 TMC435 groups (both the 100 and 150 mg doses), 53% to 68% of patients achieved rapid viral responses, compared with 2% in the control group (P < .001 for all groups vs control group). Rapid viral response meant there was undetectable virus in the blood at week 4.

The sustained viral response rates at 24 weeks (SVR24) ranged from 61% to 80% for the TMC435 groups, compared with 23% in the control group.

In the TMC435 groups, compared with the control group, previous responders had the highest SVR24 rates (85% vs 37%), followed by previous partial responders (57% to 75% vs 9%), followed by previous nonresponders (46% to 51% vs 19%).

No patients with advanced liver fibrosis achieved a virologic cure in the control group, whereas with TMC435, "there was a substantial chance for the patients to achieve sustained virologic response rates," Dr. Zeuzem reported.

TMC435 Well Tolerated

Discontinuation of treatment because of viral breakthrough was 9% to 17% in the TMC435 groups and 53% in the control group. Viral relapse occurred in 6% to 18% of the TMC435 group and 44% of the control group.

The incidence and severity of adverse events were similar in the TMC435 and control groups. Serious adverse events affected 6% to 10% of patients in the TMC435 groups and 6% in the control group. Grade 3/4 adverse events occurred in 28% to 36% of the TMC435 groups and in 26% of the control group. The most frequently reported adverse events in patients receiving TMC435 were headache, fatigue, and influenza-like illness, but these events were present at equivalent levels in the control group.

However, pruritus was more common in the TMC435 groups than in the control group (35% VS17%). Similarly, more rash of any type occurred in the TMC435 groups than in the control group (23% to 30% vs 18%). However, less than 1% of patients receiving TMC435 experienced rash of grade 3 or lower.

The incidence of adverse events leading to treatment discontinuation and serious adverse events was similar in all groups. Decreases in and recovery of hemoglobin values and neutrophil counts were equivalent in all groups. However, the TMC435 groups showed mild and reversible increases in bilirubin not accompanied by changes in any other liver parameters.

For patients receiving 150 mg of TMC435, 85% of previous relapsers achieved SVR24, 75% of previous partial responders achieved SVR24, 51% of previous nonresponders achieved SVR24, and 31% to 82% of patients with cirrhosis achieved SVR24.

Dr. Zeuzem and colleagues conclude that in patients with HCV genotype 1 who failed previous PR therapy, once-daily TMC435 plus PR was significantly more effective in producing a sustained viral response than PR plus placebo.

In comparing the different durations of administration of TMC435, Dr. Zeuzem explained that "TMC435 for 12 weeks in combination with pegylated interferon and ribavirin for 48 weeks achieves optimal biologic response rates." Longer treatment with TMC435 did not produce any better virologic responses.

The drug is now entering phase 3 trials for both treatment-naive and treatment-experienced patients.

Session moderator Mark Thursz, MBBS, MD, secretary general of the European Association for the Study of the Liver and professor of hepatology in the Department of Medicine at Imperial College, London, United Kingdom, asked Dr. Zeuzem if hepatologists need to continue to use SVR24 as the end point of a trial or if the follow-up period can be shortened by using sustained viral response at 12 weeks (SVR12) as the end point.

Dr. Zeuzem explained that current trials "typically use an SVR at week 12 of the follow-up period, and the concordance rates are extremely high [with SVR24]; therefore, SVR12 is the new standard."

He does not think there is a major difference between SVR12 and SVR24 for treatment-naive patients, nonresponders, or relapsers with an interferon-containing protocol such as this one. "I'm a little bit more conservative in trials using completely new drugs, [such as]...interferon-free regimens and all-oral regimens," Dr. Zeuzem said. He would like to see trials demonstrating the equivalence of SVR12 and SVR24 in those cases before adopting SVR12 for those drug regimens.

Dr. Thursz told Medscape Medical News that he, too, believes that SVR12 will be the new end point and will replace SVR24 as new drugs enter trials. "The only proviso is for people who've previously been treated and have been classified as null responders — that's a group of people with hepatitis C [in whom] the virus has not dropped by 2 logs [after 12 weeks of treatment]," he said. "These people are going to be really difficult to treat and very resistant to pretty much any kind of medication. I have some reservation about that group; otherwise, SVR12 is undoubtedly going to be, as it were, the standard."

Another group of particular concern is patients with advanced fibrosis or cirrhosis. "We know, certainly with interferon-based therapies, that response rates are much lower in that group. Then there is some concern in cirrhotics, particularly cirrhotics who've decompensated, that the metabolism of the drugs is going to be slightly different and may cause some problems," Dr. Thursz cautioned.

Dr. Zeuzem reports being a consultant for Abbott, Achillion, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead, Idenix, Inhibitex, iTherX, Janssen, Merck, Novartis, Presidio Pharmaceuticals, Roche, Santaris, and Vertx Pharmaceuticals. Dr. Thursz has disclosed no relevant financial relationships.

The International Liver Congress 2012: Abstract 2. Presented April 19, 2012.

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