imageSan Diego—An investigational once-daily therapy for hepatitis C virus (HCV) infection, TMC435 (Simeprevir), significantly improved rates of sustained virologic response (SVR) in patients infected with HCV genotype 1 who had prior unsuccessful treatment with pegylated-interferon (Peg-IFN) and ribavirin, according to a Phase II study presented at the 2012 Digestive Disease Week (DDW) meeting (abstract 943f).

In the trial, between 61% and 80% of patients infected with HCV genotype 1 who had previously failed treatment went on to achieve a SVR after a course of TMC435, given in conjunction with Peg-IFN and ribavirin. The SVR rates are among the highest reported in patients for whom earlier treatments have failed to eradicate the virus.

“Following treatment with TMC435 plus Peg-IFN/ribavirin, patients who failed previous treatment exhibited significantly higher SVR rates, including the difficult-to-treat prior responders with cirrhosis,” said senior investigator Fred Poordad, MD, chief medical officer of Texas Liver Institute/Alamo Medical Research and professor of medicine at the University of Texas, San Antonio, who presented the results of the double-blind, placebo-controlled, multicenter, multinational Phase IIb ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) at the DDW meeting.

TMC435 is an investigational oral therapy that inhibits HCV NS3/4A protease and has been shown to have activity against all HCV genotypes, except genotype 3. It’s delivered as a single pill that can be taken daily.

In the ASPIRE trial, investigators randomized 462 patients to one of seven treatment arms: TMC435 in 100-mg or 150-mg daily doses for 12, 24 or 48 weeks in combination with 48 weeks of Peg-IFN/ribavirin, or placebo with Peg-IFN/ribavirin for 48 weeks. All patients had chronic HCV genotype 1 infection and had documented evidence of a prior null response to therapy (<2 log10-reduction in HCV RNA by week 12 of treatment), partial response (≥2 log10-reduction in HCV RNA by week 12 of treatment but detectable viral load at the end of treatment) or relapse. One-fifth of patients had Metavir scores of F3 and 18% had scores of F4; 41% of patients had HCV genotype 1a and the remainder had genotype 1b. People co-infected with hepatitis B virus or HIV were excluded from the trial.

Patients who received TMC435 showed significantly higher rapid virologic response (RVR) and SVR rates than patients in the placebo group, with the greatest responses among patients who received the 150-mg dose daily. RVR occurred in 53% to 67% of patients receiving the 100-mg dose and in 62% to 68% of patients in the 150-mg group. In comparison, only one patient in the placebo group exhibited RVR (1 of 66); the patient had previously responded to Peg-IFN/ribavirin and relapsed.

The SVR rates ranged from 61% for patients who received 100 mg for 48 weeks to 80% in patients who received 150 mg for 48 weeks. In the control group, only 23% of patients managed to achieve SVR. Among patients who received TMC435, prior relapsers had the strongest response (77% to 89%), followed by prior partial responders (48% to 86%).

Null responders were “perhaps the most difficult to treat population,” said Dr. Poordad. Between 38% and 59% of null responders in the treatment group achieved SVR compared with 19% of null responders in the placebo group.

In the TMC435 treatment group, 9% to 17% of patients discontinued treatment due to viral breakthrough or lack of on-treatment response, which was much lower than the 53% discontinuation rate among placebo patients. Additionally, relapses occurred less often in the TMC435 group, at 6% to 18% versus 44% in the placebo group.

The incidence of adverse events (AEs) leading to treatment discontinuation and serious AEs was similar across all treatment groups, with little difference between the TMC435 and control groups. Serious AEs affected 6% to 10% of the treated patients and 6% of placebo patients. The most frequently reported AEs among TMC435-treated patients were headache, fatigue, influenza-like illness and pruritus.

Lab tests revealed that patients in the 100- and 150-mg TMC435 treatment groups had mild, transient asymptomatic bilirubin increases over time. However, the changes were not accompanied by other changes in liver parameters. Hemoglobin and neutrophil counts were similar between the treatment and control groups.

TMC435 has now moved into Phase III trials and final results from these trials are expected in January 2013. In these trials, patients are receiving the 150-mg dose with therapy administered for 12 weeks.

Donald M. Jensen, MD, professor of medicine and director of the Center for Liver Diseases at the University of Chicago, said the hepatitis C community has high expectations for TMC435, one of two new protease inhibitors now in Phase III trials.

“I think TMC435 is going to be a significant advance over telaprevir and boceprevir, in part because of the ease of administration. It seems to have fewer side effects and, since it’s a once-daily protease inhibitor, adherence should be better,” said Dr. Jensen.

The strong safety profile is what may set TMC435 apart from the already approved protease inhibitors, said Dr. Poordad.

“The distinguishing featuring is the safety and tolerability profile,” he said. “There is no anemia with this, whereas that appears to be the weakness with others. In addition, there is no rash, no anorectal symptoms.”

Future trials should address whether TMC435 with Peg-IFN/ribavirin is comparable or better than telaprevir with Peg-IFN/ribavirin, Dr. Jensen suggested. They also should give more information about AEs with the new compound.

TMC435 also is being tested in Phase II trials in combination with Bristol-Myer Squibb’s investigational compound daclatasvir (BMS-790052) and with Gilead Sciences’ nucleotide analog GS-7977.

 http://www.gastroendonews.com/ViewArticle.aspx?d=Hepatology+in+Focus&d_id=481&i=October+2012&i_id=889&a_id=21911


Dr. Poordad has served as a speaker or a member of a speaker’s bureau for Genentech, Gilead Sciences, Merck & Co., Onyx Pharmaceuticals, Salix Pharmaceuticals and Vertex Pharmaceuticals. He has received research support from Abbott Laboratories, Achillion, Anadys Pharmaceuticals, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, Gilead, Idenix Pharmaceuticals, Janssen/Tibotec, Merck & Co., Novartis, Pharmasset, Salix Pharmaceuticals and Vertex Pharmaceuticals. Dr. Jensen has served on advisory boards for Abbott Laboratories, Bristol-Myers Squibb, Boehringer-Ingelheim, Genentech, Gilead, Jansen/Tibotec, Merck & Co., and Vertex Pharmaceuticals, and has received research support from Abbott Laboratories, Bristol-Myers Squibb, Boehringer-Ingelheim, Genentech, Gilead and Janssen/Tibotec.