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EASL 2012: Simeprevir (TMC435) Improves Response Rates for Difficult-to-Treat Hepatitis C Patients


A combination of simeprevir -- better known as TMC435 -- plus pegylated interferon and ribavirin raised cure rates for genotype 1 hepatitis C patients who did not respond to previous treatment, according to a study presented at the 47th International Liver Congress (EASL 2012) last week in Barcelona.

Last year's approval of the first direct-acting antiviral agents has changed the face of treatment for chronic hepatitis C virus (HCV) infection, but several potentially more effective and better tolerated next-generation drugs are under development. Those expected to be next in line for approval will be used with pegyalted interferon/ribavirin until trials of all-oral therapy are completed.

Simeprevir is a potent once-daily HCV NS3/4A protease inhibitor. Early studies showed potent activity against HCV genotype 1, lesser activity against genotypes 2, 4, 5, and 6, and a favorable safety profile.

In the ASPIRE trial, Stefan Zeuzem from J.W. Goethe University Hospital and an international team of colleagues evaluated simeprevir added to the previous standard-of-care treatment for chronic hepatitis C.

This Phase 2b trial included 462 treatment-experienced patients with difficult-to-treat HCV genotype 1. 40% were prior relapsers (undetectable HCV RNA at the end of prior therapy but viral rebound during 24 weeks of post-treatment follow-up), 35% were prior partial responders (at least a 2 log viral load reduction at week 12 of prior therapy but still detectable at the end of treatment), and 25% were prior null responders (less than a 2 log decrease in HCV RNA by week 12 of prior therapy).

About two-thirds of participants were men, almost all were white, and the median age was 50 years. Just over 40% had HCV subtype 1a, the rest 1b; most had high HCV viral load at baseline. 17% had the favorable IL28B CC gene pattern associated with good response to interferon. Nearly 20% had advanced liver fibrosis (stage F3) and a similar proportion had cirrhosis (stage F4) at baseline. Patients with liver cancer, transplant recipients, and HIV or hepatitis B coinfected people were excluded.

Participants were randomly allocated to receive 100 mg or 150 mg once-daily simeprevir for either 12, 24, or 48 weeks in combination with pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day weight-adjusted ribavirin. In the 12- and 24-week arms, pegyalted interferon/ribavirin were continued alone through week 48. The control arm received pegyalted interferon/ribavirin plus placebo.


  • At week 4 of treatment, rapid virological response (RVR) rates were as follows:
    • 100 mg simeprevir:
      • 12 weeks: 67%;
      • 24 weeks: 59%;
      • 48 weeks: 53%;
    • 150 mg simeprevir:
      • 12 weeks: 62%;
      • 24 weeks: 68%;
      • 48 weeks: 66%;
    • Pegylated interferon/ribavirin/placebo: 2%.
  • RVR was a good predictor of sustained virological response 24 weeks after completion of therapy (SVR24).
  • Sustained response rates were as follows;
    • 100 mg simeprevir:
      • 12 weeks: 70%;
      • 24 weeks: 66%;
      • 48 weeks: 61%;
    • 150 mg simeprevir:
      • 12 weeks: 67%;
      • 24 weeks: 72%;
      • 48 weeks: 80%;
    • Pegylated interferon/ribavirin/placebo: 23%.
  • Looking at type of prior response, the SVR24 rates were as follow:
    • Relapsers:
      • 100 mg simeprevir: 85%;
      • 150 mg simeprevir: 85%;
      • Pegylated interferon/ribavirin/placebo: 37%.
    • Partial responders:
      • 100 mg simeprevir: 57%;
      • 150 mg simeprevir: 75%;
      • Pegylated interferon/ribavirin/placebo: 9%.
    • Null responders:
      • 100 mg simeprevir: 46%;
      • 150 mg simeprevir: 51%;
      • Pegylated interferon/ribavirin/placebo: 19%.
  • Among prior relapsers, those with HCV subtype 1a and 1b had similar cure rates, but among prior partial and null responders those with subtype 1b did better.
  • People with minimal fibrosis responded better overall than those with advanced fibrosis or cirrhosis.
  • Few simeprevir recipients met the stopping rule for discontinuing treatment early due to likely futility, compared with up to 75% of patients taking pegylated interferon/ribavirin alone.
  • Viral breakthrough during treatment occurred in 1% to 24% of simeprevir recipients in the various arms.
  • Viral relapse after completing treatment was seen in 3% to 16% of simeprevir  recipients.
  • Simeprevir was generally well-tolerated:
    • Rates of serious adverse events were 6% in the 100 mg simeprevir arm, 10% in the 150 mg arm, and 6% in the control arm.
    • Rates of discontinuation due to adverse events were 7%, 9%, and 5%, respectively.
    • The most common side effects across all arms were headache, fatigue, and flu-like symptoms.
    • Simeprevir recipients were more likely to experience pruritis (itching) or skin rash than those in the control arm, but severe rashes were rare (0.5%).
    • Changes in blood cell levels were similar in the simeprevir and control arms.
    • People taking simeprevir were more likely to develop elevated bilirubin, which Zeuzem explained was related to the drug's effect on 2 transporters.

"In HCV genotype 1 patients who previously failed pegylated interferon/ribavirin treatment, once-daily TMC435 administered with pegylated interferon/ribavirin was significantly more effective than pegylated interferon/ribavirin/placebo," the investigators concluded. "Once-daily TMC435 was well tolerated in this population."

As described in another presentation at the conference by Oliver Lenz from Tibotec, viral breakthrough and relapse after taking simeprevir were usually associated with signature resistance mutations at NS3 positions 80, 122, 155, and/or 168, but the distribution of mutations varied significantly between genotype 1a and 1b.

Based on the finding of somewhat better response rates in the higher-dose simeprevir arm -- especially for prior partial or null responders -- the 150 mg dose is currently undergoing testing in Phase 3 clinical trials.

Zeuzem noted that while all arms were treated for a total of 48 weeks in this study, data "clearly indicate that a treatment duration of 12 weeks achieves optimal SVR rates," suggesting that simeprevir will be suitable for response-guided therapy.

In a press release coinciding with the EASL meeting, Medivir -- which discovered simeprevir and is developing it in a partnership with Tibotec/Janssen -- announced a collaborative effort to test simeprevir in combination with Bristol-Myers Squibb's promising NS5A replication complex inhibitor daclatasvir (BMS-790052) in a Phase 3 trial, as well as a drug-drug interaction study with the nucleotide polymerase inhibitor BMS-986094 (formerly INX-189).



S Zeuzem, T Berg, E Gane, et al. TMC435 in HCV Genotype 1 Patients Who Have Failed Previous Pegylated Interferon/Ribavirin Treatment: Final SVR24 Results of the ASPIRE Trial. 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012). Barcelona, April 18-22, 2012. Abstract 2.

O Lenz, B Fevery, L Vijgen, et al. TMC435 in Patients Infected with HCV Genotype 1 Who Have Failed Previous Pegylated Interferon/Ribavirin Treatment: Virologic Analyses of the ASPIRE Trial. 47th Annual Meeting of the European Association for the Study of the Liver (EASL 2012). Barcelona, April 18-22, 2012. Abstract 9.

Other Source

Medivir AB. Medivir Announces TMC435 in an Expanded Clinical Collaboration. Press release. April 18, 2012.