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AASLD 2011: TMC435 + Interferon/Ribavirin Raises Cure Rates for Naive and Experienced Hepatitis C Patients

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Adding the HCV NS3/4A protease inhibitor TMC435 to standard pegylated interferon/ribavirin therapy led to high rates of sustained virological response  for both treatment-naive hepatitis C patients and prior non-responders, according to data released last week at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011).

Direct-acting antiviral agents that target different steps of the hepatitis C virus (HCV) lifecycle have begun to revolutionize treatment for chronic hepatitis C, but more effective therapies are needed, especially for difficult-to-treat populations.

At AASLD Michael Fried from the University of North Carolina at Chapel Hill presented final results from the Phase 2b PILLAR trial, which evaluated TMC435 plus pegylated interferon/ribavirin in 386 previously untreated genotype 1 hepatitis C patients.

About 55% of the participants were men, almost all were white, and the median age was about 46 years; rates of advanced (stage F3) liver fibrosis ranged from 9% to 23%, and between 22% and 40% had the favorable IL28B CC genotype.

Participants were randomly assigned to receive either 75 mg or 150 mg TMC435 once-daily for 12 or 24 weeks, in combination with pegylated interferon alfa-2a (Pegasys) and 1000-1200 mg/day weight-adjusted ribavirin.

Using a response-guided therapy (RGT) strategy, people with unquantifiable HCV RNA at week 4 and undetectable viral load from week 12 to week 20 could stop treatment at that point; otherwise, they continued on pegylated interferon/ribavirin alone through week 48. A control arm received standard pegylated interferon/ribavirin for 48 weeks.

Results

  • Overall, patients in the TMC435 arms had significantly higher response rates than those in the control arm.
  • Rates of rapid virological response (RVR) at week 4:
    • TMC435 75 mg for 12 weeks: 76%;
    • TMC435 75 mg for 24 weeks: 68%;
    • TMC435 150 mg for 12 weeks: 75%;
    • TMC435 150 mg for 24 weeks: 75%;
    • Standard therapy control: 5%.
  • Rates of complete early virological response (cEVR) at week 12:
    • TMC435 75 mg for 12 weeks: 91%;
    • TMC435 75 mg for 24 weeks: 93%;
    • TMC435 150 mg for 12 weeks: 94%;
    • TMC435 150 mg for 24 weeks: 95%;
    • Standard therapy control: 56%.
  • Rates of sustained virological response (SVR) at week 72 (24 weeks after completion of treatment):
    • TMC435 75 mg for 12 weeks: 82%;
    • TMC435 75 mg for 24 weeks: 75%;
    • TMC435 150 mg for 12 weeks: 81%;
    • TMC435 150 mg for 24 weeks: 86%;
    • Standard therapy control: 65%.
  • 82%, 81%, 79%, and 86%, respectively, met the RGT criteria for shorter treatment.
  • Of these, 91%, 85%, 93%, and 96%, respectively, achieved SVR.
  • Relapse rates were 11%, 19%, 9%, and 8%, respectively.
  • Among people who took the 75 mg TMC435 dose, people with HCV subtype 1b had a higher SVR rate than those with 1a (89% vs 66%), but this was no longer the case with the 150 mg dose (82% vs 84%, respectively).
  • TMC435 was generally safe and well-tolerated.
  • The most common side effects were flu-like symptoms associated with interferon, which occurred at similar rates across arms.
  • 3.6% of participants in all TMC435 arms combined discontinued treatment early due to adverse events, compared with 5.2% in the control arm.
  • Side effects did not differ according to TMC435 dose or duration.
  • Some participants receiving 150 mg TMC435 experienced mild, transient bilirubin elevation.

The researchers concluded that once-daily TMC435 with pegylated interferon/ribavirin "was more effective" than pegylated interferon/ribavirin alone, and that triple therapy with TMC435 "reduced the impact of unfavorable IL28B genotypes on virologic response."

Fried noted that 150 mg TMC435 produced significantly higher sustained response rates than standard therapy, even though the SVR rate was unexpectedly high in the control arm (most studies find rates closer to 50% for genotype 1 patients). TMC435 was more effective regardless of IL28B gene pattern, gender, or fibrosis stage, but there were not enough blacks to make a race/ethnicity comparison.

Phase III clinical trials are going forward using the 150 mg TMC435 dose.

A few days before the AASLD meeting Medivir released results from ASPIRE, a Phase 2b study of TMC-435 in patients previously treated with pegylated interferon/ribavirin who did not achieve a cure.

Below is an edited excerpt from a Medivir press release describing these findings.

Medivir Announces Final Results from TMC435 Phase IIb ASPIRE (C206) Study

TMC435-Based Therapy Significantly Improved Viral Cure Rates in Patients Who Failed Prior Treatment for Hepatitis C

ASPIRE: All TMC435 subgroups achieved substantially higher viral cure rates (SVR24) compared with control group (pegylated interferon and ribavirin alone): 85% vs. 37% in prior relapsers, 75% vs. 9% in prior partial responders and 51% vs. 19% in prior null responders

Once daily TMC435 was generally safe and well tolerated at all doses and treatment durations

Huddinge, Sweden -- November 2, 2011 -- Medivir AB (OMX: MVIR), a research-based speciality pharmaceutical company focused on infectious diseases, today announces final results from the ASPIRE study. This phase IIb study evaluated TMC435 once daily in addition to pegylated interferon (PegIFN) and ribavirin (RBV) in patients with genotype-1 chronic hepatitis C whose prior treatment with PegIFN and RBV was unsuccessful either because they relapsed, had a partial response or had a null response.

Data from the ASPIRE study showed that patients in each of these subgroups who were treated with TMC435-based combination therapy achieved superior rates of sustained virologic response (viral cure) compared with those retreated with PegIFN and RBV alone.

Charlotte Edenius, Executive VP Research and Development, of Medivir commented, "We are extremely pleased with the final results from the ASPIRE study showing high viral cure rates and a favourable safety and tolerability profile in these difficult to treat genotype-1 hepatitis C patients whose prior treatment was unsuccessful. These results may provide new optimism for people who have failed on previous therapy, including those with advanced liver disease. We are highly committed to the broad and rapid development of TMC435 and global pivotal phase III clinical trials are currently well underway”

ASPIRE (C206) -- Design

TMC435, a potent, once-daily, oral hepatitis C virus protease inhibitor, is being developed by Tibotec jointly with Medivir. The randomized, placebo-controlled, double-blind ASPIRE study evaluates the effect of TMC435 in combination with pegylated-interferon and ribavirin in 462 patients infected with genotype-1 hepatitis C virus who have failed prior treatment with PegIFN/RBV. The primary endpoint was proportion of patients with undetectable HCV RNA 24 weeks after the planned end of treatment (SVR24).

The study includes patients who have relapsed, achieved partial response, or achieved no response (null responders) to PegIFN/RBV treatment. 62 percent (287/462) of patients had advanced liver disease, periportal or septal fibrosis or cirrhosis (scarring of the liver) upon study entry (Metavir score F2-F4).

Patients were equally randomized to one of seven different treatment arms, six TMC435 treatment arms and one placebo arm. TMC435 was administered once daily at a dose of either 100 mg or 150 mg given for either 12, 24, or 48 weeks in combination with 48 weeks of PegIFN/RBV. The results are based on the intent-to-treat (ITT), population which included all randomized patients who took at least one dose of the study medication.

Results -- Efficacy
In this final analysis, all subgroups of treatment-experienced patients who failed previous PegIFN and RBV treatment, achieved substantially higher virologic response rates following treatment with TMC435-containing regimen at all doses and durations, compared with PegIFN and RBV alone.

Regardless of treatment duration all TMC435 treatment arms showed significantly improved effect on SVR24 versus PegIFN/RBV alone.

Sustained Virologic Response (SVR24) Rates in TMC435 Dose Groups (150 mg q.d.) vs Placebo

 

% (n/N)

 

TMC435
12PR48
N=66

 

TMC435
24PR48
N=68

 

TMC435
48PR48
N=65

 

All TMC435
PR48
N=199

 

Placebo
PR48
N=66

 

Relapsers
SVR24

 

76.9 (20/26)

 

88.9 (24/27)

 

88.5 (23/26)

 

84.8 (67/79)

 

37.0 (10/27)

 

Partial Responders
SVR24

 

65.2 (15/23)

 

75.0 (18/24)

 

86.4 (19/22)

 

75.3 (52/69)

 

8.7 (2/23)

 

Null Responders
SVR24

 

52.9 (9/17)

 

41.2 (7/17)

 

58.8 (10/17)

 

51.0 (26/51)

 

18.8 (3/16)

 

q.d.: once daily; PR: pegIFNalpha-2A and ribavirin; EoT: End of Treatment,
SVR24: patients with undetectable HCV RNA (<25 IU/mL Undetectable) 24 weeks after planned EoT. All TMC435 groups: p<0.001 vs placebo.
Prior Relapser: undetectable HCV RNA at EoT and detectable within 24 weeks of follow-up
Prior Partial Responders: more than 2 log reduction in HCV RNA at W12 but not achieving undetectable at EoT
Prior Null Responders: less than 2 log reduction in HCV RNA at W12

Results -- Safety and Tolerability

TMC435 was generally safe and well tolerated and overall incidence of adverse events (AEs) was similar across treatment groups. Most of the AEs were grade 1 or 2 in severity. Serious AEs (SAEs) were reported in 6.1% subjects in the placebo and in 7.8% of the patients treated with TMC435. AEs leading to treatment discontinuation were reported in 4.5% of the placebo patients and in 7.8% of the TMC435 treated patients. Patients in the TMC435 ASPIRE treatment groups had overall longer treatment duration than patients in the placebo group due to a higher frequency of early discontinuation in the placebo group due to treatment failures (i.e. reaching viral stopping rules). The most common AEs during the treatment period were headache, fatigue, pruritus and influenza-like illness. Incidence was similar across treatment groups and the level of AEs and frequency were consistent with the prior phase IIb (PILLAR) study in treatment-naïve hepatitis C patients of TMC435.

In the safety analyses, special attention was given to the following AEs of interest: hepatobiliary AEs, pruritus, rash and anemia. Most AEs of interest were grade 1 or 2 in severity and infrequently led to treatment discontinuation. For each category of AEs of interest the incidence was similar for the TMC435 treatment arms and control arm.

Mild and reversible increases in bilirubin (total, direct and indirect) were observed in TMC435 dose groups with no differences between 100 mg and 150 mg. There were no meaningful differences between treatment groups for any of the other laboratory parameters. There were no clinically significant findings on vital signs. Mean alanine aminotransferase (ALT) levels decreased in all treatment groups.

DRAGON (C215) -- Update on recently published results

The final data from the phase II Dragon study in Japan was recently published at the Japan Digestive Disease Week meeting, 20-23 October 2011 in Fukuoka, Japan. The DRAGON study is a phase II randomized, open-label, response-guided study to evaluate the efficacy, safety, and pharmacokinetics of TMC435 plus PegIFN/RBV in 92 Japanese treatment-naive patients infected with HCV genotype-1.

Addition of once daily TMC435 (100 mg) to PegIFN/RBV increased the viral cure rate (SVR24) from 46% in the PegIFN/RBV only group to 82% (32/39) in the TMC435 100mg groups. In these groups, 87% of patients were eligible to complete all treatment at Week 24 if preset criteria on virologic response were met. TMC435 was generally safe and well tolerated with no apparent difference in the safety profile between TMC435 treatment groups and the control group (PegIFN/RBV only).

About TMC435

TMC435 is a highly potent and selective once-daily (q.d.) investigational drug that is being jointly developed by Tibotec Pharmaceuticals and Medivir to treat chronic hepatitis C virus infections.

TMC435 has received “Fast Track” designation by the U.S. Food and Drug Administration (FDA) for the treatment of chronic hepatitis C (CHC) genotype-1 infection. This is based on TMC435’s potential to address unmet medical needs in the treatment of chronic HCV infection. TMC435 is currently being developed in three global phase III studies, QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In parallel with these trials, phase III studies for TMC435 in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, are ongoing.

About Medivir

Medivir is an emerging research-based specialty pharmaceutical company focused on the development of high-value treatments for infectious diseases. Medivir has world-class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is TMC435, a novel protease inhibitor that is in phase III clinical development for hepatitis C and is partnered with Tibotec Pharmaceuticals.

In June 2011, Medivir acquired the specialty pharmaceutical company BioPhausia to ensure timely commercialization of TMC435 in the Nordic markets, once approved.

For more information about Medivir, please visit the Company’s website: www.medivir.com.

11/18/11

Reference

M Fried, M Buti, GJ Dore, et al. TMC435 in Combination with Peginterferon and Ribavirin in Treatment-Naive HCV Genotype 1 Patients: Final Analysis of the PILLAR Phase IIb Study. 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2011). San Francisco, November 4-8. 2011. Abstract LB-5.

Other Source

Medivir AB. Medivir Announces Final Results from TMC435 Phase IIb ASPIRE (C206) Study. Press release. November 2, 2011.