TMC435 Boosts Hepatitis C Post-Treatment Response

SUMMARY
Genotype 1 hepatitis C patients who added the experimental HCV protease inhibitor TMC435 to pegylated interferon/ribavirin were more likely to experience sustained response 4 weeks after treatment completion than those using standard therapy alone.

Below is an edited excerpt from Medivir, which is developing TMC435 in collaboration with Tibotec, describing the ASPIRE study and its findings.

Medivir Announces Positive 48-week Interim Data from
TMC435 Hepatitis C Phase 2b ASPIRE Study in
Treatment-Experienced Genotype-1 Patients

	All TMC435 patient subgroups achieved substantially higher SVR4 rates (undetectable virus 4 weeks after end of treatment) compared to pegylated interferon and ribavirin alone
	TMC435 was safe and well tolerated at all doses and treatment durations

Huddinge, Sweden -- May 20, 2011 -- Medivir AB (OMX: MVIR), the emerging research-based specialty pharmaceutical company focused on infectious diseases, today announced results from the ASPIRE phase 2b study that evaluates the addition of once daily TMC435 to pegylated interferon and ribavirin in patients with genotype 1 chronic hepatitis C whose prior treatment with pegylated interferon (PegIFN) and ribavirin (RBV) was unsuccessful either because they relapsed, had a partial response or had a null response.

Bertil Samuelsson, CSO of Medivir, commented, "We are delighted with the encouraging efficacy and safety results shown by TMC435-based triple therapy over pegylated interferon and ribavirin, in this 48-week interim analysis of the ASPIRE study in treatment-experienced genotype 1 hepatitis C patients. This patient group is known to be the most difficult one to treat, where in particular prior null and partial responder groups respond very poorly upon retreatment with PegIFN/RBV alone. With several global phase 3 clinical trials ongoing in hepatitis C patients we are expecting the momentum to continue with regards to the development of TMC435."

ASPIRE (C206) -- Design and Week 48 Interim Analysis

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 study includes patients that have relapsed, achieved partial response, or achieved no response (null responders) to SoC [Standard of Care] treatment and where 62 percent (287/462) of patients overall 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 1 of 7 different treatment arms: 6 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 PegIFN/RBV. PegIFN/RBV treatment was continued in all patients until the study completion at week 48. This interim analysis was performed when all patients had completed 48 weeks of treatment or discontinued earlier. The analysis was done based on the intent-to-treat, ITT, population which included all randomized subjects who took at least one dose of the study medication. SVR4, Sustained Virologic Response 4 weeks after planned end of treatment data, was available for 94% and 84% of TMC435 and placebo patients respectively.

ASPIRE Results -- Efficacy

In this Week 48 interim analysis, all subgroups of treatment-experienced patients who failed previous peginterferon and ribavirin treatment, achieved substantially higher virologic response rates following treatment with TMC435-containing regimen at all doses and durations, compared with pegylated-interferon and ribavirin.

There was no relevant difference in virological response between the TMC435 150 mg dose groups who received TMC435-based triple therapy of 12 weeks, 24 weeks or 48 weeks. At end of treatment (EoT) 92%, 83% and 71% of relapser patients, partial responder patients and null responder patients taking TMC435 150 mg once daily and placebo, respectively, achieved undetectable HCV RNA levels compared to 70%, 17%, and 25% in the placebo PegIFN/RBV groups respectively. At week 4 after cessation of treatment (SVR4) 88%, 77%, and 57% of prior relapser patients, partial responder patients, and null responder patients taking TMC435 150 mg once daily and placebo, respectively, achieved undetectable HCV RNA levels, compared to 50%, 11%, and 23% in the placebo groups, respectively.

Virological Response Rates in TMC435 Dose Groups (150 mg q.d.) vs Placebo
% (n/N)	TMC435 2PR48	TMC435 24PR48	TMC435 48PR48	All TMC435 PR48	Placebo PR48
	N=66	N=68	N=65	N=199	N=66

Prior Relapser	EoT 92 (24/26)	93 (25/27)	92 (24/26)	92 (73/79)	70 (19/27)
Prior Relapser	SVR4 84 (21/25)	93 (25/27)	85 (22/26)	87 (68/78)	50 (12/24)

Prior Partial Responder	EoT 78 (18/23)	83 (20/24)	86 (19/22)	83 (57/69)	17 (4/23)
Prior Partial Responder	SVR4 64 (14/22)	86 (18/21)	82 (18/22)	77 (50/65)	11 (2/18)

Prio Null Responder	EoT 65 (11/17)	71 (12/17)	77 (13/17)	71 (36/51)	25 (4/16)
Prio Null Responder	SVR4 56 (9/16)	60 (9/15)	56 (9/16)	57 (27/47)	23 (3/13)
q.d.: once daily; PR: pegIFNalpha-2A and ribavirin; EoT: End of Treatment
SVR4: patients with undetectable HCV RNA (<25 IU/mL Undetectable) at EoT and 4 weeks after planned EoT. Prior Relapser: undetectable HCV RNA at EoT and detectable within 24 weeks of follow-up
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 8.3% of the subjects treated with TMC435 with no substantial differences seen between the TMC435 dose groups. AEs leading to treatment discontinuation were reported in 4.5% of the placebo subjects and in 8.8% of the TMC435 treated subjects. 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 caused by treatment failures (i.e. reaching viral stopping rules). The most common AEs during the treatment period were headache, fatigue, pruritis, and influenza-like illness. Incidence was similar across treatment groups and the level of AEs and frequency were consistent with prior phase 2b PILLAR study of TMC435.

In the safety analyses, special attention was given to the following AEs of interest: hepatobiliary AEs, pruritus, rash, anemia, and cardiac events. 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 with TMC435 and PegIFN/RBV.

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, nor were there any relevant changes in electrocardiogram (ECG) parameters, including QTc. Mean alanine aminotransferase (ALT) levels decreased in all treatment groups.

About TMC435 in other clinical studies

TMC435 is a once-daily (q.d.) protease inhibitor drug jointly developed by Tibotec Pharmaceuticals and, to treat chronic hepatitis C virus infections.

Three global clinical phase 3 response guided studies were recently initiated by Tibotec:

	TMC435-C208 or QUEST-1 includes approximately 375 treatment-naive patients
	TMC435-C216 or QUEST-2 includes approximately 375 treatment-naive patients
	TMC435-C3007 or PROMISE includes approximately 375 who have relapsed after prior interferon-based treatment

In parallel to the recent start of the global phase 3-studies, TMC435 is currently in a follow up phase in three phase 2b clinical trials (TMC435-C205, TMC435-C206 and TMC435-C215) in G1 treatment-naive and in G1 patients that failed previous IFN-based treatment. More safety and efficacy data from the phase 2b trials will be presented at scientific meetings later in 2011. Phase 3 programs for TMC435 are also ongoing in Japan.

For additional information for these studies, please see www.clinicaltrials.gov.

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 protease inhibitor which has recently entered phase 3 clinical development for hepatitis C and is partnered with Tibotec Pharmaceuticals.

Medivir is also marketing its first product, the unique cold sore product Xerese(TM)/Xerclear(R) which has recently been launched on the US market. Xerese(TM)/Xerclear(R), which is also approved in Europe, is partnered with GlaxoSmithKline to be sold OTC in Europe, Japan and Russia and with Meda AB in North America, Canada and Mexico. Medivir has retained the Rx rights for Xerclear(R) in Sweden and Finland.

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

5/20/11

Source
Medivir AB. Medivir Announces Positive 48-week Interim Data from TMC435 Hepatitis C Phase 2b ASPIRE Study in Treatment-Experienced Genotype-1 Patients. Press release. May 20, 2011.