Janssen Interferon-Free Regimen with Simeprevir Cures Most Patients with Genotype 1 HCV

A 12-week all-oral regimen containing the FDA-approved HCV protease inhibitor simeprevir (Olysio) plus 2 investigational direct-acting antivirals drugs being developed by Janssen cured up to 95% of people with genotype 1 hepatitis C, according to study findings presented at the Asian Pacific Association for the Study of the Liver (APASL) conference last month in Istanbul.

The advent of direct-acting antiviral agents (DAAs) than can be used in interferon-free regimens has revolutionized hepatitis C treatment. Two approved 12-week regimens -- Gilead Sciences sofosbuvir/ledipasvir (Harvoni) and AbbVie's Viekira Pak (a combination of 3 DAAs plus a ritonavir booster) -- produce sustained virological response rates between 90% and 100% for most people with HCV genotype 1, including those with liver cirrhosis and HIV/HCV coinfection. Yet there remains room for shorter duration therapies and drugs active against multiple genotypes, and approval of additional options is expected to lower the cost of treatment.

The U.S. Food and Drug Administration approved Janssen's simeprevir in November 2013 for treatment of genotype 1 HCV, but it remains at a disadvantage to the Gilead and AbbVie regimens because it must be used either with DAAs produced by other companies, which greatly increases the cost, or with interferon, which causes difficult side effects.

The studies reported at APASL looked at simeprevir in combination with 2 new drugs being developed by Janssen and its partner Medivir: the non-nucleoside HCV polymerase inhibitor TMC647055 (boosted with ritonavir) and the HCV NS5A replication complex inhibitor JNJ-56914845.

Simeprevir plus boosted TMC647055 and ribavirin cured up to 86% of treatment-naive and previously treated patients without liver cirrhosis, though the SVR rate fell to just 50% without ribavirin. A triple combination of simeprevir, boosted TMC647055, and the higher dose of JNJ-56914845 cured 95% of patients. The regimens were generally safe and well-tolerated with no major side effects.

Below is an edited excerpt from a Medivir press release summarizing the APASL presentations.

New Data on Simeprevir Presented at the Conference of the Asian Pacific Association for the Study of the Liver

Stockholm, Sweden -- March 16, 2015 -- Medivir AB (Nasdaq Stockholm: MVIR) today announced that new clinical data for the once-daily HCV protease inhibitor simeprevir have been presented at the 24th Conference of the Asian Pacific Association for the Study of the Liver (APASL) in Istanbul, Turkey. Six oral and poster presentations on three clinical studies spanning over several development programs including simeprevir in different treatment combinations, durations and populations were held.

"We have a long and fruitful relationship with our global partner Janssen on simeprevir. These data show the commitment Janssen has for the HCV area, with studies of simeprevir in a wide range of patient populations and treatment regimens," says Niklas Prager CEO of Medivir.

Major findings in the studies presented:

Interferon free combinations

• In a phase II study up to 95% cure rates were achieved in HCV genotype (GT)1 infected patients treated with a 3-DAA combination of simeprevir, TMC647055/ritonavir and JNJ-56914845.

Interferon based triple combinations

• In the phase III TIGER study in treatment-naive patients with chronic HCV GT1 infection conducted in China and Korea 89%-91% were cured with simeprevir in combination with pegylated interferon (P) and ribavirin (R) for 12 weeks followed by PR for a further 12 or 36 weeks.
• The potential to shorten the total simeprevir plus PR treatment to 12 weeks in treatment-naive hepatitis C patients is being investigated in an on-going phase III study. In the GT1 study arm 76% of the patients were eligible to shorten treatment and of those 66% achieved SVR12 (were cured). In the GT4 study arm 48% of the patients were eligible for shortened treatment and of those with evaluable outcome at the time of analysis 94% had achieved SVR4.

About the Studies

HPC2001 -- an interferon free study with 2 or 3 Direct Acting Antivirals (DAA) including simeprevir

This is an open phase IIa efficacy, safety and pharmacokinetic study of 12 weeks of simeprevir (SMV) in various interferon free combinations in HCV GT1 infected treatment naive and prior relapser patients without cirrhosis. TMC647055 is a potent non-nucleoside polymerase inhibitor and JNJ-56914845 is a potent NS5A replication complex inhibitor.

Panel 1-3 included a 2-DAA combination (SMV + TMC647055/ritonavir) at different doses +/- ribavirin (n=7-12 per arm). Up to 86% of the patients achieved SVR12 (were cured) with ribavirin while up to 50% of the patients without addition of ribavirin achieved SVR12.

Panel 4 included a 3-DAA combination of SMV + TMC647055/ritonavir and 30 or 60 mg of JNJ-56914845 (n=22 per arm). This combination treatment resulted in overall SVR12 rates of 82% and 95% in the low and high dose groups of JNJ-56914845, respectively. All GT1b patients (100%) were cured regardless of JNJ-56914845 dose, while 71% and 93% of GT1a patients achieved SVR12 with the low and high dose of JNJ-56914845, respectively.

The combination treatments in all panels were generally well tolerated.

HPC3005 -- the TIGER study in China and Korea

This is a phase III, randomized three-armed study evaluating simeprevir 150 mg (n=152) or 100 mg (n=153) or placebo (n= 152) plus PR for 12 weeks in treatment-naive genotype 1 HCV patients in China and Korea. Patients in the simeprevir arms received PR alone for a further 12 or 36 weeks based on response-guided criteria (RGT). All patients in the placebo arm received a further 36 weeks of PR alone. Primary efficacy endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12).

The treatment was generally well tolerated and highly effective, with 89% and 91% SVR12 achieved in the 100 mg and 150 mg dose groups respectively, compared to 76% in the placebo arm; each simeprevir arm demonstrating superiority. 94% of the simeprevir-treated patients were eligible for the shorter 12 weeks follow-up treatment with PR and of those 94% achieved SVR12.

HPC3014 -- shortening overall treatment to 12 weeks of simeprevir plus PR in HCV GT1 and GT4 patients


This is an on-going phase III, open-label study of efficacy and safety of 12 weeks treatment with SMV + PR in treatment-naıve GT1 and GT4 HCV infected patients with mild-to-moderate fibrosis (METAVIR F0-F2). The aim of the study is to assess whether overall treatment duration with simeprevir + PR can be shortened to 12 weeks, based on early viral kinetics including a Week 2 assessment. Patients not meeting predefined response criteria continued with additional 12 weeks of PR treatment.

Of the GT1 patients 76% (123 out of 163) were eligible for 12 weeks total treatment duration and of those 66% achieved SVR12. Higher SVR12 rates were seen in: IL28B CC genotype patients, patients with low baseline viral load, or those with mild fibrosis. Of the GT4 patients 48% (24 out of 50) were eligible for 12 weeks total treatment and of those with evaluable outcome at time of analyses 94% (16 out of 17) had achieved SVR4.

Treatment with simeprevir and PR was generally well tolerated.

The following abstracts were presented:

“Efficacy safety and pharmacokinetics of 12 weeks of simeprevir incombination with TMC647055 ritonavir and JNJ-56914845 in genotype 1 hepatitis C virus infected patients” (presented by S Bourgeois).

“Efficacy safety and pharmacokinetics of 12 weeks of simeprevir in combination with TMC647055 and ritonavir with or without ribavirin in genotype 1 hepatitis C virus infected patients” (presented by S Bourgeois).

“Simeprevir plus peginterferon ribavirin in treatment naive patients with chronic hepatitis C virus genotype 1 infection results from the phase III tiger study conducted in east asian patients living in China and Korea” (presented by L Wei).

“Simeprevir exposure in Asian treatment naive patients with chronic hepatitis C virus genotype 1 infection results from a population pharmacokinetic model in the phase III tiger study” (presented by E. Hoeben).

“Shortening overall treatment to 12 weeks of simeprevir plus pegylated interferon and ribavirin according to early virologic response in treatment naive patients with chronic HCV genotype 4 infection and mild to moderate fibrosis” (presented by T Asselah).

“Shortening overall treatment to 12 weeks of simeprevir (smv) plus Peg-IFN and RBV in treatment naïve chronic hepatitis C (CHC) genotype 1 patients assessment of baseline and early (week 2) on treatment predictors of high SVR” (presented by T Asselah).

Further details can be found at www.apasl2015.org, at www.clinicaltrials.gov, and in Hepatol Int (2015) 9 (Suppl 1):S1-S391.

About Simeprevir (Olysio)

Simeprevir is an NS3/4A protease inhibitor jointly developed by Janssen Sciences Ireland UC and Medivir AB and indicated for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. Simeprevir efficacy has been established in HCV genotype 1 and HCV genotype 4 infected patients with compensated liver disease, including cirrhosis. Janssen is responsible for the global clinical development of simeprevir and has exclusive, worldwide marketing rights, except in the Nordic countries. Medivir AB retains marketing rights for simeprevir in these countries under the marketing authorization held by Janssen-Cilag International NV. Simeprevir was approved for the treatment of chronic hepatitis C infection as part of an antiviral treatment regimen in combination with pegylated interferon and ribavirin in genotype 1 infected adults with compensated liver disease, including cirrhosis. Simeprevir was approved in September 2013 in Japan, in November 2013 in Canada and the U.S., in March 2014 in Russia and in July 2014 in Mexico and Australia.

In May 2014 simeprevir was granted marketing authorization by the European Commission (EC) for the treatment of adult patients with genotype 1 or genotype 4 chronic HCV. Following the EMA approval, it has so far been made available in several EU countries in conjunction with reimbursement. Simeprevir (Olysio) is marketed under the trade name Sovriad in Japan and Russia, Galexos in Canada and Olysio in the U.S. and European Union.

About Medivir

Medivir is a research based pharmaceutical company with a research focus on infectious diseases and oncology. We have a leading competence within protease inhibitor design and nucleotide/nucleoside science and we are dedicated to develop innovative pharmaceuticals that meet great unmet medical need. Our commercial organization provides a growing portfolio of specialty care pharmaceuticals on the Nordic market. Medivir is listed on the Nasdaq Stockholm Mid Cap List.

4/10/15

References

S Bourgeois et al. Efficacy safety and pharmacokinetics of 12 weeks of simeprevir incombination with TMC647055 ritonavir and JNJ-56914845 in genotype 1 hepatitis C virus infected patients.24th Conference of the Asian Pacific Association for the Study of the Liver (APASL). Istanbul, March 12-15, 2015.

S Bourgeois et al. Efficacy safety and pharmacokinetics of 12 weeks of simeprevir in combination with TMC647055 and ritonavir with or without ribavirin in genotype 1 hepatitis C virus infected patients.24th Conference of the Asian Pacific Association for the Study of the Liver (APASL). Istanbul, March 12-15, 2015.

Other Source

Medivir AB. New Data on Simeprevir Presented at the Conference of the Asian Pacific Association for the Study of the Liver. Press release. March 16, 2015.