HALT-C trial analysis shows reduced HCV viremia has clinical benefit...

Posted ahead of print of the American Journal of Gastroenterology on www.nature.com. A new analysis of the mammoth HALT-C trial revealed some very cool news for patients patients who achieved a significant viral load reduction while on Peg-Inf + RBV but relapsed after end of treatment (dubbed "responder relapsers). Those patients who showed improved HAI (Ishak Hepatic Activity Index) demonstrated reduced hepatic inflammation and thus less fibrosis progression and clinical complications followed out a median of 6 years than those not in that group. Bottom line, patients who were 'responder relapers' didn't go through therapy all for naught and experienced a benefit in lower fibrosis progression and it's associated complications. Hopefully this benefit will extend as well to those same patients that responded to new triple therapy but relapsed after end of treatment.


The American Journal of Gastroenterology , (12 June 2012) | doi:10.1038/ajg.2012.137


Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C

Chihiro Morishima, Mitchell L Shiffman, Jules L Dienstag, Karen L Lindsay, Gyongyi Szabo, Gregory T Everson, Anna S Lok, Adrian M Di Bisceglie, Marc G Ghany, Deepa Naishadham, Timothy R Morgan, Elizabeth C Wright and for the HALT-C Trial Group15

Abstract
OBJECTIVES:

During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.

METHODS:

Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.

RESULTS:

Among 657 patients who received full-dose peginterferon/ribavirin “lead-in” therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3–4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.

CONCLUSIONS:

Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.

Medivir and BMS partner for TMC435 and daclatasvir Phase II trial ...

Medivir press release dated on 6-29-12. Medivir/Janssen will partner with Bristol Myers Squibb for a 180 patient open-label phase II combination trial combining the protease inhibitor TMC435 with BMS's NS5A inhibitor daclatasvir both with and without ribavirin. The patient population will consist of genotype 1a and 1b treatment naive and null responder subjects. Of note in genotype 1a subjects, ribavirin will be included in both the 12 and 24 week arms. Given the  recent change in inclusion criteria in the COMMAND-3 trial, this isn't surprising. Genotype 1b subjects will be randomized to arms either with or without ribavirin. Subjects in the high-need category with F3/F4 fibrosis scores will make up approximately 35% of the population of the trial. 

Medivir announces an interferon-free phase II combination trial with TMC435 and daclatasvir to commence shortly

29-Jun-12

· The phase II interferon-free combination study with TMC435 and daclatasvir will evaluate treatment-naïve or previous null responder patients with HCV genotype 1a and 1b

· The study will include approx. 180 patients and will evaluate a combination of TMC435 and daclatasvir, with or without Ribavirin, in four different cohorts for 12 or 24 weeks of treatment

Stockholm, Sweden - Medivir AB (OMX:MVIR), the research-based pharmaceutical company focused on the development of high-value treatments for infectious diseases, announces that a phase II combination study with the investigational compound TMC435 and Bristol-Myers Squibb’s investigational compound daclatasvir will start in July. This study is part of the clinical collaboration agreement between Janssen R&D Ireland and Bristol-Myers Squibb Company (NYSE:BMY) announced on 2 December 2011 and on 18 April 2012.

TMC435 and daclatasvir (BMS-790052)
TMC435, a once daily potent NS3/4A protease inhibitor (PI) in phase III clinical development for the treatment of chronic genotype-1 hepatitis C virus (HCV) infection, will be investigated in an interferon free phase II trial in combination with Bristol-Myers Squibb´s investigational NS5A replication complex inhibitor, daclatasvir (BMS-790052), also in phase III development.

The purpose of this study is to assess the efficacy and safety of TMC435 and daclatasvir in combination with or without Ribavirin in chronic genotype-1 hepatitis C infected patients who are treatment-naive or null responders to previous Peginterferon alfa/Ribavirin therapy.

Study design
In this open label phase II study the potential to achieve sustained viral response (SVR), 12 (SVR12) and 24 (SVR24) weeks post treatment in treatment-naïve and null responder patients infected with HCV genotype 1a and 1b will be evaluated. Patients with advanced liver disease (F3/F4) will be allowed up to approx. 35% of the total treated population.

Cohort one and two will include patients with genotype 1b where TMC435 and daclatasvir will be dosed with or without Ribavirin for 12 weeks with a 36 weeks follow-up or for 24 weeks with a 24 weeks follow-up.

Cohort three and four will include patients with genotype 1a where TMC435, daclatasvir and Ribavirin will be dosed for 12 or 24 weeks with a 24 weeks post treatment follow-up.

For additional information from these recently updated studies, please see www.clinicaltrials.gov

For more information about Medivir, please contact:

Medivir Rein Piir, EVP Corporate Affairs & IR Mobile: +46 708 537 292
M:Communications medivir@mcomgroup.com
Europe: Mary-Jane Elliott, Amber Bielecka, Hollie Vile +44(0)20 7920 2330

About Hepatitis C
Hepatitis C is a blood-borne infectious disease of the liver and is a leading cause of chronic liver disease and liver transplants. The World Health Organization estimates that nearly 180 million people worldwide, or approximately 3% of the world's population, are infected with hepatitis C virus (HCV). The CDC has reported that almost three million people in the United States are chronically infected with HCV.

About Medivir
Medivir is an emerging research-based 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 in phase III clinical development for hepatitis C that is being developed in collaboration with Janssen Pharmaceuticals.

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

Medivir’s first product, the unique cold sore product Xerese®/Xerclear®, is launched in collaboration with GlaxoSmithKline to be sold OTC under the brand name ZoviDou in Europe, Japan and Russia.