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.

Forbes.com: Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Posted 6/29/12 on Forbes.com . Commentary on the implications of BMS restricting enrollment in COMMAND-3 to subjects with genotype 1b, which makes up only 25% of the genotype 1 patients here in the US. Also see http://www.viralmatters.blogspot.com/2012/06/presidio-pharmaceuticals-completes.html on a tx-naive patient having baseline resistance to PPI-668, Presidio's NS5A inhibitor.

Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Is a promising new class of drugs for treating hepatitis C going to be limited because patients with the most common genotype of the virus are likely to develop resistance to the medications? This is the possibility raised by a Wall Street analyst after learning that Bristol-Myers Squibb has altered the protocol for a clinical trial for its daclatasvir antiviral, which is believed to be the most potent in the forthcoming NS5a class of hepatitis c treatments.

According to ClinicalTrials.gov, the drugmaker changed the protocol to its COMMAND-3 trial, which compares its drug in combination with interferon and ribavirin to Incivek, a protease inhibitor sold by Vertex Pharmaceuticals, along with interferon and ribavarin. What was the change? Bristol-Myers restricted future enrollment to patients who have only genotype 1b HCV, rather than all genotype 1 patients (see this and this).

“This effectively eliminates from the trial the most common HCV genotype in the US – 75 percent of HCV is genotype 1 in the US, 80 percent of genotype 1 is genotype 1a,” Sanford Bernstein analyst Tim Anderson wrote in a recent investor note. “This change, some three months after the study started enrollment, suggests that some form of virologic failure has emerged in the patients with these genotypes… The NS5a class, as a whole, might be limited by the propensity to rapidly develop virological resistance, and by significant differences in potency from one viral genotype to another.”

He adds that the change in the protocol has “major strategic and tactical implications” for the hot and fast-growing hepatitis C market. How so? Several drugmakers are developing NS5a treatments and the possibility that these drugs generate resistance to the virus may prompt changes in how different types of medications are combined and, consequently, alter various corporate strategies for drug development, alliances and dealmaking.

Take Gilead Sciences. The drugmaker is developing an NS5a, which has the code name of GS5885, as well as another that is a nucleotide inhibitor, or nuke, which Gilead calls GS7977 and believes could be the cornerstone of the first all-oral regimen for hepatitis C. Gilead, you may recall, acquired GS7977 last fall as part of its $11 billion acquisition of Pharmasset, a bet that has transformed the investor view of the drugmaker (back story).

Two months ago, results of a study that combined daclatasvir with GS7977 suppressed hepatitis C in most patients four weeks after completing treatment, raising hopes about the prospects for a therapy that does not involve an injectable medication. But further collaboration between the two drugmakers appeared uncertain, because Gilead indicated a preference for developing its own NS5a drug with GS7977 (look here).

However, as Anderson notes, the Gilead NS5a drug is less potent than daclatasvir, which “increases the risk for Gilead of sticking with GS5885. On the Bristol side, their ‘go-it-alone’ strategy may be developing a hole, increasing the urgency of incorporating daclatasvir into an all-oral combination with a potent resistance-fighting nuke such as GS7977. This collaboration appears to have become more important to both parties,” he writes.

Both drugmakers declined comment on this topic, although late last month, Bristol-Myers ceo Lamberto Andreotti renewed a call for Gilead to jointly develop their hepatitis C medications. And Bristol-Myers has not responded to questions about the change in the trial protocol.

Looking ahead, Anderson sees greater potential for combination therapy that relies on three drugs, instead of two, including GS7977 from Gilead, since the response to NS5a drugs suggests there can be limitations to at least one of the agents that drug developers would want to use in a one-two punch. And he believes Gilead’s prospects for creating one “super-regimen” for all subtypes with GS7977 and GS5885 alone, or even with ribavirin, have fallen.

As for other drugmakers, the questions concerning the NS5a drugs may result in slightly extended utility for Incivek as well as Victrelis, another protease inhibitor that is sold by Merck. This also suggests additional jockeying surrounding the NS5a drugs being developed by Achillion Pharmaceuticals and Idenix Pharmaceuticals, since larger drugmakers may decide to adjust their strategies and portfolios in response to the changing dynamics of this class of treatments.

Genotype 1b HCV Patients Fare Better on Boceprevir

(Article from Medscape on IAS presentation culling data from the SPRINT-2 and RESPOND-2 trails that find that genotype 1a patients have a lower barrier to resistance than genotype 1b. This was also found to be true for Telaprevir as well)

Genotype 1b HCV Patients Fare Better on Boceprevir
Emma Hitt, PhD

July 22, 2011 (Rome, Italy) — Boceprevir/peginterferon plus ribavirin is associated with a small but consistently higher sustained viral response (SVR) rate and a lower rate of development of boceprevir-related resistance-associated variants (RAVs) in patients infected with hepatitis C virus (HCV) genotype 1b subtype than in those infected with genotype 1a subtype, according to new data from the SPRINT-2 and RESPOND-2 phase 3 trials.

Daria Hazuda, PhD, vice president of virus and cell biology at Merck Research Laboratories, in Whitehouse Station, New Jersey, presented the findings in a late-breaking oral session here at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention.

"It was important to do this study in order to better understand the development of resistance with boceprevir," Dr. Hazuda told Medscape Medical News. "Additional analyses of our clinical studies with boceprevir are ongoing. A 3.5-year long-term follow-up study is underway to evaluate the persistence of resistance-associated variants over time," she added.


Dr. Daria Hazuda
In the SPRINT-2 and RESPOND-2 clinical trials, Dr. Hazuda and colleagues compared the SVR to boceprevir in combination with pegylated-interferon alfa-2b plus ribavirin and the associated presence or absence of RAVs between patients with HCV genotype 1a and those with genotype 1b.

The rate of SVR among those receiving boceprevir in the 2 trials was higher in patients with genotype 1b than in those with genotype 1a (66%–73% vs 59%–64%). The number of patients with RAVs detected was higher in genotype 1a patients than in genotype 1b patients in SPRINT-2 (58% vs 48%) and in RESPOND-2 (48% vs 41%).

The researchers also found that the RAVs V36M and R155K were more common in genotype 1a patients, whereas T54A/S, A156S, and V170A were more common in genotype 1b patients.

RAVs were more common in patients with a poor interferon response (defined as a decline in viral load of less than 1 log at week 4) than in those with a good interferon response (a decline in viral load of 1 log or more at week 4) (68% vs 31%). Overall, baseline samples showed a low rate of RAVs, and most patients with RAVs still achieved SVR.

"Understanding which mutations develop and how long they persist may help us assess the potential for retreatment with first-generation protease inhibitors and, importantly, facilitate the development of next-generation protease inhibitors that can work effectively against resistant mutants," Dr. Hazuda explained.

According to Dr. Hazuda, the resistance variants observed with boceprevir are similar, if not identical, to those observed with telaprevir. "Although we do not know if retreatment will be possible, there should be no difference between these 2 first-generation protease inhibitors," she said.

Dr. Hazuda added that it is still not known how long these resistant variants last, or whether the viral population has been altered in a way to make it less likely that patients will respond to retreatment with another first-generation protease inhibitor.

"These are valuable phase 3 trial data, which emphasize the fact that the main determinant of the SVR is not the preexistence of RAVs at baseline but the response to interferon and ribavirin," said independent commentator Jean-Michel Pawlotsky, MD, professor of medicine at the University of Paris-Est, director of the Department of Virology at the Henri Mondor University Hospital in Créteil, France, and director of the Department of Molecular Virology and Immunology at the Mondor Institute of Biomedical Research.

"Patients and doctors should not be afraid of resistance to protease inhibitors," he told Medscape Medical News. "Hepatitis remains theoretically curable in 100% of cases, and new drugs will allow patients who failed on triple-combination therapy the opportunity for treatment in the future," he added.

The study was funded Merck and Co. Dr. Hazuda is an employee of Merck. Dr. Pawlotsky reports acting as a consultant to Vertex, Jannsen, Merck, and Roche.

6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention: Abstract WELBX04. Presented July 20, 2011.

Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to news@medscape.net.