September 12, 2012

HCV Research: new HCV drugs coming; interferon-free therapy

Provided by NATAP

from Jules of NATAP. There are 4 new oral HCV drugs in the middle now of phase 3 studies, the last step before FDA approval & being in pharmacy - protease inhibitor TMC435, protease BI-335, NS5A BMS-052, and nucleotide GS-7977. Will we be able to combine 3 drugs in 1 regimen (protease+052+7977), we don't know? Small interferon-free studies reported at liver meeting EASL in April 2012 found 90-100% cure rates in treatment-naive patients: A phase 2 40-patient study at EASL in treatment-naives showed 100% SVR(cure) rate with 052+7977 with 24 weeks of therapy; 2 small phase 2 studies with protease ABT450/r+ a NNRTI+rbv found 90-95% SVR(cure) rates with only 12 weeks of therapy. Phase 3 for ABT450 is expected to begin soon.

Ongoing studies include a phase 2 of 435+7977 in treatment-experienced, and you can see new planned studies immediately below. Vertex is expected to reveal any day now results from ongoing early clinical studies of the 2 Alios nucleotides. BMS is developing nucleotide INX189 (now called BMS-986094); protease 435 + this nucleotide will be studied.

A study is planned to examine interferon-free regimens including: protease ABT-450/r + NS5A ABT-267 and/or NNRTI ABT-333, with & without ribavirin.

Large HCV Drug Pipeline

In addition to the new HCV drugs in later stages of development which I discuss above there is much more going on in new HCV drug development. Boerhinger Ingelheim has a NNRTI in development along with their protease. Roche is studying in patients a potent HCV protease danoprevir/r and 2 additional drugs nucleoside mericitabine and a NNRTI, phase 3 with danoprevir is being planned. Merck is developing a potent protease MK5172 in early patient studies and a potent 2nd generation NS5A. Biotech Achillion has 2 proteases and a potent 2nd generation NS5A in early patient studies. GSK has a potent NS5A in patient studies. Biotech Presidio has potent NS5A in early patient studies. Biotech Idenix has a NS5A and a lesser potent nuke in earlier development. Gilead has along with nucleotide 7977 & NS5A 5885, also a protease and a NNRTI. BMS also has a protease and as mentioned in earlier report their nucleotide BMS-986094 (formerly INX-189), and additional new HCV drugs. And again Abbott has a protease, 2 NNRTIs, and a NS5A. In addition to Tibotec's protease TMC435 and additional drugs in early development.

All these drugs are expected to follow after the ongoing phase 3 studies of 4 new drugs described in my earlier report. Interferon-free therapy is expected to cure a lot of patients, but for some of the hardest to treat prior null responders potent 3/4-oral drug regimens will have to be explored and also just in case a potent multi-oral regimen with 2 orals +pegIFN and ribavirin looks to be very successful in early studies and will be further studied. BMS has a potent new interferon called lambda interferon which appears to have few side effects, which could be used for patients who might need an extra boost from interferon, as well as for HBV. The duration of therapy with interferon-free therapy, which used to be 48 weeks for genotype 1 patients, is expected to be shortened to 24 weeks and 12 weeks for some patients. Many of these drugs are effective for all genotypes 1-6, particularly, 2-4.

Besides good treatment we need HCV testing programs because 80% of HCV-infected in USA are undiagnosed, don't know they have HCV; there aren't enough well-trained clinicians to take care of & treat patients; we need patient-support service to keep patients in care. NYC's Dept of Health has launched just last month the first large-scale urban comprehensive $2 million HCV testing project providing new rapid HCV testing, linkage-to-care, care in community-clinics, and web-based training/case studies for clinicians by expert clinicians implemented by this project.

Medivir announces TMC435 in an expanded clinical collaboration: TMC435+BMS NS5A, TMC435+INX189

· Expanded clinical study program evaluating a combination of TMC435 and daclatasvir (BMS-790052)

· TMC435 and BMS-986094 (formerly INX-189), two direct-acting antivirals in combination, will be evaluated in clinical trial

Stockholm, Sweden - Medivir AB (OMX:MVIR), the research-based speciality pharmaceutical company focused on the development of high-value treatments for infectious diseases, announces that its development partner, Janssen R&D Ireland has broadened its clinical collaboration agreement with Bristol-Myers Squibb Company (NYSE:BMY).

· This announcement concerns an expansion of the clinical collaboration agreement between Tibotec Pharmaceuticals (now Janssen R&D Ireland) and Bristol-Myers Squibb (NYSE:BMY) announced by Bristol-Myers Squibb on 2nd December 2011

· Bristol-Myers Squibb and Janssen have agreed, pending the outcome of the upcoming phase II study, to further study daclatasvir (BMS-790052) and TMC435 in a phase III trial.

· Bristol-Myers Squibb and Janssen have agreed to conduct a drug-drug interaction study with TMC435 and BMS-986094. Results from the DDI study will guide the further evaluation of the use of TMC435 and BMS-986094 in HCV patients.

TMC435 and daclatasvir (BMS-790052)

In the agreement announced on 2ndDecember 2011, TMC435, a once daily potent NS3/4A protease inhibitor (PI) in phase III development for the treatment of genotype-1 chronic hepatitis C virus (HCV) infection will be investigated in a combination in a phase II trial with Bristol-Myers Squibb's investigational NS5A replication complex inhibitor, daclatasvir (BMS-790052), also in phase III development.

In the upcoming phase II study the companies will evaluate the potential to achieve sustained viral response 12 and 24 weeks post treatment in null responder and interferon intolerant patients with HCV genotype 1. This study is planned to start later in 2012.
TMC435 and BMS-986094 (INX-189)

The expanded clinical agreement also includes clinical evaluation of a combination of TMC435 and the nucleotide polymerase NS5B inhibitor BMS-986094, formerly known as INX-189. A drug-drug interaction (DDI) study with TMC435 and BMS-986094 will be conducted. Results from the DDI study will guide the further evaluation of the use of TMC435 and BMS-986094 in HCV patients.

Charlotte Edenius, Executive VP Research & Development, of Medivir commented: "We are very excited to see this expanded collaboration between Janssen and Bristol-Myers Squibb and to be investigating TMC435 with the nucleotide BMS-986094 and to expand the clinical collaboration evaluating TMC435 with daclatasvir. This represents one of several strategies to explore TMC435 in interferon free regimens; a development we believe will be an important advancement in the HCV field for patients."

About TMC435

TMC435 is a highly potent once-daily (q.d.) investigational drug that is being jointly developed by Janssen R&D Ireland and Medivir to treat chronic hepatitis C virus infections in genotype 1 patients.
TMC435 - On-going global phase III program in brief:

· TMC435-C208 or QUEST-1 in 375 treatment-naïve genotype-1 patients

· TMC435-C216 or QUEST-2 in 375 treatment-naïve genotype-1 patients

· TMC435-C3007 or PROMISE in 375 genotype-1 patients who have relapsed after prior interferon-based treatment

· Phase III program in Japan, includes 417 genotype-1 treatment naïve and treatment experienced patients

· TMC435-C3001 is a phase III efficacy, safety and tolerability study comparing TMC435 versus telaprevir, each in combination with Pegylated Interferon α-2a (PegINF) and ribavirin (RBV), in hepatitis C genotype-1 infected patients who were null or partial responders to prior PegINF/RBV therapy

· TMC435-C3011 is an open label, single arm phase III trial to explore the efficacy, safety and tolerability of TMC435 150 mg once daily, in combination with PegIFN/RBV in 100 treatment naïve or treatment experienced, hepatitis C genotype-4 infected patients

Medivir announces an interferon-free phase II combination trial with TMC435 and daclatasvir to commence shortly - (07/10/12)

Medivir announces TMC435 in an expanded clinical collaboration: TMC435+BMS NS5A, TMC435+INX189 - (05/30/12)

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2-6: TMC435-C202, a phase IIa, open-label study - (05/23/12)

Open-Label Study of GS-7977 + Ribavirin Pre-Transplant - (06/22/12)

A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C - (06/20/12)

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin - (06/20/12)
Interferon-Free Regimens at EASL - (04/24/12)

There are about 8 interferon-free regimens below and/or presented at EASL, in one study in 40 easier-to-treat treatment-naive patients we saw 100% cure rate with interferon-free regimen consisting of 2 HCV oral drugs Gilead's 7977+BMS' 052; and 90-05% cure rates were seen with interferon-free regimen with Abbott's 450+072+rbv.

Recent Successes and Noteworthy Future Prospects in the Treatment of Chronic Hepatitis C: TOWARD AN INTERFERON-FREE FUTURE? - (06/20/12) Ira Jcobson

"proof of the concept that HCV infection can be cured without interferon" ......"undetectable HCV RNA 4 weeks after end of treatment in 44 of 44 genotype 1 treatment-naive patients with 24 weeks of total therapy.......SVR 12 exceeding 90% over 40 genotype 1 treatment-naive patients"..."SVR 12 exceeding 90% over 40 genotype 1 treatment-naive patients" with 12 weeks therapy

HIV Coinfection With Hepatitis C Virus: Evolving Epidemiology and Treatment Paradigms - (06/20/12) "Rates of health care use and disability are 70% greater in coinfection than in HCV monoinfection"....."Studies of DAAs for coinfected patients are lagging behind those for patients with HCV monoinfection

HCV Viral Load Reduction Improved Inflammation, Fibrosis, Clinical Outcomes with PegIFn Lead-In Maintenance therapy in HALT-C - (07/10/12)

Overcoming Barriers to Care for Hepatitis C - Perspective - (07/10/12)

Hepatitis C Treatment Highlights From the 2011 American Association for the Study of Liver Disease Meeting - (07/12/12)

Global Burden of Hepatitis C: Considerations for Healthcare Providers in the United States - (06/20/12)

lack of access to screening, care, and treatment limit the use of these therapies for most persons living with HCV infection globally, and deaths from preventable cirrhosis and liver cancer continue to increase. Governments need to address viral hepatitis comprehensively by improving surveillance, prevention, care, and treatment. In the United States, healthcare providers must be cognizant of the global burden and epidemiology of HCV infection and follow current screening care and treatment recommendations


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