Hepatitis C Investigational Drugs; Interferon-free combinations

For far too many years, the standard hepatitis C treatment was a combination of interferon and the oral antiviral drug ribavirin. Hepatitis C therapies have evolved since 1991 when the FDA approved that first alfa interferon (Schering’sIntron A) to treat hepatitis C. If you're interested in viewing the timeline and the origin of Hepatitis, click here.

Flash back to over a decade ago to Interferon, which is a manufactured version of certain natural proteins that fight viruses. We had to inject three times a week, the side effects and SVR stats were to be desired, until  pegylated interferon entered the scene, which became the standard of care. At the time it was a significant step towards better treatment. The drug is modified so that it stays in the body longer hence only one injection a week. We were elated, because patients knew that with pegylated interferon those peaks and valley were no more, and the side effects would be less. But the real news was that the SVR rates were getting better, much better then Alfa interferon. We were on our way, and the HCV community thought this was the golden ticket. The excitement for many of us only lasted for a short time, or until we relasped or never responded, SVR didn't  happen for everyone. The stats for genotype 1 patients were at only 40 percent, and some genotype 1, 4 and 3  patients were left behind.

Fast forward to May 2011, and the  FDA approval of  Telaprevir/ Incivek and  Vicrelis/Boceprevir . Will it get any better ? Yes, with the promise of  inteferon-sparing combinations. Today the blog will touch on a few of these promising drugs.

For those readers who are newly diagnosed or are just starting to consider therapy here a few beneficial links on the recent new FDA approved drugs to get you started.

The FDA transcript of the May 23 teleconference briefing on both drugs is available  here.The medication guide, and prescribing information for boceprevir can be viewed here and here. As for telaprevir you can read those inserts here and here .The good news is that both drug companies are offering patient assistance programs. The SVR stats on both drugs are available in this months newsletter over at  HCV Advocate, check out the newsletter here. Today CVS Caremark announced it has put in place a Hepatitis C Support Program to Help Patients Manage New Triple Therapy Regimen, good move by the pharmacy.
Last but not least a short entry on Victrelis and Incivek can be viewed by clicking here.

This brings us to the exciting pipeline of a few new investigational drugs, including inteferon-sparing combinations. We had some big news coming from the EASL in March 2011 on Bristol-Myers interferon free combination: BMS-790052 + BMS-650032 and Pharmasset's  PSI-938 and PSI-7977 (Monotherapy) without pegylated-interferon and ribavirin. Also included in this post will be Boerhinger Ingelheim's interferon free combination BI 201335 + BI 207127 and Pharmasset’s PSI-7977 + Bristol-Myers  BMS-790052 interferon-sparing combo.

Today the buzz over at Forbes was about Pharmassets drug PSI-7977

Analyst Yaron Werber said the drug candidate, which is designated PSI-7977, could be approved as soon as mid-2014 to treat two relatively rare types of hepatitis C.

Werber said PSI-7977 could get to the market sooner if it is approved to treat hepatitis C genotypes 2 and 3, which make up a minority of cases.

In late May, Pharmasset started a mid-stage clinical trial of PSI-7977 as a treatment for hepatitis C genotypes 1, 2, and 3. Genotype 1 makes up about 70 percent of hepatitis C diagnoses. Werber said he thinks the drug "will have solid data and will be one of the dominant drugs in hepatitis C."

The analyst said Pharmasset should present study data in November and should start late-stage studies in early 2012.

April 2011

We start with Boehringer Ingelheim which has completed Phase I trials using their two oral drugs BI 207127 and BI 201335. The Phase II trial evaluating BI 207127 plus BI 201335 in PegIFN-free regimens, both with and without ribavirin, are currently underway.

Click Here For Trial Information ; Safety, Antiviral Effect and PK of BI 207127 + BI 201335 +/- RBV for 4 up to 40 Weeks in Patients With Chronic HCV Genotype 1 Infection

Excerpted From The Press Release;

Boehringer Ingelheim announced the study outline for the pivotal Phase III clinical trials designed to evaluate BI 201335, its investigational once-daily oral protease inhibitor, in both treatment-naïve and -experienced patients with chronic genotype-1 hepatitis C virus (HCV), the most challenging genotype to treat.

In parallel, the U.S. Food and Drug Administration (FDA) has granted Fast Track designations for BI 201335 plus standard-of care (SOC), and as part of the interferon-free combination with the polymerase inhibitor, BI 207127, in chronic genotype-1 HCV patients.

“We are delighted to receive the FDA’s Fast Track designation for both, our BI 201335 plus SOC, and interferon-free combination treatment approaches. If successful, the combination therapy carries the potential for patients to live without the burden of interferon’s side effects,” said Professor Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim.

Read The Press Release Here


EASL March 2011

Bristol-Myers Interferon-Free Combo Cured Hepatitis Patients
Data Presented at the March 2011 EASL showed that Bristol-Myers two investigational oral hepatitis C drugs BMS-790052 and BMS-650032, cured 4/11 people without interferon and ribavirin. These patients failed prior HCV therapy deemed as null-responders (the most difficult to treat).

In the 21-person trial, ten patients got the two drugs together with interferon and generic ribavirin. All showed no sign of the virus 12 weeks after the treatment was over. One patient had signs of virus at 24 weeks and was again virus-free in another follow-up test 35 days later.

Of 11 patients who took the Bristol-Myers combination alone, five had cleared the virus from their bodies at the end of treatment. Four remained virus-free after 24 weeks.

See Slides From NATAP

HCV Cured With out Peginterferon/ribavirin with 2 oral HCV drugs BMS790052+BMS650032: Quadruple Therapy With BMS-790052, BMS-650032 and Peg-IFN/RBV for 24 Weeks Results in 100% SVR12 in HCV Genotype 1 Null Responders: "HCV infection can be cured without interferon & ribavirin: 2 orals BMS790052+BMS650032"  - (04/02/11)

EASL
PSI-938 and PSI-7977 combination
Other remarkable news from the EASL came from the drug company Pharmasset which presented studies on the PSI-938 and PSI-7977 combination. The study was in treatment-naive, non-cirrhotic patients with genotype 1, these patients were treated with PSI-938 and PSI-7977 (Monotherapy) without pegylated-interferon and ribavirin.  Patients in the study "all" achieved undetectable in short-term followup . The drugs have high barriers to resistance, and broad genotype coverage.

Treatment with two oral drugs developed by Pharmasset resulted in 15 of 16, or 94%, of patients reporting undetectable levels of the hepatitis C virus after 14 days, according to interim results from a study released by the EASL.

The early data on  the two Pharmasset drugs PSI-938 and PSI-7977 is impressive, thus far the best data we have seen in all-oral therapy . None of the patients treated in the Pharmasset study have reported rebounding levels of hepatitis C virus, according to the research abstract, but so-called viral rebound may emerge as patients are treated longer, or when treatment is stopped and these patients are followed long-term to determine if they are truly cured.

See CCO for Capsule Summary
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Slides From NATAP
ONCE DAILY DUAL-NUCLEOTIDE COMBINATION OF PSI-938 AND PSI-7977 PROVIDES 94% HCV RNA < LOD AT DAY 14: FIRST PURINE/PYRIMIDINE CLINICAL COMBINATION DATA (THE NUCLEAR STUDY) -

The Other Pharmasset Trial; PSI-7977 and RBV With and Without PEG-IFN Genotypes 2 and 3
.First Received on December 13, 2010.   Last Updated on December 21, 2010
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3

To assess safety and tolerability of PSI-7977 400 mg and ribavirin (RBV) with and without pegylated interferon alfa 2a (PEG-IFN) in treatment naive subjects with hepatitis C (HCV) genotypes 2 or 3
Click Here For Trial Information
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January 2011
Other significant news was the clinical collaboration announcement made in January 2011 by the two pharmaceutical companies Pharmasset and Bristol Myers to evaluate the utility of BMS-790052, Bristol-Myers Squibb , in combination with Pharmasset’s-PSI-7977 for the treatment of  hepatitis C . This collaboration will speed up the process of testing medications with the end result leading to improved drugs to treat HCV. The FDA has encouraged these collaborations, and we can only hope other pharmaceutical companies will follow suit.

The Collaboration;  Pharmasset’s PSI-7977, and Bristol-Myers  BMS-790052
Pharmasset and Bristol-Myers Squibb announced  that the companies have entered into a clinical collaboration agreement to evaluate the utility of BMS-790052, Bristol-Myers Squibb’s NS5A replication complex inhibitor, in combination with PSI-7977, Pharmasset’s nucleotide polymerase inhibitor, for the treatment of chronic hepatitis C virus (HCV). This proof of concept study will evaluate the potential to achieve sustained viral response 24 weeks post treatment with an oral, once-daily treatment regimen in patients across HCV genotypes. Specifically, the study will assess the safety, pharmacokinetics and pharmacodynamics of BMS-790052 in combination with PSI-7977, with and without ribavirin, in treatment-naïve patients chronically infected with HCV genotypes 1, 2, and 3. The study is planned to start in the first half of 2011. This collaboration represents the first cross-company collaboration combining two oral agents to address a significant unmet medical need in the treatment of HCV.

The January Press Release; Pharmasset and Bristol-Myers Squibb  clinical collaboration agreement
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May 2011.
On May 26, 2011 Pharmasset and Bristol-Myers initiated a Phase 2a trial investigating the combination of Pharmasset's PSI-7977, and Bristol-Myers Squibb's  BMS-790052.  The primary endpoint of the trial is sustained virologic response.

About the Trial
This Phase 2a trial is planned to enroll approximately 84 patients with chronic HCV genotypes 1, 2 or 3 who have not been treated previously. The primary endpoint of the trial is sustained virologic response (SVR). The trial will be conducted in the U.S. Subjects will be randomized equally across each of the following arms:

• PSI-7977 400mg QD for 7 days, then add BMS-790052 60mg QD for further 23 weeks in genotype 1 subjects;
• PSI-7977 400mg QD for 7 days, then add BMS-790052 60mg QD for further 23 weeks in genotype 2 or 3 subjects;
• PSI-7977 400mg QD and BMS-790052 60mg QD for 24 weeks in genotype 1 subjects;
• PSI-7977 400mg QD and BMS-790052 60mg QD for 24 weeks in genotype 2 or 3 subjects;
• PSI-7977 400mg QD, BMS-790052 60mg QD and ribavirin for 24 weeks in genotype 1 subjects;
• PSI-7977 400mg QD, BMS-790052 60mg QD and ribavirin for 24 weeks in genotype 2 or 3 subjects.

About PSI-7977
PSI-7977 is a uracil nucleotide analog inhibitor of the NS5B polymerase being developed for the treatment of chronic HCV infection. Nucleotide analog polymerase inhibitors work by acting as alternative substrates that block the synthesis of HCV RNA, which is essential for the virus to replicate. PSI-7977 has been studied in combination with peginterferon and ribavirin for up to 12 weeks in genotype 1, 2 or 3 patients and is currently in two Phase 2b studies, one of which is investigating an interferon sparing regimen in genotype 2 or 3 patients. PSI-7977 is also being investigated in a 14-day combination study with PSI-938, a guanine nucleotide analog.

Click here for trial information;
Parallel, Open-Label, Randomized Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of PSI-7977 in Combination With BMS-790052 With or Without Ribavirin in Treatment Naive Subjects Chronically Infected With Hepatitis C Virus Genotypes 1, 2, or 3
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View The Press Release Here; PSI-7977 and BMS-790052 interferon-free trial for Geno 1,2 and 3 initiated

Recap and Other Trials Making The News;
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.Press Release; Medivir - The Phase 3 Program for TMC435 in Treatment-Naive Patients and Patients who Have Relapsed After Prior Interferon-Based Treatment
Click Here For Trial Information

From The March EASL

More On TMC435 - The ASPIRE Study
Medivir is a Sweden-based with the companies key pipeline asset, TMC435, a protease inhibitor, is in phase 2b clinical development for Hepatitis C and is partnered with Tibotec Pharmaceuticals, a Johnson & Johnson group company,.

TMC435 is a potent, once-daily, oral hepatitis C virus protease inhibitor which recently entered clinical phase 3 studies. The study enrolled patients chronically infected with genotype-1 hepatitis C virus (HCV) that had previously failed treatment with standard of care therapy (peginterferon and ribavarin). TMC435 is being jointly developed by Medivir and its partner Tibotec.

In this Week 24 interim analysis, treatment-experienced patients who failed peginterferon and ribavarin treatment achieved significantly greater virologic response rates following treatment with TMC435-containing regimen at all doses, compared with placebo. Results demonstrated that the TMC435 150 mg dose group showed the highest response, particularly in prior null responders. In this 150 mg dose group, HCV RNA levels were undetectable at week 24 for between 82% and 91% of the patients. Results also showed that there was no statistically relevant difference in safety and tolerability between the TMC435 and placebo treated groups.

May 26 Press Release; 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

March EASL
Slides From Natap; The ASPIRE Trial: TMC435 in treatment-experienced patients with genotype 1 HCV infection who have failed previous PegIFN/RBV treatment: Week 24 interim analysis -

PSI-7977 Genotypes 1,4,5,6
PSI-7977 administered in combination with pegylated interferon and ribavirin (PEG/RBV) in treatment naive patients with HCV genotypes 1,4,5,6, or indeterminate genotype.
Press Release;
Hepatitis C Phase 2b ATOMIC Trial of PSI-7977 for Multiple HCV Genotypes
Click here for Locations and Trial Information


PSI-7977 Genotypes 2 and 3
Click Here For Trial Information;
Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3
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/The Phase II trial evaluating BI 207127 plus BI 201335 in PegIFN-free regimens, both with and without ribavirin
,Click Here For Trial Information ;
Safety, Antiviral Effect and PK of BI 207127 + BI 201335 +/- RBV for 4 up to 40 Weeks in Patients With Chronic HCV Genotype 1 Infection

___________________________________

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BMS Phase 2B Study including 4 drug regimen of NS5A BMS-790052 + protease BMS-650032 + Peglambda/Rbv 
Click Here For Trial Information;
Safety Study of Pegylated Interferon Lambda Plus Single or 2 Direct Antiviral Agents With Ribavirin
Additional clinical trials can be found at  http://clinicaltrials.gov/

Related; Investigational Compound PEG-Interferon Lambda Achieved Higher Response Rates with Fewer Flu-Like and Musculoskeletal Symptoms and Cytopenias Than PEG-Interferon Alfa in Phase IIb Study of 526 Treatment-Naive Hepatitis C Patients


From The EASL In March;
More On The Four Drug Combo
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 4-Drug Combo BMS-650032, BMS-790052 pegylated Interferon-alpha (PegIFN-alpha); ribavirin (RBV)
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Quadruple therapy shows 100 percent SVR for HCV patients previously unresponsive to treatment

Is this treatment approach the next HCV therapy frontier?

Berlin, Germany, Saturday 02 April 2011: Exciting new data presented today at the International Liver CongressTM 2011 show that quadruple therapy in chronic hepatitis C (HCV) patients suppressed the emergence of resistant variants and resulted in a 100% rate of sustained virological response - undetectable HCV RNA - 12 weeks after treatment (SVR12).1

In the quadruple therapy study, HCV patients were given four drugs in combination; pegylated Interferon-alpha (PegIFN-alpha); ribavirin (RBV); and two different direct-acting antivirals (DAAs) BMS-650032 (an HCV NS3 protease inhibitor) and BMS-790052 (an HCV NS5A replication complex inhibitor).

The current standard of care (SoC) for HCV therapy is PegIFN-alpha plus RBV – a dual therapy. The addition of DAAs (currently in phase-III clinical trials) marks the next step in treatment evolution – a triple therapy. However, the new data presented today suggests that quadruple therapy could be the next generation of treatment for chronic HCV patients.

Professor Heiner Wedemeyer, EASL'S Secretary General, said: "Quadruple therapy is possibly the future of HCV treatment; this study goes a way to confirming that. While it's expected that the first DAAs and triple therapy will be approved for use later this year, quadruple therapy appears to have a more profound effect on virological response, with less of a resistance problem."

The study may also provide new hope for a growing number of HCV patients who cannot be effectively treated for chronic hepatitis with current treatments.
http://www1.easl.eu/easl2011/program/Orals/418.htm

Links;Click Here For Clinical Connections; International Search

http://www.clinicalconnection.com/

Center for Drug Evaluation and Research: www.fda.gov/cder

CenterWatch Web site: http://www.centerwatch.com/

NIH Clinical Trials Web site: http://www.clinicaltrials.gov/