This May the HCV community celebrated the recent FDA approval of Victrelis (boceprevir) and Incivek (telaprevir), I know I sure did. On May 23, the FDA approved Telaprevir/ Incivek and on May 13, Vicrelis/Boceprevir was Approved. Visitors to this blog are often new, so for reference purposes I thought a few links are in order.
Hepatitis C therapies have evolved since 1991 when the FDA approved the 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. As for those new drugs recently approved, the FDA transcript of the May 23 teleconference briefing for 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.
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 new investigational drugs, including inteferon-sparing combinations. We had some big news coming from the EASL 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.
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November 2010 the backstory;
In November of 2010 we read about directing-acting oral drugs from studies presented at the American Association for the Study of Liver Diseases. Bristol-Myers Squibb's BMS-650032 + BMS-790052, and Boerhinger Ingelheim's BI 201335 + BI 207127. The drugs showed potent early activity, but resistance was a concern. From HIV and Hepatitis; Direct-acting Drug Combos Suppress HCV without Interferon, but Resistance Remains a Concern
Results
Bristol-Myer Squibb's BMS-650032 + BMS-790052
In group A the patients treated only with BMS-790052 and BMS-650032
Seven out of 11 patients receiving BMS-790052 and BMS-650032 without pegIFNα/RBV achieved rapid virologic response, defined as undetectable viral load by week 4. However, viral breakthrough occurred in six of the 11 patients in this treatment group.
BMS-790052, BMS-650032 and pegIFNα/RBV
Nine out of 10 patients receiving the combination of BMS-790052, BMS-650032 and pegIFNα/RBV achieved complete early virologic response (cEVR), defined as undetectable viral load by week 12.
This study was presented at AASLD Nov 2010
Slides From Natap;
Can HCV Be Cured Without Peg/RBV: Combination BMS-790052, BMS-650032 and pegIFN/RBV Provides Undetectable HCV RNA Through 12 Weeks of Therapy in HCV Genotype 1 Null Responders
Results
Boerhinger Ingelheim's BI 201335 + BI 207127
The Phase Ib study, SOUND-C1, showed the combination of two oral hepatitis C virus (HCV) compounds, the protease inhibitor BI 201335 and the polymerase inhibitor BI 207127, with ribavirin reduced viral load to the lower limit of quantifiable levels in HCV treatment-naïve patients. The regimen did not include interferon through the first 28 days of treatment
Poster LB-7) New protease-polymerase inhibitor combination resulted in 73-100% rapid virological responses without pegylated interferon
New protease-polymerase inhibitor combination resulted in 73-100% rapid virological responses without pegylated interferon. In this randomised open-label trial, 32 treatment-naïve genotype-1 HCV patients received a combination of BI 207127 in either 400mg or 600mg doses three times a day (TID) with BI 201335 120mg once daily (QD) together with ribavirin (RBV) (1000/1200mg daily in two doses) for 28 days.
Poster LB-7) New protease-polymerase inhibitor combination resulted in 73-100% rapid virological responses without pegylated interferon
New protease-polymerase inhibitor combination resulted in 73-100% rapid virological responses without pegylated interferon. In this randomised open-label trial, 32 treatment-naïve genotype-1 HCV patients received a combination of BI 207127 in either 400mg or 600mg doses three times a day (TID) with BI 201335 120mg once daily (QD) together with ribavirin (RBV) (1000/1200mg daily in two doses) for 28 days.
All patients had a rapid and sharp decline in HCV viral load during the first two days, followed by a slower second phase decline. In the lower and higher dose groups, 73 and 100% of patients achieved a rapid virological response (i.e. had a HCV RNA below the lower limit of quantification after 4 weeks of treatment).
One patient experienced a viral breakthrough (increase by more then 1 LOG10 from nadir during treatment) and one other experienced a 0.7 LOG10 increase in viral load. Both patients were in the lower dose group of BI 207127 and were patients with a high baseline viral load. On day 29, all patients were switched to treatment with BI 201335 and PegIFN/RBV for an additional 44 weeks per the defined study protocol, and will be followed to evaluate sustained virological response.
“These early data suggest that there is the potential for the combination of oral anti-HCV therapies to reduce the viral load in a more tolerable, interferon-sparing regimen.
See NATAP : Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127, and ribavirin, in patients with chronic hepatitis C: the SOUND-C1 trial -
April 2011
The drug company Boehringer Ingelheim 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.
This study is currently recruiting participants.
See NATAP : Strong antiviral activity and safety of IFN-sparing treatment with the protease inhibitor BI 201335, the HCV polymerase inhibitor BI 207127, and ribavirin, in patients with chronic hepatitis C: the SOUND-C1 trial -
April 2011
The drug company Boehringer Ingelheim 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.
This study is currently recruiting participants.
Click Here For Locations and 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;
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
Slides From NATAPONCE 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) -
Trial; PSI-7977 Genotypes 2 and 3
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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
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This study is currently recruiting participants.
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This study is currently recruiting participants.
Click Here For Locations and Trial Information
January 2011
Other significant news was the clinical collaboration announcement made in January 2011 by the two pharmaceutical companiesPharmasset 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.
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 and locations;Additional clinical trials can be found at http://clinicaltrials.gov/
This study is not yet open for participant recruitment.
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 Locations and Trial Information
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
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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 Locations and 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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PSI-7977 Genotypes 2 and 3
,,This study is currently recruiting participants. ,
Click Here For Locations and 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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