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Hi bear, here we are back at HCV new drugs to talk about new and experimental drugs to treat hepatitis C. This time you can read along as we discuss a few new HCV drugs making their way down the pipeline.

Hello bear, great to see you again. As you know in 2011 the two protease inhibitors Victrellis and Incivek were FDA approved . Studies show that Incivek cured 79% of patients and Victrellis cured 69%. The term used by the medical world is SVR or Sustained Virologic Response.The bottom line is a patient is considered cured or has achieved SVR status when there is no detectable virus in the patients blood for six months after finishing treatment.

These two new FDA approved drugs still need to be used with standard therapy, right bear?

Yes,unfortunately patients still need to inject interferon and use ribavirin. But the SVR with these two drugs exceeded the old standard of care cure rates of 40 to 45 percent in genotype 1 patients.

What about patients who have cirrhosis? Or have failed prior standard therapy ? What are the stats on reaching SVR ?

Well, researchers found that Incivek, in hard-to-treat patients with hepatitis C and cirrhosis achieved a 47% sustained viral response. These patients had genotype 1 and had previously failed the standard two drug regimen of pegylated interferon plus ribavirin . Check out the link below for more information.

Telaprevir Effective in Hard-to-Treat Cirrhotic HCV

Lets just use the term Peg, because pegylated interferon is difficult for you to pronounce. So Bear, tell me about two experimental new protease inhibitors that are in phase three trials, and fill me in on this cyclophillin inhibitor.

Okay, Lets talk about the HCV drugs in phase three clinical trials that are used in combination with standard therapy or peg  and ribavirin. Currently in phase 3 trials is TMC 435, a protease inhibitor from Johnson and Johnson’s Tibotec unit.

Tell me about early interim results from the phase two trials. I remember them being released in February of 2011.

For HCV genotype 1 treatment-naïve patients using TMC 435 the SVR was 76 to 84 percent. The study was response-guided with 83% of patients being able to stop all therapy at 24 weeks.

What about the phase three trials.

Oh, you mean the QUEST studies, TMC 435 is currently being developed in three global phase III studies, QUEST-1 and QUEST-2 in treatment-naïve patients and PROMISE in patients who have relapsed after prior interferon-based treatment. In parallel with these trials, phase III studies for TMC 435 in Japan, in both treatment naive and treatment experienced hepatitis C genotype-1 infected patients, are ongoing. These phase III studies are fully recruited

You forgot to mention that TMC 435 is also being studied in combination with PSI-7977, we are talking about an interferon free combo . But more on that later. Right little bear ?

Right . Hey bear, lets hope that these drugs currently in phase three trials will give patients better tolerability, increases cure rates, with a shorter duration of therapy.

That sure is the plan. Another drug in phase three trials is BI-201335 from Boehringer Ingelheim. The Phase three trial of the boehringer drug is in combination with peg and will include 3 treatment arms. They are BI-201335 in combination with peg plus ribavirin for 12 weeks or 24 weeks of treatment compared to 48 weeks of peg  plus ribavirin without BI-201335. By the way, the FDA has granted Fast Track designations for BI-201335 plus standard-of care, and as part of the interferon-free combination with the polymerase inhibitor, BI-207127, in chronic genotype 1 Hepatitis C patients. The study is an interferon-free regimen deemed SOUND-C2 .

At the 2011 AASLD meeting we heard that in the SILEN-C1 trial of BI-201335 with standard therapy, HCV genotype 1 treatment- naïve patients achieved 82% to 84% SVR. In the trial deemed SILEN-C3, HCV genotype 1 treatment-naïve patients treated with BI-201335 plus standard therapy achieved an 80% SVR in the group that was treated for 12 weeks compared to 82% in the group that was treated for 24 weeks.You can find all this information and more by clicking on a link to HCV advocate and HCV new drug pipeline provided below.

HCV Advocate
Hepatitis C New Drug Pipeline

Another important drug in the mix is a cyclophilin inhibitor that disrupts a host function required for viral replication. This cyclophilin inhibitor formally known as DEB 025 is alisporivir from Novartis.

At the EASL in 2011 results from a Phase two study of 300 HCV genotype 1 treatment-naïve patients who were treated with alisporivir plus peg and ribavirin reported a 76% SVR rate in the group that was treated for 48 weeks compared to 55% in the group that received peg plus ribavirin without alisporivir.

Right, at the AASLD meeting in 2011 we heard of an interferon-free arm of alisporivir monotherapy and alisporivir plus ribavirin, It was reported that at week 6, 49% HCV genotype 2 and 3 treatment-naïve patients were HCV RNA undetectable. This was the highest rates seen in the alisporivir plus ribavirin arms.

The word is that these three experimental drugs,TMC 435, BI 201335 and alisporivir could be available in 2 years. Speaking of interferon free, may we ?

Yes, two drugs made headlines recently. They are Asunaprevir formally known as BMS-650032 and Daclatasvir formally known as BMS-790052 both drugs are made by Bristol-Myers Squibb.

A new term here is Quadruple Therapy. First off the four drugs used in combination were asunaprevir, daclatasvir, peg and ribavirin .The ten patients treated with all four drugs all had undetectable viral levels 12 weeks after treatment stopped, and nine still had undetectable levels after 24 and 48 weeks. This is where it gets exciting.  Another 11 patients received only asunaprevir and daclatasvir, and four of them had a sustained virologic response at 12 and 24 weeks after treatment.

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an investigational, oral, selective NS3 protease inhibitor. Please click on the link below to view the full results.

Hepatitis C Pills Clear Virus Without Injections

Another all oral combination in phase two trials is from Bristol-Myers Squibb and Pharmasset. The experimental  combo of drugs are PSI-7977 and Daclatasvir (formally known as BMS-790052).

Thats right, the Phase two studies will evaluate the potential to achieve sustained virologic response 24 weeks post treatment or cure with an oral, once-daily treatment regimen in patients across HCV genotypes 1, 2 and 3. Specifically, the study will assess the safety, pharmacokinetics and pharmacodynamics of Daclatasvir-BMS-790052 in combination with PSI-7977, with and without ribavirin In 84 treatment-naïve patients chronically infected with HCV genotypes 1, 2, and 3.

Hey bear, in November of last year they added two new treatment arms with 120 HCV genotype 1 treatment-naïve patients. Both treatment arms will study the combination of PSI-7977 and BMS-790052 with and without ribavirin for a total treatment duration of 12 weeks.

This brings us to the phase two trial with PSI-7977 and TMC 435. According to the press release this past November from Medivir and Tibotec the interferon free combination will evaluate the two combination with and without ribavirin for 12 and 24 weeks in genotype 1 patients who had a prior null response to standard therapy. 

We only covered a few drugs in this video today bear, I hope our listeners will click on the links below to view all the new drugs in development

HCV Advocate
Hepatitis C New Drug Pipeline

GS-7977 (formerly PSI-7977)
From Feb 2 2012 Gilead Sciences Earnings Call
View Transcript here
In keeping with our philosophy to develop best-in-class drugs, we (Gilead Sciences) acquired Pharmasset in order to bring PSI-7977 to our portfolio. We anticipate that we will be able to conduct and complete the clinical study and to allow the first approval of 7977 in combination with ribavirin by FDA during the first half of 2014.

Jan 2012
Gilead Sciences Completes Acquisition Of Pharmasset, Inc.
Gilead Sciences, Inc. (Nasdaq: GILD) today announced the completion of the previously announced transaction for Royal Merger Sub II Inc., a wholly-owned subsidiary of Gilead (“Merger Sub II”), to acquire Pharmasset, Inc.

Advances will continue in the race for improved hepatitis C treatments. With more direct acting antiviral combination trials to come The dream is to cure all patients with hepatitis C, and to eliminate interferon and maybe even ribavirin from HCV therapy.

Until next time, say goodbye bear

Goodbye bear

Current Recommendations for Using Telaprevir and Boceprevir in Patients With Advanced Fibrosis or Cirrhosis

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Paul J. Pockros, MD
Posting Date: December 19, 2011
Head, Division of Gastroenterology/Hepatology
Director, SC Liver Research Consortium
Clinical Director of Research, Scripps Translational Science Institute
The Scripps Clinic
La Jolla, California

Editor’s note: In this edition of Journal Options Hepatitis, we feature the 5 pivotal phase III studies that led to the approval in 2011 of boceprevir and telaprevir for the treatment of chronic hepatitis C. Each commentary in this series addresses a key issue or question of clinical relevance related to the use of these agents in clinical practice.

Patients with cirrhosis or advanced fibrosis due to hepatitis C virus (HCV) are a particularly challenging group to treat with combination therapy that includes 1 of the currently approved direct-acting antivirals (DAA), boceprevir or telaprevir. Patients with decompensated cirrhosis have the greatest need for curative therapy; however, these individuals were not studied in the pivotal trials of boceprevir and telaprevir and are not included in the prescribing information for either drug; therefore, there is significant risk associated with treating this group of patients in the absence of experience or guidelines.[1-3] Although patients with compensated cirrhosis were included in the phase III trials of both telaprevir and boceprevir, the number of these patients is too small on which to base treatment decisions with confidence. Furthermore, patients with cirrhosis who failed previous therapy—individuals comprising a significant proportion of our current patient population—do not respond as well as others to triple therapy and will often develop protease inhibitor–resistant variants at the time of treatment failure.[4]
So how should clinicians go about implementing telaprevir and boceprevir as treatment in patients with advanced fibrosis or cirrhosis? Here I describe what we know about telaprevir and boceprevir in patients with advanced liver disease based on data from the pivotal clinical trials, along with how my colleagues and I currently go about treating these individuals in clinical practice.

Compensated Cirrhosis
Implementing Telaprevir and Boceprevir
The combined data for patients with compensated cirrhosis in all 3 phase III trials of telaprevir revealed an overall sustained virologic response (SVR) rate of 62%, and combined data in fixed-duration and response-guided arms for boceprevir demonstrated an SVR rate of 48%, rates which are certainly high enough to warrant treating compensated cirrhosis.[5-9] Notably, the addition of IL28B testing does not provide sufficient specificity to aid in predicting which cases are likely to fail treatment, and thus we do not use this routinely in my practice for cirrhotic patients.[10,11]

Data from the REALIZE trial showed much lower SVR rates with telaprevir-based therapy among previous null responders to peginterferon/ribavirin with cirrhosis (14%) or bridging fibrosis (30%).[7] Similar data are not available for boceprevir because of the exclusion of null responders in the RESPOND-2 trial.[9] Subanalysis of the arm from REALIZE that received 4 weeks of lead-in treatment with peginterferon/ribavirin before addition of telaprevir indicated that a < 1 log10 IU/mL decrease in HCV RNA at Week 4 was associated with treatment failure in patients with compensated cirrhosis, whereas a ≥ 1 log10 IU/mL decrease in HCV RNA was associated with SVR in approximately 50%.[12] Although it is not recommended in the prescribing information for telaprevir, based on these findings, my colleagues and I routinely employ a 4-week peginterferon/ribavirin lead-in for all null responder patients with advanced liver fibrosis, and we do not initiate telaprevir until the HCV RNA value at Week 4 has been reviewed. For treatment-experienced patients lacking interferon sensitivity, we defer therapy for future clinical trials of quadruple therapy or interferon-free regimens (eg, daclatasvir, asunaprevir, and peginterferon/ribavirin; PSI-7977 plus ribavirin; others).[13]

Similarly, when planning to use boceprevir in patients with compensated cirrhosis, my colleagues and I implement the 4-week peginterferon/ribavirin lead-in phase, as indicated in the boceprevir prescribing information.[2] We wait to see the HCV RNA results at Week 4 before deciding whether to expose patients to boceprevir. If patients do not have at least a 1-log10 reduction in HCV RNA from baseline, we defer therapy or enroll patients in clinical trials. Other experts follow the recommendations in the prescribing information and continue therapy until the 12-week futility rule evaluation point and use response at this time point to determine whether treatment should be continued.

Duration of Therapy
Although we have no published data regarding the benefit of extending peginterferon/ribavirin therapy to 48 weeks in cirrhotic patients who achieve an extended rapid virologic response (ie, undetectable HCV RNA at Weeks 4 and 12) on telaprevir/peginterferon/ribavirin, the telaprevir prescribing information provides a small amount of data on this issue. Of 30 patients with cirrhosis who achieved an extended rapid virologic response, 67% (12 of 18) attained SVR when the duration of peginterferon/ribavirin was shortened to 24 weeks, and 92% (11 of 12) attained SVR when peginterferon/ribavirin was administered for the full 48 weeks.[1] These are very small numbers on which to base treatment decisions, and we need more robust studies in cirrhotics to evaluate the duration of peginterferon/ribavirin therapy when combined with telaprevir. Because these data are not yet available, I administer peginterferon/ribavirin for the full 48 weeks in cirrhotic patients if they can tolerate it; I shorten therapy to 24 weeks if they cannot.

With regard to boceprevir, the prescribing information clearly indicates that patients with compensated cirrhosis should receive 4 weeks of peginterferon/ribavirin followed by 44 weeks of boceprevir in combination with peginterferon/ribavirin.[2] This is based on data from clinical trials that clearly show a benefit of fixed-duration rather than response-guided therapy in this population.[2] Although the numbers are again small, among treatment-naive cirrhotic patients, SVR rates were 42% (10 of 24) with a fixed-duration 48-week regimen vs 31% (5 of 16) when response-guided therapy was employed. Among treatment-naive individuals, SVR rates were 77% (17 of 22) and 35% (6 of 17), respectively, with fixed vs response-guided therapy. Thus, when treating with boceprevir, I administer the recommended 48 weeks of peginterferon/ribavirin in cirrhotic patients if they can tolerate it. If the patient is unable to tolerate 48 weeks of peginterferon plus ribavirin, we push duration as long as possible to that point, but at least 24 weeks. It is expected that shortened durations of therapy would compromise efficacy.

Dosing
No dosage adjustment of boceprevir is recommended for patients with mild, moderate, or severe hepatic impairment.[2] Dose modification of telaprevir is not required when it is administered to patients with mild hepatic impairment (Child-Pugh A, score 5-6), although a 15% reduction in steady-state exposure was observed in HCV-negative subjects with mild hepatic impairment compared with healthy subjects.[1] When my colleagues and I treat patients with compensated cirrhosis with telaprevir, we do not adjust the telaprevir dosage. However, when treating patients with compensated cirrhosis with either protease inhibitor, we monitor weekly for expected reductions in white and red blood cell counts, and we implement higher thresholds for reducing the dosage of peginterferon or ribavirin when declines in absolute neutrophil count and hemoglobin occur. Specifically, we will normally dose-reduce ribavirin for hemoglobin levels < 10 g/dL and peginterferon for an absolute neutrophil count < 500.For more information on anemia management, see the accompanying commentary by Brian Pearlman.

Decompensated Cirrhosis
Telaprevir is not recommended for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C, score ≥ 7).[1] My colleagues and I have selected a few patients with a prior history of a single decompensation event (eg, a remote history of variceal bleeding followed by stability and low Model of End-Stage Liver Disease scores for years) to undergo triple therapy with telaprevir/peginterferon/ribavirin. This was done only after patients completed a transplant evaluation and were approved and/or listed. Thus far, 3 of 6 patients have decompensated (1 from hepatic encephalopathy, 2 because of new-onset ascites with spontaneous bacterial peritonitis), likely due to the peginterferon component of the regimen. All 3 patients were hospitalized and treatment was stopped; all recovered.

The safety and efficacy of boceprevir have not been studied in patients with decompensated cirrhosis, and the poor safety and tolerability of peginterferon/ribavirin in patients with decompensated cirrhosis remains a contraindication to treatment in this population.[8,9] My colleagues and I have not yet treated patients with decompensated cirrhosis with boceprevir. However, the data in cirrhotics in the pivotal trials of boceprevir were equally as good as those with telaprevir, so we are currently beginning to start patients on this regimen.

To date, treatment with protease inhibitor–based therapy in decompensated cirrhotics cannot be recommended outside of centers highly experienced in the management of this patient population.

Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:

Free registration is required to view the below links

• To review strategies for management of telaprevir-associated rash and anorectal symptoms, click here.
• For a better understanding of futility rules and their importance with boceprevir and telaprevir, click here.
• To review the impact of the occurrence and management of anemia with boceprevir and telaprevir, click here.
• To review rules for following response-guided therapy guidelines with telaprevir and boceprevir, click here.

Link to the original abstract