Monday, October 24, 2011

A Cure For Hepatitis C-The Pharmaceutical Companies and Us

A Cure For Hepatitis C-The Pharmaceutical Companies and Us

Hello folks, first off I would like to say that I was once a patient, just like yourself. After successfully eradicating the virus in 2000, I became committed to bringing HCV information to those people who are searching for a better understanding of this disease. This blogger does not possess any credentials nor do I have a talent for writing, what I do have is a personal understanding of being diagnosed with hepatitis C. Over ten years ago, I was where you are now, desperately seeking information for "my" shot at a cure.

This review covers the newly approved HCV protease inhibitors boceprevir and telaprevir, along with the promise of interferon free therapies.

Interferon-free treatment regimens, if successful-could be beneficial for those people with decompensated cirrhosis and for the population of HCV infected individuals who are unable to take interferon and/or ribavirin.

For the past decade standard therapy included a combination of interferon or pegylated interferon and ribavirin. In genotype 1 patients these medications only had a 40%-50% effectiveness in achieving sustained virologic response-SVR. The side effects have left some of us defeated, as for those people who did not reach SVR, little hope.

What about those adverse effects?

Hey, in the moment, or while on therapy, I recognized that side effects weren't communicated accurately in publications or rarely were they addressed in detail. The seasoned patient is all too familiar with the joint pains, headaches, fevers, insomnia, rage-don't ask, skin rashes, fatigue and nausea. However, we welcomed the challenge knowing the end result could be worth the battle.

I remember at times during my own battle with this disease I felt isolated, alone, in part because HCV isn't a disease that people rally around, for me, there was little empathy.

The heartbreaking reality is that these new drugs arrived too late and liver damage took its natural course in many brave people infected with this hideous disease. For the newly transplanted, they wait for hope. In liver recipients who have experienced HCV re-infection, their success depends on the promise of new drugs. These people would benefit most from DAA combination therapy. However, we must wait for trials and data. In January of 2011 in a press release from Vertex, we had a glimmer of hope, noted in the release;
Vertex recently completed a drug-drug interaction study of telaprevir with immunosuppressive agents commonly used following a liver transplant. Based on results from this study, Vertex and Tibotec plan to initiate in 2011 a Phase 2 study of telaprevir-based regimens in people with recurrent hepatitis C following a liver transplant.
However, there will still be a large ‘unmet need’, including patients unable to tolerate interferon or ribavirin and previous non-responders to standard therapy. The good news is that the new FDA approved drugs will give hope to many of those non-responders. Research has shown combining different DAAs increases viral suppression and helps to prevent antiviral resistance, but the ultimate goal is to develop a short-duration, interferon free oral combination, with excellent tolerability and efficacy.

The HCV community celebrated in May when the new HCV protease inhibitor agents boceprevir and telaprevir were finally FDA approved. The new protease inhibitors are both used in combination with PEG-IFN plus ribavirin and have increased the cure rate in both treatment-naïve and treatment-experienced persons.

This information on the blog today certainly isn't new, however it becomes a good starting point for the newly diagnosed, or for anyone who is considering treatment.

A good place to begin is with the AASLD guidelines;
The American Association For Study Of Liver Diseases (AASLD) recently updated its HCV guidelines for the treatment of genotype 1, the revision was needed to address the development of direct-acting antiviral (DAA) agents. To view the guidelines click here.

Victrelis - Boceprevir
Let us start with an easy summary of Merck's drug Victrelis. The complete data on Victrelis and Incivek presented in this summary is available in the new guidelines. Source links to all additional data is provided.

The SPRINT-2 trial- Never Treated
For his study, 1,097 people, 159 of whom were black, who had not been treated for hepatitis C were randomly assigned to one of three groups. All groups were treated with Pegintron and ribavirin.

1-After four weeks- one group also received a placebo for 44 weeks;
2-Another group had boceprevir added to their treatment for 24 weeks.
3-The third group was given the three drugs for 44 weeks.

Among non-black patients, 40 percent achieved a sustained response to standard care.

But as many as 68 percent of those also receiving boceprevir achieved sustained response at 28 weeks, the researchers found.

For black patients, the response rate was 23 percent for those receiving standard care
and up to 53 percent with the addition of boceprevir.

Noted;The number of black patients was small compared to non-black therefore the study may not have provided a true assessment of response.

RESPOND-2 Trial; Previously treated
These patients had been previously treated with peginterferon and ribavirin and included 403 genotype 1 patients, both prior non-responders and relapsers; about 12% were black.

Again, patients were divided into three groups similar to those in the other study. For those receiving boceprevir, the response rate was as high as 66 percent, compared with 21 percent for those receiving only peginterferon and ribavirin, the researchers found.

Among people with undetectable HCV RNA at week 8, SVR rates were 86% after 32 weeks and 88% after 44 weeks of triple therapy.

Among participants who had less than a 1 log IU/mL decrease in HCV RNA at week 4, one-third of boceprevir recipients still achieved SVR, compared with none in the control group.

"The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV (hepatitis C) genotype 1 infection, as compared with peginterferon-ribavirin alone," the authors concluded.


In November Merck will present new data analyses for VICTRELIS™ (boceprevir) at The American Association for the Study of Liver Diseases 2011 Annual Meeting.

Presentations will include results from the Phase III PROVIDE study, which evaluated the efficacy of VICTRELIS in combination with peginterferon alfa and ribavirin in adult patients with chronic HCV genotype 1 infection who had prior null response to treatment with peginterferon alfa and ribavirin alone.

This is good news, as mentioned on the blog boceprevir has not been studied in (prior null responders).

Next Up Incivek-Telaprevir

The ADVANCE trial - Never Treated
For this study, 1,095 previously untreated patients with genotype 1 and a baseline viral load of 800,000 IU/ml or more were treated with peginterferon alfa-ribavirin plus telaprevir .

A total of 75% genotype 1 patients who received peginterferon alfa-ribavirin plus telaprevir for 12 weeks followed by peginterferon alfa-ribavirin for 12 or 36 weeks (depending on response) had a sustained virologic response-SVR.
*This is compared to only a 44% SVR for patients on standard therapy for 48 weeks.

Similarly, 69% of the group who received standard therapy plus telaprevir for 8 weeks followed by peginterferon alfa-ribavirin for 16 or 40 weeks had a sustained virologic response.
A total of 58% of genotype 1 patients were eligible for the 24 weeks of total treatment duration.

The authors of ADVANCE note that rates of SVR to standard therapy are around 40–50% in patients with genotype 1 infection who had received no previous therapy. Most patients require at least 48 weeks of treatment. The ADVANCE trial showed that shorter courses can be effective when telaprevir is added to standard therapy.

The REALIZE trial -
Previously treated
Phase 3 REALIZE study enrolled 662 patients to evaluate people with genotype 1 chronic hepatitis C whose prior treatment with pegylated-interferon and ribavirin was unsuccessful either because they relapsed, had a partial response or had a null response.

Results from the phase III REALIZE trial indicated that, among prior relapsers, (SVR) sustained response rates with two telaprevir-containing regimens were 83% and 88%, compared with 24% for peginterferon alfa-2a and ribavirin plus placebo.

Lower sustained viral response rates were seen in patients who previously showed partial or no response to the two standard drugs, but they were still significantly better than in the placebo group (41% in both telaprevir arms versus 9% in the standard treatment group.

Summary of investigational Hepatitis C drugs presented in 2011 at the EASL
Telaprevir for Previously Treated Chronic HCV Infection
An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases

OPTIMIZE-HCV study to investigate different dosing regimens for telaprevir in treatment-naïve patients is on-going and is estimated to complete in October 2012.

The purpose of this study is to evaluate the effectiveness of telaprevir administered twice daily versus every 8 hours in combination with Peg-IFN-alfa-2a and ribavirin in treatment-naÃ-ve patients with chronic HCV genotype 1 infection.

Vertex will be presenting new data at The American Association for the Study of Liver Diseases 2011 Annual Meeting

Sustained viral response (SVR, or viral cure) results, from a
Phase 2 study evaluating short durations of 12- and 24-week regimens of VX-222 in combination with INCIVEK, pegylated-interferon and ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment will be presented for the first time. Additionally, new data from a Phase 2 study evaluating INCIVEK combination treatment in people co-infected with genotype 1 chronic hepatitis C and human immunodeficiency virus (HIV) will be presented at the meeting. All people in this study were new to hepatitis C treatment.

Yesterday Vertex announced the initiation of a Phase 3b study called CONCISE which will evaluate the potential for treatment with INCIVEK™ (telaprevir) combination therapy to be shortened to 12 weeks in people with genotype 1 chronic hepatitis C who have the ‘CC' variation near the IL28B gene.

About The Trial
INCIVEK is administered in combination with pegylated-interferon and ribavirin. Approximately one-third of people with hepatitis C have the ‘CC' genotype, which has been associated with higher sustained viral response (SVR, or viral cure) rates and faster response to interferon-based treatment. In this study, INCIVEK will be taken twice a day. The study is expected to enroll 350 people in the United States and Europe who are new to treatment or who have relapsed after at least one prior course of treatment with pegylated-interferon and ribavirin alone. The primary endpoint of the study is the proportion of patients who achieve a sustained viral response 12 weeks after the last planned dose of study drug (SVR12).

Update On Vertex and Alios BioPharma
As reported in June by Nature, Vertex entered into an exclusive worldwide licensing agreement with South San Francisco’s Alios BioPharma that will add two distinct nucleotide analogues to Vertex's hepatitis C portfolio.

Unlike Incivek, which targets an essential hepatitis C serine protease called NS3/4A, the two newly licensed drugs from Alios interfere with a different component of the hepatitis C replication machinery. Both agents disrupt a viral polymerase called NS5B, but the two compounds, dubbed ALS-2200 and ALS-2158, have different targets within the enzyme and work synergistically in pre-clinical cell-based studies, according to Vertex’s press release.

The addition of these compounds provides Vertex with multiple opportunities to develop potential, new, all-oral combination regimens for chronic hepatitis C

Read more from Nature , or check out the press release from Vertex

In August over at Infectious Disease was an interview with HCV experts providing information on the differences between telaprevir, and boceprevir. Below is a little on what they had to say about adverse effects.
Gandhi: A 4-week lead-in period of peginterferon plus ribavirin is given with boceprevir but not with telaprevir. In terms of adverse events, in phase 2 and phase 3 clinical trials, 49% of patients in the boceprevir groups had hemoglobin values less than 10 g/dL, compared with 28% of those in the control groups, according to findings published in The New England Journal of Medicine. Use of erythropoiesis-stimulating agents to treat anemia was more frequent in the boceprevir groups (43%) than in the control groups (24%). However, discontinuation of treatment was only about 1%. Decreased neutrophil and platelet counts were more common in the boceprevir groups, as was dysgeusia (35%-44% in boceprevir groups vs. 11%-16% in control groups).
The main adverse effects of telaprevir that have been associated with the medication include rash, anemia, nausea and other gastrointestinal symptoms, and anorectal discomfort. In clinical trials, rash developed in 56% of patients who received T+PR, compared with 34% who received PR alone. Patients with mild to moderate rashes may continue therapy with careful monitoring. Telaprevir should be stopped if a rash progresses and becomes severe, or if systemic symptoms develop.
Pockros: Frequent physical examinations and laboratory testing for anemia, rash, decreased hemoglobin and other adverse events will be needed with both of the medications.
Birnkrant: Rash and pruritus were identified in phase 2 trials of telaprevir and a monitoring and management plan was instituted for the phase 3 trials. There was also a dermatology expert panel that reviewed cases retrospectively. Clinically and histologically, the rash seen with telaprevir is comparable to that seen with pegylated interferon and ribavirin. It is described as an exematous maculopapular and papular lichenoid rash. The rash did not appear to be a drug-induced hypersensitivity type of rash. Less than 1% of subjects experienced a suspected severe rash such as Stevens-Johnson and not all occurred during telaprevir dosing period. The mechanism of rash was investigated, but remains unknown, and there were no deaths related to rash.
I’ll now turn to anemia. The most problematic adverse effect of ribavirin therapy is reversible hemolytic anemia. Telaprevir adds to the frequency and severity of this toxicity. Anemia was seen in non-clinical studies, so we knew we had to monitor for it in the clinical trials. It’s highlighted in the warnings and precaution section of the label with recommendations of how to deal with anemia such as measuring hemoglobin baseline and every 4 weeks, utilizing ribavirin dose reduction to manage anemia, and it’s important to note that Incivek should not be dose-reduced, and if discontinued, then should not be restarted.
Regarding anorectal disorders, approximately 20% of patients receiving telaprevir had an anorectal disorder compared to 5% on control. The most commonly reported disorders in this category were hemorrhoids, anorectal discomfort, and anal pruritus. The time to onset is approximately10 days. Less than 1% were serious. Most were managed with topical agents. Again for this adverse event, the mechanism is unknown and, in some, mostly remains bothersome and rarely treatment limiting.
Adverse reactions seen in greater than or equal to more than 5% higher frequency in telaprevir subjects compared with control were as follows: rash, fatigue, pruritis, nausea, anemia, diarrhea, vomiting, hemorrhoids, anorectal discomfort…or interference with taste.
Jeffrey Murray, MD, deputy director of the FDA’s antiviral products division: Besides pregnancy warnings relating to the use of boceprevir in combination with peginterferon and ribavirin, the major warnings pertaining to Victrelis are hematologic adverse events. Boceprevir can exacerbate anemia and neutropenia already seen with peginterferon and ribavirin, and in fact, the number of transfusions and dosage reductions of ribavirin were higher when Victrelis was added to a PR regimen compared to a PR regimen alone. In addition to anemia and neutropenia, other clinical adverse reactions are fatigue, nausea, headache and an unpleasant taste of the drug.
If you missed it read the complete interview here.

Another more recent article at Forbes by Ed Silverman on the' New Drug Wars' comments on how physicians view Invicek vs Victrelis.

Overall, the main benefit of this new class of hepatitis C treatments is the improvement in sustained viral load or SVR, according to the docs surveyed. While Incivek beat Victrelis on higher SVR, shorter duration and simpler protocol, the perception of superior efficacy was countered by concerns with rash, according to Decision Resources. “While it’s too soon to tell, Victrelis may fill a a niche for patients who prefer it’s side effect profile,” the firm reports.
Read more here.

Finally, recently over at FiercePharma was a survey by Sermo asking the question Which New Hepatitis C Drugs MDs Prefer

Right now we have the two new FDA approved protease inhibitors Incivek and Victrelis, these two drugs have shown to increase SVR rates by around 40% over standard therapy. Again we dare to dream of an all oral regimen, a drug which will eliminate injecting interferon, side effects, but still provide a high cure rate.

I believe in miracles, all-oral regimens-you sexy thing!
Before we get into the "dream" you may be interested in reading an article by Adam Feuerstein which gives a bit of a back story on the pharmaceutical industry and the making of interferon free therapies. Excerpt from the article;

Roche's purchase of Anadys likely provides the third drug in what might be the first (but not necessarily best) all-oral, interferon-free therapy for hepatitis C to begin phase III studies.

1-Roche executives aren't stupid; they look ahead a few years and see Pegasys sales going away
2-Roche wants to maintain or grow its Hep C franchise, it has to figure out a way to develop an all-oral (interferon-free) therapy -- and fast.

3-One way of doing this is by acquiring or partnering Hep C drugs others consider to be weak or non-competitive on their own.

4-That description fits Anadys' lead drug setrobuvir

5-InterMune's danoprevir, which Roche acquired last year, is also seen as a weak Hep C drug.

6-Roche could start relatively quickly a phase III study against Hep C that combines three oral drugs -- setrobuvir (from Anadys), RG7128 (partnered with Pharmasset and Merck's currently approved Hep C drug Victrelis, predicts Brian Skorney, biotech analyst at Brean Murray, Carret & Co. Roche and Merck have already announced plans to collaborate on Hep C.

7-Another potential Roche all-oral regimen could include setrobuvir, RG7128 and danoprevir (acquired from InterMune).
These Roche triple combinations may require longer 24-week dosing (instead of faster 8 or 12 week dosing) and may not be as potent or effective as all-oral regimens being developed by Pharmasset and others, but Roche may figure that being first is more important than being best, adds Skorney.
Read the complete article here.
Blog Note;
RG7128 is being developed by Pharmasset and Roche through our collaboration to develop nucleoside polymerase inhibitors for the treatment of chronic hepatitis C virus (HCV) infections.
RG7128 is a prodrug of a molecule we-*Pharmasset discovered named PSI-6130, an oral cytidine nucleoside analog. A prodrug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. PSI-6130 is the active component of RG7128. PSI-6130 was shown to be an inhibitor of HCV replication, specifically targeting the HCV RNA polymerase.

Heads UP
When studies are completed, the results are often presented informally at meetings arranged by a sponsor, or manufacturer, of a drug. In addition, preliminary study conclusions and some of the data may be presented at medical meetings and published as an abstract (a very brief synopsis of the study). The most comprehensive information comes from research articles published in medical journals after peer-review. Peer-review means that the paper is reviewed by two or three independent physicians or investigators with no relationship to the study authors or sponsors. In addition, the editor and associate editors of the journal also carefully review the research study methods and conclusions. These peer-reviewed studies, when published in a prestigious journal, carry great weight. The FDA also reviews every piece of the original data from the clinical trial in detail before approving a new drug for use. Every single patient record is scrutinized to confirm the accuracy of the data and the statistical analysis.

We start with Pharmasset. The company has three polymerase inhibitors in development
PSI-7977, PSI-938 and Mericitabine (RG7128). In addition Pharmasset is collaborating with other pharmaceutical companies which can speed up the process of testing medications with the end result leading to improved drugs to treat HCV. In July Pharmasset entered into a Clinical Collaboration Agreement with Tibotec Pharmaceuticals to evaluate the interferon-free treatment regimen combo of PSI-7977 and TMC435 with and without ribavirin in prior null responder, genotype 1 HCV patients. In January 2011 came the announcement of the
clinical collaboration of Pharmasset and Bristol Myers to evaluate the utility of BMS-790052, Bristol-Myers Squibb , in combination with Pharmasset’s-PSI-7977. Pharmassett also has a strategic collaboration with Roche for the development of PSI-6130 and its prodrugs, including Mericitabine (RG7128). Under the collaboration, Roche pays all development costs associated with RG7128.

More On Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in five Phase 2b trials, including abbreviated duration interferon and interferon-free regimens, in subjects with all HCV genotypes. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, is in QUANTUM, a Phase 2b interferon-free trial of PSI-7977 and PSI-938 in subjects with all HCV genotypes. Mericitabine (RG7128) continues in three Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.

The Latest On Pharmasset PSI-7977

The protocol amendment adds one arm exploring 12 weeks of PSI-7977 monotherapy in treatment naive patients with HCV genotype 1 (GT1), and one arm of PSI-7977 and ribavirin (RBV) in treatment-experienced patients with HCV genotype 2 (GT2) or genotype 3 (GT3). In addition, the previously announced arm in HCV GT1 patients with a prior "null" response to an interferon (IFN) containing regimen, which was planned to assess PSI-7977/IFN/RBV, has been modified to an IFN-free 12-week regimen of PSI-7977/RBV.
"We look forward to reporting SVR12 results from Part 1 and interim data from the PSI-7977 monotherapy arm of ELECTRON on Sunday, November 6th, 2011 at the upcoming 2011 American Association for the Study of Liver Diseases (AASLD) annual meeting. The preliminary results to be discussed at AASLD led us to expand the study to add an arm of PSI-7977 monotherapy for HCV GT1," said Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We and others continue to explore the potential of PSI-7977 for IFN-free and monotherapy treatment regimens in a broader group of individuals living with HCV of all genotypes and regardless of their response to prior treatment."

In addition to previously announced interferon-free studies of PSI-7977 by Bristol Myers Squibb and Tibotec, The National Institute of Health (NIH) recently initiated an interferon-free 24 week study of PSI-7977 400mg QD with and without ribavirin, in 60 treatment naive patients with HCV genotype 1 (GT1) in the US.

ELECTRON is an exploratory study of PSI-7977 for the treatment of chronic HCV infection. Part 1 of the trial is evaluating 12-week regimens of interferon-free PSI-7977 400mg QD with ribavirin (RBV), and three abbreviated duration peginterferon (Peg-IFN) regimens of 4, 8, or 12 weeks in treatment-naive patients with HCV GT2 or GT3. The primary endpoint of the trial is the safety and tolerability of PSI-7977 400mg QD and RBV for 12 weeks, administered with or without Peg-IFN. On May 11, 2011, Pharmasset announced the completed enrollment of Part 1 of ELECTRON:
PSI-7977 400 mg with Peg-IFN and RBV for 12 weeks (GT2/3)
PSI-7977 400 mg with RBV for 12 weeks, Peg-IFN weeks 1-8 only (GT2/3)
PSI-7977 400 mg with RBV for 12 weeks; Peg-IFN weeks 1-4 only (GT2/3)
PSI-7977 400 mg with RBV for 12 weeks (GT2/3)

In Part 2 of ELECTRON, a 5th cohort was added to explore PSI-7977 monotherapy in treatment naive patients with HCV GT2 or GT3:
PSI-7977 400 mg monotherapy for 12 weeks (n=10 GT2/3)
Following on the previously reported 100% SVR12 in treatment-naive subjects with HCV GT2/3 (PROTON), a 6th cohort was added to ELECTRON to explore an 8-week duration of PSI-7977 Peg-IFN/RBV. The previously announced 7th cohort in HCV GT1 patients with a prior "null" response to Peg-IFN, has been modified to an interferon-free 12-week regimen of PSI-7977/RBV.

PSI-7977 400 mg with Peg-IFN/RBV for 8 weeks (n=10 GT2/3 treatment-naive)
PSI-7977 400 mg with RBV for 12 weeks (n=10 GT1 null)
In Part 3 of ELECTRON, two additional IFN-free regimens will be explored in treatment-naive patients with HCV GT1 and in treatment-experienced patients with HCV GT2 or GT3.
PSI-7977 400 mg monotherapy for 12 weeks (n=25 GT1 treatment-naive)
PSI-7977 400 mg with RBV for 12 weeks (n=25 GT2/3 treatment-experienced)

September 13, 2011

Interferon-Free trial all HCV genotypes
PRINCETON, N.J., Sept. 13, 2011 /PRNewswire/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that screening has begun in a Phase 2b, international study of PSI-7977 and PSI-938, two nucleotide analog polymerase inhibitors for the treatment of chronic hepatitis C (HCV).

The QUANTUM trial will evaluate interferon-free regimens of PSI-7977 400mg QD and PSI-938 300mg QD with and without ribavirin over 12 or 24 weeks in patients with HCV who have not been treated previously. The trial will also evaluate the use of PSI-938 monotherapy.

"We are encouraged by the early efficacy and safety data being generated with our nucleotide analogs, PSI-7977 and PSI-938," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer.
"The QUANTUM trial is the first interferon-free, all-nucleotide study with an SVR endpoint. The ability to include all HCV genotypes was supported by data from the NUCLEAR study and the interferon free arms of the ELECTRON trial. Data from ELECTRON are expected later this year."

About the Phase 2b QUANTUM Trial
This study is designed to enroll approximately 450 patients with chronic HCV of all viral genotypes who have not been treated previously. The primary endpoint of the trial will be sustained virological response (SVR24). Patients will be equally randomized across the following arms:

PSI-938 only
  • PSI-938 and PSI-7977

  • PSI-7977 and ribavirin

  • PSI-938, PSI-7977, and ribavirin
All arms will be study for both 12 and 24 weeks with a placebo control of 24 weeks.
  • Placebo for 24 weeks
HCV patients will be stratified by IL28B status and baseline HCV RNA to ensure balance across cohorts. Cirrhotic and non-cirrhotic patients will be enrolled in the study.

Pharmasset / Tibotec
Study to evaluate the combination of PSI-7977 and TMC435 with and without ribavirin in prior null responder, genotype 1 HCV patients

This phase 2 proof of concept study will evaluate the potential to achieve sustained virologic response 12 weeks post treatment with an all oral, once-daily, interferon-free treatment regimen in patients infected with genotype 1 HCV. Specifically, the study will assess the safety, pharmacokinetics and pharmacodynamics of 12 and 24 weeks of PSI-7977 in combination with TMC435, with and without ribavirin, in patients chronically infected with HCV genotype 1 who had a prior null response to peginterferon alfa and ribavirin treatment.

The study is planned to start in the second half of 2011.

Bristol-Myers - Pharmasset
BMS-790052 in combination with PSI-7977

As mentioned in January both pharmaceutical companies Pharmasset and Bristol-Myers entered into a clinical collaboration, Pharmasset initiated a Phase 2a trial investigating the combination of Pharmasset's PSI-7977, a nucleotide polymerase inhibitor, and BMS-790052, Bristol-Myers Squibb's (BMY) NS5A replication complex inhibitor, for the treatment of chronic hepatitis C. The two drugs BMS-790052 in combination with PSI-7977, once-daily treatment regimen with and without ribavirin, will evaluate the treatment in naïve patients with HCV genotypes 1, 2, and 3. The primary endpoint of the trial is sustained virologic response.

Nov 3 Update
A New 12 Week, Interferon-Free Treatment Arms Added to All-Oral Combination Study of PSI-7977 and Daclatasvir (BMS-790052) for HCV Genotype 1.

This May Pharmasset, announced the start of the study;

*This study is currently recruiting participants.

Bristol-Myers Squibb
In March at the EASL meeting we heard exceptional news on two oral drugs from Bristol-Myers, BMS790052+BMS650032. The company reported in 11 genotype 1 null responders who took the Bristol-Myers combination alone, (without pegylated-interferon and ribavirin) 4 out of 11 patients achieved an SVR.

To Be Presented At This Months AASLD

The first results of a Phase IIa study of the dual DAA regimen of BMS-790052 and the NS3 protease inhibitor BMS-650032

Abstract Oral #LB-4
Dual Oral Combination Therapy with the NS5A Inhibitor BMS-790052 and the NS3 Protease Inhibitor BMS-650032 Achieved 90% Sustained Virologic Response (SVR12) in HCV Genotype 1b-Infected Null Responders

On October 18, 2011, Bristol-Myers Squibb listed the below trial @
*not yet recruiting

About The Trial
The Study will Determine the Effectiveness and Safety of a Three Drug Antiviral Combination Therapy to Treat Hepatitis C Virus (HCV) Infected Patients Not Previously Treated With Currently Available Medications

Boehringer Ingelheim
BI 207127 a nonnucleoside polymerase inhibitor, BI 201335 a protease inhibitor.

On Oct 22 Boehringer Ingelheim announced the addition of an interferon-free regimen (SOUND-C2), to its ongoing studies (SILEN-C1 and SILEN-C2).
which will include a week 12 interim analysis of SOUND-C2, a Phase IIb study evaluating an interferon-free combination of its protease inhibitor BI 201335 and its polymerase inhibitor BI 207127 – with and without ribavirin in treatment-naïve HCV infected patients.

Abbott on Friday announced interim data from mid-stage trials of its experimental hepatitis C drug combination that suggested patients could achieve a viral cure without use of interferon and that the duration of therapy could be about half as long as conventional therapies.

In the trials, 44 previously untreated patients with hepatitis C were given ritonavir with Abbott's ABT-450 and one of two Abbott polymerase inhibitors, ABT-333 or ABT-072, and ribavirin for 12 weeks. All patients who remained in the studies achieved an early virologic response at 12 weeks, and of the 10 patients to date who were tested 24 weeks after completing the treatment course, nine had achieved a sustained virologic response, the company said. Abbott plans to present more detailed data on these and other trials of the drug regimen next year.

"In other words, these patients were cured with a 12-week course of therapy without interferon," Gonzalez said.
Read more here and here.

In Sept the company announced;
In consultation with the U.S. Food and Drug Administration (FDA), the company will amend the design of ongoing clinical trials to discontinue dosing of GS 9190 in hepatitis C-infected patients who are receiving that compound in combination with pegylated interferon and ribavirin, and another direct-acting antiviral agent.

This decision follows reports of two serious adverse events in patients enrolled in two separate studies who were receiving a four-drug regimen of GS 9190, an investigational HCV NS5B polymerase inhibitor; pegylated interferon and ribavirin; and one of two protease inhibitors (GS 9451 in one study and GS 9256 in the second study). Patient safety is Gilead's top priority, and the company will therefore immediately halt the dosing of GS 9190 in patients receiving this combination of medications.

Pegylated interferon in combination with ribavirin is currently part of the standard of care treatment for patients with chronic hepatitis C. Because of the side effects that can be associated with interferon, Gilead is working to develop multiple oral antivirals that, when used in combination, may be able to reduce or eliminate the need for interferon.

Gilead does not anticipate any impact on the timelines for or goals of its planned and ongoing clinical studies evaluating an "all oral" regimen for the treatment of chronic hepatitis C. Studies that include GS 9190 but do not include pegylated interferon will continue as planned. Similarly, studies that include the combination of GS 9451 (an investigational protease inhibitor), GS 5885 (an investigational NS5A) and pegylated interferon and ribavirin will continue.
Press Release Available here

Inhibitex Reports Corporate Developments
-4.25 log10 IU/mL Reduction in HCV RNA Levels Observed with Once-Daily Administration of 200 mg INX-189-
-Conference Call Today at 9:00 a.m. EDT-
TLANTA --(BUSINESS WIRE)-- Inhibitex, Inc. (NASDAQ:INHX) today announced its financial results for the third quarter ended September 30, 2011 and provided an update on several recent corporate developments, including top-line safety and antiviral data from the first cohort in its ongoing clinical trial designed to evaluate higher doses of INX-189, an oral nucleotide polymerase inhibitor, being developed to treat chronic infections caused by hepatitis C virus (HCV), administered as monotherapy or in combination with ribavirin for seven days.

"We are very pleased with the progress we have made in the clinical development of INX-189 over the past several months, as well as the continued potent, dose-dependent antiviral activity it is demonstrating as monotherapy in genotype 1 treatment-naïve HCV patients," stated Russell H. Plumb, President and CEO of Inhibitex, Inc. "We look forward to expanding the scope of our Phase 2 program to include interferon-free combinations of INX-189 with other antiviral agents in HCV genotype 1, 2, and 3 patients in 2012."
Recent Corporate Developments

INX-189 for Chronic Hepatitis C - The Company today reported top-line safety and antiviral data from the first cohort of its ongoing clinical trial of INX-189, which is primarily designed to further evaluate the safety, tolerability, pharmacokinetics and antiviral activity of higher doses of INX-189, administered as monotherapy, or in combination with ribavirin, for seven days in treatment-naïve patients with chronic HCV genotype 1. In this study, 200 mg INX-189, dosed once-daily for seven days, continued to demonstrate potent and dose-dependent antiviral activity with a median HCV RNA reduction from baseline of -4.25 log10 IU/mL. Further, 200 mg INX-189 was generally well tolerated, and there were no serious adverse events (SAE) or dose dependent adverse events (AE) observed.

In September, the Company announced the initiation of this trial, which includes other planned cohorts of 100 mg INX-189 dosed once daily in combination with ribavirin, 100 mg INX-189 dosed twice daily as monotherapy, 100 mg INX-189 dosed with food, and possibly higher monotherapy doses of INX-189. Earlier this year, the Company reported positive top-line safety and antiviral data from its initial multiple ascending dose Phase 1b clinical trial of INX-189, whereby INX-189, when dosed once-daily at 9 mg, 25 mg, 50 mg and 100 mg for seven days, demonstrated dose-dependent antiviral activity with median HCV RNA reductions from baseline of -0.64, -1.00, -1.47, and -2.53 log10 IU/mL, respectively.

The Company also reported today that it has initiated a Phase 1 drug/drug interaction study in healthy volunteers of INX-189 and an HCV direct acting antiviral compound, the objective of which is to evaluate the safety, tolerability and pharmacokinetics of the two compounds in contemplation of the Company expanding its Phase 2 clinical development program to include interferon-free combinations of INX-189 with other antiviral agents in HCV genotype 1, 2, and 3 patients in 2012.
The Company anticipates that this study will be completed by year-end.

In September, the Company also announced the commencement of a 90-patient randomized, placebo controlled, response-guided, Phase 2 clinical trial to evaluate the safety, tolerability and antiviral activity of INX-189 in combination with pegylated interferon and ribavirin in chronic HCV-infected genotype 2 and 3 treatment-naïve patients. This ongoing clinical trial is designed to evaluate three once-daily doses of INX-189 (25 mg, 50 mg and 100 mg) administered in combination with pegylated interferon and ribavirin for 12 weeks, and includes a control arm in which patients will receive placebo and standard of care treatment (a combination of pegylated interferon and ribavirin for 24 weeks). Each INX-189 combination treatment cohort in the trial is expected to include 25 patients, and the control arm is expected to include 15 patients.

Patients in the INX-189 containing treatment arms that achieve an extended rapid viral response, or eRVR, defined as having HCV RNA below the level of detection after 28 days and 12 weeks of dosing, will stop all therapy after 12 weeks. Those patients who do not achieve an eRVR will continue receiving pegylated interferon and ribavirin for 12 additional weeks. Patients will be followed for 24 weeks after end-of-treatment to determine if they achieve a sustained viral response (SVR), which is the currently accepted definition of cure for chronic HCV infections. The Company anticipates completing enrollment in this trial around year end.

The Company is presenting two abstracts at the upcoming annual meeting of the American Association for the Study of Liver Diseases (AASLD) in San Francisco beginning November 4, 2011. On August 2, 2011, AASLD posted the titles of these abstracts on its website, which are:
Antiviral Activity and Safety of INX-08189, a Nucleotide Polymerase Inhibitor, Following 7-Days of Oral Therapy in Naïve Genotype-1 Chronic HCV Patients

Preclinical Characterization of a Series of Highly Potent Phosphorodiamidate Nucleotide Analogue Inhibitors of HepatitiC Polymerase.

*Not all interferon-free combinations were included in this review.

To view the complete HCV pipeline click here and here

Clinical Trials
To learn more about Hepatitis C virus clinical trials or to find out if a study is enrolling patients in your area, please click here.

Coming Soon

The 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD) will be held November 4-8, 2011 in San Francisco, CA

This year's Hepatitis Debrief will be led by Dr. Gregory Everson, Director of the Section of Hepatology at the University of Colorado in Denver

The session is intended to be a quick, 30-minute summary of the new data presented at The Liver Meeting®. Dr. Everson plans to design the program by reviewing accepted abstracts pertaining to clinical trials in the treatment of hepatitis C and categorize the new types of treatment into the following four program sections:
-update on Telaprevir and Boceprevir
-new triple therapy regimens
-combination drug protocols
-interferon and ribavirin free protocols

Click here for more information on this session, which is included as part of the Annual Meeting registration fee.

Abstracts To Be Presented at The American Association for the Study of Liver Diseases November 2011 Annual Meeting

Pharmaceutical Companies

Wishing you all a safe and successful journey.

1 comment: