VX950 Protease Inhibitor Telaprevir

2009-2007

Inhibitors Main Index

Latest News / Inhibitors & New Therapies

Vertex Pharmaceuticals Incorporated (Vertex) is a biotechnology company in the business of discovering, developing and commercializing small molecule drugs for the treatment of serious diseases. Telaprevir, lead drug candidate, is an oral hepatitis C protease inhibitor and one of the advanced of a new class of antiviral treatments in clinical development that target hepatitis C virus (HCV), infection.

Added Anti-Viral Halves Duration of Hepatitis C Treatment

 2009

November

Phase 2 Study of Telaprevir Administered q8h or q12h with Peginterferon Alfa-2a or Alfa-2b and Ribavirin in Treatment-Naïve Patients with Genotype 1 Hepatitis C: Final Results -

Telaprevir Vertex hep C protease inhibitor drug works well in twice daily dosing -

More than 80% of Hepatitis C Patients Treated in Study C208 Achieved an SVR with Telaprevir-Based Regimens - press release from Vertex

HCV Protease Inhibitor Telaprevir Demonstrates Good Efficacy in Both Treatment-experienced and Treatment-naive Patients

AASLD: High SVR Rates Seen with Telaprevir for Hepatitis C

More Than 80 Percent of HCV Genotype 1 Treatment-Naive Patients Achieved Sustained Virologic Response With Twice-Daily Telaprevir-Based Regimen

Nov 10

October 

August-July

Surveyed Physicians Will Treat Over 50 Percent of Hepatitis C Genotype 1-Infected Patients with the Protease Inhibitor Telaprevir
www.earthtimes.org

Forty Percent of Surveyed MCOs Will Place Only One Protease Inhibitor on Their Formularies, According to a New Report from Decision Resources

WALTHAM, Mass., Aug. 4 WALTHAM, Mass., Aug. 4 /PRNewswire/ -- Decision Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, finds that, based on profiles provided to them of emerging protease inhibitors, surveyed physicians indicate that they will prescribe Vertex/Johnson & Johnson/Mitsubishi Tanabe's telaprevir to more than 50 percent of their hepatitis C virus genotype 1-infected patients and will prescribe Schering-Plough's boceprevir to less than 30 percent of these patients. Although surveyed physicians perceive both telaprevir and boceprevir as efficacious drugs, they value (among other factors) telaprevir's shorter duration of treatment as compared to treatment duration using boceprevir.

The new Physician & Payer Forum report entitled Hepatitis C: Impact of and Receptivity to Novel Antivirals Among Payers and Prescribers finds that, among the surveyed physicians who indicate they will use both telaprevir and boceprevir for the treatment of hepatitis C virus genotype 1-infected treatment-naive patients, over 60 percent expect to start treatment for most or all of their patients with telaprevir. Surveyed physicians cite improved efficacy as the most important attribute influencing their prescribing decisions for hepatitis C virus.

"Eighty percent of the physicians we surveyed indicate that long-term efficacy is the most important attribute of novel therapies for hepatitis C virus," said Decision Resources Analyst Alexandra Makarova, M.D., Ph.D. "Nearly all surveyed physicians said that improvements in sustained virologic response in genotype 1-infected patients is the most important endpoint that will persuade them to use a novel treatment in place of currently-available therapies."

The report also finds that 40 percent of surveyed managed care organization's (MCOs) pharmacy directors indicate that they will place only one of the protease inhibitors on their formularies. Of these pharmacy directors, 10 percent expect to choose telaprevir while 30 percent say that they do not have a preference regarding telaprevir or boceprevir based on clinical data provided to them but will use cost as the basis for their selection.

Hepatitis C: Impact of and Receptivity to Novel Antivirals Among Payers and Prescribers is based on a U.S. survey of 84 gastroenterologists, 16 hepatologists and 20 MCO pharmacy directors. Their responses were compared to assess similarities and differences of opinion regarding clinical, economic and scientific factors.

Webinar
Members of the media are welcome to attend our upcoming webinar entitled On the Verge of a Paradigm Shift in the Hepatitis C Virus Market: Physician and Payer Perceptions of Telaprevir, Boceprevir and Other Key Novel Antivirals. This webinar will be held on Thursday, September 3, 2009 at 10 a.m. U.S. Eastern Time. For more information, contact Christopher Comfort at 781-296-2597.

About Decision Resources
Decision Resources (www.decisionresources.com) is a world leader in market research publications, advisory services, and consulting designed to help clients shape strategy, allocate resources, and master their chosen markets. Decision Resources is a Decision Resources, Inc. company.

Vertex Pharmaceuticals and Mitsubishi Tanabe Pharma Corporation Amend Agreement to Develop and Commercialize Telaprevir in Asia Aug 09

HCV Protease Inhibitor Telaprevir Improves Response, Halves Treatment Time For Hepatitis C Patients

New era in hepatitis C treatment

Telaprevir

Among several experimental directly-targeted antiviral agents for hepatitis C, the Vertex HCV protease inhibitor telaprevir (formerly VX-950) is furthest along in development. Final results from a pair of Phase 2b clinical trials – PROVE 1 and PROVE 2 – were published in the April 30, 2009 New England Journal of Medicine. PROVE 1, conducted in the U.S., included 250 previously untreated genotype 1 chronic hepatitis C patients (77% white), while PROVE 2, conducted in Europe, included 334 participants (94% white). Participants were randomly assigned to receive standard therapy with 180 mcg/week Pegasys plus 1000-1200 mg/day ribavirin for 48 weeks or various regimens containing telaprevir (1250 mg on day 1 then 750 mg every 8 hours) plus Pegasys, with or without ribavirin.

In PROVE 1, SVR rates were significantly higher in patients who received telaprevir/Pegasys/ribavirin for 24 or 48 weeks, but those who took the three-drug regimen for only 12 weeks did no better than those on standard dual therapy (SVR 61%, 67%, 35%, and 41%, respectively). Only 7% of patients taking telaprevir experienced viral breakthrough. In the small subgroup of African-American patients (a population that responds more poorly to interferon-based therapy), those taking telaprevir had a four-fold higher SVR rate compared with standard therapy (44% vs. 11%). Discontinuation due to adverse events was about twice as likely in the telaprevir arms compared with standard therapy (21% vs. 11%), with skin rash being the most common reason for stopping. In PROVE 2, the 12- and 24-week triple regimens performed better than standard dual therapy, which in turn worked better than the 12-week telaprevir/Pegasys regimen without ribavirin (SVR 60%, 69%, 46%, and 36%, respectively). Again, rash, itching, and anemia were more common in the telaprevir arms.

In an accompanying editorial, J. Hoofnagle wrote that these trials "suggest that the addition of telaprevir to the combination of peginterferon and ribavirin will increase rates of sustained virologic response in patients with chronic hepatitis C due to infection with HCV genotype 1 from approximately 45% to as high as 65% and will permit therapy to be limited to 24 weeks, thus avoiding the expense and side effects of prolonged therapy."

Telaprevir has also been studied in prior pegylated interferon/ribavirin nonresponders and relapsers in the PROVE 3 trial. As reported at the 2009 European Association for the Study of the Liver (EASL) meeting in April, patients receiving telaprevir/Pegasys/ribavirin had significantly higher SVR rates those taking standard dual therapy, but the 24-week arm had a higher relapse rate than the 48-week arm, indicating that longer treatment may be better for treatment-experienced patients.

http://www.hcvadvocate.org

June

EASL 2009
Alan Franciscus, Editor-in-Chief

http://www.hcvadvocate.org/news/newsLetter/2009/advocate0609.html#1

The European equivalent of the American Association for the Study of Liver Diseases (AASLD) conference is the European Association for the Study of the Liver (EASL).  This year’s EASL conference included a wealth of information about studies that have been conducted on drugs in development to treat hepatitis C.  This article will focus on coverage of the drugs furthest along in the development cycle—telaprevir and boceprevir as well some exciting news on the development of HCV therapeutic vaccines that are in early clinical development. 

Telaprevir
In previous Phase II studies of Vertex’s telaprevir, an HCV protease inhibitor, it has been reported that SVR rates have been as high as 69% in people with HCV genotype 1 who have never been treated (treatment naïve).  Retreatment with pegylated interferon plus ribavirin in people who did not achieve a sustained virological response (SVR-undetectable HCV RNA (viral load) 24 weeks post treatment) with a previous course of pegylated interferon plus ribavirin is very important because they constitute a large group of people with HCV who are in the most need for newer HCV medicines that will improve the chances for successful response to treatment.  At EASL results of a phase II study of patients who did not achieve an SVR and who were treated with the combination of telaprevir /Pegasys/ ribavirin were reported and the results are very encouraging.   

There were three groups in the study:

Group A:  telaprevir, Pegasys, ribavirin for 12 weeks followed by Pegasys plus ribavirin for an additional 12 weeks (total treatment duration = 24 weeks).

Group B:  telaprevir, Pegasys, ribavirin for 24 weeks followed by Pegasys plus ribavirin for an additional 24 weeks (total treatment duration = 48 weeks). 

Group C:  Pegasys plus ribavirin for a total treatment duration of 48 weeks (standard of care). 

A total of 453 patients were enrolled and received at least one dose of the study drug.  (See Table 1 for SVR results)

Definitions of Prior Non-Response

Non-responders: people who never achieved an undetectable HCV RNA (viral load) during or at the end of HCV treatment.

Relapsers:  people who became HCV viral load undetectable during to the end of the HCV treatment period, but who later became HCV RNA (viral load) positive during the follow-up period. 

Breakthroughs:  people who achieved an undetectable HCV viral load during treatment, but who later had detectable HCV viral load before the end of the treatment period.

Table 1: SVR results by type of prior response:

Safety
Vertex reported that the side effects were consistent with prior studies of telaprevir/Pegasys/ribavirin.  Seventeen out of 339 patients (5%) discontinued therapy due to skin rash and three out of 339 patients (1%) due to anemia.    Growth factors were allowed in the study but only two out of 339 patients in the telaprevir groups were given growth factors to treat anemia.  

Comment:
Even though the total number of patients in the study was small, the overall SVR rates are impressive.  Another study, the REALIZE study, has been launched by Tibotec (Vertex’s European partner) that will enroll about 650 treatment-experienced patients, and the results should give us a better picture of the effectiveness of a regime that includes the combination of telaprevir, pegylated interferon and ribavirin, as well as hopefully confirm the prior results.   

Boceprecir
The final results of the SPRINT-1 study of boceprevir, an HCV protease inhibitor used in combination with PegIntron plus ribavirin, were also released at EASL.  The patients in the study were HCV genotype 1 patients who had never been treated (treatment naïve) for hepatitis C.

The study had two parts:
Part 1:  To evaluate boceprevir (800 mg – three times a day), PegIntron and ribavirin in standard doses with different treatment durations.  Total of 5 different treatment groups – two of the arms also had a lead-in phase with PegIntron plus ribavirin (without boceprevir).  In this part of the study the various treatment regimes were compared to PegIntron plus ribavirin (standard of care (control group)) for 48 weeks.   (520 patients total)

Part 2: To evaluate boceprevir, PegIntron and ribavirin treatment: two different doses of ribavirin (800-1400 mg/day vs. 400-1000 mg/day); 48 weeks of treatment with the triple combination of boceprevir/PegIntron/ribavirin.  No lead-in phase.  (75 patients total)

Part 1 Results
An SVR rate of 75% (77 out of 103 patients) was highest in the arm that received the lead-in of PegIntron plus ribavirin for 4 weeks followed by 44 weeks of boceprevir /PegIntron/ ribavirin (total treatment duration = 48 weeks) vs. an SVR of 38% in the group that received the current standard of care therapy of PegIntron plus ribavirin.  In the group that received the lead-in of PegIntron plus ribavirin for 4 weeks followed by 24 weeks of the triple combination of boceprevir/PegIntron/ribavirin (total treatment duration = 28 weeks) the SVR rates were only 56%, which confirmed that the optimal treatment duration for the triple combination (boceprevir, PegIntron, ribavirin) therapy is 48 weeks. 

Safety Results
Treatment discontinuations due to side effects in Part 1 of the study were between 9 and 19% in the boceprevir arms compared to 8% in the arm without boceprevir.  The most common side effects reported were fatigue, anemia, nausea and headache. 

Anemia (hemoglobin decreasing to less than 10 g/dL) occurred in about 50% of people in the boceprevir arms compared to about 1/3 in the arm without boceprevir.  Erythropoietin (EPO-growth factor) was allowed in the study—26% of patients used EPO in the arm without boceprevir compared to 39-51% who used EPO in the groups that received boceprevir. 

Part 2 Results
In Part 2 (low dose ribavirin) it was found that the SVR rate was 36% vs. 50% in the standard dose group (both in combination with boceprevir and PegIntron).  This information confirms that standard doses of ribavirin are needed to increase SVR rates even with the addition of boceprevir.  

Comments
The results are impressive—75% SVR rates.  However, the increase in anemia seen in the patients who received boceprevir is a cause for concern that could limit the usefulness of boceprevir.  Another concern is that EPO was allowed and used in the clinical trials.  The use of EPO raises many concerns including:  

• EPO is not currently approved by the FDA to treat HCV treatment-related anemia.  It is unlikely that the vast majority of patients who develop anemia from HCV treatment will be able to use EPO since there are strong warnings about the use of EPO that are now listed on the FDA approved EPO package insert.  

• If EPO is used, will it be covered by most insurance companies?  This seems highly unlikely in the light of the warnings about and the cost of EPO.   

• How did the use of EPO affect the treatment outcome?  Would more patients have dropped out of the study if EPO wasn’t used?  If so, that could decrease the listed SVR rates. 

• Does boceprevir now have an advantage over the other HCV drugs in development that have not been able to or rarely used EPO?

• Does boceprevir now have a disadvantage over the other HCV drugs in development because EPO was used in the clinical trials?  Will physicians decide not to prescribe boceprevir due to anemia if patients do not have access to the use of EPO?

We may find out some of the answers when phase III studies are completed, but most likely the real answers will come when and if boceprevir is approved by the FDA to treat HCV. 

Erythropoietin or EPO:
Erythropoietin or EPO is a hormone that is naturally produced by the kidneys, and to a lesser extent by the liver, that helps stimulate the bone marrow to produce red blood cells that will increase the oxygen-carrying capacity of the blood.  Synthetic EPO (brand name Epogen, Procrit) is an injectible medicine that has been approved by the Food and Drug Administration (FDA) to treat anemia caused by kidney failure, the HIV medication AZT, and cancer.   Most people have heard of EPO related to its illegal use as a performance-enhancing drug by some athletes.  In 2007, the FDA issued a Public Health Advisory and required a black box warning on the product information labeling about the potential health risks of using EPO.
Box

HCV Vaccines
The discovery of protective or therapeutic vaccines has proven difficult, but reports from EASL on various therapeutic vaccines are encouraging.  Therapeutic vaccines work to stimulate the immune system to fight an infection and may have a use in ‘boosting’ the effectiveness of current and future medications to treat hepatitis C. 

TG4040:  Results from a phase I study were released and it was found that 6 out of 15 patients given the therapeutic vaccine, TG4040, had a viral load reduction of 0.5 to 1.4 log10 IU/mL from baseline.  The next step in the development process is a new clinical trial of TG4040 in combination with pegylated interferon plus ribavirin.  The new trial is expected to begin in 2010.  

GI-5005:  Treatment with GI-5005, a therapeutic HCV vaccine (plus pegylated interferon/ribavirin) was compared to pegylated interferon/ribavirin (without GI-5005).  The combination that included GI-5005 was found to produce 8% to 12% higher rates of HCV viral load reductions at twelve weeks in HCV genotype 1 treatment-naïve patients compared to those in the group who did not receive GI-5005. 

ChronVac-C DNA vaccine:  Data on the first DNA vaccine was released at EASL.  In a proof of concept study, 12 HCV genotype 1 treatment-naïve patients were given various doses of the therapeutic vaccine.  In 4 out of 6 patients who received the two highest doses there were viral load reductions exceeding 0.5 log10 that lasted for 2 weeks to greater than 10 weeks.  The HCV viral load reductions correlated with specific immune response thereby satisfying the proof of concept.

In the trials of HCV vaccines listed above, the vaccines were safe and well-tolerated.

In addition to the above studies, there were many reports on drugs being developed to treat hepatitis C.  These drugs are in very early development and a summary of the results can be found on the HCV Advocate Drug Pipeline web page.
 

May

New HCV Drugs

  New England Journal of Medicine Publishes Promising Data from PROVE 1 and PROVE 2 Studies of HCV Protease Inhibitor Telaprevir

By Liz Highleyman

http://www.hivandhepatitis.com/hep_c/news/2009/051209_a.html

Several directly targeted oral antiviral agents are currently under study for the treatment of chronic hepatitis C virus (HCV) infection, with the HCV NS3/4A serine protease inhibitor telaprevir (formerly known as VX-950) expected to be the first out of the pipeline. Telaprevir is being developed by Vertex Pharmaceuticals in collaboration with Tibotec and Mitsubishi Tanabe Pharma.

Presented previously at medical conferences, final data from a pair of Phase 2b clinical trials of telaprevir -- PROVE 1 and PROVE 2 -- were published for the first time in the April 30, 2009 New England Journal of Medicine. The 2 reports and an editorial are available free online.

PROVE 1 was conducted in the U.S. and PROVE 2 in Europe; therefore they had somewhat different patient populations. Both studies assessed previously untreated participants with HCV genotype 1. PROVE 1 included 250 participants at some 40 U.S. sites; most (63%) were men, the mean age was 48 years, and 77% were white. PROVE 2 included 334 participants in Austria, France, Germany, and the U.K.; again, about 60% were men, but the mean age was slightly younger, at 44 years, and almost all (94%) were white. For reasons that are not well understood, white patients respond better to interferon-based therapy than black patients.

Study participants were randomly assigned to receive standard therapy using 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin for 48 weeks (effective in about 50% of genotype 1 patients), or else various regimens containing telaprevir (1250 mg on day 1 then 750 mg every 8 hours) or a matching placebo plus Pegasys with or without ribavirin:

Telaprevir + Pegasys + ribavirin for 12 weeks (T12PR12) -- PROVE 1 and PROVE 2;

Telaprevir + Pegasys with no ribavirin for 12 weeks (TP12) -- PROVE 2 only;

Telaprevir + Pegasys + ribavirin for 12 weeks, followed by Pegasys + ribavirin without telaprevir for an additional 12 weeks (T12/PR24) -- PROVE 1 and PROVE 2.

Telaprevir + Pegasys + ribavirin for 12 weeks, followed by Pegasys + ribavirin without telaprevir for an additional 36 weeks (T12/PR48) -- PROVE 1 only;

Pegasys + ribavirin without telaprevir for 48 weeks (standard-of-care control arm, PR48) -- PROVE 1 and PROVE 2.

The primary outcome in both studies was sustained virologic response (SVR), or undetectable HCV RNA 24 weeks after completion of treatment.

PROVE 1 Results:

SVR rates were significantly higher in the 24-week and 48-week triple therapy arms compared with standard therapy, but no better in the arm that received only 12 weeks of treatment:
 

67% in the T12PR48 group;
61% in the T12PR24 group;
41% in the PR48 group;
35% in the T12PR12 group.

Viral breakthrough occurred in 7% of patients receiving telaprevir.

African-American patients had a 4-fold higher SVR rate in the telaprevir arms compared with the standard therapy arm (44% vs 11%), but this subgroup was too small to have much statistical validity.
 

The rate of discontinuation due to of adverse events (AEs) was about twice as high in the 3 arms that received telaprevir (collectively 21%) compared with the standard therapy arm 11%).

Skin rash was the most common reason for discontinuation of telaprevir.

Based on these findings, the study authors concluded, "Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events."

PROVE 2 Results:

The SVR rate was significantly higher in the 48-week telaprevir triple therapy arm compared with standard therapy, and the 12-week triple regimen performed better than the short regimen without ribavirin:
 

69% in the T12PR48 group;
60% in the T12PR12 group;
46% in the PR48 group;
36% in the T12PR12 group.

The AEs that occurred more frequency in the telaprevir arms were pruritus (itching), rash, and anemia.

"In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy," the researchers concluded. "Response rates were lowest with the regimen that did not include ribavirin."

"Currently available therapies for patients infected with HCV can be difficult to tolerate and less than half the patients who start the yearlong treatment regimen achieve the ultimate goal of having an undetectable level of virus in their bodies," PROVE 1 lead investigator John McHutchison said in a press release issued by Vertex. "In these Phase 2 clinical trials, up to 69 percent of patients in the 24-week telaprevir-based treatment arm had undetectable virus levels after 24 weeks, and even though telaprevir does produce side effects of its own, its addition to standard therapy allowed us to shorten the duration of treatment."

Telaprevir has also been studied in treatment-experienced patients who did not achieve sustained response with a prior course of pegylated interferon plus ribavirin (both complete non-responders and relapsers).

As reported at the recent annual meeting of the European Association for the Study of the Liver (EASL 2009), treatment groups receiving a telaprevir-containing regimen had significantly higher SVR rates than the standard therapy arm, but the 24-week arm had a higher relapse rate than the 48-week arm, leading the investigators to suggest that the longer course may be more appropriate for treatment-experienced patients.

Telaprevir is now being tested in a larger population of treatment-naive patients in the Phase 3 ADVANCE trial, focusing on 24-week response-guided regimens consisting of either 8 or 12 weeks of telaprevir plus pegylated interferon and ribavirin for 24 or 48 weeks.

Editorial

In an accompanying editorial, Jay Hoofnagle of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) reviewed progress in the field of hepatitis C treatment over the past 25 years, from conventional interferon alfa monotherapy, to today's standard-of-care pegylated interferon plus ribavirin (which reduces the risk of relapse), to the forthcoming directly targeted oral anti-HCV agents.

"These phase 2 trials suggest that the addition of telaprevir to the combination of peginterferon and ribavirin will increase rates of sustained virologic response in patients with chronic hepatitis C due to infection with HCV genotype 1 from approximately 45% to as high as 65% and will permit therapy to be limited to 24 weeks, thus avoiding the expense and side effects of prolonged therapy," Hoofnagle wrote.

"An obvious question is why telaprevir was given for only 12 weeks and not continued with the peginterferon and ribavirin for a total of 24 or 48 weeks," he continued. "The reason was the side effects. In both studies, telaprevir was associated with an increased rate of anemia, nausea, diarrhea, pruritus, and rash. The rashes tended to be severe, to arise after 8 weeks of treatment, and to increase in frequency thereafter. The nature and cause of the rashes were not elucidated."

Hoofnagle noted that the SVR rates seen in PROVE 1 and PROVE 2 might not be as high as expected based on preliminary studies, in which a triple regimen of telaprevir/pegylated interferon/ribavirin "led to decreases of the HCV RNA to undetectable levels within a few weeks in almost all patients."

End-of-treatment response rates using telaprevir in these trials were similar to those achieved with the use of peginterferon plus ribavirin, but sustained response rates were greater in the triple therapy arms. Therefore, he suggested, "the enhanced response rates with telaprevir may be due to the prevention of viral breakthrough and relapse and may occur only in patients who have at least a partial response to peginterferon."

"Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment -- an era of antiviral agents developed specifically to target this virus," Hoofnagle concluded. "Other HCV-specific agents, including other protease inhibitors, helicase and polymerase inhibitors, and molecular agents that interfere with viral replication, are likely to follow. Combinations of these new agents with drugs currently in use may ultimately provide effective therapy for all patients with hepatitis C, the promised goal of decades of research."

5/15/09

References

JG McHutchison, GT Everson, SC Gordon, and others. Telaprevir with Peginterferon and Ribavirin for Chronic HCV Genotype 1 Infection. New England Journal of Medicine. 360(18): 1827-1838. April 30, 2009. (Free full text).

C Hézode, N Forestier, G Dusheiko, and others. Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection. New England Journal of Medicine. 360(18): 1839-1850. April 30, 2009. (Free full text).

J Hoofnagle. A Step Forward in Therapy for Hepatitis C [Editorial]. New England Journal of Medicine. 360(18): 1899-1901. April 30, 2009. (Free full text).

Other Source

Vertex Pharmaceuticals. New England Journal of Medicine Publishes Landmark Clinical Studies of the Investigational Hepatitis C Virus Protease Inhibitor Telaprevir. Press release. April 29, 2009.

Vertex's Telaprevir

Vertex had a fairly quiet EASL conference, mainly because telaprevir is in the middle of phase III studies that won't have data available until next year. Still, the company did present previously disclosed data showing that telaprevir is capable of significantly improving cure rates in the most difficult-to-treat patients who had failed prior treatment with the current standard drug regimen for hepatitis C -- a 48-week course of long-acting interferon plus ribavirin.

This data keeps telaprevir ahead of its hepatitis C rivals because no other drug has yet shown the ability to improve the cure rates for both patients new to therapy as well as those who have failed prior therapy.

Telaprevir was the "butt" of some negative EASL chatter due to an anecdotal report that the drug was causing severe anal itching in patient(s). One EASL attendee described the side effect as "fire in the hole."

All jokes aside, itchy rash is a well-known and documented side effect of telaprevir, but there have been no confirmed reports of anal pruritis (the medical term for anal itching) in any of the telaprevir studies presented to date. In fact, patient discontinuation rates due to telaprevir-induced rash appear to be on the decline, as doctors and patients learn how to better manage the side effect.

 This should lead to higher cure rates for telaprevir in the ongoing phase III studies compared to the already high rates seen in the phase II trials.

Additional Information

New England Journal Of Medicine Publishes Landmark Clinical Studies Of The Investigational Hepatitis C Virus Protease Inhibitor Telaprevir

 Telaprevir Effective for Genotype 2 But Not For Genotype 3 -

Telaprevir with Peginterferon and Ribavirin for Chronic HCV Genotype 1 Infection...PROVE1 in NEJM 4/2009

TELAPREVIR IN HEPATITIS C GENOTYPE-1-INFECTED PATIENTS WITH PRIOR NON-RESPONSE, VIRAL BREAKTHROUGH OR RELAPSE TO PEGINTERFERON-ALFA-2A/B AND RIBAVIRIN THERAPY: SVR RESULTS OF THE PROVE3 STUDY

A Step Forward in Therapy for Hepatitis C EDITORIAL -

NEJM April 30 2009
 
Jay H. Hoofnagle, M.D.
From the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
 
"An obvious question is why telaprevir was given for only 12 weeks and not continued with the peginterferon and ribavirin for a total of 24 or 48 weeks. The reason was the side effects. In both studies, telaprevir was associated with an increased rate of anemia, nausea, diarrhea, pruritus, and rash. The rashes tended to be severe, to arise after 8 weeks of treatment, and to increase in frequency thereafter. The nature and cause of the rashes were not elucidated....
 
...A second question is why the rate of sustained virologic response to the combination of telaprevir, peginterferon, and ribavirin was not higher. In preliminary studies, this combination led to decreases of the HCV RNA to undetectable levels within a few weeks in almost all patients.11,12,13 Nevertheless, at the end of the treatment period in these two trials, only 57% and 70% of patients had undetectable HCV RNA levels, end-of-treatment response rates that can be achieved with the use of peginterferon and ribavirin alone.5,6,7 Because the relapse rates were lower among patients receiving telaprevir than among those receiving standard therapy, the sustained virologic response rates were higher with telaprevir. Therefore, the enhanced response rates with telaprevir may be due to the prevention of viral breakthrough and relapse and may occur only in patients who have at least a partial response to peginterferon....
 
....Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment - an era of antiviral agents developed specifically to target this virus. Other HCV-specific agents, including other protease inhibitors,14 helicase and polymerase inhibitors, and molecular agents that interfere with viral replication,15 are likely to follow. Combinations of these new agents with drugs currently in use may ultimately provide effective therapy for all patients with hepatitis C, the promised goal of decades of research."
 
The therapy of hepatitis C began almost 25 years ago with a small trial of recombinant human interferon alfa.1 The rationale for using interferon was its broad antiviral effects and the suspicion that it might be active against the still-undiscovered agent of non-A, non-B hepatitis. Indeed, interferon had striking effects, lowering serum aminotransferase levels and, in a proportion of patients, inducing a lasting improvement in serum enzyme levels. Not until the discovery of the hepatitis C virus (HCV) were the effects of interferon understood; treatment resulted in a decrease in HCV RNA levels, which led to a sustained absence of virus in a proportion of patients.2 The difficulty was that interferon required parenteral injections, had multiple adverse effects, and resulted in a poor overall response rate. Nevertheless, interferon was approved for use for hepatitis C treatment in the United States in 1992.
 
The second important advance in hepatitis C therapy came with the use of ribavirin. Ribavirin is a nucleoside analogue known to have activity against several flaviviruses. When HCV was identified as a flavivirus, ribavirin was an obvious treatment choice. Ribavirin had little effect on serum HCV RNA levels but led to improvements in aminotransferase levels and histologic characteristics of the liver.3 More importantly, when combined with interferon, ribavirin increased the rate of sustained virologic response.4 Interferon and ribavirin given in combination for 48 weeks yielded rates of sustained virologic response of 40 to 50%, two to three times those obtained with interferon alone.3 Ribavirin was approved for use as an adjunct to interferon therapy of hepatitis C in 1998.
 
A third advance in therapy of hepatitis C came soon thereafter, with the introduction of pegylated forms of interferon that allowed for once-weekly (rather than thrice-weekly) injections. Peginterferon yielded higher rates of sustained virologic response than standard interferon: 45 to 55% after a 48-week course of peginterferon and ribavirin.5 The response rates varied according to HCV genotype. Among patients infected with genotypes 2 and 3 (approximately 25% of patients in the United States), rates of sustained virologic response were 70 to 80% and were achieved with a 24-week course and reduced doses of ribavirin.6 In contrast, rates of sustained virologic response among patients infected with genotype 1 (approximately 70% of patients in the United States) were less satisfactory, ranging from 40 to 50% and requiring 48 weeks of full doses of ribavirin. In some populations, response rates were even lower, with rates of approximately 25 to 30% among blacks.7 Higher doses and longer courses of therapy increased rates of sustained virologic response minimally and usually were associated with increased side effects.3 Peginterferon was approved in the United States in 2001.
 
Almost 10 years later, a fourth advance in hepatitis C therapy is still awaited but now may be close at hand. Two articles in this issue of the Journal describe results of phase 2 trials involving telaprevir (formerly known as VX-950).8,9 Telaprevir is a specific inhibitor of the HCV protease and is one of several molecules developed according to a rational drug design based on the molecular structure of HCV.10 Telaprevir is peptidomimetic, meaning that it resembles the HCV polypeptide that is cleaved by the viral protease, a necessary step in replication. However, telaprevir has an electrophilic "serine-trap warhead" that forms a covalent bond with the catalytic serine residue of the protease, blocking its activity. Telaprevir, an agent developed specifically to target HCV, represents a new era of therapy for hepatitis C.
 
Telaprevir has profound effects on HCV replication in cell culture and in animal models.10 In phase 1 studies of chronic hepatitis C, a 1-to-2-week course of telaprevir lowered HCV RNA levels by 2 to 5 log10 IU per milliliter.11 As expected, this short-term therapy was followed by a rebound in viral levels after the drug was stopped. Furthermore, telaprevir resistance appeared rapidly, and viral levels trended upward during the last days of treatment. The combination of telaprevir and peginterferon appeared to provide more profound viral suppression and less viral resistance.12,13 Some patients treated with peginterferon and ribavirin for a full 48 weeks after the short course of therapy with telaprevir, peginterferon, and ribavirin had a sustained virologic response.
 
These phase 1 studies led to the design of the two trials reported here, by McHutchison et al. in the United States (ClinicalTrials.gov number, NCT00336479 [ClinicalTrials.gov] )8 and HŽzode et al. in Europe (NCT00372385 [ClinicalTrials.gov] ).9 The trial designs were somewhat complex. Telaprevir was given for 12 weeks only, in combination with peginterferon alfa-2a with or without ribavirin, which were given for either for the same 12 weeks or for a total of 24 or 48 weeks. The control group received the standard therapy of peginterferon and ribavirin for 48 weeks. Standard therapy yielded rates of sustained virologic response of 41% and 46%, respectively. In comparison, telaprevir given for 12 weeks combined with peginterferon and ribavirin given for 24 weeks yielded response rates of 61% and 69%, both significant increases over the responses to standard therapy.
 
The other regimens tested had less satisfactory results. The stopping of all therapy at 12 weeks yielded lower rates of sustained virologic response than seen with continuation of therapy through 24 weeks, and the use of peginterferon and telaprevir without ribavirin was associated with high rates of relapse. Finally, in the study by McHutchison et al., the continuation of peginterferon and ribavirin for a total of 48 weeks, including the initial 12-week course of all three agents, was no more effective than the 24-week regimen (rate of sustained virologic response, 67% and 61%, respectively). These phase 2 trials suggest that the addition of telaprevir to the combination of peginterferon and ribavirin will increase rates of sustained virologic response in patients with chronic hepatitis C due to infection with HCV genotype 1 from approximately 45% to as high as 65% and will permit therapy to be limited to 24 weeks, thus avoiding the expense and side effects of prolonged therapy.
 
An obvious question is why telaprevir was given for only 12 weeks and not continued with the peginterferon and ribavirin for a total of 24 or 48 weeks. The reason was the side effects. In both studies, telaprevir was associated with an increased rate of anemia, nausea, diarrhea, pruritus, and rash. The rashes tended to be severe, to arise after 8 weeks of treatment, and to increase in frequency thereafter. The nature and cause of the rashes were not elucidated.
 
A second question is why the rate of sustained virologic response to the combination of telaprevir, peginterferon, and ribavirin was not higher. In preliminary studies, this combination led to decreases of the HCV RNA to undetectable levels within a few weeks in almost all patients.11,12,13 Nevertheless, at the end of the treatment period in these two trials, only 57% and 70% of patients had undetectable HCV RNA levels, end-of-treatment response rates that can be achieved with the use of peginterferon and ribavirin alone.5,6,7 Because the relapse rates were lower among patients receiving telaprevir than among those receiving standard therapy, the sustained virologic response rates were higher with telaprevir. Therefore, the enhanced response rates with telaprevir may be due to the prevention of viral breakthrough and relapse and may occur only in patients who have at least a partial response to peginterferon.
 
Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment - an era of antiviral agents developed specifically to target this virus. Other HCV-specific agents, including other protease inhibitors,14 helicase and polymerase inhibitors, and molecular agents that interfere with viral replication,15 are likely to follow. Combinations of these new agents with drugs currently in use may ultimately provide effective therapy for all patients with hepatitis C, the promised goal of decades of research.
 
No potential conflict of interest relevant to this article was reported.

www.natap.org

April-March

New Drugs In Devolvement

Vertex Pharmaceuticals Announces Acceptance of Telaprevir and VCH-222 Abstracts for Presentation at EASL Annual Meeting

Vertex Pharmaceuticals Strengthens HCV Drug Development Portfolio, Adds Novel Polymerase Inhibitors to Shape New Combinations with Telaprevir
 

Vertex Acquires VCH-222 and VCH-759, Two Experimental Oral HCV Polymerase Inhibitors

Vertex Outlines 2009 Business Priorities: Registration Programs in Hepatitis C and Cystic Fibrosis; Balanced Investment to Maintain Financial Strength

Vertex / ViroChem:
In early March 2009, Vertex announced that it will acquire Canadian biotech ViroChem for $100 million in cash and about 10.7 million shares of Vertex common stock.  ViroChem has two HCV non-nucleoside polymerase inhibitors, VCH-222 and VCH-759.  ViroChem’s HCV polymerase inhibitors are in early development and will now be developed by Vertex and combined with Vertex’s HCV development pipeline.  Vertex announced that it expects to begin a combination study of telaprevir with a ViroChem HCV polymerase inhibitor in the second half of 2009.  In addition to the combination study with telaprevir, Vertex announced that it is also planning additional studies of ViroChem’s HCV polymerase inhibitors in combination with pegylated interferon plus ribavirin.
Source:  Company Press Release.

http://www.hcvadvocate.org/news/newsLetter/2009/advocate0409.html#3

Feb-Jan

Telaprevir Phase 3 Studies Update - (01/12/09)

December 2008

New Study:  Telaprevir in Treatment Experienced Patients
—Alan Franciscus, Editor-in-Chief

On October 15, 2008 Tibotec announced that it will begin screening patients for a large phase III study to evaluate the combination of telaprevir, pegylated interferon plus ribavirin in treatment experienced patients who did not achieve a sustained virological response to a previous course of treatment with pegylated interferon plus ribavirin.  Tibotec is Vertex’s commercial partner that is conducting clinical trials outside of the United States, Canada and Mexico.

This worldwide study will enroll about 650 HCV patients.  According to the company press release the U.S. centers have begun screening patients, and other global study centers are expected to begin the screening process within the next couple of weeks.  The study will include null responders, partial responders and relapsers. 

The REALIZE Study

The study will include 3 arms:

1.   Telaprevir dosed at 750 mg q8h (every eight hours) for 12 weeks in combination with standard doses of pegylated interferon plus ribavirin, followed by 36 weeks of treatment with pegylated interferon plus ribavirin alone;

2.   Delayed start arm – 4 weeks of treatment with pegylated interferon plus ribavirin, followed by telaprevir dosed at 750 mg q8h for 12 weeks in combination with standard doses of pegylated interferon and ribavirin, followed by another 32 weeks of pegylated interferon and ribavirin alone;

3.   Control Arm – standard doses of pegylated interferon plus ribavirin dosed for 48 weeks.

The study has been named REALIZE (Re-treatment of Patients with Telaprevir-based Regimen to Optimize Outcomes).

Currently, Vertex is conducting another large phase III study of telaprevir in combination with pegylated interferon plus ribavirin for the treatment of genotype 1 treatment naïve patients called the ADVANCE trial.  The ADVANCE trial is expected to enroll about 1050 patients in the U.S., Europe and certain other countries.  It is expected that the results from the ADVANCE study will be used to apply to the Food and Drug Administration for marketing approval of telaprevir in the U.S.  

For more information about the ADVANCE and REALIZE studies visit www.clinicaltrials.gov. 

Source:  Company Press Release

 

Additional December News...........

December 2008

AASLD: New Drugs in Development

A Study of Telaprevir Combined with Peginterferon Alfa-2a and Ribavirin in Patients with Well-documented Non-response or Relapse After Previous Peginterferon Alfa-2a and Ribavirin Treatment: Interim Analysis

New Study:  Telaprevir in Treatment Experienced Patients

New HCV Drugs at AASLD: Vertex is Focus at Hepatitis C Meeting

A Phase 2b Study of Telaprevir with Peginterferon-Alfa-2a and Ribavirin in Hepatitis C Genotype 1 Null and Partial Responders and Relapsers Following a Prior Course of Peginterferon-Alfa-2a/b and Ribavirin Therapy: PROVE3 Interim Results

Telaprevir in Combination with Peginterferon-a-2a With or Without Ribavirin in the Treatment of Chronic Hepatitis C Treatment-Naive Genotype 1: Final Results of the PROVE2 Study (conducted in Europe) -

NOV

AASLD: New Clinical Data Support Broad Profile for Telaprevir in Patients with Genotype 1 Hepatitis C Virus (HCV) Infection -

Vertex Treatment May Also Help Non-Responders

Denise Treating With Protease Inhibitor Telaprevir Vertex-950

 On this Web Site : Terry was in the boceprevir trial 6 mth SVR!! 

Or read it on our Forum : TERRY boceprevir trial six month SVR

Phase 2 Study of Telaprevir Administered q8h or q12h with Peginterferon Alfa-2a or Alfa-2b and Ribavirin in Treatment-naive Patients with Genotype 1 Hepatitis C: Week 12 Interim Results - (11/26/08)
 
A Study of Telaprevir Combined with Peginterferon Alfa-2a and Ribavirin in Patients with Well-documented Non-response or Relapse After Previous Peginterferon Alfa-2a and Ribavirin Treatment: Interim Analysis - (11/20/08)
 
Telaprevir in Combination with Peginterferon-a-2a With or Without Ribavirin in the Treatment of Chronic Hepatitis C Treatment-Naive Genotype 1: Final Results of the PROVE2 Study (conducted in Europe) - (11/06/08)
 
A Phase 2b Study of Telaprevir with Peginterferon-Alfa-2a and Ribavirin in Hepatitis C Genotype 1 Null and Partial Responders and Relapsers Following a Prior Course of Peginterferon-Alfa-2a/b and Ribavirin Therapy: PROVE3 Interim Results - (11/06/08)