Telaprevir Combo Works for HCV Patients with Prior Unsuccessful Treatment

SUMMARY: The REALIZE study showed that adding telaprevir to standard hepatitis C therapy increased sustained response rates for people with previous unsuccessful treatment attempts, researchers reported this week at EASL 2011.

Vertex's lead investigational hepatitis C virus (HCV) protease inhibitor, telaprevir, is currently undergoing review by the U.S. Food and Drug Administration (FDA), along with Merck's protease inhibitor boceprevir.

Direct-acting anti-HCV drugs will bring about a new paradigm in treatment for chronic hepatitis C, especially for hard-to-treat patients with HCV genotype 1 who did not achieve a sustained virological response (SVR), or cure, with a prior course of standard therapy consisting of pegylated interferon plus ribavirin.

At the European Association for the Study of the Liver's International Liver Congress (EASL 2011) this week in Berlin, researchers presented final results from a Phase 3 study of telaprevir plus pegylated interferon/ribavirin in treatment-experienced patients, including "null responders" who showed little or no decrease in HCV viral load, partial responders, and relapsers who experienced initial viral suppression but their HCV bounced back after the end of therapy.

Below is an edited excerpt from a press release issued by telaprevir developer Vertex describe the REALIZE study and its findings.

Results From Phase 3 REALIZE Study Showed Telaprevir-Based Therapy Significantly Improved SVR (Viral Cure) Rates in People Whose Prior Treatment For Hepatitis C Was Unsuccessful

	All major subgroups achieved significantly higher viral cure rates with telaprevir-based therapy compared to pegylated interferon and ribavirin: 86% vs. 24% in prior relapsers, 57% vs. 15% in prior partial responders and 31% vs. 5% in prior null responders.
	No clinical benefit was observed in delaying telaprevir therapy by four weeks (lead-in) compared to starting telaprevir, pegylated-interferon and ribavirin simultaneously.
	Safety and tolerability results were consistent with prior Phase 3 studies of telaprevir.

Berlin -- March 31, 2011 -- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced final results from its pivotal Phase 3 REALIZE study that evaluated 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. Data from the study showed that people in each of these subgroups who were treated with telaprevir-based combination therapy achieved superior rates of sustained viral response (SVR, or viral cure) compared to those treated with pegylated interferon and ribavirin alone.

REALIZE also evaluated whether viral cure rates could be further improved by delaying the start of telaprevir by four weeks, during which time patients received four weeks of pegylated-interferon and ribavirin alone (lead-in), compared to a simultaneous start. The data showed no clinical benefit to a lead-in for people treated with telaprevir-based combination therapy. Safety and tolerability results were consistent with results from the prior Phase 3 studies of telaprevir. These data were presented today at The International Liver Congress 2011, 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. REALIZE was conducted by Vertex's collaborator, Tibotec BVBA.

"Patients with chronic hepatitis C who undergo re-treatment with currently available medicines rarely achieve a viral cure and remain at an increased risk for advancing to more serious liver disease," said Stefan Zeuzem, MD, Professor of Medicine and Chief of the Department of Medicine at the JW Goethe University Hospital, Frankfurt, Germany and principal investigator for REALIZE. "These data are important because they showed that viral cure rates were three to six times higher for patients treated with a telaprevir-based regimen compared to re-treatment with currently available medicines."

Among those in the simultaneous start arm of REALIZE, 83 percent (121/145) of prior relapsers, 59 percent (29/49) of prior partial responders and 29 percent (21/72) of null responders achieved viral cures compared to 24 percent (16/68), 15 percent (4/27) and 5 percent (2/37), respectively, who received pegylated interferon and ribavirin. The viral cure rates among those in the lead-in arm were 88 percent (124/141) among prior relapsers, 54 percent (26/48) among prior partial responders and 33 percent (25/75) among prior null responders. In a combined endpoint analysis of the two telaprevir-based treatment arms, 86 percent (245/286) of prior relapsers, 57 percent (55/97) of prior partial responders and 31 percent (46/147) of prior null responders achieved viral cures.

"The REALIZE results are encouraging, especially considering people in this study had been unsuccessfully treated in the past and many already had scarring of the liver," said Robert Kauffman, MD, PhD, Senior Vice President and Chief Medical Officer for Vertex. "Rates of viral cure among those treated with telaprevir-based regimens were similar between the simultaneous and delayed start arms of the study, supporting the conclusion that there was no clinical benefit to a lead-in strategy with telaprevir."

In this study, 48 percent (316/662) of patients overall had advanced liver fibrosis or cirrhosis (scarring of the liver) and 89 percent (586/662) of patients overall had high amounts of hepatitis C virus (high viral load; HCV RNA ? 800,000 IU/mL) upon study entry.

Summary of REALIZE Results

REALIZE is the only Phase 3 hepatitis C study to date of a direct-acting antiviral medicine in development that was designed to evaluate people whose prior treatment was unsuccessful, including those who had a null response. [Editor's note: Merck's RESPOND-2 study tested boceprevir in prior non-responders and relapsers.]

In this study, patients were randomized 2:2:1 to two telaprevir-based treatment arms (simultaneous or lead-in) or a control arm of 48 weeks of pegylated interferon and ribavirin alone. Patients in the telaprevir treatment arms received a total of 12 weeks of telaprevir-based combination therapy. In the lead-in arm, patients received four weeks of pegylated interferon and ribavirin followed by telaprevir in combination with pegylated interferon and ribavirin for 12 weeks followed by 32 weeks of pegylated interferon and ribavirin alone. For those in the simultaneous start arm, the telaprevir-based combination was followed by an additional 36 weeks of pegylated-interferon and ribavirin alone. The primary endpoint of the REALIZE study was SVR in each of the two telaprevir treatment arms compared to the control arm and for the three groups of people included in the study. The total treatment time for all patients in REALIZE was 48 weeks.

REALIZE
SVR Results % (n)	Prior Relapsers (n=354)*	Prior Partial Responders (n=124)*	Prior Null Responders (n=184)*
TVR-based Simultaneous Start Arm+	83% (121/145)	59% (29/49)	29% (21/72)
TVR-based Lead-In Arm++	88% (124/141)	54% (26/48)	33% (25/75)
Control Arm+++	24% (16/68)	15% (4/27)	5% (2/37)
[TVR = telaprevir; q8h = every 8 hours] *The SVR rates observed were statistically significant when compared with the control arm (p <0.001). +Simultaneous start: 12 weeks of telaprevir (750 mg, q8h), Pegasys (PEG, pegylated-interferon alfa-2a) & Copegus (RBV, ribavirin), followed by 36 weeks of PEG & RBV alone. ++Lead-in: 4 weeks of PEG & RBV alone followed by 12 weeks of telaprevir (750 mg, q8h), PEG & RBV, followed by 32 weeks of PEG & RBV alone. There was no clinical benefit with the use of a four-week lead in with no significant improvement in SVR rates and no significant reduction in virologic failure and relapse rates in the lead-in start arm compared to the simultaneous start arm. +++Control: 12 weeks of placebo, PEG & RBV, followed by 36 weeks of Peg & RBV alone.
Prior Relapser: Defined as a person whose hepatitis C virus was undetectable at the completion of at least 42 weeks of a prior course of therapy but whose virus became detectable during the follow-up period. Prior Partial Responder: Defined as a person who achieved at least a 2 log10 reduction in HCV RNA at week 12, but whose hepatitis C virus never became undetectable by week 24 of a prior course of therapy. Prior Null Responder: Defined as a person who achieved a less than 2 log10 reduction in HCV RNA at week 12 of a prior course of therapy.

Safety and Tolerability Information for the Phase 3 Studies of Telaprevir

The safety and tolerability results of the telaprevir-based combination regimens were consistent across the Phase 3 studies. The most common adverse events were fatigue, pruritis [itching], nausea, headache, rash, anemia, flu-like symptoms, insomnia and diarrhea with the majority being mild to moderate. Rash and anemia occurred more frequently in the telaprevir-based treatment arms compared to the control group.

Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. More than 90 percent of rash was mild to moderate and primarily managed with the use of topical corticosteroids and/or antihistamines. Anemia was primarily managed by reducing the dose of ribavirin.

To optimize each patient's opportunity to achieve viral cure in the Phase 3 studies, sequential discontinuation of the medicines was recommended as a strategy to manage certain adverse events. This strategy allowed patients to continue on pegylated-interferon and ribavirin after stopping telaprevir. Discontinuation of all medicines due to either rash or anemia during the telaprevir/placebo treatment phase was 1 percent to 3 percent in the telaprevir treatment arms.

About the Study

REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled, global study. The majority of clinical trial sites were in Europe. The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based combination regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one course of prior treatment with interferon-based therapy.

Status of Telaprevir Regulatory Applications

The regulatory applications for the approval of telaprevir have been granted Priority Review by the U.S. Food and Drug Administration (FDA) and Health Canada and accelerated assessment by the European Medicines Agency for the treatment of people with genotype 1 chronic hepatitis C. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA). The applications include data from three registration studies, ADVANCE, ILLUMINATE and REALIZE, which evaluated telaprevir in combination with pegylated-interferon and ribavirin in people with hepatitis C who were new to treatment as well as those who did not achieve a viral cure after treatment with currently available medicines. For complete information on the telaprevir clinical trials or a fact sheet on the trial designs visit: www.vrtx.com/press.cfm.

About the Telaprevir Development Program

Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 chronic hepatitis C who had not been treated for their disease previously as well as people who had been treated before but did not achieve a viral cure.

Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.

About Vertex

Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.

Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.

Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.

For more information and to view Vertex's press releases, please visit www.vrtx.com.
4/1/11

Source
Vertex Pharmaceuticals. Results From Phase 3 REALIZE Study Showed Telaprevir-Based Therapy Significantly Improved SVR (Viral Cure) Rates in People Whose Prior Treatment For Hepatitis C Was Unsuccessful. Press release. March 31, 2011.