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

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.

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:

o   67% in the T12PR48 group;

o   61% in the T12PR24 group;

o   41% in the PR48 group;

o   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 24-week telaprevir triple therapy arm compared with standard therapy, and the 12-week triple regimen performed better than the short regimen without ribavirin:

o   69% in the T12PR24 group;

o   60% in the T12PR12 group;

o   46% in the PR48 group;

o   36% in the T12P12 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 theaddition of telaprevir to the combination of peginterferon andribavirin will increase rates of sustained virologic responsein patients with chronic hepatitis C due to infection with HCVgenotype 1 from approximately 45% to as high as 65% and willpermit therapy to be limited to 24 weeks, thus avoiding theexpense and side effects of prolonged therapy," Hoofnagle wrote.

"An obvious question is why telaprevir was given for only 12weeks and not continued with the peginterferon and ribavirinfor a total of 24 or 48 weeks," he continued. "The reason was the side effects.In both studies, telaprevir was associated with an increasedrate of anemia, nausea, diarrhea, pruritus, and rash. The rashestended to be severe, to arise after 8 weeks of treatment, andto increase in frequency thereafter. The nature and cause ofthe 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 "ledto decreases of the HCV RNA to undetectable levels within afew weeks in almost all patients."

End-of-treatmentresponse rates using telaprevir in these trials were similar to those achieved with the use of peginterferonplus ribavirin, but sustained response rates were greater in the triple therapy arms. Therefore, he suggested, "the enhanced response rateswith telaprevir may be due to the prevention of viral breakthroughand relapse and may occur only in patients who have at leasta 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."

5/12/09

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.