SUMMARY: Vertex Pharmaceuticals' hepatitis C virus (HCV) NS34A protease inhibitor telaprevir added to pegylated interferon plus ribavirin improved sustained virological response rates for previously untreated patients with hard-to-treat HCV genotype 1, and enabled many to reduce treatment duration to 24 weeks, according to 2 Phase 3 studies presented this week at the American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston.

By Liz Highleyman

Current standard therapy for chronic hepatitis C consists of pegylated interferon plus ribavirin for 24 weeks (HCV genotypes 2 and 3) or 48 weeks (genotypes 1 or 4). Interferon-based therapy can cause difficult side effects, however, and only about half of people with hard-to-treat HCV genotype 1 achieve a cure.

The first novel oral drugs that directly target steps of the viral lifecycle -- such as HCV protease and polymerase inhibitors -- are in the final stages of development. Most studies to date have looked at these agents in combination with pegylated interferon plus ribavirin, but some have started testing all-oral combinations without interferon.

A pair of HCV protease inhibitors, Vertex's telaprevir and Merck's boceprevir, and, are furthest along in the development pipeline, and many experts expect that they will be approved next year.

ADVANCE

The Phase 3 ADVANCE trial assessed the safety and efficacy of 2 telaprevir-based response-guided therapy regimens compared with standard pegylated interferon/ribavirin for treatment-naive genotype 1 hepatitis C patients.

The study included 1088 participants. About 60% were men, 9% were black (a group that responds more poorly to interferon), 77% had high HCV RNA viral load (>800,000 IU/mL), and just over 20% had bridging fibrosis or cirrhosis.

All participants started therapy with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin. Patients were evenly allocated to 3 arms. People in one arm received only standard therapy, while those randomly assigned to the other 2 arms also took 750 mg 3-times-daily telaprevir for either 8 or 12 weeks.

Participants who achieved extended rapid virological response (RVR) -- defined as undetectable HCV RNA viral load at both 4 and 12 weeks -- were treated for a total of 24 weeks, while those without extended RVR were treated for a total of 48 weeks.

Results

	66% of patients in the 8-week telaprevir arm and 68% in the 12-week telaprevir arm achieved RVR at week 4, compared with 9% in the standard therapy arm.
	57%, 58%, and 8%, respectively, achieved extended RVR at weeks 4 and 12.
	In an intent-to-treat analysis, significantly more patients in the telaprevir arms achieved sustained virological response (SVR), or continued undetectable HCV RNA at 24 weeks after completion of treatment:
	8-week telaprevir combination: 69%; 12-week telaprevir combination: 75%; Standard therapy: 44%.
	Among patients who achieved extended RVR, most achieved SVR in all arms (83%, 89%, and 97%, respectively).
	Relapse rates after finishing therapy were 9% in both telaprevir arms and 28% in the standard therapy arm.
	Among black patients, 58% and 62% in the 8-week and 12-week telapravir arms achieved SVR, compared with 25% in the standard therapy arm.
	Among people with advanced fibrosis or cirrhosis, SVR rates were 53%, 62%, and 33%, respectively.
	The most common adverse events in the telaprevir arms (reported by > 25% of patients) were fatigue, pruritus (itching), nausea, headache, anemia, rash, flu-like symptoms, insomnia, fever, and diarrhea.
	8% of patients in the 8-week telaprevir arm, 7% in the 12-week telaprevir arm, and 4% in the standard therapy arm discontinued treatment due to adverse events:
	0.5%, 1.4%, and 0.0%, respectively, discontinued due to skin rash; 3.3%, 0.8%, and 0.6%, respectively, did so due to anemia.

"A significantly greater proportion of patients achieved SVR with 12-week and 8-week telaprevir-based combination regimens...compared with [standard therapy] control arm," the investigators concluded. "The safety and tolerability profile of telaprevir in the ADVANCE trial was consistent with the profile previously reported, with an improvement in treatment discontinuation rates due to adverse events, including rash and anemia."

In another analysis from the ADVANCE trial, researchers measured HCV RNA (using a test with a limit of quantification of 25 IU/mL) and performed population sequencing of the HCV NS34A protease in blood samples from patients who did not achieve SVR.

Similar proportions of patients in the 8-week and 12-week telaprevir arms experienced virological failure at both week 4 and week 12 while taking telaprevir (2.7% vs 3.3%). But the rate of virological failure after week 12, while taking only pegylated interferon/ribavirin, was somewhat higher in the 8-week telaprevir arm compared with the 12-week arm (10.2% vs 5.0%).

Treatment failure during the pegylated interferon/ribavirin continuation period was associated with wild-type HCV and lower-level telaprevir-resistant variants, the researchers noted, suggesting that 4 additional weeks of telaprevir may further reduce the chances of virological failure. Among 91 patients with available sequencing data who had telaprevir-resistant variants after failing to achieve SVR, 60% no longer had evidence of resistant variants at the end of the study.

"These results suggest that telaprevir continued to exert antiviral pressure on wild-type and lower-level [resistant] variants between weeks 8 and 12, thus reducing subsequent virologic failure during the pegylated interferon/ribavirin treatment phase in the [12-week telaprevir] T12 arm," they concluded.

ILLUMINATE

The Phase 3 ILLUMINATE trial was designed to confirm both the use of response-guided therapy and to evaluate whether there was any benefit to extending total treatment duration from 24 to 48 weeks.

This study included 540 treatment-naive genotype 1 chronic hepatitis C patients. About 60% were men, nearly 14% were black, and 11% had liver cirrhosis. All participants started triple combination therapy using 750 mg 3-times-daily telaprevir, 180 mcg/week pegylated interferon alfa-2a, and 1000-1200 mg/day weight-adjusted ribavirin. (This study did not include a standard therapy control arm.)

Participants who achieved extended RVR at weeks 4 and 12 were randomly assigned at week 20 to continue on pegylated interferon/ribavirin (without telaprevir from week 12 onward) for a total of either 48 or 24 weeks. Everyone who did not achieve extended RVR was treated for 48 weeks. Patients who did not experience at least a 2 log drop in viral load at week 12 or who had detectable HCV RNA at week 24 were considered to have virological failure and discontinued treatment.

Results

	In an intent-to-treat analysis, the overall SVR rate was 72% (including 60% of blacks and 63% of patients with advanced fibrosis or cirrhosis).
	72% of study participants achieved RVR at week 4 and 65% achieved extended RVR at weeks 4 and 12; 322 extended RVR patients were randomized to the 24-week or 48-week arms.
	92% of patients in the 24-week arm and 88% in the 48-week arm achieved SVR.
	The difference fell within the pre-set 10.5% margin, allowing the researchers to conclude that 24-week treatment was non-inferior to 48 weeks for these early responders.
	88% of blacks who experienced extended RVR went on to achieve SVR in both the 24-week and 48-week arms.
	82% and 88%, respectively, of people with advanced fibrosis/cirrhosis who achieved extended RVR went on to achieve SVR.
	7% of patients overall stopped treatment early due to virological failure.
	17% of participants overall discontinued study drugs due to adverse events, most often fatigue (22 people) or anemia (12 people).
	3 patients discontinued due to anemia and 3 people due to skin rash during the telaprevir treatment phase.

"Among patients who achieved extended RVR, a 24-week telaprevir-based regimen was non-inferior to 48-week telaprevir-based regimen," the ILLUMINATE team concluded.

"Among extended RVR randomized patients, there were more adverse events and adverse event-related treatment discontinuations in the 48-week versus 24-week arm," they continued. "These results support response-guided therapy for telaprevir-based regimens in treatment-naive patients."

"Many patients today are not motivated to begin hepatitis C therapy given the year-long treatment time and low cure rates with approved therapies," said Kenneth Sherman from the University of Cincinnati College of Medicine in a press release issued by Vertex. "Data from the ILLUMINATE study are extremely promising and showed that high viral cure rates and shorter treatment duration may be possible for the majority of people who have not been treated previously."

"In our Phase 3 program, starting people with 12 weeks of telaprevir-based combination therapy resulted in significant improvements in viral cure rates, regardless of race, extent of liver damage or experience with prior treatment," Vertex Senior Vice President and Chief Medical Officer Robert Kauffman said in the company press release. "The results of the ADVANCE and ILLUMINATE studies represent a major milestone in the development of telaprevir and offer hope for doctors and the millions of people living with hepatitis C who need new and more effective medicines."

Vertex announced last week that partner Tibotec is starting a new multinational Phase 3 clinical trial for treatment-naive patients, called OPTIMIZE, looking at a more convenient regimen of telaprevir administered twice rather than 3-times-daily.

Investigator affiliations:

Jacobson study (ADVANCE): Weill Cornell Medical College, New York, NY; Duke University Medical Center, Durham, NC; Royal Free and University College, London, UK; St Louis University School of Medicine, St Louis, MO; University of Pennsylvania School of Medicine, Philadelphia, PA; California Pacific Medical Center, San Francisco, CA; Hopital Beaujon, Paris, France; Vertex Pharmaceuticals, Cambridge, MA; Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany.

Kieffer study (ADVANCE): Vertex Pharmaceuticals, Cambridge, MA; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc, Titusville, NJ. Zeuzem study (EXTEND): Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany; Johns Hopkins University School of Medicine, Baltimore, MD; INSERM Unit 871, Lyon, France; University of Cincinnati College of Medicine, Cincinnati, OH; University of Padova, Padova, Italy; Harvard School of Public Health, Boston, MA; Tibotec BVBA, Mechelen, Belgium; Vertex Pharmaceuticals, Cambridge, MA; Tibotec Inc., Titusville, NJ; Duke University Medical Center, Durham, NC.

Sherman study (ILLUMINATE): University of Cincinnati College of Medicine, Cincinnati, OH; Northwestern University, Chicago, IL; Beth Israel Deaconess Medical Center, Boston, MA; University of Florida, Gainesville, FL; Johns Hopkins University School of Medicine, Baltimore, MD; University of Colorado Denver, Aurora, CO; University of North Carolina at Chapel Hill, Chapel Hill, NC; Vertex Pharmaceuticals Incorporated, Cambridge, MA; Cedars-Sinai Medical Center, Los Angeles, CA.

11/2/10

References

IM Jacobson, JG McHutchison, GM Dusheiko, and others. Telaprevir in Combination with Peginterferon and Ribavirin in Genotype 1 HCV Treatment-Naïve Patients: Final Results of Phase 3 ADVANCE Study. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 211.

TL Kieffer, DJ Bartels, J Sullivan, and others. Clinical Virology Results from Telaprevir Phase 3 Study ADVANCE. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-11.

KE Sherman. SL Flamm, NH Afdhal, and others. Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naive Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response: Final Results of Phase 3 ILLUMINATE Study. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-2.

Other Source
Vertex Pharmaceuticals. New Data From Phase 3 Studies Showed Superior SVR (Viral Cure) Rates Achieved with Telaprevir-Based Combination Therapy in People with Hepatitis C, Regardless of Race or Stage of Liver Disease. Press release. October 30, 2010.