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AASLD 2012: Telaprevir and VX-222 Pair Well in Interferon-free Regimens, VX-135 on the Horizon

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An all-oral regimen of telaprevir, VX-222, and ribavirin for 12 weeks was generally well-tolerated and produced sustained response in approximately 70% of previously untreated chronic hepatitis C patients, including those with hard-to-treat HCV subtype 1a, according to study findings presented at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this month in Boston.

The recent approval of the first direct-acting antiviral drugs for hepatitis C has ushered in a new era of treatment, but many patients and providers are awaiting all-oral regimens without interferon and its difficult side effects.

The ZENITH trial evaluated the safety, tolerability, and antiviral activity of telaprevir (Incivek) -- one of the HCV protease inhibitors approved last year -- plus the experimental non-nucleoside polymerase inhibitor VX-222, both developed by Vertex Pharmaceuticals. Participants received these 2 drugs either alone in a dual regimen, in combination with ribavirin in a triple regimen, or with both ribavirin and pegylated interferon alfa-2a (Pegasys) in a quadruple regimen.

Ira Jacobson from Weill Cornell Medical College presented data from an interim analysis of people receiving the all-oral triple regimen. Investigators previously reported that the quadruple regimen worked well, producing sustained virological response rates up to 90% at 12 weeks post-treatment (SVR12). The dual regimen was less effective, with a significant number of viral breakthroughs, however, and this arm was discontinued early.

In this analysis of the triple regimen, participants were stratified according to HCV subtype 1a or 1b, the latter being easier to treat. They received 1125 mg twice-daily telaprevir plus 400 mg twice-daily VX-222 plus ribavirin. Those with undetectable HCV RNA at weeks 2 and 8 and no viral breakthrough were eligible to stop all treatment at that point; others continued on pegylated interferon/ribavirin alone for 24 more weeks.

The analysis included 23 participants with HCV 1a and 23 people with HCV 1b. All were treatment-naive and did not have liver cirrhosis. About 75% of the combined study population consisted of men, about 80% were white, and the median age was approximately 50 years. One-third had the favorable IL28B CC gene pattern associated with good interferon response. Nearly 90% in both groups had high baseline viral load (HCV RNA > 800,000 IU/mL).

Results

  • At 4 weeks, 91% of people in both the 1a and 1b groups had HCV RNA below the level of quantification (< 25 IU/mL), but the rate of undetectable HCV RNA (< 15 IU/mL) was lower in the 1a group, at 57%.
  • At 12 weeks, 83% of participants in both the 1a and 1b groups had undetectable HCV RNA.
  • 6 patients (26%) in the HCV 1a group and 5 people (22%) in the 1b group were eligible to stop treatment at week 12.
  • Overall SVR12 rates were 73% for 1a patients and 70% for 1b patients.
  • Among participants eligible to stop treatment at week 12, SVR12 rates were 67% for 1a and 100% for 1b.
  • Among those who continued on pegylated interferon/ribavirin through week 36, SVR 12 rates were 93% and 85%, respectively.
  • 3 patients experienced viral breakthough prior to week 12; all had IL28B non-CC gene patterns and were found to have resistant virus.
  • The triple regimen was generally safe and well-tolerated.
  • No participants experienced serious adverse events during the first 12 weeks on triple therapy, and only 1 person discontinued due to side effects (elevated creatine kinase).
  • The most common adverse events were diarrhea (50%), rash (37%), nausea and itching (both 30%), and fatigue (24%).
  • 15% of patients developed mild anemia (hemoglobin < 10 g/dL), but none had severe anemia (< 8.5 g/dL).

These results, the researchers concluded, "support further study of the combination of VX-222 plus telaprevir as part of an all oral, interferon-free treatment for patients infected with HCV genotype 1." They noted that the incidence and severity of adverse events was lower for the triple regimen than for the quadruple regimen that included pegylated interferon.

Jacobson pointed out that people with genotype 1a took longer to clear HCV RNA than those with genotype 1b. Although overall sustained response rates were similar, the 1b group did better on the 12-week all-oral regimen, while those with 1a did better with interferon/ribavirin added. Studies are underway to test a longer course of all-oral triple therapy, he said.

In a related study, Maria Rosario and colleagues from Vertex assessed whether impaired liver function affects the pharmacokinetics and tolerability of VX-222. They found that administration of multiple oral doses of 400 mg VX-222 was safe and well tolerated for people with mild or moderate hepatic impairment. VX-222 exposures were higher than those seen in healthy volunteers, "but this increase would not be expected to impact virologic response," they concluded.

VX-135

Vertex is also developing VX-135, aonce-daily uridine nucleotide HCV polymerase inhibitor licensed from Alios BioPharma (also known as ASL-2200).

Patrick Marcellin from Hopital Beaujon in Paris and colleagues reported that in a Phase 1 study, VX-135 demonstrated potent antiviral activity over 7 days in treatment-naive patients with HCV genotype 1. A dose of 200 mg once-daily reduced viral load by a median of 4.5 log.

Safety data indicated that VX-135 was well tolerated at the doses tested. The most common side effects were mild-to-moderate headache and diarrhea, and there were no serious adverse events, clinically significant laboratory abnormalities, or discontinuations for these reasons. The researchers concluded that VX-135 "has the potential to be an important, once-daily component of all-oral, interferon-free combination regimens."

Vertex plans to test VX-135 in Phase 2 trials of 12-week all-oral regimens in combination with telaprevir and ribavirin. The company also recently announced that it has entered into agreements with GlaxoSmithKline and Janssen to test VX-135 in combination with GSK's NS5A inhibitor GSK2336805 and Janssen's HCV protease inhibitor simeprevir (formerly TMC435).

11/28/12

References

IM Jacobson, MS Sulkowski, EJ Gane, et al. VX-222, Telaprevir and Ribavirin in Treatment-Naive Patients with Genotype 1 Chronic Hepatitis C: Results of the ZENITH Study Interferon-Free Regimen. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 231.

M Rosario, C Li, K Alves, et al. Effect of Hepatic Impairment on the Pharmacokinetics of VX-222: Results from a Multicenter Phase 1 Study. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 1880.

P Marcellin, S Popa, A Berliba, et al. ALS-2200, a novel once-daily nucleotide HCV polymerase inhibitor, demonstrates potent antiviral activity over 7 days in treatment-naïve genotype 1 (GT1) patients. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 86.

H Tan, J Deval, H Kang, et al. ALS-2200, a Novel Once-Daily Nucleotide HCV Polymerase Inhibitor, Demonstrates Potent Antiviral Activity over 7 Days in Treatment-Naive Genotype 1 (GT1) Patients. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 1882.

Other Sources

Vertex Pharmaceuticals. Data from Viral Kinetic Study Showed Rapid Reduction of HCV RNA with ALS-2200 (VX-135), Vertex's Oral Nucleotide Analogue in Development for the Treatment of Hepatitis C. Press release. November 10, 2012.

Vertex Pharmaceuticals. Vertex Announces Agreements to Develop Interferon-free VX-135 Regimens for Hepatitis C. Press release. November 1, 2012.