Telaprevir and VX-222 pair well in interferon-free regimen, VX-135 on the horizon

An all-oral regimen of telaprevir, VX-222 and ribavirin for 12 weeks was generally well-tolerated and produced sustained virological response in approximately 70% of previously untreated chronic hepatitis C patients, according to findings from the ZENITH study presented at The Liver Meeting 2012, the 63^rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) last month in Boston.

The recent approval of the first direct-acting antiviral drugs for hepatitis C has brought about 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 (Incivo/Incivek) – one of the HCV protease inhibitors approved last year – plus the experimental non-nucleoside HCV polymerase inhibitor VX-222, both developed by Vertex Pharmaceuticals.

Participants received these two 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 produced sustained virological response rates up to 90% at 12 weeks post-treatment (SVR₁₂). The dual regimen was less effective and led to a significant number of viral break-throughs, and this arm was therefore 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 1125mg twice-daily telaprevir plus 400mg twice-daily VX-222 plus ribavirin. People with undetectable HCV RNA at weeks 2 and 8 and no viral break-through were eligible to stop all treatment at that point; others continued on pegylated interferon plus ribavirin alone for 24 more weeks.

The analysis included 23 participants with HCV 1a and 23 patients 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 favourable IL28B 'CC' host genotype associated with good interferon response. Nearly 90% in both groups had high baseline viral load (HCV RNA > 800,000 IU/mL).

After four weeks of treatment, 91% of people in both the HCV 1a and 1b groups had viral load below the level of quantification (< 25 IU/mL), but the rate of undetectable viral load (< 15 IU/mL) was lower in the 1a group, at 57%. After 12 weeks, however, 83% of participants in both the 1a and 1b groups had undetectable HCV RNA.

Six participants (26%) in the HCV 1a group and five (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.

Amongst participants eligible to stop treatment at week 12, the SVR₁₂ rates were 67% for patients with HCV 1a and 100% for those with 1b. Amongst those who continued on pegylated interferon/ribavirin through week 36, SVR₁₂ rates were 93 and 85%, respectively.

Three people experienced viral break-though prior to week 12; all had IL28B non-'CC' host genotypes 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 one person discontinued treatment due to side-effects. The most common adverse events were diarrhoea (50%), rash (37%), nausea (30%), itching (30%) and fatigue (24%). Although 15% of patients developed mild anaemia (hemoglobin < 10 g/dL), none had severe anaemia (< 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".

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, whilst 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 VX-222 were safe and well-tolerated for people with mild or moderate liver 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 (also known as ASL-2200), a once-daily uridine nucleotide HCV polymerase inhibitor. Patrick Marcellin, from Hopital Beaujon in Paris, and colleagues reported that in a phase 1 study, VX-135 demonstrated potent antiviral activity over seven days in treatment-naive patients with HCV genotype 1. A dose of 200mg once-daily reduced viral load by a median 4.5 log.

VX-135 was well tolerated at the doses tested. The most common side-effects were mild-to-moderate headache and diarrhoea, 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 indicated that it plans to test VX-135 in phase 2 trials of 12-week all-oral regimens in combination with telaprevir and ribavirin. The company also announced that it has entered into separate 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).