Randomized Trial of Valopicitabine (NM 283), Alone or with Peginterferon, vs Retreatment with Peginterferon Plus Ribavirin in Nonresponders to Peginterferon Alfa

Individuals with chronic hepatitis C virus (HCV) infection who have failed on the current standard of care (peginterferon alfa plus ribavirin) currently have no viable therapeutic options. There are increasing numbers of such patients worldwide.

An ongoing open label, randomized Phase IIb study is comparing five treatment options in 173 patients with chronic hepatitis C. All these patients had failed to reach undetectable levels of HIV RNA following >/= three months of therapy with peginterferon plus ribavirin. Individuals known to have responded and then relapsed, were excluded from the study.

Enrolled patients had baseline serum HCV RNA ≥ 105 IU/mL (by TaqMan PCR) and compensated liver disease.

The 5 treatment option arms are

• NM 283 monotherapy (monoRx, 800 mg/d),
• 3 investigational combination (comboRx) arms with different NM 283 dosing (400 mg/d; 800 mg/d; or dose-ramping 400 to 800 mg/d followed by 800 mg/d) + pegIFN, and
• pegIFN/RBV re-treatment.

PegIFNa-2a is dosed at 180 mg SQ/week with RBV 1000-1200 mg p.o. daily. Patients were randomized 2:2:2:2:1 to the 5 regimens (min 38 pts for each comboRx arm; 19 pts for NM 283 monotherapy).

Results at Week 12

“At 12 weeks, the combination of valopicitabine plus peginterferon alfa-2a (Pegasys) produced a statistically significant improvement in suppression of hepatitis C virus (HCV) replication and a significantly higher proportion of patients achieving an early virologic response (EVR) compared to patients re-treated with Pegasys and ribavirin,” said principal investigator Christopher O’Brien, MD.“

The authors conclude, “In HCV genotype-1 non-responders to pegIFN/RBV, NM 283 (valopicitabine) + pegIFN produces significantly greater suppression of HCV replication compared to re-treatment with pegIFN/RBV.”

“Antiviral efficacy for the NM283 + pegIFN arms was proportional to NM 283 dose.”

“These results support continued evaluation of NM283 + pegIFN in pegIFN/RBV nonresponders as well as treatment-naïve pts with CHC.”

Discussion

“At 12 weeks, the combination of valopicitabine plus Pegasys produced a statistically significant improvement in suppression of hepatitis C virus (HCV) replication and a significantly higher proportion of patients achieving an early virologic response (EVR) compared to patients retreated with Pegasys and ribavirin,” said Dr. O’Brien. “These are promising results, particularly for the many treatment-refractory patients in urgent need of new therapeutic options,” he said.

At 12 weeks of treatment, the two higher-dose arms of valopicitabine plus Pegasys showed significantly greater suppression of serum HCV RNA compared to the ribavirin plus Pegasys re-treatment arm (p = 0.01).

At week 12, mean HCV RNA reductions in the two high-dose arms of valopicitabine plus Pegasys were 2.5 log ₁₀ and 2.8 log ₁₀, with 63 percent and 71 percent of patients achieving an EVR.

In comparison, patients in the Pegasys plus ribavirin re-treatment control arm showed a mean HCV RNA reduction of 1.9 log₁₀, with 41 percent of patients achieving an EVR. EVR is defined as a greater than 2 log₁₀ reduction in viral load from baseline.

Discussion

These are promising results, particularly for the many HCV patients in urgent need of new therapeutic options.

These encouraging data support continued evaluation of combination treatment with valopicitabine and pegylated interferon in both treatment-refractory and treatment-naïve hepatitis C patients,” commented Nathaniel Brown, M.D., executive vice president of clinical development and chief medical officer of Idenix Pharmaceuticals, the Cambridge, MA company that is developing the drug.

A Phase III study of valopicitabine in treatment-refractory patients is expected to start in early 2006.”

In the current Phase IIb clinical trial, valopicitabine has demonstrated satisfactory safety and tolerance overall. A low percentage of patients on valopicitabine have discontinued due to adverse events. Two serious adverse events were considered attributable to combination treatment with valopicitabine plus pegylated interferon (anemia and dehydration).

To date, there has been no predominant treatment-limiting adverse event or laboratory abnormality observed for combination treatment with valopicitabine and pegylated interferon.

11/14/05

Reference
C O’Brien and others. Randomized Trial of Valopicitabine (NM283), Alone or with Peg-Interferon, vs Retreatment with Peg-Interferon plus Ribavirin (PegIFN/RBV) in Hepatitis C Patients with Previous Non-Response to PegIFN/RBV: First Interim Results. Abstract 63186. 56^th annual meeting of the American Association for the Study of Liver Diseases (56^th AASLD). November 11-15, 2005. San Francisco, CA.