Idenix cuts dosing of valopicitabine in hepatitis C trial

Dose-related gastrointestinal side effects observed in trials of hepatitics C clinical trials.

25 March 2006
DELHI, INDIA

Idenix Pharmaceuticals, Inc., a Cambridge-based biopharmaceutical company, has modified its ongoing phase IIb clinical trials to reduce valopicitabine dosing levels from 800 mg/day to 200 mg/day or 400 mg/day.

The announcement follows result of dose-related gastrointestinal side effects observed in both treatment-naive and treatment-refractory patients receiving 800 mg dose regimens of valopicitabine. The modifications to these ongoing trials have been discussed and agreed with the US Food and Drug Administration (FDA).

The original protocol for the ongoing 48-week phase IIb clinical trial in treatment-naive patients included five randomized treatment arms, all involving dosing regimens of valopicitabine, administered once-daily, in combination with pegylated interferon alfa-2a (Pegasys) 180 ug per week:

(A) pegylated interferon beginning on Day 8 plus valopicitabine ramping

from 400 mg to 800 mg beginning at Day 29;

(B) valopicitabine 200 mg beginning on Day 1 plus pegylated interferon

beginning on Day 8;

(C) valopicitabine ramping from 400 mg to 800 mg beginning on Day 1 plus

pegylated interferon beginning on Day 8;

(D) valopicitabine 800 mg beginning on Day 1 plus pegylated interferon

beginning on Day 8; and

(E) valopicitabine 800 mg plus pegylated interferon, both beginning on Day 1.

The protocol amendment requires patients in arms A, C, D and E who have current serum HCV RNA levels below 600 IU/mL and are tolerating treatment, to be randomized to continue study treatment with either valopicitabine 200 mg/day plus pegylated interferon or valopicitabine 400 mg/day plus pegylated interferon. All patients who do not meet the amended criteria are being discontinued from the clinical trial. All patients in group B will continue in the trial according to the original treatment regimen.

In this ongoing clinical trial, the antiviral activity of valopicitabine combined with pegylated interferon through week eight indicates marked suppression of serum HCV RNA and a significant percentage of patients with viral clearance (PCR-negativity below 30 IU/ml as measured by the Roche TaqMan PCR assay) in all study arms. At week eight of study treatment, mean HCV RNA reductions and percentage of patients with viral clearance were 3.9 log10 and 48 percent in arm B, the low dose arm, compared to 4.5 log10 and 56 percent in arm D, the best-performing high dose arm in the trial.

To date, a higher proportion of gastrointestinal-related adverse events have been observed in the 800 mg dose valopicitabine arms (arms A, C, D and E) as compared to the 200 mg dose valopicitabine arm (arm B). Based on current preliminary information from all arms, in this trial approximately 16 percent of patients have discontinued due to gastrointestinal side effects, and a total of three serious adverse events considered attributable to valopicitabine have been reported (two percent of valopicitabine-treated patients).

The original protocol for the ongoing phase IIb clinical trial in treatment-refractory patients was designed to evaluate three dosing regimens of valopicitabine, administered once-daily, in combination with pegylated interferon alfa-2a (Pegasys) 180 ug with the initial dose of pegylated interferon administered on day 8, compared to retreatment with combination therapy of pegylated interferon plus ribavirin. The dosing regimens included:

(A) valopicitabine 800 mg monotherapy;

(B) valopicitabine 400 mg plus pegylated interferon;

(C) valopicitabine ramping from 400 mg to 800 mg during Week 1 and

continuing thereafter with 800 mg plus pegylated interferon;

(D) valopicitabine 800 mg plus pegylated interferon; and

retreatment with combination therapy of pegylated interferon plus

ribavirin.

The protocol amendment allows patients who have serum HCV RNA levels below 1,000 IU/mL and are tolerating treatment to continue on therapy. Patients who do not meet the amended criteria are being discontinued from the clinical trial. All patients in arm B will continue on the original treatment regimen. Patients in arms C and D, the higher dose regimens, meeting the revised criteria will be reduced to 400 mg/day of valopicitabine plus pegylated interferon. All patients in arm A have discontinued from the trial in accordance with pre-defined efficacy criteria set forth in the original study protocol.

As in the treatment-naive study, moderate to severe gastrointestinal side effects have been more common in the higher-dose arms (i.e., arms with valopicitabine dosed at 800 mg/day). Based on current preliminary information from all arms, in this trial approximately five percent of patients have discontinued treatment due to gastrointestinal side effects, and a total of six serious adverse events considered attributable to valopicitabine have been reported (four percent of valopicitabine-treated patients).

Valopicitabine is an investigational compound for the treatment of hepatitis C that is currently being evaluated in ongoing clinical trials. The most commonly occurring adverse events are gastrointestinal side effects. For most of the patients experiencing gastrointestinal side effects, the side effects (nausea, vomiting, and occasionally diarrhea) are generally mild to moderate, transient, and resolve while remaining on treatment.

However, the new data indicate that at the 800 mg/day dosing level, while most patients still report only mild side effects, a higher proportion report moderate or severe intensity to the gastrointestinal side effects compared to observations at the 200 to 400 mg/day dosing level, and may result in treatment discontinuation.

Hepatitis C is an infectious liver disease caused by the hepatitis C virus (HCV). HCV infection becomes chronic in 75 to 85 percent of individuals after their initial infection. It is the most common chronic blood-borne infection in the United States. Chronic HCV infection inflames the liver, causing progressive liver damage that can lead to cirrhosis (liver scarring), hepatocellular carcinoma (liver cancer), liver failure, and death. Hepatitis C related liver failure is the most common indication for liver transplantation in the United States.

The Centers for Disease Control and Prevention estimates that 4 million Americans have been infected with HCV, and 2.7 million of these carry chronic HCV infections. Worldwide, the World Health Organization estimates that 170 million individuals carry chronic HCV infection, with 3 to 4 million new infections each year. As the prevalence of severe liver disease attributable to hepatitis C rises, deaths due to complications from hepatitis C infection, currently 8,000 to 10,000 per year in the United States, are increasing and are expected to triple by 2010.

Idenix is developing its hepatitis B clinical product candidates, telbivudine and valtorcitabine, in collaboration with Novartis Pharma AG under a development and commercialization arrangement established in May 2003. The collaboration arrangement further provides that Novartis Pharma AG and Idenix will co-promote telbivudine and valtorcitabine and other product candidates that Novartis Pharma AG has licensed, if successfully developed and approved for marketing, in the United States, France, Germany, Italy, Spain and the UK. Novartis Pharma AG holds the exclusive license to commercialize telbivudine and valtorcitabine in the rest of the world. The collaboration also provides Novartis Pharma AG with an exclusive option to license and collaborate with Idenix in the development and commercialization of other product candidates in Idenix's portfolio, including valopicitabine (NM283).