Phase 1 OPTIMA Trial Finds Controlled-release Nitazoxanide Improves Response to Pegylated Interferon plus Ribavirin

Researchers are studying a variety of approaches to improve response to interferon-based therapy for hepatitis C virus (HCV) infection. One agent under study, nitazoxanide, is a thiazolide anti-infective with activity against a variety of protozoa, bacteria, and viruses; it is currently FDA-approved for the treatment of Cryptosporidium and Giardia (under the brand name Alinia).

In laboratory studies, nitazoxanide and its active metabolite, tizoxanide, potently inhibited HCV replication. In the STEALTH-C1 trial, genotype 4 chronic hepatitis C patients who received nitazoxanide prior to pegylated interferon, with or without ribavirin, responded more rapidly and had a higher sustained virological response (SVR) rate than those receiving standard therapy.

At the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) this past October, Romark Laboratories researchers presented promising data on nitazoxanide in combination with pegylated interferon/ribavirin in patients with other HCV genotypes, and combined with directly targeted "STAT-C" agents in vitro.

Last week Romark announced new data on a controlled release formulation of nitazoxanide that may enable less frequent administration. Below is an edited excerpt of a press release from the company describing the study and its findings.

Romark Announces Presentation of New Data for Controlled Release Nitazoxanide in Chronic Hepatitis C Studies presented at the 19th Conference of the Asian Pacific Association for the Study of the Liver (APASL) Demonstrated Favorable Pharmacokinetics and Significant Reduction in Viral Load Tampa, Fla. -- February 17, 2009 -- Romark Laboratories, a privately held biopharmaceutical company, today announced results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus (HCV) infection. In the phase II study in treatment-naive patients infected with HCV genotype 4, 82% (n=17) and 100% (n=16) of patients receiving low and high doses of controlled release nitazoxanide, respectively, experienced undetectable serum HCV RNA (<12 IU/mL) after 12 weeks of combination therapy with peginterferon and ribavirin. The data, part of Romark's OPTIMA HCN (OPTImizing MAnagement of Hepatitis C with Nitazoxanide) development program, were presented this weekend in an oral presentation at the 19th Conference of the Asian Pacific Association for the Study of the Liver (APASL) in Hong Kong. The presentation titled "Controlled Release Tablet Improves Pharmacokinetics, Viral Kinetics and Tolerability of Nitazoxanide for Treatment of Chronic Hepatitis C," abstract FP052, was given by Emmet B. Keeffe, MD of the Romark Institute for Medical Research, Tampa, FL. "We continue to be encouraged by the results of the ongoing nitazoxanide clinical development program," said Jean-Francois Rossignol, MD, Director of the Romark Institute for Medical Research and discoverer of nitazoxanide. "These data show that controlled release nitazoxanide exhibits favorable pharmacokinetics and tolerability, and -- in combination with the standard of care therapy -- robust antiviral activity in a small number of patients with HCV genotype 4. We look forward to reporting interim data from our U.S. studies evaluating the standard nitazoxanide tablet in patients with chronic hepatitis C genotype 1 later this year." In the Phase I study, OPTIMA HCN-1, a total of 12 healthy adult volunteers were enrolled to evaluate pharmacokinetics following oral administration of nitazoxanide at 675 mg or 1,350 mg twice daily with food for seven days. This was a randomized, double blind crossover study. The 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide produced trough plasma concentrations of tizoxanide, the active metabolite of nitazoxanide, that were approximately 3 x and 12 x the trough concentrations observed in historical studies using a standard nitazoxanide 500 mg tablet. Controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events (primarily GI-related) reported. In a subsequent Phase II study, OPTIMA HCN-2, a total of 41 treatment-naive patients with chronic hepatitis C genotype 4 were randomized to receive nitazoxanide at 675 mg (n=17), nitazoxanide at 1,350 mg (n=16) or placebo (n=8) twice daily for four weeks followed by the same regimen plus standard of care with peginterferon alfa-2a (Pegasys; 180 micrograms once per week) and ribavirin (Copegus; 1,000 or 1,200 mg daily according to body weight) for 36 weeks (48 weeks for the placebo arm). Interim virologic response rates are as follows: for the low and high-dose nitazoxanide arms, rapid virologic response (RVR, HCV RNA < 12 IU/mL after 4 weeks of combination therapy) 59% and 63% respectively, compared with 50% for the placebo group; complete early virologic response (cEVR, HCV RNA < 12 IU/mL after 12 weeks of combination therapy) 82% and 100%, respectively, compared with 63% for the placebo group; early virologic response (EVR, greater than or equal to 2 log10 decline in HCV RNA after 12 weeks of combination therapy) 88% and 100%, respectively, compared with 63% for placebo. In this study, a dose-related decline in serum HCV RNA was observed beginning on day 4 of combination therapy and was maintained through week 16. Controlled release nitazoxanide was also shown to be well-tolerated without serious adverse events or drug discontinuations secondary to adverse events in these patients with chronic hepatitis C. "These studies further demonstrate our commitment to optimizing treatment of chronic hepatitis C using nitazoxanide as an integral part of anti-hepatitis C therapy," added Dr. Rossignol. "We are excited about the development of controlled release nitazoxanide and plan to study once daily dosing in future trials." About Nitazoxanide and Hepatitis C Nitazoxanide, the first of a new class of broad spectrum antiviral drugs known as the thiazolides, is undergoing worldwide development as a treatment of chronic hepatitis C. Nitazoxanide is a potent inhibitor of hepatitis C virus (HCV) replication in HCV genotype 1-derived replicon cell lines, and in vitro studies have shown that it does not induce mutations in the virus that confer resistance. In phase II clinical trials, the addition of nitazoxanide to peginterferon alfa-2a with or without ribavirin significantly increased sustained virologic response rates in patients with chronic hepatitis C infected with HCV genotype 4. Phase II clinical trials of the standard nitazoxanide (Alinia) tablet are ongoing in the United States in patients with HCV genotype 1.

For more information, see www.romark.com.

2/27/09

Source
Romark Laboratories. Romark Announces Presentation of New Data for Controlled Release Nitazoxanide in Chronic Hepatitis C. Press release. February 17, 2009.