Interim Data Show Nitazoxanide (Alinia) Improves Anti-HCV Activity When Added to Pegylated Interferon plus Ribavirin

The addition of the experimental anti-HCV drug nitazoxanide (Alinia) may significantly increase sustained response rates when added to pegylated interferon plus ribavirin, according to data presented at the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007) in Boston (November 2-6, 2007).

Nitazoxanide, produced by Romark Laboratories, is already approved as a treatment for diarrhea caused by Giardia or Cryptosporidium. Its anti-HCV activity was discovered by chance when it was noted that patients receiving the drug to treat parasitic infections also experienced improvement in their hepatitis C.

Egyptian researchers studied 120 chronic hepatitis C patients with HCV genotype 4, which is the predominant type in Egypt but uncommon in the U.S. and Europe. Most clinical trials group genotypes 1 and 4 together as "hard to treat," but some studies have indicated that genotype 4 responds better than genotype 1 to interferon-based therapy. Most study participants were treatment-naive, but 24 were prior non-responders to interferon-based therapy.

Participants were randomly assigned to receive one of 3 regimens:

• Standard therapy with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 weight-based ribavirin for 48 weeks;

• Nitazoxanide monotherapy (500 mg twice daily) for 12 weeks, then nitazoxanide plus pegylated interferon for an additional 36 weeks;

• Nitazoxanide monotherapy for 12 weeks, then triple-therapy with nitazoxanide plus pegylated interferon plus ribavirin for 36 additional weeks.

Results

• Interim results 12 weeks after completion of treatment (known as SVR-12) showed that 79% of treatment-naive patients in the nitazoxanide triple-therapy group achieved undetectable HCV RNA compared with 43% in the standard therapy arm.

• Among treatment-naive patients, rapid virological response, early virological response, and end-of-treatment response rates were lowest in the standard therapy arm, intermediate in the nitazoxanide/pegylated interferon arm, and highest in the triple-therapy arm.

• Among treatment-experienced subjects, all rates were higher in the nitazoxanide/pegylated interferon arm than in the triple-therapy arm (no such patients were included in the standard therapy arm).

• Adverse events were similar across the 3 treatment groups, except for an expected significantly lower incidence of anemia in the group that did not receive ribavirin.

Evaluation for standard 24 week post-treatment SVR is ongoing. Romark has commenced a U.S. study of nitazoxanide for chronic hepatitis C. However, since the drug is already approved for another indication, physicians may choose to prescribe it "off label" for patients with HCV.

Below is an excerpt of a press release from Romark announcing the findings:

Phase II Study Shows that Nitazoxanide Significantly Improves Response to Standard of Care in Patients with Chronic Hepatitis C

TAMPA, Fla., Nov. 2 -- PRNewswire -- Romark Laboratories, a privately-owned biotechnology company, today announced results of a randomized Phase II clinical trial showing that 79% of interferon-naive patients with chronic hepatitis C genotype 4 receiving nitazoxanide plus the standard of care had a sustained virologic response (SVR), or undetectable level of virus, 12 weeks following treatment, compared to 43% of patients receiving the standard of care without nitazoxanide. The patients treated with nitazoxanide also experienced no relapse and no more side effects than patients who received the standard of care. Interim results from this Phase II clinical trial will be presented on Tuesday November 6 in an oral presentation at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston.

"Patients treated with nitazoxanide responded earlier and maintained their responses without relapse after receiving only 36 weeks of treatment with peginterferon and ribavirin," said Dr. Emmet B. Keeffe, Chief of Hepatology at Stanford University School of Medicine. "These data suggest the emergence of a new therapeutic approach for treating hepatitis C. While more study is needed to confirm these results in a broader population of patients, nitazoxanide appears to increase the potency of interferon without increasing toxicity or inducing resistance."

Study Details

This Phase II randomized, controlled trial was conducted at two centers in Egypt and is part of the company's STEALTH C (Studies to Evaluate Alinia for Treatment of Hepatitis C) clinical development program, which is designed to evaluate the safety and efficacy of nitazoxanide tablets in combination with peginterferon or peginterferon and ribavirin (standard of care) in patients with chronic hepatitis C.

In the trial, 96 treatment-naive patients with chronic hepatitis C genotype 4 were randomized into three groups to receive either 48 weeks of standard of care treatment (n=40), 12 weeks of nitazoxanide followed by 36 weeks of nitazoxanide plus peginterferon (a dual regimen, n=28), or 12 weeks of nitazoxanide followed by 36 weeks of nitazoxanide plus standard of care treatment (a triple regimen, n=28). An additional 24 interferon-experienced patients were randomized to receive 12 weeks of nitazoxanide followed by either the dual regimen (n=12) or the triple regimen (n=12) for 36 weeks. Patients received 180 microgram injections of pegylated interferon (Pegasys(R)) once per week; nitazoxanide was administered as one 500 mg tablet twice daily; and ribavirin was administered as 1,000 or 1,200 mg daily according to weight.

Results

At 12 weeks following the end of treatment, naive patients who received a triple regimen that included standard of care and nitazoxanide showed a significantly higher SVR (HCV RNA <10 IU/mL, Abbott m2000) than the group receiving the standard of care regimen (79% vs. 43%, respectively) (p=0.006). The data also suggest a potential for eliminating or reducing the role of ribavirin in treating hepatitis C. Patients treated with a dual regimen of nitazoxanide and peginterferon showed an SVR at week 12 following the end of treatment that was not inferior to standard of care (68% vs. 43%, respectively) (+25%; 95% CI: -1%, +47%). Of 24 treatment-experienced patients, the triple regimen (n=12) resulted in an SVR of 25% at week 12 post-treatment, and the dual regimen group (n=12) had an SVR of 8%.

"Results from this trial validate a new approach to treating HCV that focuses on the interaction between the virus and the cell," said Jean-Francois Rossignol, M.D., Director of the Romark Institute for Medical Research. "With confirmation provided by this data we are aggressively pursuing development of nitazoxanide and related drugs to treat chronic hepatitis C and other viral diseases."

Nitazoxanide is the first of a new class of small molecule drugs called thiazolides that inhibit replication of a broad range of viruses. The drug was discovered by Dr. Rossignol and was initially developed by Romark and approved for marketing in the United States as the first treatment of cryptosporidiosis. Serendipitously, the development of nitazoxanide for treating cryptosporidiosis led to the discovery of its antiviral properties and ultimately to the discovery of a promising new class of antiviral drugs.

Romark is currently conducting a U.S. Phase II trial with nitazoxanide plus standard of care in patients with hepatitis C genotype 1 who were previously treated with interferon. The Company also plans to initiate a Phase II trial in treatment naive patients early in 2008.

About Alinia

Alinia (nitazoxanide) is indicated in the United States for treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia in patients 1 year of age and older. Alinia has not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients. The most common adverse events reported by patients receiving Alinia have been abdominal pain, diarrhea, headache and nausea. In controlled trials, the frequency of these events has been similar to patients receiving a placebo. Alinia is an investigational new drug in the United States for treating chronic hepatitis C.

Romark Institute for Medical Research, Tampa, FL, USA; Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA; Department of Gastroenterology and Hepatology, University of Tanta, Faculty of Medicine, Tanta, Egypt; Department of Tropical Medicine and Infectious Diseases, University of Alexandria, Faculty of Medicine, Alexandria, Egypt.

11/13/07

Sources

J Rossignol, A Elfert, Y El-Gohary, and others. Interim Data from a Randomized Controlled Trial of Nitazoxanide-Peginterferon-Ribavirin, Nitazoxanide-Peginterferon and Peginterferon-Ribavirin in the Treatment of Patients with Chronic Hepatitis C Genotype 4. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston. November 2-6, 2007. Abstract 178.

Romark Laboratories. Phase II Study Shows that Nitazoxanide Significantly Improves Response to Standard of Care in Patients with Chronic Hepatitis C. Press release. November 2, 2007.