Romark Announces Data from Clinical Trial of Nitazoxanide in Patients with Genotype 1 Chronic Hepatitis C Who Previously Failed Treatment with Peginterferon Plus Ribavirin

Study Results Presented as Late-Breaking Oral Communication at the International Liver Congress™ 2010

Press Release: April 19, 2010

Tampa, FL - Romark Laboratories announced final results from its STEALTH C-2 clinical trial, a phase 2 clinical study of nitazoxanide plus peginterferon and ribavirin in patients with genotype 1 chronic hepatitis C who had previously failed to respond to peginterferon and ribavirin. Study results were presented as a late breaking oral communication at the International Liver Congress&trade 2010, the 45th Annual Meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria.

The study was a randomized, double-blind, placebo controlled trial conducted at ten centers in the United States in patients with genotype 1 chronic hepatitis C who had previously failed to respond (never achieved undetectable HCV RNA) to peginterferon plus ribavirin. Sixty-four patients were randomized 2:1 to receive nitazoxanide 500 mg twice daily for four weeks followed by 48 weeks of nitazoxanide plus standard therapy (Pegasys® and Copegus®, F. Hoffman LaRoche) or placebo for 4 weeks followed by 48 weeks of placebo plus standard therapy. Patients were discontinued from the study if they did not achieve at least 1 log10 drop in serum HCV RNA after 4 weeks of combination therapy, at least 2 log10 drop after 12 weeks of combination therapy, or undetectable HCV RNA after 28 weeks of combination therapy. The primary endpoint was sustained virologic response 24 weeks after the end of treatment (SVR). Secondary endpoints included RVR, cEVR, EVR and ETR (see definitions below). SVR occurred in 7% (3/42) of patients treated with nitazoxanide 500 mg twice daily plus standard therapy versus 0% (0/22) of patients treated with placebo plus standard therapy. Safety analyses showed no serious adverse events attributable to nitazoxanide. The only adverse event attributed to nitazoxanide was mild to moderate intermittent diarrhea.

PR= Peginterferon alfa-2a (Pegasys®) and Ribavirin (Copegus®); RVR= serum HCV RNA <10 IU/mL after 4 weeks of combination therapy; cEVR= serum HCV RNA <10 IU/mL after 12 weeks of combination therapy; EVR= 2 log10 decrease in HCV RNA after 12 weeks of combination therapy; ETR= serum HCV RNA <10 IU/mL at end of treatment.
¹One patient with RVR showed a 1.83 log10 decrease in HCV RNA during 4 weeks of monotherapy.
²All 3 patients with SVR had a cEVR, 2 of whom had an RVR;
³One subject was a prior relapser and excluded from efficacy analysis.
Differences in response rates were not statistically significant due to sample size.

Approximately 60% of the patients enrolled in the study were null responders to prior treatment (<2 log10 drop in serum HCV RNA after 12 weeks of treatment with peginterferon plus ribavirin), 20% were partial responders (>2 log10 drop after 12 weeks of prior treatment with peginterferon plus ribavirin, but never reached undetectable HCV RNA). Historical quantitative HCV RNA was insufficient to classify the remaining 20% patients as either null or partial responders. Forty-one percent (41%) of the patients enrolled had advanced stage 3 or 4 hepatic fibrosis.

The patients achieving SVR were caucasian with high baseline viral loads (>800,000 IU/mL). Each of theses responders achieved undetectable HCV RNA during the first 12 weeks of combination therapy. Two of the three had a partial response to prior treatment. One of the responders had advanced hepatic fibrosis.

"We have studied nitazoxanide in a wide range of patients representative of the broad range of patients with chronic hepatitis C," said Jean-François Rossignol, M.D., Ph.D., Chairman and Chief Science Officer of Romark and inventor of nitazoxanide. "This was a particularly difficult-to-treat patient population. The data suggests that nitazoxanide will be most relevant in patients with partial response to prior therapy or in prior relapsers. In phase 3 clinical trials, we plan to use our 675 mg controlled release tablets, which allow for administration of a higher dose with an improved pharmacokinetic profile. We also plan to investigate combinations with direct acting antiviral drugs."

Nitazoxanide, the first of a new class of broad spectrum antiviral drugs called the thiazolides,^1,2,3 is an investigational new drug for treating chronic hepatitis C. It is a potent inhibitor of hepatitis C virus in replicon studies,² and laboratory studies indicate that it does not induce viral mutations that confer drug resistance.³ In replicon studies, nitazoxanide is synergistic with interferon and direct acting antivirals.^2,4 In clinical trials in patients with genotype 4 chronic hepatitis C, the addition of nitazoxanide to peginterferon with or without ribavirin improved SVR rates without increasing toxicity associated with peginterferon and ribavirin.^5,6 The AIDS Clinical Trials Group (ACTG) in the United States is studying nitazoxanide plus peginterferon and ribavirin for treating chronic hepatitis C in patients coinfected with HIV.

Data from the company's STEALTH C-3 clinical trial communicated on Thursday of last week at the International Liver Congress™ in Vienna showed that the addition of nitazoxanide to standard therapy improved SVR12 rates by more than one-third in treatment-naïve patients with genotype 1 chronic hepatitis C. In that study, 35% of the patients had advanced stage 3 or 4 hepatic fibrosis. Final results of the STEALTH C-3 study will be reported at a late breaking forum of the American Gastroenterological Association Institute during Digestive Disease Week in May of this year.

"Because of its novel mechanism and safety profile, we expect nitazoxanide to play an important role in a broad range of patients with chronic hepatitis C, said Emmet B. Keeffe, Chief Medical Officer of Romark Laboratories. "Patients with chronic hepatitis C are diverse in many respects with patient and virus characteristics that affect treatment outcomes (HCV genotype, viral load, stage of liver disease, IL28B genotype, race, body weight, coinfection with HIV or hepatitis B virus, and ability to tolerate treatment). The trend in therapy of chronic hepatitis C has been toward individualized therapy with combinations of antiviral drugs. There is a need for a new class of safe drugs with novel mechanism that can be used in combination with current standard therapy or with other new classes of drugs to improve treatment outcomes."

About Hepatitis C
Hepatitis C is a blood-borne infectious disease that is caused by the hepatitis C virus (HCV). It is the most common cause of chronic hepatitis in the U.S. and may eventually lead to cirrhosis, liver cancer and liver failure. The disease is transmitted by contact with HCV-infected blood. A large majority of those infected do not show symptoms, but fatigue, abdominal pain and nausea can be common. The current standard treatment of care, peginterferon and ribavirin, is effective in about half of all patients treated. Treatment outcomes vary based on a number of factors including genotype, viral load, genetic factors, stage of liver disease, co-infections and ability to adhere to treatment. According to the Centers for Disease Control, HCV affects an estimated 3.2 million Americans.

About Romark Laboratories
Romark Laboratories, L.C. is a biopharmaceutical company committed to the discovery and development of innovative new small molecules for treating infectious diseases and cancers.

¹ Rossignol JF, La Frazia S, Chiappa L, Ciucci A, Santoro MG. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J Biol Chem 2009; 284:29798-29808.
² Korba BE, Montero AB, Farrar K, et al. Nitazoxanide, tizoxanide, and other thiazolides are potent inhibitors of hepatitis B virus and hepatitis C virus replication. Antivir Res. 2008;77:56-63.
³ Korba BE, Elazar M, Lui P, et al. Studies of the potential for hepatitis C virus resistance to nitazoxanide or tizoxanide. Antimicrob Agents Chemother. 2008;52:4069-4071.
⁴ Korba BE, Elazar M, Liu P, et al. Potential role for nitazoxanide in combination with STAT-C agents for the inhibition of HCV replication without the development of resistance. Hepatology. 2008;48(suppl):356A.
⁵ Rossignol JF, Elfert A, El-Gohary Y, et al. Improved virologic response in patients with chronic hepatitis C genotype 4 treated with nitazoxanide plus peginterferon alfa-2a with or without ribavirin. Gastroenterology. 2009;136:856-862.
⁶ Rossignol JF, Elfert A, Keeffe EB. Treatment of chronic hepatitis C using a 4-week lead-in with nitazoxanide before peginterferon plus nitazoxanide. J Clin Gastroenterol. In press.