Romark Reports Phase-2 Data for Nitazoxanide in HCV
[Nitazoxanide (a.k.a. Alinia) is something of a wildcard in the HCV arena insofar as many commentators do not know what to make it. The drug is approved to treat diarrhea caused by parasites and it only emerged as a possible therapy for HCV at the AASLD meeting in 2007 (#msg-24218770). Chugai (a subsidiary of Roche), recently licensed the rights to commercialize nitazoxanide in Japan, although the financial terms were not disclosed.
The phase-2 trial described here is for a controlled-release form of nitazoxanide and is limited to genotype-4 HCV, which is a very much smaller market than geno-1 and geno-2/3. Romark has a separate phase-2 trial in progress using the standard-release form of the drug on genotype-1 patients (#msg-28598768).]
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., Feb. 17 /PRNewswire/ -- 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.[This compared to 63% in the control arm—see below.]
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, M.D. 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, M.D., 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 3x and 12x 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 percent 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.
About Romark Laboratories
Romark Laboratories (www.romark.com), a privately held biopharmaceutical company, has discovered and developed a new class of small molecule antivirals known as thiazolides. The Company is developing nitazoxanide, the first of the thiazolide class, for the treatment of chronic hepatitis C, and is developing other new thiazolides for treating viral diseases including chronic hepatitis B, herpes and influenza. Alinia® (nitazoxanide) is approved by the U.S. Food and Drug Administration and marketed by Romark for the treatment of infections caused by Cryptosporidium or Giardia.‹
[Nitazoxanide made a big splash at AASLD back in 2007 (#msg-24218770), but little has been heard about it since. I don’t see what all the fuss was about.
This PR is about the phase-2 trial in genotype-1 patients using a BID formulation; Romark reported data from a separate phase-2 in genotype-4 patients using a qD formulation in 2009 (#msg-35738696).]
›Romark Announces Final Data From Clinical Trial of Nitazoxanide in Treatment-Naive Patients With Genotype 1 Chronic Hepatitis C
Study Presented at Late-Breaking Forum of the American Gastroenterological Association Institute during Digestive Disease Week 2010 Shows Higher SVR Rate for Patients Receiving Nitazoxanide plus Standard Therapy
Tuesday May 4, 2010, 3:45 pm EDT
TAMPA, Fla., May 4 /PRNewswire/ -- Romark Laboratories announced results from its STEALTH C-3 clinical trial, a phase 2 clinical study of nitazoxanide in treatment-naive patients with genotype 1 chronic hepatitis C. Study results were presented this afternoon as an oral communication at a late breaking forum of the American Gastroenterological Association Institute (AGA Institute) during Digestive Disease Week 2010 in New Orleans, Louisiana.
The study was a randomized, double-blind, placebo controlled trial conducted at thirteen centers in the United States in patients with genotype 1 chronic hepatitis C, 35% of whom had advanced stage 3 or 4 fibrosis. One-hundred and twelve patients were randomized to receive either nitazoxanide (500 mg twice daily) plus peginterferon alfa-2a (Pegasys®, F. Hoffman LaRoche) and ribavirin (Copegus®, F. Hoffman LaRoche) (n=75) or placebo plus Pegasys® and Copegus® (n=37). The primary endpoint of the study was sustained virologic response (SVR, undetectable HCV RNA 24 weeks after the end of treatment).
SVR occurred in 44% of patients treated with nitazoxanide plus standard therapy for 48 weeks versus 32% of patients treated with placebo plus standard therapy.[A 44% SVR rate after 48 weeks is nothing to write home about.] SVR rates were consistently higher in subsets of patients with high baseline viral load (41% vs. 29%) and in African Americans (38% vs. 20%). Safety analyses showed the rate of serious adverse events were similar for the nitazoxanide and placebo treatment groups. The only adverse events significantly associated with nitazoxanide were mild to moderate intermittent diarrhea and discolored urine.
Results of the STEALTH C-3 study are consistent with previously reported data from studies of nitazoxanide plus Pegasys® and Copegus® in treatment-naive patients with genotype 4 chronic hepatitis C.(1,2) The STEALTH C-3 study is the first trial of nitazoxanide in treatment-naive patients with genotype 1 chronic hepatitis C.
"We are pleased to achieve these results in a population representative of the broad range of hepatitis C patients in the United States, including 35% with advanced fibrosis," said Jean-Francois Rossignol, M.D., Ph.D., Chairman and Chief Science Officer of Romark and inventor of the drug. "We plan to initiate phase 3 clinical trials of nitazoxanide using our 675 mg controlled release tablets in combination with peginterferon with or without ribavirin later this year. The 675 mg controlled release tablets deliver a higher dose of nitazoxanide with a better pharmacokinetic profile. Additional clinical trials using the 675 mg controlled release tablets in genotype 1 and 4 patients are underway and include reduction of the duration of peginterferon to 24 weeks with and without ribavirin. We also plan to investigate combinations with direct acting antiviral drugs. Ultimately, we expect nitazoxanide to play an important role in a broad range of patients with chronic hepatitis C."[I doubt it.]
Nitazoxanide, the first of a new class of broad spectrum antiviral drugs called the thiazolides, is an investigational new drug for chronic hepatitis C. It is a potent inhibitor of hepatitis C virus (HCV) in replicon studies, and laboratory studies indicate that it does not induce viral mutations that confer drug resistance. Nitazoxanide is synergistic with interferon and direct acting antivirals in replicon studies. (4,6) In patients with chronic hepatitis C, the addition of nitazoxanide has not resulted in an increase in the toxicity associated with peginterferon and ribavirin. Studies in patients with genotype 4 chronic hepatitis C suggest that nitazoxanide may be used to replace ribavirin. 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.
"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)," said Emmet B. Keeffe, Chief Medical Officer of Romark Laboratories. "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. We believe nitazoxanide can play an important role in these combinations."
…About Romark Laboratories
Romark Laboratories, L.C. (www.romark.com) is a biopharmaceutical company committed to the discovery and development of innovative new small molecules for treating infectious diseases and cancers.‹
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