Romark Announces Presentation of New Data for Nitazoxanide inChronic Hepatitis C at EASL 2008

Findings Include 80% SVR12 Rate with Nitazoxanide-Based Combination Therapy and New Insights into Mechanism of Action of Nitazoxanide

MILAN, Italy, April 23, 2008 /PRNewswire/ -- Romark Laboratories, a privately held biopharmaceutical company, today announced that data from studies of nitazoxanide in chronic hepatitis C virus (HCV) infection are being communicated in four presentations made at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), held in Milan, Italy this week.

"These new studies confirm earlier data suggesting synergistic activity between nitazoxanide and peginterferon in genotype 4 patients and provide a first look at sustained virologic response in a limited number of genotype 1 patients," said Jean-Francois Rossignol, M.D., Director of the Romark Institute for Medical Research and discoverer of nitazoxanide. "These data also provide interesting insights into the mechanism of action of nitazoxanide and confirm previous findings related to its safety."

    The four presentations include:


    -- An oral presentation, titled, "Randomized Controlled Trial of

       Nitazoxanide-Peginterferon-Ribavirin, Nitazoxanide-Peginterferon and

       Peginterferon-Ribavirin in the Treatment of Patients with Chronic

       Hepatitis C Genotype 4," reported final 24-week post-treatment

       sustained virologic response (SVR) rates for the company's STEALTH C-1

       trial.


       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 (SOC) 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 SOC with peginterferon plus ribavirin (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

       peginterferon alfa-2a (Pegasys(R), Hoffman LaRoche) 180 micrograms once

       per week; nitazoxanide was administered as one 500 mg tablet twice

       daily; and ribavirin (Copegus(R), Hoffman LaRoche) was administered as

       1,000 or 1,200 mg daily according to body weight. Analysis of data was

       by intention to treat.


       In treatment-naive patients, combination therapy with nitazoxanide plus

       SOC resulted in a SVR24 rate of 79%, compared with 50% for those

       treated with SOC without nitazoxanide (P=0.023). When nitazoxanide was

       combined with peginterferon alone, the observed SVR24 rate in this

       group was 61%.  In 24 treatment-experienced patients, the addition of

       nitazoxanide to SOC for 36 weeks resulted in a 25% rate of SVR,

       compared with 8% when nitazoxanide was combined with peginterferon

       alone.  The patients treated with nitazoxanide experienced no more side

       effects than patients who received the SOC.


       Interim results of this trial were presented at the 58th Annual Meeting

       of the American Association for the Study of Liver Diseases (AASLD) in

       Boston, MA.(1)



    -- A poster presentation, titled "Evaluation of a 4-week Lead-in Phase

       With Nitazoxanide Prior to Nitazoxanide+Peginterferon in Treating

       Chronic Hepatitis C," demonstrated that reducing a nitazoxanide lead-in

       phase from 12 to 4 weeks, followed by the addition of SOC therapy, does

       not compromise virologic response rates in a patient population with

       different genotypes, predominately genotype 4.


       Replicon studies and an early clinical experience (unpublished)

       indicated that treatment with nitazoxanide alone prior to adding

       interferon potentiates the activity of combination therapy with

       nitazoxanide plus peginterferon.  The STEALTH C-1(2) trial used 12

       weeks of lead-in therapy with nitazoxanide alone.  This clinical study

       was designed to evaluate the effect of reducing the lead-in phase from

       12 weeks to 4 weeks.


       In this Phase II study, 44 patients (40 with HCV genotype 4; 3 with HCV

       genotype 1; and 1 with HCV genotype 2) received 4 weeks of nitazoxanide

       500 mg twice daily followed by Pegasys(R) (peginterferon alfa-2a) and

       nitazoxanide for 36 weeks.  Romark's STEALTH C-1 trial (see description

       above) was used as an historical control, where randomized patients

       were treated for 12 weeks with nitazoxanide before adding SOC treatment.

       Analysis of data was by intention to treat.


       Thirty-five of 44 patients (80%) treated with a 4-week lead-in phase of

       nitazoxanide followed by the addition of peginterferon for 36 weeks

       experienced a SVR 12 weeks after the end of treatment (SVR12) compared

       to 50% in the SOC historical control group (P = 0.004), 61% in patients

       receiving a 12-week lead-in with nitazoxanide followed by 36 weeks of

       nitazoxanide plus peginterferon, and 79% in patients receiving a 12-

       week lead-in with nitazoxanide followed by 36 weeks of nitazoxanide

       plus SOC.


       Of the 44 patients in the study, 78% (n=40) of patients with HCV

       genotype 4, 100% (n=3) of patients with HCV genotype 1, and 100% (n=1)

       of HCV genotype 2, had undetectable virus at 12 weeks following end of

       treatment.


       Adverse events reported for these 44 patients were similar to those

       reported in the STEALTH C-1 trial.  Patients treated with nitazoxanide

       experienced no more side effects than patients who received the SOC

       therapy.  Only one of the 44 patients discontinued therapy due to

       noncompliance.  There were no serious adverse events or

       discontinuations due to adverse events.


"These data show that the nitazoxanide lead-in phase prior to standard of care treatment can be reduced from 12 to 4 weeks with no apparent impact on virologic response rates," said Jean-Francois Rossignol, M.D., Director of the Romark Institute for Medical Research and lead author of the study.

    -- Data from a poster presentation, "Randomized, Double-Blind Placebo-

       Controlled Trial of Nitazoxanide in the Treatment of Patients with

       Chronic Hepatitis C Genotype 4" showed that nitazoxanide monotherapy

       for 24 weeks did not produce adverse events significantly different

       from that of a placebo and suggest that monotherapy with nitazoxanide

       may be effective in achieving SVR in a limited subset of patients with

       low viral load.


       In this randomized, controlled study, 50 treatment-naïve patients with

       chronic hepatitis C genotype 4 were randomized to receive one

       nitazoxanide 500 mg tablet or a matching placebo tablet twice daily for

       24 weeks.  Baseline viral loads and other disease characteristics were

       similar between groups. Seven of 23 patients (34%) receiving

       nitazoxanide monotherapy achieved undetectable serum HCV RNA after 24

       weeks of therapy, compared with 0 of 24 patients receiving placebo

       (P=0.004).  Four of these 7 treatment responders (4/23, or 17%) had a

       SVR 24 weeks after completion of therapy.  Patients not achieving

       undetectable HCV RNA did not show significant reductions in viral load

       or alanine aminotransferase (ALT) levels.  Patients responding to

       nitazoxanide treatment had lower viral loads at baseline.  Adverse

       events were typically mild to moderate and occurred with similar

       frequency and severity between the nitazoxanide and placebo groups.


"The study demonstrated the safety of long-term nitazoxanide exposure in patients with chronic hepatitis C. Importantly, this data suggests that thiazolides have an interferon-like mechanism and as a class may have a role as single agent therapy in some patients," said Dr. Emmet Keeffe, chief medical officer for Romark and co-author of the study.

    -- An oral presentation by Brent Korba, Ph.D. of, Georgetown University

       Medical Center, described preclinical studies showing that treatment of

       cells harboring HCV replicons with nitazoxanide or its primary

       metabolite, tizoxanide, does not induce viral mutations conferring

       resistance to nitazoxanide, tizoxanide, interferon, ribavirin or 2'C-

       methyl cytidine (a polymerase inhibitor).  The presentation, titled,

       "Studies of the Potential for Resistance to Nitazoxanide or Tizoxanide

       in HCV-Containing Replicon Cell Lines," also demonstrated that

       treatment of HCV replicon cells with tizoxanide potentiates the

       antiviral effect of subsequent treatment with interferon (8-fold

       decrease in concentration of interferon required to inhibit virus

       replication by 90%).


"Data presented in each of these communications has provided important information in guiding the ongoing clinical development of nitazoxanide," said Dr. Rossignol.

Romark is currently enrolling patients for two U.S. clinical trials studying nitazoxanide for the treatment of hepatitis C genotype 1.

About Nitazoxanide

Nitazoxanide belongs to a new class of small molecule cell signaling modulators (CSMs) called the thiazolides. Like interferons, thiazolides modulate cell signaling pathways involved in the host cell's innate defense against viruses. Thiazolides can be administered orally and are not associated with side effects commonly associated with use of interferon. Nitazoxanide was discovered by Jean-Francois Rossignol, M.D., Ph.D., Chairman and Chief Science Officer of Romark, and was initially developed by Romark and approved for marketing in the United States as a treatment of cryptosporidiosis.

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. According to the Centers for Disease Control, HCV affects an estimated 4.1 million Americans.

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. Alinia(R) (nitazoxanide) is approved by the U.S. Food and Drug Administration and marketed by Romark for the treatment of Cryptosporidium and Giardia infection.

    REFERENCES:


    (1) 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, J. Rossignol et. al.; Proceeds from the 58th Annual

        Meeting of the American Association for the Study of Liver Disease

        2007, Abstract #178 (presented November 6, 2007).


    (2) Ibid.

Posted: April 2008

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