Findings Include 80% SVR12 Rate with Nitazoxanide-Based Combination Therapy
and New Insights into Mechanism of Action of Nitazoxanide
MILAN, Italy, April 23 /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
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
-- 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
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
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-nave 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. For more information please visit please visit http://www.romarktrials.com or http://www.clinicaltrials.gov and enter the search term "nitazoxanide hepatitis United States."
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 (http://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.
(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).
|SOURCE Romark Laboratories|
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