Nitazoxanide
Added to Standard Therapy Improves Response in Patients with Genotype 4 HCV: STEALTH-C1
Study
By
Liz Highleyman  Nitazoxanide
(Alinia) belongs to a new class of small molecules called thiazolides that modulate
cell signaling pathways involved in a host cell's innate defense against viruses.
This mechanism of action is related to that of interferon, but thiazolides can
be administered orally and are not associated with similar side effects.
Nitazoxanide
is approved in the U.S. for treatment of gastroenteritis due to Cryptosporidium
parvum (cryptosporidiosis) and Giardia lamblia (giardiasis). Preclinical
studies have demonstrated that it also exhibits antiviral activity against both
hepatitis C virus (HCV) and hepatitis
B virus (HBV). Several
presentations at the recent 43rd annual meeting of the
European Association for the Study of the Liver (EASL) last month in Milan
looked at nitazoxanide for the treatment of hepatitis C. STEALTH
C-1 The
discoverer of nitazoxanide, Jean-Francois Rossignol of Romark Laboratories, and
colleagues conducted the randomized controlled STEALTH C-1 trial to assess the
safety and efficacy of nitazoxanide plus pegylated interferon, with or without
ribavirin, in 120 patients with genotype 4 chronic hepatitis C at 2 centers in
Egypt. Participants
were sequentially allocated into 3 treatment arms:
•
180
mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day ribavirin
for 48 weeks (standard of care) (n = 40 treatment-naive);
•
500 mg twice-daily
nitazoxanide monotherapy for 12 weeks followed by nitazoxanide plus pegylated
interferon for an additional 36 weeks (n = 28 treatment-naive + 12 treatment-experienced);
•
Nitazoxanide monotherapy
for 12 weeks followed by nitazoxanide plus both pegylated interferon and ribavirin
for 36 weeks (n = 28 treatment-naive + 12 treatment-experienced).
The
primary endpoint was sustained virological response (SVR), or HCV RNA <10 IU/mL
24 weeks after the end of treatment. Secondary endpoints included HCV RNA <10
IU/mL at week 4 (rapid virological response, or RVR), at week 12 (early virological
response, EVR), and at the end-of-treatment (ETR). Results
•
Among the 96 treatment-naive
patients, the SVR rate was 79% in the triple therapy arm, compared with 61% in
the nitazoxanide-pegylated interferon dual therapy arm, and 50% in the standard-of-care
arm (P = 0.023).
•
Among the 24 treatment-experienced
patients, the SVR rate was 25% in the triple therapy arm compared with 8% in the
nitazoxanide-pegylated interferon arm.
•
RVR, EVR, and ETR
rates are shown in the table below (see next study description).
•
Adverse events
were generally similar across all 3 treatment arms.
•
The exception was
that the rate of anemia was significantly lower in the group that did not receive
ribavirin.
Based
on these findings, the investigators concluded, "The addition of nitazoxanide
to pegylated interferon or pegylated interferon-ribavirin improved virologic response
rates compared with pegylated interferon-ribavirin therapy without increase in
adverse events." 4-week
Lead-in In
a related poster, the investigators presented results from a study in which the
lead-in nitazoxanide monotherapy phase was shortened to 4 rather 12 weeks. In
this study, 44 treatment-naive Egyptian patients (40 with genotype 4; 3 with genotype
1; 1 with genotype 2) received 500 mg twice-daily nitazoxanide for 4 weeks followed
by nitazoxanide plus 180 mcg/week pegylated interferon for 36 weeks, without ribavirin.
Sustained response rates at 12 weeks (SVR12) were reported. Results
•
80%
of patients treated with the 4-week lead-in dual therapy regimen achieved SVR12,
compared with 50% in the standard-of-care arm of STEALTH C-1 (used as a historical
control) (P = 0.004).
•
RVR,
EVR, and ETR rates for the 4-week lead-in, as well as the 12-week lead-in in STEALTH
C-1, are shown in the table below.
•
All
the genotype 1 and 2 patients responded to the 4-week lead-in regimen.
•
Adverse
events were similar to those observed in STEALTH C-1.
•
There
were no serious adverse events or discontinuations due to adverse events.
The
investigators concluded that, "The nitazoxanide lead-in phase used in the
STEALTH C-1 trial can be reduced from 12 weeks to 4 weeks without compromising
RVR, EVR, and ETR rates." The
results from these 2 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," Rossignol said in a press release issued by Romark. "These
data also provide interesting insights into the mechanism of action of nitazoxanide
and confirm previous findings related to its safety." The
second study, he added, "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." Resistance Researchers
also reported results from a laboratory study of the potential for development
of resistance to nitazoxanide and its primary metabolite, tizoxanide. Huh-7 cells
harboring HCV replicons were exposed to increasing concentrations of nitazoxanide
and tizoxanide. Based
on their findings, they concluded that tizoxanide resistance can be generated
in HCV replicon-containing cell lines, but that development of resistance to nitazoxanide
or tizoxanide did not induce resistance to interferon or ribavirin. In fact, treatment
of HCV replicon cells with tizoxanide heightened the antiviral effect of subsequent
interferon treatment. They added that tizoxanide resistance is conferred by changes
in the cell line, not by mutations in the HCV replicon. Romark
Institute For Medical Research, Tampa, FL; Division of Gastroenterology and Hepatology,
Department of Medicine, Stanford University School of Medicine, Palo Alto, CA;
Department Of Gastroenterology and Hepatology, University of Tanta, Tanta, Egypt;
Department of Hepatology, Gastroenterology and Infectious Diseases, University
of Benha, Benha, Egypt; Department of Tropical Medicine and Infectious Diseases,
University of Alexandria, Alexandria, Egypt; Department of Microbiology and Immunology,
Georgetown University Medical Center, Washington, DC. Further
Clinical Trials
Based
on promising results to date, Romark recently announced that it will expand its
clinical development program for nitazoxanide, including trials to asses its safety
and efficacy in individuals with HCV genotype 1, the most common type in the U.S.
Below
is an excerpt from the company press release describing ongoing and planned trials: Romark
Laboratories Initiates Phase II Study of Nitazoxanide in Treatment-Naive Patients
with Chronic Hepatitis C Genotype 1 Trial
Marks Third Study in Company's STEALTH C Clinical Program to Evaluate Nitazoxanide
in the Treatment of Chronic Hepatitis C
TAMPA, Fla., April 18 -- Romark
Laboratories, a privately held biopharmaceutical company, today announced that
it has begun enrolling patients in a U.S. clinical trial to evaluate nitazoxanide
for the treatment of chronic hepatitis C. Preliminary data from the study is expected
in the second half of 2008.
The study, STEALTH C-3 (Studies to Evaluate
Alinia for Treatment of Hepatitis C), is a Phase II randomized, double-blind,
placebo-controlled clinical trial designed to evaluate the safety and efficacy
of nitazoxanide in combination with peginterferon alpha-2a (Pegasys, Roche) and
ribavirin (Copegus, Roche) in treatment naive patients with chronic hepatitis
C infected with genotype 1.
The primary objective of STEALTH C-3 is to
evaluate sustained virologic response (SVR) with a treatment regimen of 4 weeks
of nitazoxanide lead-in therapy followed by 48 weeks of standard of care plus
nitazoxanide versus 4 weeks of placebo lead-in followed by 48 weeks of standard
of care and placebo. The trial will enroll 60 patients at 15 centers in the U.S.
"Earlier clinical studies in patients with chronic hepatitis C infected
with genotype 4 have shown that nitazoxanide improves virologic response rates
when used in combination with standard of care," said Dr. Emmet B. Keeffe,
Chief Medical Officer of Romark. "This study and our ongoing STEALTH C-2
trial, are designed to evaluate the effect of treatment with nitazoxanide plus
standard of care in patients with genotype 1. Future clinical trials will explore
new combinations and treatment durations, including current and emerging HCV therapies."
STEALTH
C Clinical Development Program
STEALTH C-3 is the latest in a series
of clinical trials aimed at gaining a broad understanding of how nitazoxanide
may benefit patients with chronic hepatitis C genotype 1 when used in combination
with peginterferon and ribavirin. Other studies in the STEALTH C program include
the following:
•
STEALTH C-2, a
randomized, double-blind, placebo-controlled trial currently enrolling up to 60
patients in the U.S. with chronic hepatitis C genotype 1 who have previously failed
to respond to the standard of care with peginterferon and ribavirin. This trial
is designed to evaluate the effectiveness and safety of nitazoxanide administered
500 mg twice daily for 4 weeks followed by nitazoxanide plus standard of care
for 48 weeks compared to placebo for 4 weeks followed by standard of care plus
placebo for 48 weeks.
•
STEALTH C-1, an
international study in 120 treatment-naive and interferon-experienced patients
with chronic hepatitis C genotype 4. Interim results from the randomized controlled
Phase II clinical trial were presented at the 58th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD) in Boston, MA and demonstrated
that 79 percent of interferon-naive patients with chronic hepatitis C genotype
4 receiving nitazoxanide plus the standard of care had a sustained viral response
(SVR) at 12 weeks following treatment, compared to 43 percent 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. Final study results (SVR-24) will be presented at the European
Association for the Study of the Liver (EASL) in April 2008 [Ed. Note: described
above].
To
learn more about Romark clinical trials currently under way, or to find out if
a study is recruiting patients in your area, please visit www.romarktrials.com
or www.clinicaltrials.gov
(for the latter, enter the search terms "nitazoxanide hepatitis United States.")
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 (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.
|
5/06/08
References JF
Rossignol, A Elfert, Y El-Gohary, and others. Randomized controlled trial of nitazoxanide-peginterferon-ribavirin,
nitazoxanide-peginterferon and peginterferon-ribavirin in the treatment of patients
with chronic hepatitis C genotype 4. 43rd annual meeting of the European Association
for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008. JF
Rossignol, SM Kabil, Y El-Gohary, and others. Randomized double blind placebo-controlled
trial of nitazoxanide in the treatment of patients with chronic hepatitis C genotype
4. EASL 2008. JF
Rossignol, A Elfert, EB Keeffe. Evaluation of a 4 week lead-in phase with nitazoxanide
prior to nitazoxanide + peginterferon in treating chronic hepatitis C. EASL 2008. BE
Korba, JS Glenn, MS Ayers, and others. Studies of the potential for resistance
to nitazoxanide or tizoxanide. EASL 2008. Other
Sources Romark
Laboratories. Romark Announces Presentation of New Data For Nitazoxanide in Chronic
Hepatitis C at EASL 2008. Press release. April 23, 2008. Romark
Laboratories. Romark Laboratories Initiates Phase II Study of Nitazoxanide in
Treatment-Naive Patients With Chronic Hepatitis C Genotype 1. Press release.
April 18, 2008 |
