Clevudine
is an oral, once-daily nucleoside analog that has previously been evaluated in
14 clinical trials including more than 800 individuals. The current Phase 3 studies
will be conducted in 856 nucleoside treatment-naive patients with chronic HBV
at approximately 140 global clinical sites to support registration (regulatory
approval) of clevudine in the Americas and Europe.
Pharmasset licensed
these territories from Bukwang Pharmaceuticals, which recently received South
Korean regulatory approval and began marketing clevudine in South Korea under
the brand name Levovir.
Following are more details from Pharmasset about
initiation of the clevudine Phase 3 trials in the U.S.:
"Based
upon prior 24 week treatment results, we are optimistic that clevudine will demonstrate
superiority to Hepsera [adefovir] in its ability to suppress HBV DNA and normalize
liver enzyme levels after 48 weeks of treatment," stated Dr. Michelle Berrey,
Pharmasset's Vice President, Clinical Development & Chief Medical Officer.
"We also expect to build upon the results from earlier studies that
demonstrated clevudine's ability to provide a sustained virologic response, or
SVR, for chronic HBV infection. If we are able to demonstrate SVR for HBV in these
studies, clevudine could offer patients and their physicians an important new
disease management option that might reduce the need for further therapeutic intervention
after a defined treatment period."
Registration
Studies for New Drug Application (NDA)
The clevudine Phase
3 registration program includes two 48-week clinical trials designed to demonstrate
the superiority of clevudine 30 mg over Hepsera (adefovir dipivoxil) 10 mg, each
administered once daily as monotherapy.
Clevudine Study 305 will enroll
approximately 376 chronic hepatitis B "e" antigen positive patients
(HBeAg+), and clevudine Study 306 will enroll approximately 480 chronic hepatitis
B "e" antigen negative patients (HBeAg-). Pharmasset plans to submit
the 48-week data from these studies to the FDA as the basis for clevudine marketing
approval in the U.S.
The primary endpoint for the registration studies
is a composite endpoint measuring the proportion of patients with both undetectable
serum HBV DNA and normalized liver enzyme (ALT) levels following 48 weeks of monotherapy.
The registration studies will also assess improvement in liver histology,
hepatitis B "e" antigen (eAg) seroconversion, decreases in the reservoir
of HBV hepatic cccDNA, and quantitative eAg and surface antigen (sAg). The clevudine
registration studies will be conducted in the United States, Canada, Brazil, the
United Kingdom, Spain, Greece, Turkey, Romania, Czech Republic, Australia, New
Zealand, Singapore, Hong Kong, and Taiwan.
After the primary registration data have been
obtained at week 48, the Phase 3 studies will continue to week 96 to gather additional
safety and efficacy data, as well as to assess clevudine's sustained virological
response (SVR) rate for HBV. SVR is a measure of undetectable virus 24 weeks after
stopping therapy, which clevudine previously demonstrated in Bukwang's South Korean
registration studies.
At week 72, HBeAg- patients in Study 306 who have
been treated with clevudine and have suppressed HBV DNA and normalized ALT levels
will be randomized to continue active clevudine or switch to placebo. The purpose
is to determine the proportion of patients who sustain a virological response
24 weeks after stopping clevudine treatment at week 96.
HBeAg+ patients
in Study 305 that have been treated with either clevudine or Hepsera and undergo
eAg seroconversion (loss of eAg with suppressed HBV DNA and normalized ALT) will
discontinue therapy at week 72. SVR will be assessed in these HBeAg+ patients
for clevudine and Hepsera 24 weeks after stopping treatment at week 96.
South
Korean Registration Studies for Clevudine
Bukwang received
marketing approval for clevudine from the South Korean FDA based on two 24-week,
randomized (3:1), double-blind, placebo-controlled, multi-center South Korean
Phase 3 registration trials in 337 patients. Study 301 enrolled 248 HBeAg+ patients
who received clevudine 30 mg or placebo once daily, and Study 302 enrolled 89
HBeAg- patients who received clevudine 30 mg or a placebo once-daily. All patients
were evaluated for an additional 24 weeks of follow-up care without clevudine
treatment.
After 24 weeks of clevudine treatment, 59% of HBeAg+ patients
achieved undetectable HBV DNA (< 300 copies/mL) and 92% of HBeAg- patients
achieved undetectable HBV DNA. These results were statistically significant compared
to placebo. In addition to the potent antiviral suppression, 16% of the HBeAg-
patients who received clevudine demonstrated SVR 24 weeks after stopping therapy,
versus 0% of the patients who had received the placebo. In Study 303, a South
Korean open-label, follow-on study of clevudine, Bukwang observed similar findings
to those noted above for Studies 301 and 302. Twelve weeks after completing a
48-week course of therapy, 80% of HBeAg- patients had undetectable HBV DNA.
Clevudine
was generally safe and well tolerated by patients with chronic HBV. Serious adverse
events during treatment in Studies 301 and 302 and during follow-up indicated
that a higher percentage of placebo-treated patients had seriously elevated liver
enzyme levels. Otherwise, there was no meaningful difference between clevudine
and placebo in the incidence of serious adverse events.
About
Pharmasset
Pharmasset is a clinical-stage pharmaceutical company
committed to discovering, developing, and commercializing novel drugs to treat
viral infections. Pharmasset's primary focus is on the development of oral therapeutics
for the treatment of HBV, HCV, and HIV.
Pharmasset is currently developing
three product candidates. Clevudine, for the treatment of chronic HBV infection,
is in Phase 3 clinical trials for registration in the Americas and Europe. Clevudine
is already approved for HBV in South Korea and marketed by Bukwang Pharmaceuticals
in South Korea under the brand name Levovir.
R7128,
an oral treatment for chronic HCV infection, is in a Phase 1 clinical trial
through a strategic collaboration with Roche. Racivir, which is being developed
for the treatment of HIV in combination with other approved HIV drugs, has completed
a Phase 2 clinical trial.
10/05/07
Source
Pharmasset, Inc. Pharmasset Commences Dosing in Phase 3 Registration Studies
of Clevudine for HBV. Press Release. October 1, 2007.
