Viramidine
Phase I Clinical Studies of Viramidine-A Liver-Targeting Prodrug of Ribavirin
Although ribavirin in combination with interferon has proven reasonably
effective in the treatment of chronic HCV, use of the drug is limited by its
many toxicities and side effects. There is a pressing need to develop
alternative therapies for the interferon/ribavirin combination.
Viramidine is a liver-targeting prodrug of ribavirin. It is efficiently
converted to ribavirin by adenosine deaminases and effects similar direct and
indirect anti-viral activities as ribavirin.
Pharmacokinetic (PK) studies in monkeys demonstrated that viramidine is orally
absorbed and preferentially taken up by the liver where the majority of the
prodrug is converted to ribavirin. Animal toxicology studies resulted in no
clinical side effects and minimal drop in hemoglobin in monkeys dosed at
viramidine 600 mg/kg/day for 28 days while greater proportion of animals dosed
at ribavirin 300 mg/kg/day experienced greater decrease in hemoglobin.
The aim of the current study was to characterize the safety and PK profiles of
single dosing, the effect of food, and multiple dosing of viramidine in humans.
A rising-single dose (RSD) study to evaluate the safety, tolerability and PK
profiles of viramidine at oral doses of 200, 600 and 1200 mg in male adult
healthy volunteers (N=8 on viramidine vs. 2 on placebo per dose group) was
conducted.
For the effect of food (FE), 36 adult male subjects were enrolled into 2 groups.
Eighteen received viramidine 600 mg after 10-hr fasting and 18 received
viramidine after a modified high fat breakfast. Subjects were crossed over to
receive viramidine in reverse fasting/fed condition after a 6-wk washout.
A rising multiple-dose (RMD) study to determine the safety, PK and
pharmacodynamics of viramidine at 400 mg BID, 600 mg BID and 800 mg BID for 4
weeks has been initiated in patients with chronic hepatitis C.
RSD and FE study - 57 healthy adult male subjects at mean age of 27.5 years
(19-53 yrs) and mean weight of 76.4 kg (51-100 kg) completed the study. All
doses of viramidine were safe and well tolerated.
All but one Hepseraerse events (AEs) were mild and comparable between the
different dose levels of viramidine. Viramidine was orally absorbed and
efficiently converted to ribavirin with Cmax for both compounds at Tmax of 2.5-3
hrs. Higher AUCs for viramidine-derived ribavirin compared to that of
viramidine, by 2-3 folds, at all dose levels were observed.
Both Cmax and AUCs of viramidine-derived ribavirin were proportionally higher
with increasing dose. Viramidine was not detectable in RBCs. AUC of
viramidine-derived ribavirin in RBCs was about half of that compared to
ribavirin dosing (historical data). Both viramidine and ribavirin were excreted
in urine.
Mean AUC and Cmax of viramidine-derived ribavirin were 20% and 40% higher,
respectively, after fed than fasting. RMD study is in progress with results
available for presentation at AASLD.
Conclusions:
(1) Single doses of viramidine up to 1200 mg are safe and well tolerated in
humans.
(2) Viramidine is orally absorbed and efficiently converted into ribavirin.
(3) The linear relationship between Cmax and AUC of viramidine-derived ribavirin
with viramidine dose indicates dose proportionality.
(4) The exposure of viramidine-derived ribavirin to RBC is about half that after
ribavirin dosing suggesting a lesser potential in inducing hemolytic anemia than
ribavirin.
(5) The marginal effects of food are not likely to be clinically relevant when
the treatment duration is as long as 48 weeks.
01/22/03
Reference
S Arora and others. PHASE I CLINICAL STUDIES OF VIRAMIDINE - A LIVER-TARGETING
PRODRUG OF RIBAVIRIN. Abstract 773. 53rd AASLD. November 1-5, 2002. Boston, MA.
Hepatology 2002: Vol 36 No 4, Pt 2 of 2.
http://www.hivandhepatitis.com/hep_c/news/012203b.html
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March 5th, 2004
Valeant Pharmaceuticals International (VRX) Reports Published 24-Week Data
Abstracts For Viramidine
Source: PRNewswire
COSTA MESA, Calif.-- Valeant Pharmaceuticals today reported that a portion
of its 24-week data from the Viramidine(TM) Phase 2 clinical trial was
published by the European Association for the Study of the Liver (EASL) on
its Web site. Valeant had submitted the 24-week data for presentation at the
upcoming EASL Conference in Berlin, Germany. Valeant is developing
Viramidine, a nucleoside (guanosine) analog, in oral form for the treatment
of hepatitis C in conjunction with a pegylated interferon.
The 24-week data shows that Viramidine demonstrated antiviral activity
comparable to that of ribavirin, when used in combination with peginterferon
alfa-2a in treatment naïve patients, but with a significantly lower
incidence of anemia.
Specifically, the portion of the data released by EASL shows that following
24 weeks of treatment, there was no significant difference between
Viramidine (800-1600 mg/day) versus ribavirin in the proportion of patients
with greater than or equal to 2 log10 reduction or non-detectable HCV RNA
(83 percent versus 83 percent, respectively). There were also significantly
fewer patients in the Viramidine groups with anemia (hemoglobin < 10g/dL)
when compared with the ribavirin arm (2 percent versus 24 percent; p <
0.001). Among patients receiving the 400 mg BID and 600 mg BID doses of
Viramidine, there were no cases of defined anemia. Other adverse events were
similar among treatment groups.
The full 24-week data for the Phase 2 clinical trial will be presented at
the EASL Conference.
A Phase 3 clinical trial of Viramidine compared to ribavirin in combination
with pegylated interferon was initiated in the fourth quarter of 2003.
About Valeant
Valeant Pharmaceuticals International is a global, publicly traded,
research-based specialty pharmaceutical company that discovers, develops,
manufactures and markets a broad range of pharmaceutical products. More
information about Valeant can be found at http://www.valeant.com/.
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements within the meaning of
the federal securities laws relating to expectations, plans or prospects for
Valeant Pharmaceuticals, including funding and conducting clinical trials
and expected research and development expenses. These statements are based
upon the current expectations and beliefs of Valeant Pharmaceuticals'
management and are subject to certain risks and uncertainties that could
cause actual results to differ materially from those described in the
forward- looking statements. These risks and uncertainties include market
conditions and other factors beyond Valeant Pharmaceuticals' control, the
company's success in identifying and enrolling patients in the clinical
trials program, the absence of adverse events that would require the
clinical trials to be prematurely terminated, clinical results that indicate
continuing clinical and commercial pursuit of Viramidine is advisable, and
the risk factors and other cautionary statements discussed in Valeant
Pharmaceuticals' filings with the U.S. Securities and Exchange Commission.
For further information please contact: Jeff Misakian of Valeant
Pharmaceuticals, +1-714-545-0100, ext. 3309.
Valeant Pharmaceuticals
CONTACT: Jeff Misakian of Valeant Pharmaceuticals, +1-714-545-0100, ext.3309
Web site: http://www.valeant.com/
http://www.hcvadvocate.org/news/newsRev/2004/NewsRev-38.html#7
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Barron's(3/27) Research Reports: How Analysts -2-
Dow Jones - Mar. 25, 2006
-- Price $14.85 on March 21
by Think Equity
Viramidine [a drug for treating chronic hepatitis C in treatment-naive patients]
did not meet the non-inferiority efficacy endpoint on an overall intent-to-treat
basis in the Viser1 clinical study. Only 38% of patients in the viramidine
treatment arm achieved sustained virologic response, compared to 52% patients in
the ribavirin-treatment control arm. In our opinion, this is a failure and the
drug is dead. We maintain our Sell rating and 13 price target.
Anemia rates . . . were lower in viramidine-treated patients (5%) than those
receiving ribavirin (24%) . . . But without efficacy, even the cleanest safety
profile is meaningless. Valeant reinforced that they will continue investing in
this program and still expect to launch the drug before the end of 2007. We
think this is a poor strategy . . . Our overall investment thesis (Sell) is
predicated on the expected failure of viramidine, now in Phase III clinical
studies (Viser1 and Viser2).
http://www.therapeuticsdaily.com/news/article.cfm?contentValue=822749&contentTyp\
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