Here's the actual abstract (thanks, JL!).... sorry if this has been posted before, but I don't remember it and I'm too lazy to search......
DOSE-RANGING STUDY OF VX-497, A NOVEL, ORAL IMPDH INHIBITOR, IN PATIENTS WITH
HEPATITIS C. abstract 990
Theresa Wright, UCSF, San Francisco, CA; Mitchell L Shiffman, Med Coll
Virginia, Richmond, VA; Steven Knox, Ene Ette, Robert S Kauffman, John Alam,
Vertex Pharmaceuticals Inc, Cambridge, MA
VX-497, is an investigational orally-active inhibitor of inosine
monophosphate dehydrogenase (IMPDH), a key enzyme in the de-novo pathway of
purine biosynthesis. VX-497 has been shown to have in vitro anti-viral
activity across a broad range of DNA and RNA viruses, including a pestivirus
structurally related to Hepatitis C virus. The combination of interferon alfa
and ribavirin (another, unrelated, IMPDH inhibitor) has become the standard
therapy for chronic Hepatitis C, but leads to a sustained anti-viral response
in only about 40% of treated patients, while producing hemolytic anemia in
most patients. Thus, additional therapies are needed. This double-blind,
placebo-controlled study was conducted to evaluate the safety, and
pharmacokinetics, and preliminarily assess clinical activity of a 28 day oral
course of treatment with VX-497 at 3 dose levels (100, 200 and 400 mg Q8hr)
in 30 interferon non-responsive adult patients with active Hepatitis C.
Patients had compensated liver disease with biopsy-proven hepatic
inflammation, elevated ALT (>1.3X nl) and presence of HCV RNA (by PCR,
National Genetics Institute) in plasma. Patients were required to have been
non-responsive to a previous course of >8 weeks duration of interferon alfa
alone; patients with cirrhosis were excluded. Ten patients were enrolled in
each treatment group. At the time of abstract submission, preliminary data
were available for the first 2 dose groups. Seven patients were randomized to
treatment with VX-497 (100 mg Q8hr) and 3 to placebo in the first group and
8, plus 2 to placebo, in the second (200 mg Q8hr). Preliminary
pharmacokinetic (PK) data revealed linearity in PK with no significant
accumulation. The mean (CV%) steady-state Cmax and AUC (0-24) were 1748
ng/mL(69.7%) and 3543 ng*hr/mL(55.8%), respectively, in the 100 mg group, and
3195 ng/mL (62.5%) and 8210 ng*hr/mL(69.5%), respectively, in the 200 mg
group. A statistically significant reduction, compared to baseline, in serum
ALT in patients treated with 200 mg TID of VX-497 was observed (-24%; 95% CI
-10%, -39%), while non-significant changes in ALT, compared to baseline, were
observed in the patients receiving placebo and 100 mg TID of VX-497. No
consistent changes in plasma HCV RNA were observed in these 2 dose groups,
but detailed analysis of pharmacodynamic effects is ongoing. Treatment was
well tolerated, with no premature discontinuations or clinically notable
changes in hematologic parameters or renal function. Thus, treatment of
interferon-non-responsive Hepatitis C patients with VX-497, 200 mg TID for 28
days, results in a significant reduction in serum ALT compared to baseline
and is well tolerated. The full data, including results from the 400 mg dose
group are being generated and will be available for presentation. Disclosure:
This study was supported by a grant from Vertex Pharmaceuticals, Inc.
|
