Report 10 from Dallas Liver meeting, 50th Annual AASLD Meeting, Nov 5-9

VX-497: initial findings in human dose ranging study
Jules Levin, NATAP

summary: in this preliminary dose-ranging study of 30 interferon non-responsive adult patients with active Hepatitis C. A statistically significant reduction, compared to baseline, in serum ALT in patients treated with 200 mg TID of VX-497 was observed, 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. 

I spoke with Vertex official at Dallas meeting about this study. Since IFN non-responders were the participants it may not be totally surpising that they did not see HCV RNA decline from VX-497. Future studies are being discussed and will likely include a potentially more responsive study group.

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. (In speaking with Vertex official HCV RNA declines were not seen, but as stated above the study participants were previous IFN non-responders). Disclosure: This study was supported by a grant from Vertex Pharmaceuticals, Inc.