Session Title: Category 13. LATE-BREAKERS
Presentation Date: Apr 15, 2010
ANTIVIRAL ACTIVITY, PHARMACOKINETICS, AND TOLERABILITY OF AZD7295, A NOVEL NS5A INHIBITOR, IN A PLACEBO-CONTROLLED MULTIPLE ASCENDING DOSE STUDY IN HCV GENOTYPE 1 AND 3 PATIENTS
E. Gane1*, G.R. Foster2, J. Cianciara3, C. Stedman4, S. Ryder5, M. Buti6, E. Clark7, D. Tait7
1Auckland City Hospital, Auckland, New Zealand, 2Queen Mary University of London, The Royal London Hospital, London, UK, 3Regional Hospital of Infectious Diseases, Warsaw, Poland, 4Christchurch Clinical Studies, Christchurch, New Zealand, 5Nottingham University Hospitals NHS Trust, Nottingham, UK, 6Hospital Universitario Valle Hebron, Barcelona, Spain, 7Arrow Therapeutics Ltd, London, UK. *email@example.com
Background: AZD7295 is a selective inhibitor of HCV NS5A with in vitro antiviral activity of 7nM and 1.24µM against HCV genotype 1b and 1a replicons respectively, with significant liver concentration in preclinical studies. This study assessed safety, tolerability, pharmacokinetics and antiviral activity of AZD7295 in HCV-infected patients.
Methods: AZD7295 oral solution or placebo (4:1) was administered for 5 days to treatment-naïve and treatment-experienced patients without cirrhosis. Groups 1 and 2 (n=10, genotype 1a/1b, stratified according to subtype) received 90mg q8h and 233mg q8h respectively. Group 3 (n=6, genotype 3) received 90mg q8h and Group 4 (n=5, genotype 1b) received 350mg q12h. Blinded PK, safety, and virology data are provided. Unblinded data will be available.
Results: HCV RNA declined in a dose dependent manner in HCV genotype 1b patients with mean log declines from baseline of -1.2 to -2.1 by Day 6. HCV RNA levels did not change in genotype 1a or genotype 3 patients. Cmax (at 1.0-1.5h) was 97.9ng/ml after 90mg q8h and 304.4ng/ml after 233mg q8h. Steady-state Cmin was 29.5 and 145.5ng/ml, and AUC(0-8h) was 294 and 1031 hr*ng/mL. There were no treatment-related laboratory or ECG abnormalities, SAEs, or discontinuations. Most common AEs across all treatments were headache in 13 (42%), loose stools in 7 (23%), nausea in 6 (19%), backache in 5 (16%) and flatulence in 5 patients (16%). Gastrointestinal AEs were more frequent at higher doses which contained higher volumes of excipients.
Conclusions: AZD7295 was well tolerated at repeated doses of up to 700mg daily. AZD7295 shows potent antiviral activity in genotype 1b patients. Genotype 1a and genotype 3 patients showed no antiviral effects, consistent with plasma levels being below in vitro IC50 values. A phase 2 study using a new formulation of AZD7295 in combination with pegylated IFN/ribavirin is planned in HCV genotype 1b patients.
[Mean HCV RNA by genotype and dose]