2003 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

LATE-BREAKING ABSTRACTS 2003 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 . 1 Auckland City Hospital, Auckland, New Zealand; 2 Queen Mary University of London, The Royal London Hospital, London, UK; 3 Regional Hospital of Infectious Diseases, Warsaw, Poland; 4 Christchurch Clinical Studies, Christchurch, New Zealand; 5 Nottingham University Hospitals NHS Trust, Nottingham, UK; 6 Hospital Universitario Valle Hebron, Barcelona, Spain; 7 Arrow Therapeutics Ltd, London, UK E-mail: [email protected] Background: AZD7295 is a selective inhibitor of HCV NS5A with in vitro antiviral activity of 7nM and 1.24mM 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 90 mg q8h and 233 mg q8h respectively. Group 3 (n = 6, genotype 3) received 90 mg q8h and Group 4 (n = 5, genotype 1b) received 350 mg 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 1.0–1.5 h) was 97.9 ng/ml after 90 mg q8h and 304.4 ng/ml after 233 mg q8h. Steady-state Cmin was 29.5 and 145.5 ng/ml, and AUC(0–8 h) 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 700 mg 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.

2004 DETECTION OF MIXTURES OF HEPATITIS C VIRUS (HCV) TYPES M. Holodniy1 , R.S. Diaz2 , R.L. Mathis3 , P.M. Feorino3 , C. Loveday4 , Z. Grossman5 , R. Kantor6 , Y.W. Tang7 , R.M. Lloyd Jr.3 . 1 AIDS Research Center, VA Palo Alto Healthcare System, Palo Alto, CA, USA; 2 Retrovirology Laboratory, Federal University of S˜ ao Paulo, S˜ ao Paulo, Brazil; 3 CSO, Research Think Tank, Inc., Buford, GA, USA; 4 ICVC Charitable Trust HQ, Buckinghamshire, UK; 5 Clinical Virology Laboratory and National Reference Laboratory, Sheba Medical Center, Ramat Gan, Israel; 6 Division of Infectious Diseases, Brown University Medical School, Providence, RI, 7 Molecular Infectious Diseases Laboratory, Vanderbilt University Medical Center, Nashville, TN, USA E-mail: [email protected] Background: Response to approved treatments for Hepatitis C Virus infection is worse with HCV genotype one (the most common genotype) compared with other HCV genotypes. Genotype determination is routine for clinical trials. Detection of mixtures is not currently available; it may be desirable to detect minor populations of HCV genotypes, since this may impact response to therapy. Methods: A 15-member virus panel was constructed from patientderived virus containing genotypes 1b, 2b & 3a, mixed at ratios of 10:90, 30:70, 50:50; ≤30,000 HCV RNA copies/mL each. Ratio targets were confirmed by clonal analysis (n = 50 each). The panel was blinded, randomized, genotyped and reported using the TRUGENE® 5 NC genotyping kit. TRUGENE® FASTA files were downloaded into a novel reporting module, MixuTYPE™ and compared to the original TRUGENE® genotype. A second MixuTYPE™ analysis was performed on 63 patient genotypes previously genotyped by Vanderbilt University Clinic. FASTA sequences obtained from testing with the TRUGENE® 5 NC genotyping assay were downloaded into the MixuTYPE™ reporting module and subsequent results were compared between the two methods. A confirmatory test was also run on these specimens using either HCV Inno-LiPA or HCV Invader assays at Vanderbilt. Specimens containing confirmed mixtures of two different HCV TYPES were cloned (n = 50) for complete characterization. Results: The HCV TRUGENE 5 NC assay using the integrated OpenGene® reporting system were correctly identified mixtures in 3 of 15 (20%) of the characterized mixture panel while MixuTYPE™ correctly identified 15 of 15 from TRUGENE® FASTA sequences. The correctly identified genotypes were all from the 1b/3a mixture panel set at 30:70, 50:50 and 70:30 ratios. Sixty-three retrospective patient specimen genotypes obtained by HCV TRUGENE® 5 NC assay were sent for re-analysis of the original genotype using MixuTYPE™. No mixtures were identified during the original testing while MixuTYPE™ identified mixtures in 5 of 63 (7%). Confirmatory testing and subsequent clonal analysis confirmed MixuTYPE™ results in 5 of 5 samples. Conclusions: HCV-infected patients may have mixed genotypes, reflecting multiple exposures. The ability to detect HCV genotype mixtures may be important for treatment now, and if anti-HCV therapies are developed which differ in response rates based on HCV genotype.

Mean HCV RNA by genotype and dose.

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Journal of Hepatology 2010 vol. 52 | S459–S471