icon-folder.gif   Conference Reports for NATAP  
 
  EASL 48th Annual Meeting
April 24th - 28th 2013
The Netherlands, Amsterdam
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ALS-2200, A Novel Once-daily Nucleotide HCV Polymerase Inhibitor, Demonstrated Potent Antiviral Activity In Treatment-na´ve Patients with Compensated Cirrhosis or Genotype 2-4 Chronic Hepatitis C
 
 
  Reported by Jules Levin
EASL 2013 April 26, 2013
 
P. Marcellin1, S.Popa2, A. Streinu-Cercel3, N. Boyer1, D. Dospinoiu3, A, Patat4, N. Ghicavii2, V.Garg5, R.S.Kauffman5, M.Koziel5, M.J. Tong6, S.M.Chanda7, Q.Zhang7, C.Westland7, L.Beigelman7, L.M.Blatt7, and J.Fry7 1. Hopital Beaujon, Clichy, France, 2. Republican Clinical Hospital, Chisinau, Moldova, 3. National Institute of Infectious Diseases, Bucharest, Romania, 4. Biotrial, Rennes, France, 5. Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA, 6. Liver Center, Huntington Medical Research Institutes, Pasadena, CA, USA, 7. Alios BioPharma, South San Francisco, CA, USA

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Introduction
 
· ALS-2200 is a uridine nucleotide analog, which has demonstrated
- Potent, highly selective inhibition of HCV replication in vitro
- No in vitro cross-resistance to other direct acting antivirals
- Pan-genotypic activity in replicon cell lines
· Long half-life of the nucleoside triphosphate (NTP) of ALS-2200 observed in human hepatocytes makes it suitable for once daily dosing
 
Study Design
 
Study Objectives

 
· Primary Objective
· To evaluate the safety and tolerability of single and multiple doses of ALS-2200 administered to healthy subjects and to patients with chronic hepatitis C (CHC)
 
· Key Secondary Objectives
· To evaluate the viral dynamics of multiple doses of ALS-2200 in patients with CHC
· To evaluate the pharmacokinetics of single and multiple doses of ALS-2200 and its metabolites in healthy subjects and patients with CHC
· To evaluate the safety and tolerability of multiple doses of ALS-2200 given with or without ribavirin (RBV) to patients with CHC
 
Multiple Ascending Dose (MAD) Phase
· Once daily 7-day dosing with ALS-2200 solution or placebo
· Patients were confined to a phase 1 unit on Day -1 through Day 9 and followed up through Day 31
· Safety and PK evaluated prior to each dose escalation
· Safety assessments included physical exams, vital signs, ECGs, clinical laboratory assessments and adverse events
· HCV RNA evaluated at central laboratory using the Roche COBAS« Taqman« HCV Assay v2.0 (LLOQ=25 IU/mL)
· Initiation of triple therapy allowed after completion of follow-up

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MAD Phase Key Patient Selection Criteria
· Patients with CHC aged 18-65 years old
· No prior treatment for CHC
· HCV RNA viral load ≥105 to <108 IU/mL
· Compensated cirrhotic cohort: ≥104 to <108 IU/mL
· Serum ALT < 5 x ULN
· Liver biopsy within two years or Fibroscan evaluation within 6 months prior to screening that clearly excludes cirrhosis
· Except for compensated cirrhotic cohort who had to have demonstrated cirrhosis on biopsy or Fibroscan evaluation
· Absence of hepatocellular carcinoma confirmed by an ultrasound and AFP ≤ ULN
· Creatinine clearance >50 mL/min
 
Single Ascending Dose (SAD) Phase Summary
 
· Forty-eight healthy male subjects received single doses of up to 800 mg ALS-2200 or placebo, which were well tolerated
· No subjects prematurely discontinued the study
· No serious adverse events (SAEs) and no maximum tolerated dose identified
· No clinically significant changes in laboratory values, ECGs or vital signs
· All AEs were mild or moderate in severity
· Single dose PK demonstrated rapid oral absorption and systemic conversion of the pro-drug by the liver. ALS-369, the parent nucleoside, was the major metabolite in systemic circulation.

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