Session Title: Category 13. LATE-BREAKERS
Presentation Date: Apr 15, 2010
VIROLOGICAL RESPONSE, SAFETY, AND PHARMACOKINETIC PROFILE FOLLOWING SINGLE- AND MULTIPLE-DOSE ADMINISTRATION OF ACH-0141625 PROTEASE INHIBITOR TO HEALTHY VOLUNTEERS AND HCV GENOTYPE-1 PATIENTS
V. Detishin1, W. Haazen2, H. Robison3, L. Robarge3, E. Olek3*
1Clinical Hospital of Infectious Diseases and, INNOPHAR MO S.R.L., Chisnau, Moldova, 2SGS Life Science Services, Antwerpen, Belgium, 3Achillion Pharmaceuticals, Inc., New Haven, CT, USA. *firstname.lastname@example.org
Background and Aims: ACH-0141625 is a highly potent and specific HCV NS3/4A protease inhibitor. A phase 1 study was conducted to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity following single- and multiple-dose administration of ACH-0141625 to male and female healthy volunteers and HCV genotype-1 patients.
Methods: In the single-dose segment 18 healthy subjects received doses of 50-2000 mg ACH-0141625 or placebo in an alternating panel, multiple period, dose escalation scheme. In the multiple dose segment, 18 healthy subjects received doses of 600 mg BID or 1000 mg BID of ACH-0141625 or placebo for 5 days in a double-blind serial-panel study. In addition, 18 HCV patients randomized in a 2:1 ratio to received 500 mg BID or 600 mg BID of ACH-0141625 or placebo for 5 days in a double-blind serial panel segment. All patients were followed for 12 days. Clinical safety evaluations (adverse events, clinical chemistry, hematology, urinalysis, vital signs and ECG) were performed throughout each segment. Plasma samples for ACH-0141625 pharmacokinetic data were collected. Viral load measurements were taken for the HCV patients.
Results: Mean age among patients was 41, BMI 25.9 +/-3.79 SD , and mean log10 VL at baseline was 5.9. A > 3 log10 maximal drop in HCV RNA was observed in all subjects treated with 500 and 600 mg ACH-0141625. No response was seen with placebo. No breakthrough was observed during treatment. Maximal VL decline achieved was 4.25 and 3.94 log10 for 500 mg BID and 600 mg BID, respectively. Two patients in the 600 mg BID dose group achieved HCV RNA BLQ (15 IU/mL). In patients receiving ACH-0141625 a sustained mean 2.53 log10 decline was observed at Day 12. ACH-0141625 showed supra-dose proportional plasma exposure at doses below 1000 mg. There were no serious AEs, nor were there any discontinuations due to AEs. AEs were mild or moderate and transient.
Conclusions: ACH-0141625 is generally safe and well-tolerated, and exhibits plasma pharmacokinetics and viral load reduction that support once or twice daily dosing. The sustained viral load suppression observed among patients treated with ACH-0141625 at Day 12 suggests a potential advantage that warrants continued investigation.