ITMN-191 Phase 1A A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics (PK) of Single Ascending Oral Doses of the NS3/4A Protease Inhibitor ITMN 191 in Healthy Subjects
W. Z. Bradford1; C. Rubino2; S. Porter1; A. Forrest2; L. M. Blatt1; A. A. Patat3
1. Intermune, Inc, Brisbane, CA, USA.
2. ICPD/Ordway Research Institute, Inc., Albany, NY, USA.
3. Biotrial, Rennes, France.
Background: ITMN-191 is a highly potent and selective inhibitor of the HCV NS3/4A serine protease that was specifically designed to achieve high liver concentrations with modest systemic exposure. Preclinical studies demonstrate a potency of 1.8 nM in an HCV genotype 1 replicon, and liver:plasma concentration ratios of 10:1 and 120:1 in rats and primates, respectively. The aim of the present study was to evaluate the safety, tolerability, and PK of single ascending doses of ITMN-191 in healthy adults.
Methods: In a double-blind, placebo-controlled study, healthy adult subjects were randomized to receive a single oral dose of ITMN-191 or matched placebo in a Phase 1 research facility. Study drug was administered orally in doses ranging from 2-1600 mg. In each of 4 cohorts, 8 and 2 subjects received ITMN-191 or placebo, respectively. In order to assess the effect of food on ITMN-191 PK, an additional 2 cohorts of 12 subjects each received ITMN-191 or placebo (10:2) in both the fed and fasted states, separated by a 5-day washout period.
Results: A total of 64 subjects were randomized and all completed the study. There were no serious adverse events (AE) or clinically significant laboratory or ECG abnormalities. AE’s were similar between groups, with the exception of a higher frequency of mild and transient diarrhea and abdominal pain in the ITMN-191 group at the highest tested dose (1600 mg). The PK of ITMN-191 was linear over a dose range of 100 – 800 mg; the relationship between dose and exposure was more than proportional at the 1600 mg dose. Co-administration with food increased the expected trough (based on q8h and q12h dosing intervals), and increased the AUC by 40-50%.
Conclusion: ITMN-191 was safe and well tolerated over the range of studied doses. AE’s were generally mild and transient, with no evidence of clinically significant laboratory abnormalities or ECG changes. These findings are consistent with the target PK profile that informed the molecular design of ITMN-191 and, given the predicted liver concentrations, suggest that doses in the lower range of those studied are likely to result in significant antiviral activity with modest systemic exposure.
Mean (±SD) for selected ITMN-191 PK parameters
Single Dose(mg) N Cmax (ng/mL) AUC0-∞
2 8 0.20 (0.05) 0.28 (0.06)
100 8 25.4 (20.1) 24.8 (12.1)
200 8 44.4 (37.2) 36.4 (14.8)
400(Fasted) 10 69.4 (30.2) 88.6 (41.9)
400(Fed) 10 75.2 (61.6) 122 (48.1)
800 8 318 (286) 240 (136)
1600(Fasted) 10 622 (309) 693 (172)
1600(Fed) 10 528 (392) 1070 (380)