Single and Multiple Dose Pharmacokinetics and Safety in on-hiv-infected Healthy Subjects Dosed with 66368, an Oral HIV Attachment Inhibitor Richard ettles, Caly Chien, Erica Elefant, Xiaodong Wang, Ellen Chung, Li Zhu, Duxi Zhang, Yaoshi Wu, Anna Persson, Dennis Grasela
HIV- Attachment Inhibition to Block HIV- Entry CD4 binding Coreceptor binding Virus-cell fusion Attachment inhibitor gp4 gp2 Fusion inhibitors CCR5 antagonists CD4 Cell membrane CCR5/CXCR4 (R5/X4) CXCR4 antagonists ettles RE, et al. CROI, Feb 27 Mar 2, 2; Boston, MA. Oral presentation 49
66368: Prodrug of a ext Generation HIV- Attachment Inhibitor 626529 Increased potency (~6-fold) and slower off-rate (~6-fold) compared to prior attachment inhibitor (48843) Prodrug and extended release formulations developed to address dissolution issues and rapid clearance O OMe O O O P OH OH CH 3 O Ph OMe H CH 3 O O O Ph 66368 626529 Spectrum of activity against HIV- with median IC 5 in low nm range Synergistic or additive antiviral effects in combination with 9 marketed anti-hiv drugs ettles RE, et al. CROI, Feb 27 Mar 2, 2; Boston, MA. Oral presentation 49
Phase, Double-blind, -controlled, Ascending Single-dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 66368 in Healthy Subjects (Study AI438) 4
Study Design: Ascending Single Dose Sequential dose groups receiving increasing doses of 66368 or placebo 2 3 4 5 6 7 8 9 2 2 mg 4 mg mg 4 mg 2 mg 3 mg 44 mg 6 mg 8 mg mg 2 mg + RTV 2 mg ot Dosed 88 subjects randomized and received study drug Within each dose group subjects were randomized to receive 66368 or placebo (n=2) in a 3: ratio Subjects were confined to the clinical facility for at least 72 hours after study drug administration mg RTV given 2 hours prior, in combination with, and 2 hours after 66368 o subjects were dosed in the 2 mg group, immediate release; RTV, ritonavir 5
Baseline Characteristics Of the 88 subjects randomized in this study, 66 were male and 22 were female The majority (n=47, 53%) of subjects were Caucasian The mean age of subjects was 3 years with a range from 8 to 45 years Across treatment groups Body weight ranged from 59.2 to.7 kg BMI ranged from 9. to 29.9 kg/m 2 o clear differences in baseline characteristics noted between the dose groups 6
Mean Plasma Concentration-Time Profiles of Selected Ascending Doses of 66368 626529* Concentration (ng/ml), 5 5 2 25 3 35 4 45 5 *626529, the active moiety of 66368, immediate release Time (h) Dose of 66368 2 mg mg 2 mg 3 mg 6 mg 8 mg mg 7
Summary of Pharmacokinetic Results 626529, the active moiety of 66368: Appeared rapidly in plasma T max was approximately h C max and AUC increased greater than dose proportional from 2- mg Terminal T half ranged from 7 to 2 h 66368 plasma concentrations were generally < LLOQ (. ng/ml) suggesting efficient pre-systemic conversion to 626529 Urinary recovery of 626529 was < 3.3% RTV increased 626529 AUC ~.8 fold RTV, ritonavir
Adverse Events Dose of 66368 (mg) 2 4 4 2 3 44 6 8 2 + RTV All BMS (n=66) (n=22) Subjects with AE(s), n (%) 2 (33.3) (6.7) 2 (33.3) (6.7) (6.7) 3 (5.) 4 (66.7) 5 (83.3) (6.7) 2 (3.3) 7 (3.8) Deaths, n (%) Serious AE(s), n (%) Discontinuations due to AE(s), n (%) Most frequently reported treatment-emergent adverse events (occurring in at least 5% of total subjects), n (%) ausea (6.7) 2 (33.3) 3 (5.) (6.7) 7 (.6) 2 (9.) Headache (6.7) (6.7) 2 (33.3) 2 (33.3) 6 (9.) (4.5) AE, adverse event;, immediate release; RTV, ritonavir 9
Phase, Double-blind, -controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 66368 and its Active Moiety, 626529 in Healthy Subjects (Study AI4384)
Study Design: Day Multiple Ascending Dose mg 66368 or (n=2), Q8H 2 mg 66368 or (n=2), Q8H 6 mg ER 66368 or (n=2), plus mg RTV, Q2H 2 mg ER 66368 or (n=2), Q2H 2 mg ER 66368 or (n=2), plus RTV Q2H Panel Panel 2 Panel 3 Panel 4 Panel 5 4 non-hiv infected healthy subjects randomized and received study drug Within each dose panel subjects were randomized to receive 66368 or placebo (n=2) in a 3: ratio ER, extended release;, immediate release; RTV, ritonavir
Baseline Characteristics mg 66368 Q8H 2 mg 66368 Q8H 6 mg ER 66368 plus mg RTV, Q2H 2 mg ER 66368 Q8H 2 mg ER 66368 plus mg RTV Q2H plus mg RTV (n=4) Overall (=4) Male/Female 3/3 4/2 5/ 6/ 6/ 4/2 3/ 3/9 Age, years; median (min, max) 32 (23-45) 32 (22-44) 29 (23-44) 36 (22-44) 36 (22-44) 29 (22-42) 29 (8-35) 33 (8-45) Race, n (%) Caucasian Black/African American Asian Indian/Alaska native 2 (33) (7) 2 (33) (7) 3 (5) (7) 2 (33) 5(83) (7) 2 (33) 4 (67) 3 (5) 3 (5) 4 (67) 2 (33) 3 (75) (25) 7 (43) 7 (43) 5 (3) (3) Weight, kg; median (min, max) BMI, kg/m 2 ; median (min, max) 7.4 (54.4-8.) 22.2 (2.4-28.6) 73. (64.6-82.7) 25.3 (23.9-28.4) 86.8 (68.2-2.) 28.4 (23.-3.7) 82. (69.3-93.7) 26.2 (2.7-29.2) 79.7 (68.-92.8) 24.9 (2.9-32.) 85.7 (78.7-99.4) 3. (24.8-3.4) 77.8 79.9 (66.2-8.2) (54.4-2.) 27.8 (26.7-29.3) 26.4 (2.7-32.) ER, extended release;, immediate release; RTV, ritonavir
Mean 626529* Steady State Plasma Concentration Time Profiles: Day 8 Dose of 66368 6 mg 626529 Concentration (ng/ml) 4 2 8 6 24 2 mg 6 mg ER + RTV 2 mg ER 2 mg ER + RTV 8 6 24 32 4 48 *626529, the active moiety of 66368 ER, extended release;, immediate release; RTV, ritonavir Time (h) 3
Summary of Pharmacokinetic Results Median 626529 T max ranged from.5 2. h and 4 5 h for and ER, respectively Mean 626529 plasma terminal T half on Day ranged from 3.2 to 4.5 h and 7 4 h for and ER (w/wo RTV), respectively 66368 was readily absorbed and converted to 626529 following multiple doses of and ER Steady state was generally reached by Days 2 to 3 The geometric mean accumulation index for C max, C min, and AUC(TAU) ranged from. to.7 ER, extended release;, immediate release; RTV, ritonavir 4
Effect of RTV: Mean 626529* Plasma Concentration-Time Profiles, Day Concentration (ng/ml) 756 63 54 378 252 26 8 6 24 8 6 24 Dose of 66368 2 mg ER 2 mg ER + RTV Time (h) Treatment and comparison 2 mg 66368 ER =6 2 mg 66368 ER + RTV =6 Adjusted GMR (9% CI) o RTV as reference C max (ng/ml) Geo. Mean (CV) 4547.6 (25) 746.63 (34).64 (.35,2.37) C min (ng/ml) Geo. Mean (CV) 338.28 (29) 399.22 (73) 4.36 (.93,8.866) AUC (TAU) (ng.h/ml) Geo. Mean (CV) 23785.3 (26) 5228.54 (4) 2.2 (.334,3.34) *626529, the active moiety of 66368 ER, extended release; RTV, ritonavir 5
Mean 626529* Plasma Concentration Time Profiles: vs ER Formulation 626529 Concentration (ng/ml) 4 2 8 6 4 2 Dose of 66368 2 mg ER mg 2 4 6 8 2 Time (h) 626529 Concentration at 2 hours (ng/ml) mg 2 mg ER *626529, the active moiety of 66368 Study AI4384 ; Study AI438 ER, extended release;, immediate release 6
Adverse Events mg 66368 Q8H 2 mg 66368 Q8H 6 mg ER 66368 plus mg RTV, Q2H 2 mg ER 66368 Q2H 2 mg ER 66368 plus mg RTV Q2H plus mg RTV (n=4) Overall (=4) Subjects with AE(s), n (%) 5 (83.3) 3 (5.) 4 (66.7) (6.7) 5 (83.3) 3 (5.) 4 (.) 25 (62.5) Deaths, n (%) Subjects with serious AE(s), n (%) Discontinuations due to AE(s), n (%) Treatment-related AEs, n (%) 2 (33.) 3 (5.) (25) 6 (5.) Incidence of AEs reported for at least % subjects (in all subjects), n (%) Pruritus (6.7) (6.7) 2 (33.3) 2 (33.3) (25.) 7 (7.5) ausea 3 (5.) (6.7) (6.7) (6.7) 6 (5.) Headache (6.7) 2 (33.3) 2 (33.3) (25.) 6 (5.) Flatulence 4 (66.7) (6.7) 5 (2.5) Rash (6.7) 2 (33.3) (25.) 4 (.) AE, adverse event; ER, extended release;, immediate release; RTV, ritonavir
Summary 66368, an oral prodrug of the HIV- attachment inhibitor 626529, when administered as an ER formulation lowers Cmax and maintains C2 66368 was generally safe and well tolerated in non-hivinfected healthy subjects administered for up to days up to a total daily dose of 24 mg Together with available results in HIV-infected subjects, the data support initiation of Phase IIb clinical trials of 66368 as part of combination antiretroviral therapy A PK/PD analysis will be presented later today (abs _8) A Phase IIb study in treatment-experienced subjects is planned to start in 2 ER, extended release
Acknowledgements Thank you to all the Phase I participants Bristol-Myers Squibb Rick Bertz, Ih Chang, Mike Furlong, George Hanna, Heather Sevinsky