Single and Multiple Dose Pharmacokinetics and Safety in Non-HIV-Infected Healthy Subjects Dosed with BMS , an Oral HIV Attachment Inhibitor

Transcription

1 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

2 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

3 66368: Prodrug of a ext Generation HIV- Attachment Inhibitor 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 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

4 Phase, Double-blind, -controlled, Ascending Single-dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of in Healthy Subjects (Study AI438) 4

5 Study Design: Ascending Single Dose Sequential dose groups receiving increasing doses of or placebo 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 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 o subjects were dosed in the 2 mg group, immediate release; RTV, ritonavir 5

6 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

7 Mean Plasma Concentration-Time Profiles of Selected Ascending Doses of * Concentration (ng/ml), *626529, the active moiety of 66368, immediate release Time (h) Dose of mg mg 2 mg 3 mg 6 mg 8 mg mg 7

8 Summary of Pharmacokinetic Results , 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 plasma concentrations were generally < LLOQ (. ng/ml) suggesting efficient pre-systemic conversion to Urinary recovery of was < 3.3% RTV increased AUC ~.8 fold RTV, ritonavir

9 Adverse Events Dose of (mg) 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

10 Phase, Double-blind, -controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of and its Active Moiety, in Healthy Subjects (Study AI4384)

11 Study Design: Day Multiple Ascending Dose mg or (n=2), Q8H 2 mg or (n=2), Q8H 6 mg ER or (n=2), plus mg RTV, Q2H 2 mg ER or (n=2), Q2H 2 mg ER 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 or placebo (n=2) in a 3: ratio ER, extended release;, immediate release; RTV, ritonavir

12 Baseline Characteristics mg Q8H 2 mg Q8H 6 mg ER plus mg RTV, Q2H 2 mg ER Q8H 2 mg ER 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 ( ) 22.2 ( ) 73. ( ) 25.3 ( ) 86.8 ( ) 28.4 ( ) 82. ( ) 26.2 ( ) 79.7 ( ) 24.9 ( ) 85.7 ( ) 3. ( ) ( ) ( ) 27.8 ( ) 26.4 ( ) ER, extended release;, immediate release; RTV, ritonavir

13 Mean * Steady State Plasma Concentration Time Profiles: Day 8 Dose of mg Concentration (ng/ml) mg 6 mg ER + RTV 2 mg ER 2 mg ER + RTV *626529, the active moiety of ER, extended release;, immediate release; RTV, ritonavir Time (h) 3

14 Summary of Pharmacokinetic Results Median T max ranged from.5 2. h and 4 5 h for and ER, respectively Mean 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 was readily absorbed and converted to 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

15 Effect of RTV: Mean * Plasma Concentration-Time Profiles, Day Concentration (ng/ml) Dose of mg ER 2 mg ER + RTV Time (h) Treatment and comparison 2 mg ER =6 2 mg ER + RTV =6 Adjusted GMR (9% CI) o RTV as reference C max (ng/ml) Geo. Mean (CV) (25) (34).64 (.35,2.37) C min (ng/ml) Geo. Mean (CV) (29) (73) 4.36 (.93,8.866) AUC (TAU) (ng.h/ml) Geo. Mean (CV) (26) (4) 2.2 (.334,3.34) *626529, the active moiety of ER, extended release; RTV, ritonavir 5

16 Mean * Plasma Concentration Time Profiles: vs ER Formulation Concentration (ng/ml) Dose of mg ER mg Time (h) Concentration at 2 hours (ng/ml) mg 2 mg ER *626529, the active moiety of Study AI4384 ; Study AI438 ER, extended release;, immediate release 6

17 Adverse Events mg Q8H 2 mg Q8H 6 mg ER plus mg RTV, Q2H 2 mg ER Q2H 2 mg ER 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

18 Summary 66368, an oral prodrug of the HIV- attachment inhibitor , when administered as an ER formulation lowers Cmax and maintains C 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 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

19 Acknowledgements Thank you to all the Phase I participants Bristol-Myers Squibb Rick Bertz, Ih Chang, Mike Furlong, George Hanna, Heather Sevinsky