Brett-Smith, ATAC, 2/24/02 Stavudine Extended Release (Zerit XR;

Brett-Smith, ATAC, 2/24/02 Stavudine Extended Release (Zerit XR; d4T XR) Stavudine Prolonged Release Capsules ATAC Meeting 2/24/02 Brett-Smith, ATAC, 2/24/02 XR/PRC Formulation Simplification of HAART regimen Extended release formulation required to address short half-life of d4T Formulation d4T beads Extended release coating Coated beads packaged in capsule Brett-Smith, ATAC, 2/24/02 XR/PRC Dose Selection Provide equivalent AUC to 40 mg BID

dose (30 mg BID if < 60 kg) lower absorption from colon than from stomach/upper intestine (26% vs approx 100%) XR/PRC releases drug over 16-18 hrs XR/PRC delivers drug in lower intestine Brett-Smith, ATAC, 2/24/02 Plasma Concentration (ng/mL) Stavudine (d4T) XR/PRC Exposure of XR vs IR: AI455-114 1000 100 10 IR-Fasting XR-Fasting 1 0 4 8 12 16 20 24 Hour

Parameter Cmax [ng/mL] AUC(24 h) [ng.h/mL] Trt IR XR IR XR Geometric Mean 692.4 338.4 3567.1 3131.4 Point Estimate (90% CI) 0.489 (0.431, 0.555) 0.879 (0.835, 0.925) Brett-Smith, ATAC, 2/24/02 Stavudine XR/PRC: Summary of Clinical Pharmacology Studies Total daily exposure (AUC) for 100 mg XR is equivalent to 40 mg BID IR, uncorrected for dose Cmax is ~50% lower and Cmin is ~2-3 fold higher for XR vs IR

XR may be taken without regard to meals Single-dose and steady-state kinetics of XR are similar (no accumulation) d4T XR exhibits linear kinetics over 37.5-100 mg Brett-Smith, ATAC, 2/24/02 Stavudine XR/PRC Development AI455-096: Proof of Principle Study N = 150 antiretroviral-naive adults AI455-099: Pivotal Study N = 783 antiretroviral-naive adults Both Randomized, active-controlled for 48 weeks d4T XR 100 mg QD + 3TC + EFV vs d4T IR 40 mg BID + 3TC + EFV AI455-110: Long-term follow-up Open-label maintenance of 096/099 regimens Safety monitoring and durability years 2 and 3 Brett-Smith, ATAC, 2/24/02

096/099 Study Design Screening Enrollment (stratified: HIV RNA <30,000 or 30,000) Randomization 1:1 Patients 60 kg Group I Group II d4T XR 100 mg QD d4T IR placebo 40 mg BID d4T XR placebo 100 mg QD d4T IR 40 mg BID Patients <60 kg d4T XR 75 mg QD d4T IR placebo 30 mg BID d4T XR placebo 75 mg QD d4T IR 30 mg BID All subjects received 3TC 150 mg BID + EFV 600 mg QD EFV NFV allowed in cases of EFV intolerance Brett-Smith, ATAC, 2/24/02 Key Inclusion Criteria: 096/099 ART naive 7/<30 days of NRTI, NNRTI, or PI therapy No ART during the 14 days prior to randomization

HIV RNA 5000 (096); 2000 (099) CD4 100 75 for patients with no prior AIDS-defining event Lab values 14 days prior to initiating therapy Serum creatinine 1.5 x ULN Total serum lipase 1.4 x ULN AST/ALT <3 x ULN Brett-Smith, ATAC, 2/24/02 Baseline Characteristics 096* d4T XR (n = 74) d4T IR (n = 76) 34 34 Male 54 (73) 58 (76) Female 20 (27)

18 (24) White 55 (74) 50 (66) Black 14 (19) 14 (18) 5 (7) 10 (13) American/Alaskan Native 1 (1) Asian/Pacific Islander 1 (1) North America 50 (68) 56 (74) South America 24 (32)

20 (26) Age, median, years Gender, n (%) Race, n (%) Hispanic/Latino Region, n (%) *No differences between treatment groups were observed Brett-Smith, ATAC, 2/24/02 Baseline Characteristics 096 d4T XR n = 74 d4T IR n = 76 P-value .63 HIV RNA, log10 copies/mL Median 4.69 4.63 Range 2.35.9 2.95.9

Median 354 261 Range 75953 63962 CD4, cells/L .14 Brett-Smith, ATAC, 2/24/02 Patient Disposition 096 Patients, n (%) d4T XR n = 75 d4T IR n = 80 Randomized 75 (100) 80 (100) Never treated 1 (1) 4 (5) 74 (99)

76 (95) 7 (9) 14 (18) Disease progression 2 (3) 2 (3) Subject withdrew 2 (3) 1 (1) Adverse event 1 (1) 5 (6) Nonadherence 1 (1) 4 (5) Lost to follow-up 1 (1) 2 (3) 67 (91)

62 (82) Treated Premature D/C prior to wk 48 Total treated patients completing wk 48 Brett-Smith, ATAC, 2/24/02 096: HIV RNA Mean Change (SE) From Baseline On Treatment Log HIV RNA 0.0 0.5 d4T XR (n = 74) 1.0 d4T IR (n = 76) 1.5 2.0 2.5 2.64 2.74 3.0 3.5 BL 4 8 12

16 24 32 40 48 68 65 67 60 62 58 Week d4T XR: 74 68 72 d4T IR: 76 68 70 71 71 71 70 70 69 71 65 Brett-Smith, ATAC, 2/24/02 096: Patients With HIV RNA

ITT: NC=F (Treated Subjects) d4T XR (n = 74) 100 On-Treatment Values d4T IR (n = 76) %<400 78% 88% Patients (%) 80 67% 82% 60 50% 56% 49% 60% 40 %<50 20 0 BL 4 8 12 16

24 Week 32 40 48 Brett-Smith, ATAC, 2/24/02 096: CD4 Count Mean Change From Baseline 400 CD4 (cells/L) d4T XR (n = 74) d4T IR (n = 76) 300 232 200 195 100 0 BL 4 8 12 16

24 32 40 48 67 65 68 60 62 55 Week d4T XR: d4T IR: 74 65 70 70 76 64 70 68 70 69 71 68 68 63 Brett-Smith, ATAC, 2/24/02 096: Selected Clinical Adverse Events Related to Study Regimen (Grade 2) Patients, n (%) d4T XR

n = 74 d4T IR n = 76 Neuropathy 1 (1) 8 (11) Headache 5 (7) 1 (1) Fatigue 4 (5) 2 (3) Nausea 3 (4) 3 (4) Diarrhea 3 (4) 1 (1) Vomiting 2 (3)

2 (3) GI Disorder 3 (4) 0 Brett-Smith, ATAC, 2/24/02 096:EFV NFV Due to Intolerance Patients, n (%) Event Total Switches Rash d4T XR n = 74 d4T IR n = 76 1 (1) 6 (8) 3 (4) CNS side effects 1 (1) (dizziness and impaired concentration) 3 (4)

All 7 switches occurred at or before day 33 of treatment Brett-Smith, ATAC, 2/24/02 096:Discontinuation Due to AEs Patients, n (%) d4T XR n = 74 d4T IR n = 76 Any event* 2 (3) 7 (9) GI bleeding 1 (1) Peripheral neurologic symptoms 1 (1) 4 (5) Facial muscle wasting 1 (1) Rash

1 (1) Severe nausea, vomiting and headache 1 (1) Event *Some patients D/C after wk 48: d4T XR, n=1; d4T IR, n=2 Brett-Smith, ATAC, 2/24/02 096: Selected Laboratory Abnormalities (Grade 3/4) Patients, n (%) d4T XR n = 74 d4T IR n = 76 AST/SGOT 2 (3) 3 (4) ALT/SGPT 2 (3) 3 (4) Alkaline Phosphatase

1 (1) Hemoglobin 1 (1) 1 (1) Other lab parameters, including fasting triglycerides, total cholesterol, and HDL cholesterol were similar between treatment groups Brett-Smith, ATAC, 2/24/02 096: Lactate Levels Minimum 25%-tile Median 75%-tile Maximum Lactate (mmol/L) 8 6 4 2 0 XR IR Baseline XR 12 IR

XR 24 IR Week XR 48 IR Brett-Smith, ATAC, 2/24/02 096 Conclusions Over 24-48 weeks, d4T XR (QD) in triple combination with 3TC + EFV was similar to d4T IR (BID) with regard to HIV RNA

099 VRT-ITT Virologic Response Rates: Week 24 % undetectable 100 <400 c/mL d4T XR d4T IR 75 <50 c/mL 50 25 0 BL 4 8 12 16 20 24 Reference: Study BMS AI455-099. Pollard R et al. 9th CROI, Seattle, Feb 2002. Poster 411-W

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