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 n Simplification of HAART regimen n Extended release formulation required to address short half-life of d4T n Formulation —d4T beads —Extended release coating —Coated beads packaged in capsule

Brett-Smith, ATAC, 2/24/02 XR/PRC Dose Selection n Provide equivalent AUC to 40 mg BID dose (30 mg BID if < 60 kg) n lower absorption from colon than from stomach/upper intestine (26% vs approx 100%) n XR/PRC releases drug over hrs n XR/PRC delivers drug in lower intestine

Brett-Smith, ATAC, 2/24/02 Stavudine (d4T) XR/PRC Exposure of XR vs IR: AI ParameterTrtGeometric MeanPoint Estimate (90% CI) C max [ng/mL] IR XR – (0.431, 0.555) AUC(24 h) [ng.h/mL] IR XR – (0.835, 0.925) Hour Plasma Concentration (ng/mL) IR-Fasting XR-Fasting

Brett-Smith, ATAC, 2/24/02 Stavudine XR/PRC: Summary of Clinical Pharmacology Studies n Total daily exposure (AUC) for 100 mg XR is equivalent to 40 mg BID IR, uncorrected for dose n C max is ~50% lower and C min is ~2-3 fold higher for XR vs IR n XR may be taken without regard to meals n Single-dose and steady-state kinetics of XR are similar (no accumulation) n d4T XR exhibits linear kinetics over mg

Brett-Smith, ATAC, 2/24/02 Stavudine XR/PRC Development n AI : Proof of Principle Study —N = 150 antiretroviral-naive adults n AI : Pivotal Study —N = 783 antiretroviral-naive adults n Both —Randomized, active-controlled for 48 weeks —d4T XR 100 mg QD + 3TC + EFV vs d4T IR 40 mg BID + 3TC + EFV n AI : 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 Group I d4T XR 100 mg QD d4T IR placebo 40 mg BID Group II d4T XR placebo 100 mg QD d4T IR 40 mg BID d4T XR 75 mg QD d4T IR placebo 30 mg BID d4T XR placebo 75 mg QD d4T IR 30 mg BID Patients  60 kg Patients <60 kg Screening Enrollment (stratified: HIV RNA <30,000 or  30,000) Randomization 1:1 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 n ART naive —  7/<30 days of NRTI, NNRTI, or PI therapy —No ART during the 14 days prior to randomization n HIV RNA  5000 (096);  2000 (099) n CD4  100 —  75 for patients with no prior AIDS-defining event n 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* Age, median, years 3434 Gender, n (%) Male 54 (73)58 (76) Female 20 (27)18 (24) Race, n (%) White55 (74)50 (66) Black14 (19)14 (18) Hispanic/Latino5 (7)10 (13) American/Alaskan Native–1 (1) Asian/Pacific Islander – 1 (1) Region, n (%) North America50 (68)56 (74) South America24 (32)20 (26) *No differences between treatment groups were observed d4T XR (n = 74)d4T IR (n = 76)

Brett-Smith, ATAC, 2/24/02 Baseline Characteristics 096 HIV RNA, log 10 copies/mL Median Range2.3–5.92.9–5.9 CD4, cells/  L Median Range75–95363–962 d4T XR n = 74 d4T IR n = 76 P-value

Brett-Smith, ATAC, 2/24/02 Patient Disposition 096 Randomized75 (100)80 (100) Never treated1 (1)4 (5) Treated74 (99)76 (95) Premature D/C prior to wk 487 (9)14 (18) Disease progression2 (3)2 (3) Subject withdrew2 (3)1 (1) Adverse event1 (1)5 (6) Nonadherence1 (1)4 (5) Lost to follow-up1 (1)2 (3) Total treated patients completing wk 4867 (91)62 (82) d4T XR n = 75 d4T IR n = 80 Patients, n (%)

Brett-Smith, ATAC, 2/24/02 096: HIV RNA Mean Change (±SE) From Baseline –3.5 BL Log  HIV RNA Week d4T XR: d4T IR: –2.64 –3.0 –2.5 –2.0 –1.5 –1.0 –0.5 –0.0 –2.74 d4T XR (n = 74) d4T IR (n = 76) On Treatment

Brett-Smith, ATAC, 2/24/02 096: Patients With HIV RNA <LOQ ITT: NC=F (Treated Subjects) BL Patients (%) Week %<50 %<400 78% 67% 50% 49% d4T XR (n = 74) d4T IR (n = 76) On-Treatment Values 88% 82% 60% 56%

Brett-Smith, ATAC, 2/24/02 096: CD4 Count - Mean Change From Baseline BL  CD4 (cells/  L) Week d4T XR: d4T IR: d4T XR (n = 74) d4T IR (n = 76)

Brett-Smith, ATAC, 2/24/02 096: Selected Clinical Adverse Events Related to Study Regimen (  Grade 2) Neuropathy1 (1)8 (11) Headache5 (7)1 (1) Fatigue4 (5)2 (3) Nausea3 (4)3 (4) Diarrhea3 (4)1 (1) Vomiting2 (3)2 (3) GI Disorder3 (4)0 d4T XR n = 74 d4T IR n = 76 Patients, n (%)

Brett-Smith, ATAC, 2/24/02 096:EFV  NFV Due to Intolerance Total Switches1 (1)6 (8) Rash–3 (4) CNS side effects1 (1)3 (4) (dizziness and impaired concentration) Event d4T XR n = 74 d4T IR n = 76 Patients, n (%) All 7 switches occurred at or before day 33 of treatment

Brett-Smith, ATAC, 2/24/02 096:Discontinuation Due to AEs Any event*2 (3)7 (9) GI bleeding1 (1) – Peripheral neurologic symptoms1 (1)4 (5) Facial muscle wasting–1 (1) Rash – 1 (1) Severe nausea, vomiting and headache –1 (1) *Some patients D/C after wk 48: d4T XR, n=1; d4T IR, n=2 Event d4T XR n = 74 d4T IR n = 76 Patients, n (%)

Brett-Smith, ATAC, 2/24/02 096: Selected Laboratory Abnormalities (  Grade 3/4) AST/SGOT2 (3)3 (4) ALT/SGPT2 (3)3 (4) Alkaline Phosphatase1 (1)– Hemoglobin1 (1)1 (1) Other lab parameters, including fasting triglycerides, total cholesterol, and HDL cholesterol were similar between treatment groups d4T XR n = 74 d4T IR n = 76 Patients, n (%)

Brett-Smith, ATAC, 2/24/02 096: Lactate Levels XRIRXRIRXRIRXRIR Week Lactate (mmol/L) 25%-tile Minimum Maximum 75%-tile Baseline Median

Brett-Smith, ATAC, 2/24/ Conclusions n Over weeks, d4T XR (QD) in triple combination with 3TC + EFV was similar to d4T IR (BID) with regard to —HIV RNA <LOQ —CD4 cell changes —Safety profile

Brett-Smith, ATAC, 2/24/02 Zerit XR/PRC Data at CROI n 24 week results -099; Poster 411-W, Session 60; n -096 Population PK substudy Poster 430-W, Session 62; n Single vs multiple dose PK; Poster 429-W, Session 62 n All Wed 4:30-6:30 pm

Brett-Smith, ATAC, 2/24/ VRT-ITT Virologic Response Rates: Week 24 % undetectable <400 c/mL <50 c/mL Reference: Study BMS AI Pollard R et al. 9th CROI, Seattle, Feb Poster 411-W