Update on Atazanavir and the Early Access Program AIDS Treatment Activists Coalition Seattle, Washington February

Atazanavir Profile n Azapeptide inhibitor of HIV protease n Dosed 400 mg QD with food (2 capsules) n Favorable potency and resistance profile n Superior lipid profile to NFV or RTV/SQV n Safety, efficacy, tolerability demonstrated in Phase II Studies l Rapidly, durably suppresses HIV RNA l Durably increases CD4 count

Atazanavir: Antiviral Properties n Azapeptide inhibitor of HIV protease n Potent activity in vitro 2–19 times more potent than available PIs IC 50 2–5 nM IC 90 8–12 nM n Demonstrated potency in vivo 1.5 log decline in HIV RNA n Favorable resistance profile in vitro

Dose Selection: Probability of 1.5 Log Δ in HIV RNA by Week 2 Supports 400 mg Dose ) 500 N=22 N=13 N=21 Mean values: 200 mg QD 400 mg QD 500 mg QD

Gong. Antimicrob Agents Chemother 2000;44:2319. Atazanavir Sensitivity Clinical Isolates n Atazanavir displays a distinct sensitivity profile against a large panel of resistant isolates —Sensitivity retained against 71 of 74 (96%) isolates resistant to 1 to 2 PIs —Reduced sensitivity to atazanavir observed against isolates resistant to 4 or 5 PIs n Multiple amino acid substitutions required to significantly lose sensitivity

Atazanavir: PK Properties n Favorable oral bioavailability (> 50%) n Increased absorption in fed state n Prolonged t1/2 - comfortable Cmin cushion over IC50 n Distributes widely (CSF, semen) n Metabolized via CYP3A4 Ki =2.2  M, versus ritonavir (Ki =0.1  M), indinavir (Ki =0.4  M)

CMIN= ng/mL CMIN= ng/mL CMIN=33+20 ng/mL CMIN=19+16 ng/mL Effect of a Light Meal upon Steady- State PK at 200 and 400 mg QD N=14 N=6 N=14 N=6

Drug-Drug Interaction Studies: Completed with dosing implications

PK Data: ATV/RTV

PK Data: ATV (300 mg) +/- RTV

Drug-Drug Interaction Studies: Completed with dosing implications

Hyperbilirubinemia: Bilirubin Physiology * ICT = Intracellular transport

ATV 200 mgATV 400 mgATV 500 mgATV 600 mg Atazanavir Bilirubin Elevations Events (%) Seven patients discontinued for bilirubin elevations Grade 3-4 = > 2.5 x ULN Dose reductions for grade 4 = > 5 x ULN Treated (N) % 15% 12% 24% - data from AI /008

Hyperbilirubinemia: Relationship to dose and reversibility (Light meal)

Hyperbilirubinemia: Conclusions n Unconjugated hyperbilirubinemia, 40% n Scleral icterus, 5-10% n Without clinical significance - asymptomatic - without effect on liver enzymes - no effect on virologic/CD4 response n Rapidly reversible with drug interruption

Electrocardiogram Changes n Observations - dose dependent asymptomatic increases in QTc and PR intervals n Safety analyses - preclinical (ion channels, HERG) - clinical (ECGs, drug-drug effects)

ECG Signal

Naive Experienced Salvage Nelfinavir -037 (NFV) -007, -008 (NFV) -034 (EFV) Efavirenz Atazanavir Clinical Program -009 (RTV/SQV) -043 (LOP/R) -900 (EAP) RTV

AI (Stage I n = 98, Stage II n = 322) Treatment-Naive ATV 200, 400 or 500 mg QD vs + ddI + d4T NFV 750 mg TID 2 weeks monotherapy ATV 400 or 600 mg QD vs + d4T + 3TC NFV 1250 mg BID AI (n = 467) Treatment-Naive ATV 400/600mg QD + SQV 1200 mg QD2 NRTIs vs + (sensitive) RTV 400mg BID + SQV 400 mg BID AI (n = 85) Treatment-Experienced Atazanavir Phase II Studies

0.0 B/L Week –2.0 –3.0 –1.0 –0.5 –1.5 –2.5 Change (log 10 c/mL,  SE) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) Sanne. ICAAC; Study 008: Atazanavir vs Nelfinavir HIV RNA Median Change From Baseline

Study 008: Atazanavir vs Nelfinavir Treatment Response at 48 Weeks (ITT) LOQ = 400 c/mL 100 B/L Week Subjects (%) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) LOQ = 50 c/mL Sanne. ICAAC; 2001.

Study 008: Atazanavir vs Nelfinavir Treatment Response (As Treated) Week Subjects (%) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) *P<0.05, atazanavir vs nelfinavir. Sanne. ICAAC; LOQ = 400 c/mL 400 c/mL 100 B/L LOQ = 50 c/mL 50 c/mL *

Study 008: Atazanavir vs Nelfinavir CD4 Median Change From Baseline 300 B/L Week CD4 (cells/mm 3,  SE) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) Sanne. ICAAC; 2001.

Study 008: Atazanavir vs Nelfinavir Clinical Adverse Events* at 48 Weeks Diarrhea 36 (20) † 29 (15) † 51 (56) Infection 75 (42)107 (55)44 (48) Headache 45 (25) 52 (27)24 (26) Pain (abdomen) 33 (19) 43 (22)12 (13) Periph neuro symptoms 32 (18) 42 (22)19 (21) Rash 39 (22) 34 (17)17 (19) Nausea 38 (21) 35 (18)16 (18) Atazanavir 400 mg600 mg Nelfinavir (n = 178)(n = 195)(n = 91) *Grade 1-4, reported with a frequency of >20% in any treatment group. † P<0.0001, atazanavir 400 mg and 600 mg vs nelfinavir. Sanne. ICAAC; 2001.

Study 009: ATV/SQV vs RTV/SQV in Subjects With Prior Failure Previous ARV Therapy ATV 400 mg 600 mg NFV (n = 32) (n = 27) (n = 23) Any PI28 (88) 23 (85) 20 (87) IDV16 (50) 7 (26) 5 (22) NFV12 (38) 18 (67) 15 (65) RTV 1 (3) 1 (4) 1 (4) SQV3 (9) 0 0 Any NNRTI6 (19) 6 (22)7 (30) DLV0 0 1 (4) EFV2 (6) 1 (4) 3 (13) NVP4 (13)4 (15)4 (17) Emivirine0 1 (4) 0 Haas. ICAAC; 2001.

Group: Number at risk Atazanavir 400: Atazanavir 600: Ritonavir: –0.5 – Change (  SE) –2.0 –1.0 B/L Week Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA: Mean Change From Baseline ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) Haas. ICAAC; 2001.

Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA Response (>1.0 log 10 or LOQ = 50 c/mL) B/L Week Responders (%) 0 40 ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) Haas. ICAAC; 2001.

Study 009: ATV/SQV vs RTV/SQV in Subjects With Prior Failure CD4 Median (SE) Cell Count B/L CD4 250 Week Haas. ICAAC; ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) Group: Number at risk ATV 400: ATV 600: RTV:

AI Total CholesterolTriglycerides Group: Number at risk Atazanavir 400: Atazanavir 600: Ritonavir: Mean change (%) B/L Week Atazanavir 400 mg (n = 32) Atazanavir 600 mg (n = 27) Ritonavir (n = 23)– – –15 – Group: Number at risk –30 –60 60 B/L Week Total Cholesterol and Triglycerides at 24 Weeks Atazanavir 400 mg (n = 32) Atazanavir 600 mg (n = 27) Ritonavir (n = 23)

Treatment ExperiencedTreatment Naive Phase III overview 1st treatment2nd treatmentHeavily experienced AI vs efavirenz AI vs nelfinavir in non PI failuresAI with tenofovir vs lopinavir/r in > 2 failure AI vs lopinavir/r in PI failures

Atazanavir General Goals for Phase III n Compare efficacy to EFV in ARV-naive population n Compare safety, tolerability and efficacy vs LPV/RTV in PI-failure population n Assess role in highly treatment experienced population when combined with RTV and tenofovir

Atazanavir Phase III Study 034 n Double blind, double dummy, randomized n N = 810 naive subjects, powered for % <LOQ n EFV vs Atazanavir: AZT + 3TC as NRTI n Metabolic endpoints —Insulin, C-peptide —DEXA, CT —Fasting Lipids n Assessment of reduction in CV risk

Atazanavir Phase III Study 037 n Double blind, double dummy, randomized n N = 400 PI-naive subjects, NRTI-experienced powered for % <LOQ n Atazanavir vs NFV: genotype to select NRTI n Metabolic endpoints —Insulin, C-peptide —DEXA, CT —Fasting Lipids n Assessment of reduction in CV risk

Atazanavir Phase II/III Study 043 n Open label, randomized, for PI-failure, n = 200 n Atazanavir vs LPV/RTV genotype to select NRTI n Metabolic endpoints insulin, C-peptide, LDL, T-Chol, HDL, TG n Assessment of CV risk reduction n QOL assessments

Atazanavir Phase II/III Study 045 n Open-label, randomized, comparative study n 3-class, 2-regimen failure n 3-arm —ATV/RTV + tenofovir and NRTI —ATV/SQV + tenofovir and NRTI —LPV/RTV + tenofovir and NRTI n 2 week single substitution n Assess HIV RNA and lipid safety

Atazanavir EAP n Initiation, April 2002 (pending FDA comments) n Global program for patients in need n Entry criteria n Concomitant ARV agents n Data collection

Atazanavir EAP: eligibility n Absolute CD4 count < 300 cells/mm3 n Plasma HIV RNA > 5000 cp/ml n Unable to construct an alternate regimen - virologic failure or - intolerance n Refractory Treatment-related hyperlipidemia independent of - HIV RNA - CD4 count

Atazanavir EAP: Exclusions n Cardiac n Liver Enzymes n Need for certain ARV agents n Clinical and ECG criteria n ALT, bilirubin n Ritonavir, Kaletra, Indinavir, Efavirenz

Atazanavir EAP n Infrequent study visits n 2-month drug supply n Limited mandatory safety data collection - ALT, bilirubin - ECGs (2)

Atazanavir EAP n Study conduct through CRO (PPD) - North America Tel: 1 (877) Europe and Australia individual numbers by country PPD Brussels