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Update on Atazanavir and the Early Access Program

Update on Atazanavir and the Early Access Program. AIDS Treatment Activists Coalition Seattle, Washington February 24 2001. Atazanavir Profile. Azapeptide inhibitor of HIV protease Dosed 400 mg QD with food (2 capsules) Favorable potency and resistance profile

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Update on Atazanavir and the Early Access Program

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  1. Update on Atazanavir and the Early Access Program AIDS Treatment Activists Coalition Seattle, Washington February 24 2001

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

  3. Atazanavir: Antiviral Properties • Azapeptide inhibitor of HIV protease • Potent activity in vitro2–19 times more potent than available PIs IC50 2–5 nM IC90 8–12 nM • Demonstrated potency in vivo 1.5 log decline in HIV RNA • Favorable resistance profile in vitro

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

  5. Atazanavir SensitivityClinical Isolates • 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 • Multiple amino acid substitutions required to significantly lose sensitivity Gong. Antimicrob Agents Chemother 2000;44:2319.

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

  7. Effect of a Light Meal upon Steady-State PK at 200 and 400 mg QD N=14 CMIN=220+184 ng/mL CMIN=133+101 ng/mL N=6 CMIN=33+20 ng/mL N=14 N=6 CMIN=19+16 ng/mL

  8. Drug-Drug Interaction Studies:Completed with dosing implications

  9. PK Data: ATV/RTV

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

  11. Drug-Drug Interaction Studies:Completed with dosing implications

  12. Hyperbilirubinemia: Bilirubin Physiology ATV IDV * ICT = Intracellular transport

  13. Atazanavir Bilirubin Elevations - data from AI424-007/008 70 Grade 3-4 = > 2.5 x ULN 60 Dose reductions for grade 4 = > 5 x ULN 50 Events (%) 40 30 20 24% 12% 15% 10 0% 0 ATV 200 mg ATV 400 mg ATV 500 mg ATV 600 mg Treated (N) 102 279 107 195 Seven patients discontinued for bilirubin elevations

  14. Hyperbilirubinemia:Relationship to dose and reversibility (Light meal)

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

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

  17. ECG Signal

  18. Atazanavir Clinical Program -037 (NFV) -007, -008 (NFV) -045 + RTV Nelfinavir -043 (LOP/R) -034 (EFV) -009 (RTV/SQV) -900 (EAP) Efavirenz Salvage Naive Experienced

  19. Atazanavir Phase II Studies AI424-007 (Stage I n = 98, Stage II n = 322) Treatment-Naive 2 weeks monotherapy ATV 200, 400 or 500 mg QD vs+ ddI + d4T NFV 750 mg TID AI424-008 (n = 467) Treatment-Naive ATV 400 or 600 mg QD vs+ d4T + 3TC NFV 1250 mg BID AI424-009 (n = 85) Treatment-Experienced ATV 400/600mg QD + SQV 1200 mg QD 2 NRTIs vs+ (sensitive) RTV 400mg BID + SQV 400 mg BID

  20. Study 008: Atazanavir vs NelfinavirHIV RNA Median Change From Baseline 0.0 Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) –0.5 –1.0 Change (log10 c/mL, SE) –1.5 –2.0 –2.5 –3.0 B/L 8 20 40 4 12 16 44 48 28 24 32 36 Week Sanne. ICAAC; 2001.

  21. Study 008: Atazanavir vs Nelfinavir Treatment Response at 48 Weeks (ITT) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) 100 80 LOQ = 400 c/mL 60 Subjects (%) LOQ = 50 c/mL 40 20 0 B/L 8 20 28 40 4 12 16 24 32 36 44 48 Week Sanne. ICAAC; 2001.

  22. Study 008: Atazanavir vs Nelfinavir Treatment Response (As Treated) Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) 100 * 80 LOQ = 400 c/mL 60 LOQ = 50 c/mL Subjects (%) 40 20 0 B/L 8 20 40 4 12 16 44 48 28 24 32 36 Week *P<0.05, atazanavir vs nelfinavir. Sanne. ICAAC; 2001.

  23. Study 008: Atazanavir vs NelfinavirCD4 Median Change From Baseline Atazanavir 400 mg (n = 181) Atazanavir 600 mg (n = 195) Nelfinavir (n = 91) 300 250 200 CD4 (cells/mm3, SE) 150 100 50 0 B/L 8 20 28 40 4 12 16 24 32 36 44 48 Week Sanne. ICAAC; 2001.

  24. Study 008: Atazanavir vs Nelfinavir Clinical Adverse Events* at 48 Weeks Atazanavir 400 mg 600 mg Nelfinavir (n = 178) (n = 195) (n = 91) 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) *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.

  25. 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 PI 28 (88) 23 (85) 20 (87) IDV 16 (50) 7 (26) 5 (22) NFV 12 (38) 18 (67) 15 (65) RTV 1 (3) 1 (4) 1 (4) SQV 3 (9) 0 0 Any NNRTI 6 (19) 6 (22) 7 (30) DLV 0 0 1 (4) EFV 2 (6) 1 (4) 3 (13) NVP 4 (13) 4 (15) 4 (17) Emivirine 0 1 (4) 0 Haas. ICAAC; 2001.

  26. Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA: Mean Change From Baseline 0.0 ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) –0.5 Change (SE) –1.0 –1.5 –2.0 B/L 4 8 12 16 20 24 Week Group: Number at risk Atazanavir 400: 34 30 30 30 29 29 29 Atazanavir 600: 28 23 24 22 23 20 22 Ritonavir: 23 20 20 17 18 14 13 Haas. ICAAC; 2001.

  27. Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA Response (>1.0 log10 or LOQ = 50 c/mL) ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) 100 80 60 Responders (%) 40 20 0 8 16 B/L 4 12 20 24 Week Haas. ICAAC; 2001.

  28. Study 009: ATV/SQV vs RTV/SQV in Subjects With Prior Failure CD4 Median (SE) Cell Count ATV 400 mg (n = 34) ATV 600 mg (n = 28) RTV (n = 23) 650 600 550 500 CD4 450 400 350 300 250 B/L 4 8 12 16 20 24 Week Group: Number at risk ATV 400: 34 30 30 31 28 28 29 ATV 600: 28 24 25 23 23 21 22 RTV: 23 19 20 18 18 15 13 Haas. ICAAC; 2001.

  29. Atazanavir 400 mg (n = 32) Atazanavir 600 mg (n = 27) Ritonavir (n = 23) Atazanavir 400 mg (n = 32) Atazanavir 600 mg (n = 27) Ritonavir (n = 23) AI424-009 Total Cholesterol and Triglycerides at 24 Weeks Total Cholesterol Triglycerides 210 25 180 20 150 15 120 10 90 Mean change (%) 5 0 60 –5 30 –10 0 –15 –30 –20 –60 B/L 4 8 12 16 20 24 B/L 4 8 12 16 20 24 Week Week Group: Number at risk Atazanavir 400: 32 31 30 30 28 28 27 Atazanavir 600: 27 24 24 21 21 19 20 Ritonavir: 23 20 20 17 17 15 13 Group: Number at risk 27 20 22 19 19 17 15 22 14 13 12 9 10 13 18 12 10 10 9 9 8

  30. Phase III overview Treatment Naive Treatment Experienced 1st treatment 2nd treatment Heavily experienced AI424-034 vs efavirenz AI424-037 vs nelfinavir in non PI failures AI424-045 with tenofovir vs lopinavir/r in > 2 failure AI424-043 vs lopinavir/r in PI failures

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

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

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

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

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

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

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

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

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

  40. Atazanavir EAP • Study conduct through CRO (PPD)- North America Tel: 1 (877) - 726 - 7327- Europe and Australia individual numbers by country PPD Brussels + 32 27232899

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