Update on Atazanavir and the Early Access Program

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 vitro 219 times more potent
  than available PIs IC50 25 nM IC90 812 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 ? in HIV
RNA by Week 2 Supports 400 mg Dose
Mean values
200 mg QD
400 mg QD
500 mg QD
N21
500
400
N13
200
N22
)
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 2000442319.
6
Atazanavir PK Properties

• Favorable oral bioavailability (gt 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
N14
CMIN220184 ng/mL
CMIN133101 ng/mL
N6
CMIN3320 ng/mL
N14
N6
CMIN1916 ng/mL
8
Drug-Drug Interaction StudiesCompleted with
dosing implications
9
PK Data ATV/RTV
10
PK Data ATV (300 mg) /- RTV
11
Drug-Drug Interaction StudiesCompleted 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 gt 2.5 x ULN
60
Dose reductions for grade 4 gt 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
HyperbilirubinemiaRelationship 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
(No Transcript)
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ECG Signal
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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
20
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
21
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
16
48
4
20
8
12
40
44
32
24
28
36
Week
Sanne. ICAAC 2001.
22
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
16
48
4
20
8
12
40
44
32
24
28
36
Week
Sanne. ICAAC 2001.
23
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
16
48
4
20
8
12
40
44
32
24
28
36
Week
Plt0.05, atazanavir vs nelfinavir. Sanne. ICAAC
2001.
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Study 008 Atazanavir vs Nelfinavir CD4 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
16
48
4
20
8
12
40
44
32
24
28
36
Week
Sanne. ICAAC 2001.
25
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 gt20 in
any treatment group.

Plt0.0001, atazanavir 400 mg and 600 mg vs
nelfinavir. Sanne. ICAAC 2001.
26
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.
27
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.
28
Study 009 Atazanavir/SQV vs RTV/SQV in Subjects
With Prior Failure HIV RNA Response (gt1.0 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.
29
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 1
8 18 15 13
Haas. ICAAC 2001.
30
AI424-009
Total Cholesterol and Triglycerides at 24 Weeks
Total Cholesterol
Triglycerides
210
25
180
20
150
15
120
10
Mean change ()
90
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
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Phase III overview
Treatment Experienced
Treatment Naive
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 gt
2 failure
AI424-043 vs lopinavir/r in PI failures
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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

33
Atazanavir Phase III Study 034

• Double blind, double dummy, randomized
• N 810 naive subjects, powered for ltLOQ
• EFV vs Atazanavir AZT 3TC as NRTI
• Metabolic endpoints
• Insulin, C-peptide
• DEXA, CT
• Fasting Lipids
• Assessment of reduction in CV risk

34
Atazanavir Phase III Study 037

• Double blind, double dummy, randomized
• N 400 PI-naive subjects, NRTI-experienced
  powered for ltLOQ
• Atazanavir vs NFV genotype to select NRTI
• Metabolic endpoints
• Insulin, C-peptide
• DEXA, CT
• Fasting Lipids
• Assessment of reduction in CV risk

35
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

36
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

37
Atazanavir EAP

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

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Atazanavir EAP eligibility

• Absolute CD4 countlt 300 cells/mm3
• Plasma HIV RNAgt 5000 cp/ml
• Unable to construct an alternate regimen -
  virologic failure or- intolerance

• Refractory Treatment-related hyperlipidemia
  independent of - HIV RNA - CD4 count

39
Atazanavir EAP Exclusions

• Cardiac
• Liver Enzymes
• Need for certain ARV agents

• Clinical and ECG criteria
• ALT, bilirubin
• Ritonavir, Kaletra, Indinavir, Efavirenz

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Atazanavir EAP

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

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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