Stavudine Extended Release Zerit XR d4T XR Stavudine Prolonged Release Capsules ATAC Meeting 22402

1
Stavudine Extended Release(Zerit XR d4T
XR)Stavudine Prolonged Release CapsulesATAC
Meeting2/24/02
2
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

3
XR/PRC Dose Selection

• Provide equivalent AUC to 40 mg BID dose (30 mg
  BID if lt 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

4
Stavudine (d4T) XR/PRC Exposure of XR vs IR
AI455-114
1000
100
Plasma Concentration (ng/mL)
10
IR-Fasting
XR-Fasting
1
0
4
8
12
16
20
24
Hour
Parameter
Trt
Geometric Mean
Point Estimate (90 CI)
Cmax
IR
692.4

ng/mL
XR
338.4
0.489 (0.431, 0.555)
AUC(24 h)
IR
3567.1

ng.h/mL
XR
3131.4
0.879 (0.835, 0.925)
5
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

6
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

7
096/099 Study Design
Screening
Enrollment (stratified HIV RNA lt30,000 or
?30,000)
Randomization 11
Patients ?60 kg
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
Patients lt60 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
8
Key Inclusion Criteria 096/099

• ART naive
• ?7/lt30 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 lt3 x ULN

9
Baseline Characteristics 096
d4T XR (n 74)
d4T IR (n 76)
Age, median, years 34 34 Gender, n () Male
54 (73) 58 (76) Female 20 (27) 18 (24) Race,
n () White 55 (74) 50 (66) Black 14 (19) 14
(18) Hispanic/Latino 5 (7) 10
(13) American/Alaskan Native 1
(1) Asian/Pacific Islander 1 (1) Region, n
() North America 50 (68) 56 (74) South
America 24 (32) 20 (26) No differences between
treatment groups were observed
10
Baseline Characteristics 096
d4T XRn 74
d4T IRn 76
P-value
HIV RNA, log10 copies/mL Median 4.69 4.63 .63 Ra
nge 2.35.9 2.95.9 CD4, cells/?L Median 354 26
1 .14 Range 75953 63962
11
Patient Disposition 096
Patients, n ()
d4T XRn 75
d4T IRn 80
Randomized 75 (100) 80 (100) Never treated 1
(1) 4 (5) Treated 74 (99) 76 (95) Premature D/C
prior to wk 48 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) Total treated patients
completing wk 48 67 (91) 62 (82)
12
096 HIV RNA Mean Change (SE) From Baseline
On Treatment
0.0
0.5
d4T XR (n 74)
1.0
d4T IR (n 76)
1.5
Log ? HIV RNA
2.0
2.5
2.64
2.74
3.0
3.5
BL
4
12
8
16
24
32
40
48
Week
d4T XR 74 68 72 71 71 70 71 68 67 62 d4T
IR 76 68 70 71 70 69 65 65 60 58
13
096 Patients With HIV RNA ltLOQ ITT NCF
(Treated Subjects)
d4T XR (n 74)
On-Treatment Values
100
d4T IR (n 76)
lt400
78
88
80
67
82
60
50
56
Patients ()
49
60
40
lt50
20
0
BL
4
12
8
16
24
32
40
48
Week
14
096 CD4 Count -Mean Change From Baseline
400
d4T XR (n 74)
d4T IR (n 76)
300
232
200
195
? CD4 (cells/?L)
100
0
BL
4
12
8
16
24
32
40
48
Week
d4T XR 74 65 70 70 70 71 68 67 68 62 d4T
IR 76 64 70 68 69 68 63 65 60 55
15
096 Selected Clinical Adverse Events Related to
Study Regimen (?Grade 2)
Patients, n ()
d4T IRn 76
d4T XRn 74
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
16
096EFV? NFV Due to Intolerance
Patients, n ()
d4T XRn 74
d4T IRn 76
Event
Total Switches 1 (1) 6 (8) Rash 3 (4) CNS
side effects 1 (1) 3 (4)(dizziness and impaired
concentration)
All 7 switches occurred at or before day 33 of
treatment
17
096Discontinuation Due to AEs
Patients, n ()
d4T XRn 74
d4T IRn 76
Event
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) Some patients D/C after wk 48 d4T XR, n1
d4T IR, n2
18
096 Selected Laboratory Abnormalities (?Grade
3/4)
Patients, n ()
d4T XRn 74
d4T IRn 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
19
096 Lactate Levels
Minimum
8
25-tile
Median
75-tile
6
Maximum
Lactate (mmol/L)
4
2
0
XR
IR
XR
IR
XR
IR
XR
IR
12
24
48
Baseline
Week
20
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 ltLOQ
• CD4 cell changes
• Safety profile

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Zerit XR/PRC Data at CROI

• 24 week results -099
• Poster 411-W, Session 60
• -096 Population PK substudy
• Poster 430-W, Session 62
• Single vs multiple dose PK
• Poster 429-W, Session 62
• All Wed 430-630 pm

22
099 VRT-ITTVirologic Response Rates Week 24
lt400 c/mL
lt50 c/mL
undetectable
Reference Study BMS AI455-099. Pollard R et al.
9th CROI, Seattle, Feb 2002. Poster 411-W