brett-smith, atac, 2/24/02 stavudine extended release (zerit ® xr; d4t xr) stavudine prolonged...
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Brett-Smith, ATAC, 2/24/02
Stavudine Extended Release(Zerit® XR; d4T XR)
Stavudine Prolonged Release Capsules
ATAC Meeting2/24/02
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Brett-Smith, ATAC, 2/24/02
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
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Brett-Smith, ATAC, 2/24/02
XR/PRC Dose Selection
Provide equivalent AUC to 40 mg BID dose (30 mg BID if < 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
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Brett-Smith, ATAC, 2/24/02
Stavudine (d4T) XR/PRC Exposure of XR vs IR: AI455-114
Parameter Trt Geometric Mean Point Estimate (90% CI)
Cmax
[ng/mL]IRXR
692.4338.4
–0.489 (0.431, 0.555)
AUC(24 h)[ng.h/mL]
IRXR
3567.13131.4
–0.879 (0.835, 0.925)
0 4 8 12 16 20 24
Hour
1
10
100
1000
Pla
sma
Co
nce
ntr
atio
n (
ng
/mL
)
IR-Fasting
XR-Fasting
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Brett-Smith, ATAC, 2/24/02
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
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Brett-Smith, ATAC, 2/24/02
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
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Brett-Smith, ATAC, 2/24/02
096/099 Study Design
Group I
d4T XR 100 mg QDd4T IR placebo 40 mg BID
Group II
d4T XR placebo 100 mg QDd4T IR 40 mg BID
d4T XR 75 mg QDd4T IR placebo 30 mg BID
d4T XR placebo 75 mg QDd4T 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 QDEFV NFV allowed in cases of EFV intolerance
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Brett-Smith, ATAC, 2/24/02
Key Inclusion Criteria: 096/099 ART naive
7/<30 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 <3 x ULN
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Brett-Smith, ATAC, 2/24/02
Baseline Characteristics 096*
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
d4T XR (n = 74) d4T IR (n = 76)
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Brett-Smith, ATAC, 2/24/02
Baseline Characteristics 096
HIV RNA, log10 copies/mL
Median 4.69 4.63 .63
Range 2.3–5.9 2.9–5.9
CD4, cells/L
Median 354 261 .14
Range 75–953 63–962
d4T XRn = 74
d4T IRn = 76 P-value
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Brett-Smith, ATAC, 2/24/02
Patient Disposition 096
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)
d4T XRn = 75
d4T IRn = 80
Patients, n (%)
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Brett-Smith, ATAC, 2/24/02
096: HIV RNA Mean Change (±SE) From Baseline
–3.5
BL 4 128 16 24 32 40 48
Lo
g
HIV
RN
A
Weekd4T XR: 74 68 72 71 71 70 71 68 67 62d4T IR: 76 68 70 71 70 69 65 65 60 58
–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
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Brett-Smith, ATAC, 2/24/02
096: Patients With HIV RNA <LOQ ITT: NC=F (Treated Subjects)
100
80
60
40
20
0
BL 4 128 16 24 32 40 48
Pa
tie
nts
(%
)
Week
%<50
%<40078%
67%
50%
49%
d4T XR (n = 74)
d4T IR (n = 76)
On-Treatment
Values
88%
82%
60%
56%
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Brett-Smith, ATAC, 2/24/02
096: CD4 Count -Mean Change From Baseline
400
300
200
100
0
BL 4 128 16 24 32 40 48
C
D4
(c
ells
/L
)
Weekd4T XR: 74 65 70 70 70 71 68 67 68 62d4T IR: 76 64 70 68 69 68 63 65 60 55
232
195
d4T XR (n = 74)
d4T IR (n = 76)
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Brett-Smith, ATAC, 2/24/02
096: Selected Clinical Adverse Events Related to Study Regimen (Grade 2)
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
d4T XRn = 74
d4T IRn = 76
Patients, n (%)
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Brett-Smith, ATAC, 2/24/02
096:EFV NFV Due to Intolerance
Total Switches 1 (1) 6 (8)
Rash – 3 (4)
CNS side effects 1 (1) 3 (4)(dizziness and impaired concentration)
Event
d4T XRn = 74
d4T IRn = 76
Patients, n (%)
All 7 switches occurred at or before day 33 of treatment
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Brett-Smith, ATAC, 2/24/02
096:Discontinuation Due to AEs
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, n=1; d4T IR, n=2
Eventd4T XRn = 74
d4T IRn = 76
Patients, n (%)
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Brett-Smith, ATAC, 2/24/02
096: Selected Laboratory Abnormalities (Grade 3/4)
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
d4T XRn = 74
d4T IRn = 76
Patients, n (%)
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Brett-Smith, ATAC, 2/24/02
096: Lactate Levels
0
2
4
6
8
XR IR XR IR XR IR XR IR
Week
Lac
tate
(m
mo
l/L)
25%-tile
Minimum
Maximum
75%-tile
Baseline 12 24 48
Median
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Brett-Smith, ATAC, 2/24/02
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 <LOQ
— CD4 cell changes
— Safety profile
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Brett-Smith, ATAC, 2/24/02
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 4:30-6:30 pm
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Brett-Smith, ATAC, 2/24/02
099 VRT-ITTVirologic Response Rates: Week 24
0
25
50
75
100
BL 4 8 12 16 20 24
d4T XR
d4T IR
% u
nd
etec
tab
le
<400 c/mL
<50 c/mL
Reference: Study BMS AI455-099. Pollard R et al. 9th CROI, Seattle, Feb 2002. Poster 411-W