Brett-Smith, ATAC, 2/24/02 Stavudine Extended Release (Zerit ® XR; d4T XR) Stavudine Prolonged...

Brett-Smith, ATAC, 2/24/02

Stavudine Extended Release(Zerit® XR; d4T XR)

Stavudine Prolonged Release Capsules

ATAC Meeting2/24/02


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


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


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


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


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


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


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


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)


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


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 (%)


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


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%


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)


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 (%)


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


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 (%)


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 (%)


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


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


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


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

Brett-Smith, ATAC, 2/24/02 Stavudine Extended Release (Zerit ® XR; d4T XR) Stavudine Prolonged...

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