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Transcript of Update on Atazanavir and the Early Access Program AIDS Treatment Activists Coalition Seattle,...
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
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
Atazanavir: Antiviral Properties
Azapeptide inhibitor of HIV protease
Potent activity in vitro 2–19 times more potent than available PIs
IC50 2–5 nMIC90 8–12 nM
Demonstrated potency in vivo 1.5 log decline in HIV RNA
Favorable resistance profile in vitro
Dose Selection: Probability of 1.5 Log Δ in HIV RNA by Week 2 Supports 400 mg Dose
200
400
)
500
N=22
N=13
N=21
Mean values:
200 mg QD
400 mg QD
500 mg QD500 mg QD
Gong. Antimicrob Agents Chemother 2000;44:2319.
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
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)
CMIN=220+184 ng/mL
CMIN=133+101 ng/mL
CMIN=33+20 ng/mL
CMIN=19+16 ng/mL
Effect of a Light Meal upon Steady-State PK at 200 and 400 mg QD
0 4 8 12 16 20 24Time (h)
10
100
1000
10000
Plasma Concentration (ng/mL)
400 mg-Fasted
400 mg-Fed
200 mg-Fasted
200 mg-Fed
Adj IC90
N=14
N=6
N=14N=6N=6
Drug-Drug Interaction Studies:Completed with dosing implications
Drug Actual Result Recommendation
SQV 4- to 7-fold ↑ SQV AUC( 800 -1600 )SQV at mg QD
↔ ATV AUC
Dosing recommendation ATV400 + 1200 QD SQV mg QD
with a high fat meal
/RTV ATV(400 mg
)QD
2.3- fold↑ ATV AUC( 100 )RTV at mg QD2.6- fold↑ ATV AUC( 200 )RTV at mg QD
↔ ritonavir AUC
Safe and well tolerated 200 RTV at mg QD has little
100 advantage over mg QD
/RTV ATV(300 mg
)QD
3.2- fold↑ ATV AUC( 100 )RTV at mg QD
↔ ritonavir AUC
Safe and well tolerated
PK Data: ATV/RTV
0 2 4 6 8 1012141618202224
Time (h)
10
100
1000
10000
BMS-232632 Plasma Concentration (ng/mL)
B200
N=14
B200+R100
N=6
B200+R200
N=8
B400
N=16
B400+R100
N=8
B400+R200
N=8
PK Data: ATV (300 mg) +/- RTV
0 4 8 12 16 20 24Time (h)
100
1000
10000
BMS-232632 Plasma Concentration (ng/mL)
BMS-232632 alone
Day 10
BMS-232632/Ritonavir
Day 15
BMS-232632/Ritonavir
Day 20
Drug-Drug Interaction Studies:Completed with dosing implications
Drug (s) Actual Result Recommendation
EFV 70% ↓ ATV AUC↔ efavirenz AUC
Repeat study with↑ ATV dosing No adjustment for EFV
/EFV RTV(100 )mg QD
Addition of RTVüATV AUC 3.4-fold(versus ATV alone
at 400 mg QD))↔ efavirenz AUC
↔ RTV AUC
(versus historic values)
Repeat study with ATV 600 mgNo adjustment for EFVConsider ↓RTV to 100 mg QD
RBC
B? ALB
+GSTB
B? 1 G or? 2G
2MRP
hepatocyte
UDP? 1 1GT Aenzyme
Canaliculus
Sinusoid
BB
Nucleus( 6, 7)Alleles
Hemolysis Transport
Export
Glucuronidation
Uptake *ICT
Hyperbilirubinemia: Bilirubin Physiology
* ICT = Intracellular transport* ICT = Intracellular transport
0
10
20
30
40
50
60
70
ATV 200 mg ATV 400 mg ATV 500 mg ATV 600 mg
Atazanavir Bilirubin ElevationsE
ven
ts (
%)
Seven patients discontinued for bilirubin elevations
Grade 3-4 = > 2.5 x ULN
Dose reductions for grade 4 = > 5 x ULN
Treated (N) 102 279 107 195
0%15%
12%24%
- data from AI424-007/008
Hyperbilirubinemia:Relationship to dose and reversibility
1 2 3 4 5 6 7 8 9 10 11 12 13 14Study Day
0
20
40
60
80
100
120
140
Total Bilirubin (umol/L)
Subj 1
Subj 2
Subj 3
Subj 4
600 mg 400 mg 200 mgQD Doses
(Light meal)(Light meal)
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
Electrocardiogram Changes
Observations- dose dependent asymptomatic increases in QTc and PR intervals
Safety analyses - preclinical (ion channels, HERG)- clinical (ECGs, drug-drug effects)
ECG SignalECG Signal
Naive Experienced Salvage
Nelfinavir
-037(NFV)
-007, -008(NFV)
-034(EFV)
Efavirenz
Atazanavir Clinical Program
-009 (RTV/SQV)
-043 (LOP/R)
-900 (EAP)
-045 + RTV
AI424-007 (Stage I n = 98, Stage II n = 322) Treatment-Naive
ATV 200, 400 or 500 mg QDvs + ddI + d4T NFV 750 mg TID
2 weeks monotherapy
ATV 400 or 600 mg QDvs + d4T + 3TCNFV 1250 mg BID
AI424-008 (n = 467) Treatment-Naive
ATV 400/600mg QD + SQV 1200 mg QD 2 NRTIsvs + (sensitive)RTV 400mg BID + SQV 400 mg BID
AI424-009 (n = 85) Treatment-Experienced
Atazanavir Phase II Studies
0.0
B/L 16 484 208 12 40 443224 28 36
Week
–2.0
–3.0
–1.0
–0.5
–1.5
–2.5
Ch
ang
e (l
og
10 c
/mL
,
SE
) Atazanavir 400 mg (n = 181)
Atazanavir 600 mg (n = 195)
Nelfinavir (n = 91)
Sanne. ICAAC; 2001.
Study 008: Atazanavir vs NelfinavirHIV RNA Median Change From Baseline
Study 008: Atazanavir vs Nelfinavir Treatment Response at 48 Weeks (ITT)
LOQ =LOQ =400 c/mL400 c/mL
100100
B/LB/L 1616 484844 202088 1212 4040 444432322424 2828 3636
WeekWeek
00
6060
8080
4040
2020
Su
bje
cts
(%)
Su
bje
cts
(%)
Atazanavir 400 mg (Atazanavir 400 mg (nn = 181) = 181)
Atazanavir 600 mg (Atazanavir 600 mg (nn = 195) = 195)
Nelfinavir (Nelfinavir (nn = 91) = 91)
LOQ =LOQ =50 c/mL50 c/mL
Sanne. ICAAC; 2001.
Study 008: Atazanavir vs Nelfinavir Treatment Response (As Treated)
WeekWeek
Su
bje
cts
(%)
Su
bje
cts
(%)
Atazanavir 400 mg (Atazanavir 400 mg (nn = 181) = 181)
Atazanavir 600 mg (Atazanavir 600 mg (nn = 195) = 195)
Nelfinavir (Nelfinavir (nn = 91) = 91)
**PP<0.05, atazanavir <0.05, atazanavir vsvs nelfinavir. nelfinavir.Sanne. ICAAC; 2001.Sanne. ICAAC; 2001.
LOQ =LOQ = 400 c/mL400 c/mL
100100
B/LB/L 1616 484844 202088 1212 4040 444432322424 2828 363600
6060
8080
4040
2020
LOQ =LOQ = 50 c/mL50 c/mL
**
Study 008: Atazanavir vs Nelfinavir
CD4 Median Change From Baseline
300300
B/LB/L 1616 484844 202088 1212 4040 444432322424 2828 3636
WeekWeek
100100
00
200200
250250
150150
5050CD
4 (c
ells
/mm
CD
4 (c
ells
/mm
33 , ,
SE
)S
E)
Atazanavir 400 mg (Atazanavir 400 mg (nn = 181) = 181)
Atazanavir 600 mg (Atazanavir 600 mg (nn = 195) = 195)
Nelfinavir (Nelfinavir (nn = 91) = 91)
Sanne. ICAAC; 2001.
Study 008: Atazanavir vs Nelfinavir Clinical Adverse Events* at 48 Weeks
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)
AtazanavirAtazanavir
400 mg400 mg 600 mg600 mg Nelfinavir Nelfinavir((nn = 178) = 178) ((nn = 195) = 195) ((nn = 91) = 91)
*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.
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.Haas. ICAAC; 2001.
Group: Number at riskAtazanavir 400: 34 30 30 30 29 29 29Atazanavir 600: 28 23 24 22 23 20 22Ritonavir: 23 20 20 17 18 14 13
––0.50.5
––1.51.5
0.00.0
Ch
ang
e (
Ch
ang
e (
SE
)S
E)
––2.02.0
––1.01.0
B/LB/L 44 88 1212 1616 2020 2424
WeekWeek
Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA:
Mean Change From Baseline
ATV 400 mg (ATV 400 mg (nn = 34) = 34)
ATV 600 mg (ATV 600 mg (n n = 28)= 28)
RTV (RTV (nn = 23) = 23)
Haas. ICAAC; 2001.Haas. ICAAC; 2001.
Study 009: Atazanavir/SQV vs RTV/SQV in Subjects With Prior Failure HIV RNA Response (>1.0 log10 or LOQ = 50 c/mL)
B/LB/L 44 88 1212 1616 2020 2424
WeekWeek
6060
8080
100100
2020
Res
po
nd
ers
(%)
Res
po
nd
ers
(%)
00
4040
ATV 400 mg (ATV 400 mg (nn = 34) = 34)
ATV 600 mg (ATV 600 mg (nn = 28) = 28)
RTV (RTV (nn = 23) = 23)
Haas. ICAAC; 2001.Haas. ICAAC; 2001.
Study 009: ATV/SQV vs RTV/SQV in Subjects With Prior Failure CD4 Median
(SE) Cell Count
400400
500500
550550
B/LB/L
350350
600600
650650
450450
300300
CD
4C
D4
250250
WeekWeek44 88 1212 1616 2020 2424
Haas. ICAAC; 2001.Haas. ICAAC; 2001.
ATV 400 mg (ATV 400 mg (nn = 34) = 34)
ATV 600 mg (ATV 600 mg (nn = 28) = 28)
RTV (RTV (nn = 23) = 23)
Group: Number at riskATV 400: 34 30 30 31 28 28 29ATV 600: 28 24 25 23 23 21 22RTV: 23 19 20 18 18 15 13
AI424-009
Total Cholesterol Triglycerides
Group: Number at riskGroup: Number at riskAtazanavir 400:Atazanavir 400: 3232 3131 3030 3030 2828 2828 2727Atazanavir 600: Atazanavir 600: 2727 2424 2424 2121 2121 1919 2020Ritonavir:Ritonavir: 2323 2020 2020 1717 1717 1515 1313
Mea
n c
han
ge
(%)
Mea
n c
han
ge
(%)
B/LB/L 44 88 1212 1616 2020 2424
WeekWeek
Atazanavir 400 mg (n = 32)Atazanavir 600 mg (n = 27)Ritonavir (n = 23)
––55
10101515
––1010
20202525
––1515––2020
0055
Group: Number at riskGroup: Number at risk2727 2020 2222 1919 1919 1717 15152222 1414 1313 1212 9 9 1010 13131818 1212 1010 1010 9 9 9 9 8 8
303000
210210
––3030––6060
6060
B/LB/L 44 88 1212 1616 2020 2424WeekWeek
1801801501501201209090
Total Cholesterol and Triglycerides at 24 Weeks
Atazanavir 400 mg (n = 32)Atazanavir 600 mg (n = 27)Ritonavir (n = 23)
Treatment ExperiencedTreatment Naive
Phase III overview
1st treatment 2nd treatment Heavily experienced
AI424-034 vs efavirenz
AI424-037 vs nelfinavir
innon PI failures AI424-045
with tenofovir vs lopinavir/rin > 2 failure
AI424-043 vs lopinavir/r
inPI failures
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
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
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
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
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
Atazanavir EAP
Initiation, April 2002 (pending FDA comments)
Global program for patients in need Entry criteria Concomitant ARV agents Data collection
Atazanavir EAP: eligibility
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: Exclusions
Cardiac
Liver Enzymes
Need for certain ARV agents
Clinical and ECG criteria
ALT, bilirubin
Ritonavir, Kaletra, Indinavir, Efavirenz
Atazanavir EAP
Infrequent study visits 2-month drug supply Limited mandatory safety data
collection - ALT, bilirubin- ECGs (2)
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