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)


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

(%)




**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)




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)


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)


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


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

update on atazanavir and the early access program aids treatment activists coalition seattle,...

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