NDA 21-567 Atazanavir Kendall A. Marcus, M.D. Medical Reviewer Division of Antiviral Drug Products

NDA 21-567 Atazanavir

Kendall A. Marcus, M.D.

Medical Reviewer

Division of Antiviral Drug Products

Presentation Outline

• NDA Submission Overview• Efficacy Summary - Tom Hammerstrom,

Ph.D.• Clinical Virology - Lisa Naeger, Ph.D.• Safety Issues

– Hyperbilirubinemia– Lipid Profiles– Effects on the QT and PR Interval

• Conclusions

NDA Overview

• Submission Date: December 20, 2002• Proposed Dosage: Atazanavir 400 mg

once daily• Proposed Indication: Treatment of HIV

infection

Phase 2 Dose-Finding Studies Treatment Naïve Patients

AI424-007 N=420

• ATV: 200 mg, 400 mg, and 500 mg

• NFV 750 mg tid

Each given with d4T/ddI.

AI424-008 N=467

• ATV: 400 mg and 600 mg

• NFV 1250 mg bid

Each given with d4T/3TC.

Phase 3 Studies

AI424-034 Treatment-naïve subjects (n=810)

• ATV 400 mg daily

• EFV 600 mg daily

Each given with AZT/3TC (Combivir)

AI424-043 Subjects failing PI based regimens (n=300)

• ATV 400 mg daily

• LPV/RTV bid

Optimized background of 2 NRTIs based on phenotypic testing.

Phase 3 Studies

AI424-045* Patients failing at least 2 regimens containing drugs from all three classes (n=358)

• ATV 300 mg/RTV 100 mg once daily

• ATV 400 mg/SQV 1200 mg once daily

• LPV/RTV bid

Background therapy of tenofovir and one NRTI.

*16 week data on roughly 33 patients/arm submitted with initial NDA submission.

Other Supportive Studies

• AI424-041 and AI424-044 – Rollover studies for Phase 2

• PACTG 1020-A– PK and safety study in infants, children, and

adolescents

• AI424-900 - Expanded access protocol

• AI424-009 (N=85)– Small Phase 2 study of treatment experienced patients

comparing ATV/SQV to RTV/SQV

Atazanavir Resistance

Lisa K. Naeger, Ph.D.

Antiviral Advisory Committee Meeting

May 13, 2003

In vitro Selection

Virus strain: mutations

RF: V32I, L33F, M46I, A71V, I84V, N88S

LAI: L10Y/F, I50L, L63P, A71V, N88S

NL4-3: V32I, M46I, I84V, L89M

3 Different Strains of HIV-1 were serially selected with ATV for 4-5 months

(200 - 500 nM)

Fold ATV Resistance

183

93

96

I50L Mutation

• ATV resistance corresponded to the presence of I50L and A71V in the protease of recombinant viruses from 8 clinical isolates.

• 2- to 17-fold decreases in ATV susceptibility were observed in viruses containing the I50L and A71V mutation

I50L Mutation

• Viruses containing the I50L mutation either alone or in combination with A71V remained susceptible to APV, IDV, NFV, and RTV.

• Insertion of the I50L substitution into HIV-1 resulted in replication impaired viruses. The addition of the A71V change with I50L restores some viability.

ATV Clinical Resistance Analyses

• Mutations Associated with ATV-Resistance

– Phenotypic and genotypic analyses of evaluable clinical isolates from patients on ATV-containing regimens who experienced virologic failure or discontinued before suppression from studies 007, 008, 034, 009 and 043

• Baseline Phenotype and Genotype Analysis

• Cross-Resistance

Evaluable Clinical Isolates from Patients on ATV-Containing Regimens who Experienced Virologic

Failure or Discontinued before Suppression

All Studies

Naïve Trials007, 008,

034ARV-ExperiencedTrials 009 and 043

Evaluable isolates 160 93 63Mean 6.6 2.6 12.2

Median 1.4 1.04 2.8

ATV >2.5-fold 50 (31%) 14 (15%) 32 (51%)Mean 18.9 11.7 22.9

Median 9.6 8.7 11

Mutations Associated with ATV-Resistance in Naïve-trials

• 14 ATV-resistant clinical isolates– 11 (79%) developed the I50L

mutation• Median 9-fold change in ATV resistance• 7 of these 11 also developed the A71V

mutation• Development ranged from 2 to 80 weeks (mean = 40 weeks)

Phenotype of ATV-Resistant Isolates that Developed the I50L Mutation In

Naïve Trials

n Baseline*Post-

Baseline*

Fold-changefrom

Baseline P valueATV 10 0.87 9.43 10.9 0.004APV 10 0.69 0.47 0.69 0.11IDV 5 0.88 0.41 0.47 0.005LPV 4 0.98 0.28 0.28 0.06RTV 10 1.06 0.23 0.22 0.0007SQV 10 0.75 0.34 0.45 0.000005NFV 10 1.22 0.71 0.59 0.002

* Average fold-change from reference strain

Mutations Associated with ATV-Resistance in Experienced trials

• 32 ATV-resistant clinical isolates –ATV Treatment (21)

• 5 isolates developed the A71V or T mutation

• 2 isolates developed the I84V mutation (5-fold change from BL)

• 2 developed the N88S or D mutation (4-fold change from BL)

Mutations Associated with ATV-Resistance in Experienced trials

–ATV/SQV Treatment (11)• 5 isolates developed the I84V

mutation (14-fold change from BL)• 4 isolates developed the A71V or T

mutation• 2 isolates developed the L90M

mutation• 2 isolates developed the M46I

mutation

Cross-Resistance of the Virologic Failure Clinical Isolates that were ATV-Resistant from Treatment- Experienced Patients in Trials 009 and 043

ATV APV LPV SQV RTV IDV NFV

%resistantisolates

- 37% 47% 81% 87% 91% 100%

Median fold-change in

ATVsusceptibility

11 1.7 2 5.6 7 7.8 28

(N = 32)

Baseline Analysis

Baseline Phenotypic Analysis of 009 and 043

0

10

20

30

40

50

60

70

80

90

100

PI NRTI NNRTI

% R

esis

tan

ce

56%74%

20%

• 24% of the Isolates from 009 and 043 showed ATV-

Resistance at Baseline

Cross-Resistance of Baseline ATV-Resistant Isolates from 009 and 043

0

20

40

60

80

100

120

NFV IDV LPV RTV SQV

% R

esis

tanc

e 100%

47% 43%

62% 59%

Response Based on Baseline Genotype

Response of Antiretroviral-Experienced Patients from Studies 009 and 043

0

10

20

30

40

50

60

70

80

90

100

I84V L90M A71V N88 M46I

PI Mutation at Baseline

% o

f V

iro

log

ic F

ail

ure

s a

nd

DC

s

ATVOther

Cross-Resistance

Cross-resistance of HIV-1 Clinical Isolates by Phenotype

(Percent Resistant)

ATV-ResistantN = 416

APV-ResistantN = 236

IDV-Resistant

N = 58

LPV-ResistantN = 285

RTV-ResistantN = 465

SQV-ResistantN = 303

NFV-ResistantN = 677

ATV 100% 91% 79% 87% 75% 95% 61%APV 51% 100% 50% 67% 50% 61% 34%IDV 79% 97% 100% nd 82% 82% 53%LPV 69% 93% nd 100% 70% 73% 49%RTV 84% 98% 88% 99% 100% 92% 65%SQV 69% 78% 40% 71% 60% 100% 45%NFV 100% 97% 97% 97% 94% 99.7% 100%

Baseline phenotypic data from all studies

Cross-Resistance of HIV-1 Clinical Isolates by Genotype

(Percent Resistant)

I84VN = 95

G48VN = 32

L90MN = 343

V82N = 285

D30NN = 166

I50VN = 8

I50LN = 20

ATV 93% 94% 66% 64% 38% 12% 95%APV 84% 41% 41% 42% 5% 100% 0%IDV 100% nd 66% 74% 12% nd 0%

LPV 89% 75% 54% 74% 7% 100% 0%RTV 98% 94% 77% 83% 11% 87% 0%SQV 94% 97% 60% 44% 20% 25% 0%NFV 95% 100% 85% 79% 98% 50% 0%

Baseline genotypic and phenotypic data from all studies.

ATV Resistance Against PI-Resistant Clinical Isolates (n = 551)

Number ofIsolates

Resistantto 1 PI

(n = 157)

Number ofIsolates

Resistantto 2 PIs(n = 57)

Number ofIsolates


Number ofIsolates


Number ofIsolates

Resistantto 5 PIs

(n = 142)

19 (12%) 11 (19%) 65 (66%) 81 (84%) 135 (95%)

Number of ATV-resistant isolates (%)

ATV Susceptibility Against PI-Resistant Clinical Isolates (n = 551)

Number ofMarketed PIs

that Isolates areResistant To

Median fold-changein ATV susceptibility

1 1.62 2.13 4.04 6.25 22.0

ATV Resistance Summary• I50L mutation is specific for ATV resistance and is

the predominant mutation developing in antiretroviral therapy-naïve patients

• Viruses with the I50L mutation remain susceptible to other PIs

• Mutations L90M, I84V, N88S/D and A71V/T appear to confer ATV resistance and reduce the clinical response to ATV

• There is a clear trend toward ATV resistance as isolates become resistant to three or more PIs

Atazanavir Efficacy Results

Thomas Hammerstrom, PhD

Division of Antiviral Drug Products

Phase II and III Clinical Trials

• Pivotal Phase III Trial - 34– Endpoint = Percent Sustained < 400 copies/mL

to Week 48, Time Averaged Difference from Baseline (TAD)

– ART Naïve Population– Control is Efavirenz

• Phase II Trials - 7 and 8– Endpoint = Percent < 400, TAD– ART Naïve Population– Control is Nelfinavir

Phase II and III Clinical Trials

• Pivotal Phase III Trial - 43– Endpoint = TAD– ART Experienced Population– Control is Kaletra

Results in Trials with ART Naïve Subjects

Percent Sustained <400 copies/mL to Week 48

Trial Arm %<400 95% Interval ATV - Con

34 EFV 251 / 405 62%

ATV 271 / 405 67% -1.5%, 11.6%

7 NFV 62 / 103 60%

ATV 62 / 103 60% -13.8%, 13.0%

8 NFV 54 / 91 63%

ATV 121 / 181 69% -5.0%, 19.4%

Results in Trial with ART Experienced Subjects

Trial 43, ATV vs Kaletrafor 24 Weeks

Endpoint Arm Estimate 95% Interval

%<400 KAL 98 / 150 = 65%

ATV 70/150 = 47% -30%, -7.9%

TAD KAL -1.65

ATV -1.39 .078, .44

Is ATV Better than Placebo ART Experienced Subjects?Two Meta-analysis Methods:

1. Calculate Difference of ATV and Placebo from Trial 43 and Kaletra Trials

2. Compare Confidence Intervals for ATV + 2 NRTI’s in Trial 43 with Confidence Intervals for 2 NRTI’s alone from other NDA’s

ATV vs Placebo% <400

Source Arm Estimate DIFF SEE

Trial 43 ATV 70/150 = 47%KAL 98 / 150 = 65% -19% 5.73%

Trial 863 KAL 259 / 326 = 79%

NFV 233 / 327 = 71% 8% 3.36%

Trial 511 NFV 66/ 99 = 67%

PLA 7/ 101 = 7% 60% 5.37%

Imputed ATV

PLAC 49% 8.54%

ATV vs Placebo% <400


Trial 43 ATV 70/150 = 47%KAL 98 / 150 = 65% -19%

5.73%

Trial 888 KAL 84 / 148 = 57%

S. PI 46 / 140 = 33% 24% 5.69%

Imputed ATV

Selected PI 5% 8.07%

ATV vs Control% <400

Source Control Difference 95% Interval

Trial 43 KAL -19% -30%, -7.9%

Imputed Sel PI 5% -10.8%, 21%

Discounted Sel PI 4.5% -12.3%, 23%

Imputed PIacebo 49% 32%, 66%

Percent BLQ with 95% Limits

0% 20% 40% 60% 80% 100%

Percent BLQ

3 Drug Test Arms 2 Drug Control Arms

3 Drug Control Arms ATV, Trial 43

ATV vs PlaceboTAD, Week 24


Trial 43 ATV -1.39KAL -1.65 .26 .093

Trial 863 KAL -1.798

NFV -1.801 .003 .057

Trial 511 NFV -1.77

PLA -1.40 -.37 .083

Imputed ATV

PLAC -.107 .137

ATV vs PlaceboTAD, Week 24


Trial 43 ATV -1.39KAL -1.65 .26

.093

Trial 888 KAL -.972

S. PI -.867 -.104 .078

Imputed ATV

Selected PI .156 .121

ATV vs ControlTAD, Week 24

Source Control Difference 95% Interval

Trial 43 KAL .26 .078, .44

Imputed Sel PI .156 -.081, .393

Imputed Placebo -.107 -.376, .162

TAD with 95% Limits

-3.00 -2.50 -2.00 -1.50 -1.00 -0.50 0.00

TAD

3 Drug Test Arms 2 Drug Control Arms

3 Drug Control Arms ATV, Trial 43

Efficacy Conclusions

1. Equal or Better than NFV or EFV on %<400 at week 48 in 3 Trials with Naïve Subjects

2. 95% Lower Limits on %<400 no more than 5% worse than NFV or EFV in 2 out of 3 Trials


3. Equal or Better than NFV or EFV on TAD at week 48 in 2 out of 3 Trials with Naïve Subjects

4. 95% Upper Limits on TAD no more than .28 log copies worse than NFV or EFV in all 3 Trials


5. Statistically Significantly Worse than Kaletra on both %<400 and TAD at week 24 in 1 Trial with Experienced Subjects

6. Indirect Imputations: Support for Efficacy on Primary Endpoint, Ambiguity on Secondary Endpoint


6. Indirectly shown at least 33% better than placebo, no more than 10% worse than selected PI on %<400

7. 95% Confidence Limits on %<400 higher than limits seen on all 2 drug combinations in previous NDA’s


8. Indirectly shown no more than .16 log copies worse than Placebo on TAD at week 24

9. 95% Confidence Limits on TAD comparable to limits seen on several 2 drug combinations in previous NDA’s

Safety Issues

Hyperbilirubinemia

HyperbilirubinemiaToxicity Grading Scale

• Total bilirubin toxicity grading scale

Grade 1 1.1 – 1.5 x ULN

Grade 2 1.6 – 2.5 x ULN

Grade 3 2.6 – 5.0 x ULN

Grade 4 > 5.0 x ULN

• Upper limit of normal for total bilirubin 1.0 - 1.5 mg/dL

• Upper limit of normal for direct bilirubin 0.2 - 0.5 mg/dL

Studies 007 & 008HyperbilirubinemiaDose Dependence

0%

10%

20%

30%

40%

50%

60%

70%

200mg 400mg 500mg 600mg

Bilirubin (Grade 3 & 4)

Dose Reduction

0%

25%

50%

75%

100%

Study 007 & 008(N=279)

91% 47%

Study 034(N=404)

86% 33%

Study 043(N=144)

74% 20%

Grade 1-4 Grade 3-4

Percentage of Subjects with HyperbilirubinemiaAtazanavir - 400mg

Incidence of Jaundice and Scleral Icterus Phase 2 and 3 Clinical Studies

Atazanavir - 400 mg

Study 007/41008/44N=279

034

N=404

043

N=144Percentage of Subjects

Jaundice 9 11 10

Scleral Icterus 8 11 6

Total Subjects* 16 21 15

*Patients may have reported one or both events.

Three patients in 034 (1%) and 2 patients in 043 (1%) discontinued for jaundice or scleral icterus without grade 4 hyperbilirubinemia.

Grade 4 Hyperbilirubinemia and Dose Reduction

Study 034N=404

043N=144

Number with Gd 4 Total Bilirubin (%)

Gd 4 Bilirubin 26 (6) 4 (2)Dose Reduction 20 (5) 2 (1)Discontinuation 1 (<1) 0 (0)

Atazanavir - 400 mg

Study 034 Mean Total and Direct Bilirubin

Atazanavir - 400 mg

0

1

2

3

4

5

6

7

<2.5 2.5-5.0 >5.0

Mean (mg/ dl)

Bilirubin (mg/ dl)

Total Bilirubin Direct Bilirubin

Total Bilirubin > 10 mg/dL

Occurred in 10 patients across clinical trials • 4/10: transient, predominantly unconjugated (DB 0.3

mg/dl)

• 1/10: diagnosed w/SHL, DB - 0.6 mg/dl

• 5/10: also with other LFT abnormalities– 4 with viral hepatitis (A, B, C)– One had a total bilirubin > 10 mg/dl prior to randomization

which resolved prior to treatment and then worsened temporarily on study.

LFT Abnormalities - ATV versus NFV Background: ddI/d4T

Study007

Grade 1-4 LFTs

ATVN=101

NFVN=100

Percentage of SubjectsAST/SGPT 64 46

ALT/SGOT 63 47

Total Bili 89 13Alk Phos 16 8

LFT Abnormalities: ATV versus EFV Background: AZT/3TC

Study034

Grade 1-4 LFTs

ATVAZT/3TC

EFVAZT/3TC

N=404 N=401Percentage of Subjects

AST/SGPT 25 31

ALT/SGPT 18 22

Total Bili 86 3

Alk Phos 8 12

Discontinuations Due to Hepatotoxicity/Abnormal LFTs

All Studies• Atazanavir - 15/1596 (1%)

– Ten had chronic hepatitis B or C– One had acute hepatitis B– One had history of hepatic steatosis– Three subjects with no apparent risk factors

• Comparators - 8/892 (1%)– Five had chronic hepatitis B or C– One had acute hepatitis B– One was hep B core Ab positive but surface Ab and antigen

negative– One on RTV/SQV w/ no apparent risk factors

HyperbilirubinemiaConclusions

• Inhibition of UGT 1A1• Predominantly unconjugated • Reversible upon discontinuation of atazanavir• Jaundice/scleral icterus are likely to be common

adverse events in clinical practice resulting in more frequent discontinuations than seen in clinical trials.

• Risk for hepatotoxicity similar to other marketed ARV

Lipid Profiles

Study 034 Lipid Profiles at Week 48

Percent Change from Baseline

-15

-10

-5

0

5

10

15

20

25

30

TOT C LDL HDL TG

ATV

EFV

Pe

r ce

nt C

ha

nge

fro

m B

ase

line

Pe

rce

nt C

ha

nge

fro

m B

ase

line

Study 034 Lipid Profiles at Baseline and Week 48

0

2

4

6

8

10

12

14

16

ATV EFV ATV EFV ATV EFV

Baseline

F/u

Pe

rce

nta

ge

of

Su

bje

cts

Pe

rce

nt a

ge

of

Su

bj e

cts

TC>240TC>240

LDL>160LDL>160

TG>400TG>400

Study 043Lipid Profiles at Week 24

Percent Change from Baseline

-10

0

10

20

30

40

50

60

70

TOTALCHOL

LDL HDL TG

ATV

LPV/r

Pe

rce

nt

Ch

an

ge

fr o

m B

ase

line

Pe

rce

nt

Ch

an

ge

fr o

m B

ase

line

Study 043 Lipid Profiles at Baseline and 24 Weeks

0

5

10

15

20

25

ATV LPV/ r ATV LPV/ r ATV LPV/ r

Baseline

F/u

mg

/dL

mg

/dL

TC>240TC>240

LDL>160LDL>160

TG>400TG>400

TRIALS 7 & 8, CHANGE IN FASTING TGONLY SUBJECTS WITH FASTING BASELINE

-20

-10

0

10

20

30

40

50

60

70

80

0 20 40 60 80 100 120

WEEKS

CH

AN

GE

IN F

AS

TIN

G T

RIG

LY

CE

RID

ES

LipodystrophyTreatment-Naïve Studies

Study 034 007/041ATV EFV ATV

alldoses

NFV

Percentage of SubjectsAny Event 15 12 22 18

Lipodystrophy* 9 7 13 10

Weight gain 3 1 1 1

Weight loss 3 4 13 11

* * Includes events of lipoatrophy, lipohypertrophy, and lipodystrophy.Includes events of lipoatrophy, lipohypertrophy, and lipodystrophy.

CV Events -Myocardial Infarction

• Three MIs in atazanavir-treated patients and three MIs in patients receiving comparators

• One subject receiving RTV/SQV underwent three vessel bypass surgery

Lipid ProfilesConclusions

• Lipid effects of atazanavir appeared to persist through 108 weeks of treatment, although data from phase 2 trials is limited by study design.

• Benefits for treatment-experienced patients less well defined as factors other than current protease inhibitor use appear to contribute at least to hypertriglyceridemia.

• Lipid effects do not appear to be associated with a

reduced incidence of lipodystrophy. • Cardiovascular benefit is unknown at this time.

Evaluation of the QT Interval

In Vitro Evaluation of Potential Cardiac Effects

• Modest inhibition of IKr (HERG) - 15% at 30 µM• Moderate inhibition of Ca channels - IC50 of 10 µM• Weak inhibition of Na channels - IC50 > 30 µM• In Purkinje fiber studies, a dose-dependent increase in

mean action potential duration was observed.

Study 076

• 3-treatment, 3-period crossover study • 72 subjects received multiple, once-daily

doses of atazanavir • Subjects assigned atazanavir 400 mg, 800

mg, and placebo in six different sequences• Washout period of 14 days

QTc Changes by Correction Formula

QTcB at Tmax from baseline to 800 mg dose is 7.9 msec

(95% CI 2.8, 12.9) QTcF at Tmax

from baseline to 800 mg dose is -1.6 msec

(95% CI -4.2, 1.1)

20 40 60 80 100 120Heart Rate (bmp)

0.30

0.35

0.40

0.45

QT

cB (

sec

ond

s)

20 40 60 80 100 120Heart Rate (bmp)

0.30

0.34

0.38

0.42

0.46

QT

cF(s

econ

ds)

Studies 034 and 043Prolonged QTc Intervals

Study 034• Incidence of prolonged QTc intervals similar between

atazanavir and efavirenz regimens (2%).• One subject receiving efavirenz had a QTc interval >

500 msec.

Study 043• Nine subjects (ATV, 2 subjects; LPV/RTV, 7 subjects)

experienced a post-baseline QTc prolongation.

Study 034 and 043 CV Events Potentially Related to Arrhythmia

• Sudden death or torsades de pointes• CV events leading to treatment discontinuation • CV events coded as SAEs • Grade 3 - 4 CV events• All CV events

Events reviewed - No events of sudden death, torsades de pointes, events suspicious for TdP, or an imbalance between treatment arms in events potentially attributable to TdP was observed.

Effect of Atazanavir on the QT IntervalConclusions

• Data from placebo-controlled study 076 limited by lack of positive control (e.g. moxifloxacin)

• Current data indicates that atazanavir has little or no effect on the QT interval; however, the overall risk is unknown

• No signal for increased risk relative to comparators was identified in clinical trials

Evaluation of the PR Interval

Causes of PR Interval Prolongation and AV Block

• Medications - e.g. antihypertensives, digoxin

• Fibrosis of the conduction system

• Ischemic heart disease

• Valvular or congenital heart disease

• Cardiomyopathy

• Myocarditis

First Degree AV BlockClinical Significance

ACC/AHA/NASPE 2002 Guidelines for Implantation of Cardiac Pacemakers and Antiarrythmic Devices

Class II B recommendation:

First degree AV block greater than 300 msec in patients with LV dysfunction and symptoms of congestive heart failure in whom a shorter AV interval results in hemodynamic improvement

Study 076 (Healthy Volunteers)

Plot of Mean PR Versus Time Since Dosing

Study 034 PR Interval

Time Mean PR Interval

Post-dose (min, max)

msec

EFV 2-3 hours 153 (101, 251)

ATV* 2-3 hours 160 (110, 287)

*Maximum PR intervals: 265 - 307

Study 034 First Degree AV Block

Treatment Incidence of First Degree AV Block (%)

Males Females Total

Efavirenz 3 0 2

Atazanavir 4 6 4.5




msec

NFV 2-3 hours 158 (97, 203)

ATV* 2-3 hours 164 (120, 243)

*Maximum PR intervals: 234 - 250

Studies 041 and 044First Degree AV Block

Study Dose N 1st Degree

AV Block (%)

041 ATV 400 148 5

NFV 47 9

044 ATV 400 172 9

ATV 600 127 14




msec

LPV/r 2-3 hours 157 (114, 250)

ATV* 2-3 hours 157 (114, 209)

*Maximum PR Intervals: 194 - 218

Study 043 First Degree AV Block

Treatment Incidence of First Degree AV Block (%)

Males Females Total

Lopinavir/r 6 4 6

Atazanavir 7 3 6

Case Narratives - Other Conduction Abnormalities Potentially Related to

Atazanavir

• On day 1053 of therapy in study 007/041, a 43 year old male intentionally ingested a large number of ATV/3TC/d4T pills

• Received activated charcoal• Severely prolonged PR interval with bifascicular block

was observed on ECG• Patient was monitored for 5 days until ECG

normalized

Case Narratives - Other Conduction Abnormalities Potentially Related to

Atazanavir

• A 50 year old male with HTN was hospitalized on day 11 of ATV/ 3TC/DLV/TDF for angina and SOB

• On verapamil SR for HTN• An ECG showed junctional rhythm with retrograde

atrial activation. ARV medications held• One day following admission an ECG showed

persistence of junctional rhythm• Two days following admission the patient was found

unresponsive with idioventricular rhythm• Autopsy showed 90% LAD without infarct

Effects on PR Interval Conclusions

• Dose dependent prolongation of the PR interval• First degree AV block most common abnormality

observed• Incidence of first degree block appears to be

similar to that observed with selected PIs• Severe prolongation (> 300 msec) or more serious

events appear to be rare

Pediatric ProtocolPACTG 1020-A

• Atazanavir + 2 NRTIs• 48 enrolled; 29 continuing on study• Adverse event profile in these patients

appears similar to adults• Due to wide variability of pK data in all age

cohorts, a dose has not yet been defined for any group

Drug-Drug Interactions

Drug-Drug Interactions

• Potential interaction with ATV– CYP3A inhibitor, inducer, or substrate– drugs that increase pH– drugs that cause PR prolongation– 2C9 (e.g. warfarin) or 1A2 (e.g. theophyline) -

not studied

Drug Interactions - Diltiazem

• Diltiazem – CYP 3A substrate + inhibitor

– PR prolongation

– ATV diltiazem Cmax and AUC ~ 100%

PR interval (msec)200-250 >250

Study day

Count (%) Count (%)6 (atazanavir) 10 (33%) 0 (0%)

11 (atazanavir + diltiazem) 14 (46.7%) 4 (13.3%)23 (diltiazem) 3 (11%) 0 (0%)

Drug Interactions - Oral Contraceptives

• Co-administration of atazanavir and ethinyl estradiol/norethindrone (Ortho-Novum 7/7/7) was evaluated

Cmax AUC

Ethinyl estradiol 1.15 1.48

Norethindrone 1.67 2.10

AtazanavirOverall Conclusions

• Antiviral activity similar to efavirenz or nelfinavir in treatment-naive patients

• Inferior to lopinavir/r in treatment-experienced patients, but multiple analyses indicate activity in this population

• Low pill burden may enhance compliance in selected patients

• Unique resistance pathway in treatment-naïve subjects


• Hyperbilirubinemia appears to be due to inhibition of UGT 1A1 and reversible with treatment discontinuation

• Risk for hepatotoxicity appears to fall within the range of that seen with other ARV medications


• Dose-dependent prolongation of the PR interval• Incidence of first degree AV block appears to be

similar to that observed in lopinavir/ritonavir and nelfinavir treated patients

• Clinically significant events due to prolongation of the PR interval appear to be rare

• Effects of atazanavir on the QT interval appear to be minimal


• Favorable lipid profile as compared to selected protease inhibitors and efavirenz

• Impact on cardiovascular events unknown • Does not appear to “reverse” triglyceride elevations

seen in treatment-experienced patients• Does not appear to result in a decreased incidence

of lipodystrophy

QuestionsQuestions

Question 1Question 1 • Do the efficacy and safety of atazanavir support its

approval for the treatment of HIV infection? As part of your discussion please comment on:

» Treatment effects seen in naїve and experienced patients

» Hyperbilirubinemia observed in clinical trials

» The effect of atazanavir on the PR and QT intervals

Question 2Question 2

• If atazanavir is recommended for approval, does its safety profile warrant additional clinical or laboratory monitoring?


• Does the effect of atazanavir on lipid parameters offer patients a clinically significant advantage over other treatment options?


• Based on the resistance data, what recommendations would you have regarding its use in naïve and experienced patients?


• Please provide recommendations for any Phase 4 studies of atazanavir?

Documents

NDA 21-567 Atazanavir Kendall A. Marcus, M.D. Medical Reviewer Division of Antiviral Drug Products