1

RaltegravirNDA 22-145

Sarah M. Connelly, MDDivision of Antiviral Products Advisory Committee Meeting

September 5, 2007

2

Raltegravir: Overview

• Efficacy review

• Resistance data

• Safety review

• Conclusions

3

Efficacy Review

4

Efficacy: Overview

• Trial design: treatment-experienced– Pivotal Phase 3 : Protocols 018 and 019– Phase 2 dose finding: Protocol 005

• Demographics and Baseline Characteristics

• Week 16 and 24 analyses

• Subgroup analyses– PSS

– Number of protease inhibitors in OBT

– Enfuvirtide, darunavir use

5

Efficacy: Phase 3 Trial DesignProtocols 018 and 019

Raltegravir 400 mg bid + OBT vs Placebo + OBT

• Identical design at different geographic locations

• Inclusion criteria:– Treatment-experienced– HIV-1 RNA>1,000 copies/mL– Resistant to > 1 drug from each: NNRTI, NRTI, PIs

• 2:1 randomization

• Primary Efficacy Endpoint: – Week 16 % subjects with HIV-1 RNA < 400 copies/mL

• Virologic failure > Week 16 could enter open-label

6

Efficacy: Phase 2 Dose FindingProtocol 005

• Treatment-experienced

• 200, 400, 600 mg raltegravir bid versus placebo– Each in combination w/ OBT

• Subject inclusion criteria:– HIV-1 RNA > 5,000 copies/mL– CD4 > 50 cells/mm3

– Resistant to > 1 drug from each: NNRTI, NRTI, PIs

• Duration: At least 24 weeks double-blind

7

Efficacy: DemographicsProtocol 018 Protocol 019

Raltegravir Placebo Raltegravir Placebo

# Subjects randomized and treated

232 118 230 119

Gender – n (%)

Male

Female

195 (84)

37 (16)

103 (87)

15 (13)

210 (91)

20 (9)

107 (90)

12 (10)

Race – n (%)

White

Black

Asian

Hispanic

Other

175 (75)

18 (8)

14 (6)

6 (3)

19 (8)

96 (81)

5 (4)

5 (4)

1 (1)

11 (9)

126 (55)

48 (21)

2 (1)

47 (20)

7 (3)

77 (65)

21 (18)

1 (1)

18 (15)

2 (2)

Geographic regions – n (%)

North America

Central/South America

Asian Pacific

Europe

0 (0)

23 (10)

38 (16)

171 (74)

0 (0)

11 (9)

20 (17)

87 (74)

192 (84)

38 (17)

0 (0)

0 (0)

99 (83)

20 (17)

0 (0)

0 (0)

8

Efficacy: Baseline CharacteristicsProtocol 018 Protocol 019

Raltegravir Placebo Raltegravir Placebo

# Subjects randomized and treated

232 118 230 119

Age, years- Mean (Median) 46 (46) 44 (43) 45 (45) 47 (47)

Duration of ART

years – Median 11 10 10 10

AIDS – % 94 90 91 92

CD4 - Mean (Median)

<50 - %

156 (140)

30

153 (105)

34

146 (102)

34

163 (132)

32

HIV-1 RNA (log10 copies/mL) – Mean (Median)

>100,000 - %4.6 (4.8)

33

4.5 (4.6)

28

4.7 (4.8)

38

4.7 (4.7)

38

HBV and/or HCV

co-infection - % 21 23 12 8

9

Efficacy: Baseline CharacteristicsProtocol 018 Protocol 019

Raltegravir Placebo Raltegravir Placebo

# Subjects randomized and treated

232 118 230 119

Phenotypic Sensitivity Score (PSS) – %

0

1

2

> 3

19

29

29

19

18

33

28

18

10

34

33

18

19

27

28

23

Genotypic Sensitivity Score (GSS) – %

0

1

2

> 3

30

33

25

11

29

41

19

11

20

44

24

11

26

40

23

8

10

Efficacy: Week 16 Analysis

Protocol 018 Protocol 019

Raltegravir

N=232

Placebo

N=118

Raltegravir

N=230

Placebo

N=119

<400 copies/mL – n (%)* 179 (77) 49 (42) 180 (78) 51 (43)

<50 copies/mL– n (%) 146 (63) 40 (34) 143 (62) 43 (36)

CD4 change from baseline – mean (SD)

81 (94) 32 (73) 84 (96) 39 (74)

*p value <0.001 for both protocols

11

Efficacy: Week 24 Analysis*Protocol 018 Protocol 019

Raltegravir

N=232

Placebo

N=118

Raltegravir

N=230

Placebo

N=119

*Subjects with Week 24 Data – n (%) 158 (68) 81 (69) 128 (56) 69 (58)

<400 copies/mL – n (%) 120 (76) 33 (41) 97 (76) 27 (39)

<50 copies/mL – n (%) 95 (60) 28 (35) 83 (65) 23 (33)

CD4 change from baseline –

Mean (SD)83 (98) 33 (71) 92 (98) 39 (71)

Virologic failure – n (%)

Week 16 Nonresponder

Week 24 Rebound

36 (15)

5 (2)

31 (13)

63 (53)

44 (37)

19 (16)

40 (17)

9 (4)

31 (13)

58 (49)

33 (28)

25 (21)

Discontinuation by Week 24 – n (%)

Due to Adverse Events

Due to Other

4 (2)

1 (<1)

4 (3)

0 (0)

4 (2)

5 (2)

1 (1)

2 (2)

Death by Week 24 – n (%) 3 (1) 3 (3) 3 (1) 0 (0)

12

Efficacy: Subgroup AnalysesHIV-1 RNA <50 copies/mL at Week 16

Protocol 018 Protocol 019 Total

Responders/ Evaluable (%)

RaltegravirN=232

Placebo N=118

RaltegravirN=230

Placebo N=119

RaltegravirN=462

Placebo N=237

PSS of OBT

0 19/44 (43) 0/21 (0) 12/23 (52) 1/23 (4) 31/67 (46) 1/44 (2)

1 44/67 (66) 13/39 (33) 40/78 (51) 9/32 (28) 84/145 (58) 22/71 (31)

2 47/67 (70) 11/33 (33) 54/75 (72) 15/33 (45) 101/142 (71) 26/66 (39)

≥ 3 30/44 (68) 13/21 (62) 30/41 (73) 15/27 (56) 60/85 (71) 28/48 (58)

# Active PIs In OBT

0 56/100 (56) 7/55 (13) 31/66 (47) 7/42 (17) 87/166 (52) 14/97 (14)

≥ 1 85/123 (69)

32/61 (52)

108/155 (70)

35/76 (46)

193/278 (69)

67/137 (49)

Number (#) of active protease inhibitors (PI) determined by phenotypic resistance test

13

Efficacy: Subgroup AnalysesHIV-1 RNA <50 copies/mL at Week 16

ENF = enfuvirtide, DRV = darunavir

%

Responders/ Evaluable (%)

Raltegravir Placebo

Naïve ENF and naïve DRV 39/45 (87) 16/23 (70)

Naïve ENF and no DRV 33/46 (72) 13/25 (52)

No ENF and naïve DRV 56/81 (69) 24/49 (49)

No ENF and no DRV 118/197 (60) 21/93 (23)

0

10

20

30

40

50

60

70

80

90

100

+ENF/+DRV +ENF/-DRV -ENF/+DRV -ENF/-DRV

87

70 72

52

69

49

60

23

Raltegravir

Placebo

14

Efficacy: Summary

• Raltegravir + OBT displays significantly greater antiviral activity as compared to OBT alone in treatment-experienced subjects– Week 16 HIV-1 RNA <400 copies/mL

• Supported by– Week 16 HIV-1 RNA <50 copies/mL– Δ CD4 from baseline– Week 24 data– Subgroup analyses

15

Resistance Data

16

Microbiology Resistance DataProtocols 005, 018 and 019

• Paired sequence analysis of baseline and on-treatment samples from 77 subjects with evidence of virologic failure– 75/77 (97%) genotypic mutations in the HIV-1 integrase

coding region

• 3 key mutations, Y143C/H/R, Q148H/K/R, or N155H– Observed in 65/75 subjects (87%)– Detected as early as Day 27– ↓ susceptibility in cell culture to raltegravir

• Q148 H/K/R 24 to 46-fold • N155H 13-fold

17

Microbiology Resistance Data

• Each of 3 key mutations usually accompanied by > 1 additional mutation:

L74M/R, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226C/D/F/H, S230N/R, and D232N

– G140A/S/Q148H/K/R double mutation most frequent (35%, 27/77)

• ↑resistance 257 to 521-fold

– E92Q /N155H double mutation (9%, 7/77) • ↑resistance 64-fold

18

Safety Review

19

Safety Overview

• Mortality

• Discontinuations due to Adverse Events (AEs)

• Serious AEs

• Common AEs

• Select AEs– Malignancy – AIDS defining conditions– Rash– Hepatic events

– Creatine kinase– Renal events– Subgroups:

• OBT (+)atazanavir• HBV/HCV co-infection

20

Mortality• 16 deaths through Safety Update Report data

– 12 during double-blind (DB) phase– 1 death due to conditions present at screening– 1 death “post-study”; last raltegravir dose not

confirmed• No deaths in treatment-naïves

RaltegravirN=595

PlaceboN=282

Protocol 005 4 0

Protocol 018 4 3

Protocol 019 5 0

Total 13 (2.2%)

3 (1.1%)

21

MortalityRaltegravirDose or Placebo

Cause of Death Total DaysOn Tx

Days Post-Txto Death

Protocol 005

200 mg Laceration, Suicide 4 9

200 mg Lymphadenopathy, Splenic abscess, Pleural effusion 510 20

400 mg Acute Myocardial Infarction 375 On Tx

600 mg Sepsis, Shock, Bradycardia, Cardiorespiratory Arrest 137 3

Protocol 018

Placebo MAC, End Stage AIDS 78 5

Placebo Urosepsis 86 16

Placebo Pneumonia 19 6

400 mg B-cell Lymphoma 280 42

400 mg Lymphoma, MAC, Shock, Multi-organ Failure 93 2

400 mg Pneumonia, Rectal Hemorrhage, Septic Shock 73 11

400 mg Cryptococcal Meningitis 78 12

Protocol 019

400 mg Lymphoma 62 7

400 mg Hepatic Neoplasm Malignant 75 3

400 mg PML 185 53

400 mg Aspergillosis, TB 31 20

400 mg CAD 200 On Tx

22

Mortality Analysis of Baseline Characteristics

Subjects who died were more advanced at baseline

Deaths on Raltegravir

N=13

Deaths on Placebo

N=3

All Other Subjects

N=861

Age Mean (Median) 45.4 (47) 52.3 (51) 45.2 (45)

Baseline HIV RNA log10

Mean (Median) 5.3 (5.2) 5.5 (5.4) 5.1 (4.7)

Baseline CD4 Mean (Median) 103 (65) 4.7 (4) 173 (140)

Proportion Baseline CD4 <50 - % 46 100 26

Last CD4Mean (Median) 136 (108) 7 (7) 270 (234)

23

Mortality: Similar to Salvage Trials

Week 24 Mortality per 100 Patient-Yrs in Other Clinical Trials

ENF Mortality at Wk 24 Analysis of TORO trials

TPV/r Mortality at Wk 24 Analysis of RESIST trials

DRV/r Mortality at Wk 24 Analysis of POWER trials

ENF +/-OBR

OBR TPV/r +/-OBR

CPI/r +/-OBR

DRV/r +/-OBR

CPI/r +/- OBR

10/663(1.5%)

5/334(1.5%)

12/582(2.0%)

7/577(1.2%)

6/513(1.2%)

0/124(0 %)

Mortality rate= 3.3

Mortality rate= 3.3

Mortality rate= 4.5

Mortality rate= 2.6

Mortality rate= 2.6

Mortality rate= 0.0

Source: NDA 21-897 Team Leader MemorandumENF = enfuvirtide; OBR = optimized background regimen; TPV/r = tipranavir/ritonavir; CPI/r= comparator protease inhibitor/ritonavir; DRV/r = darunavir/ritonavir

Raltegravir (N=595) Placebo (N=282)

By Week 24

Number of deaths 8 3

Person years exposure 282.1 120.8

Mortality rate per 100 patient-years 2.8 2.5

Week 24 Mortality per 100 Patient-Yrs in Trt-Exp Subjects: As Treated

24

Mortality: Summary

• Mortality rates and causes of death appear similar to those observed in other clinical trials enrolling similar subject populations

• All deaths considered unrelated to study therapy by investigators

• Our review of the cases supports investigator assessment

25

Study Discontinuations

Protocol 004 Protocols 005, 018, 019

RaltegravirN= 160 (%)

EFV N= 38 (%)

RaltegravirN=595 (%)

PlaceboN=282 (%)

Lack of Efficacy 2 (1.3%)

0 (0)

1 (0.2%)

2 (0.7%)

Adverse Event 1 (0.6%)

0 (0)

13 (2.2%)

6 (2.1%)

Lost to Follow Up

3 (1.9%)

0 (0)

1 (0.2%)

0(0)

Consent Withdrawn

4 (2.5%)

3 (7.9%)

2(0.3%)

1 (0.4%)

Other 1 (0.6%)

0 (0)

0 (0)

0 (0)

Total 11 (6.9%)

3 (7.9%)

17(2.9%)

9(3.2%)

26

Study Discontinuations Associated with AEsProtocol Raltegravir Control

004 AST/ALT

005 Laceration/Suicide

Sepsis/Bradycardia/Cardiorespiratory arrest

Lipoatrophy

AST/ALT

018, 019 Lymphoma/MAC/Shock End Stage AIDS

Lymphoma (recurrent) Pneumonia

Hepatocellular carcinoma Urosepsis

CAD Nausea

Dehydration w/ TB/Aspergillosis Hepatitis C

Cryptococcal meningitis (recurrent)

Pneumonia/Hepatitis/Rectal hemorrhage

Renal failure

Obsessive thoughts

Flatulence

27

Serious Adverse Events (SAE)

• 20.7% raltegravir vs 22.5% control– Pneumonia most common (1.2% and 1.3%, respectively)

• Review of investigator assessed drug-related SAEs– 16 drug-related SAEs in 13 subjects– Raltegravir N=8 (1.1 %, 8/755)

Gastritis, Renal failure (2), Hepatitis complicated by IRS and treatment for thyrotoxicosis, Herpes

simplex, Hypersensitivity

• 14 subjects discontinued due to SAE (1.3%)

28

Common Adverse Events: Treatment-Experienced

• 438 raltegravir and 247 placebo subjects with > 1 AE

• Majority mild to moderate in intensity

• Most common AEs occurring in > 10%, observed with similar frequency in each study arm :

– Diarrhea

– Injection site reactions (due to enfuvirtide use)

– Nausea

– Headache

29

Common AEs

Clinical AEs reported more frequently (≥ 2% difference) in raltegravir-treated subjects

Raltegravir400 mg bid

N=507

PlaceboN=282

n % n %

Subjects with > 1 AE 438 86.4% 247 87.5%

Fatigue 40 7.9% 13 4.6%

Nasopharyngitis 31 6.1% 11 3.9%

Rash 27 5.3% 7 2.5%

Herpes zoster 21 4.1% 2 0.7%

30

Focused Analyses of AEs of Interest

• Malignancy• AIDS Defining Conditions• Rash• Hepatic Events• Creatine Kinase• Renal events• Concomitant atazanavir• HBV/HCV Co-infection

31

Malignancy21 malignancies in 20 subjects through SUR

No malignancies observed in placebo-treated subjects at time of SUR

20 malignancies in 19 subjects20 malignancies in 19 subjects

1 switched placebo→open-label raltegravir1 switched placebo→open-label raltegravir

2 subjects from EAP2 subjects from EAP

1 squamous cell ca of vocal 1 squamous cell ca of vocal cordcord

EFV arm Protocol 004EFV arm Protocol 004

Raltegravir Control

32

Malignancy - July Update• 36 malignancies in 31 subjects

30 malignancies in 26 subjects30 malignancies in 26 subjects

2 placebo switched→open-label raltegravir2 placebo switched→open-label raltegravir

*Double Blind: 22 in 19 subjects*Double Blind: 22 in 19 subjects

6 malignancies in 5 subjects6 malignancies in 5 subjects2 in 1 EFV-treated subject2 in 1 EFV-treated subject

4 in placebo-treated subjects4 in placebo-treated subjects

Raltegravir Control

Protocol Treatment Arm N subjects with Malignancy

004 EFV 1

200 mg raltegravir 1

400 mg raltegravir 2

005 200 mg raltegravir 1

400 mg raltegravir 1

018/019 Placebo 4

400 mg raltegravir 21

33

Malignancy: Types

Raltegravir-treated subjects Squamous cell ca: anogenital N=7

Anal (N=3) Carcinoma in situ (N=4)

Squamous cell carcinoma: skin N=6 Kaposi’s sarcoma N=5 Lymphoma N=4 Basal cell carcinoma N=3 Hodgkin’s disease

N=2 Rectal cancer N=1 Hepatocellular carcinoma N=1 Squamous cell carcinoma: other N=1

Onset 25 – 557 days

Control subjects Squamous cell carcinoma:

anogenitalN=2

Anal (N=2) Lymphoma N=1 Basal cell carcinoma N=1 Squamous cell carcinoma: other

N=1 Metastatic neoplasm N=1

Onset >200 days

34

Malignancy: July UpdatePhase 2 and 3: Double Blind Phase

Raltegravir

N=755

PEY=824

Control

N=320

PEY=262

# Malignancies 22 6

# Subjects with >1 Malignancy 19 5

# Recurrences 8 2

Time to Onset, days - Median 98 285

% Subjects with >1 Malignancy 2.5 1.6

Malignancy Rate, adjusted for PEY 2.3 1.9

PEY = Patient exposure years

35

Malignancy: July UpdateTreatment-Experienced Protocols

Raltegravir

N=595

PEY=539

Placebo

N=282

PEY=195

# Malignancies 18 4

# Subjects with >1 Malignancy 16 4

# Recurrences 6 1

Time to Onset, days - Median 73 285

% Subjects with >1 Malignancy 2.7 1.4

Malignancy Rate, adjusted for PEY 3.0 2.1

*Prior SUR Malignancy Rate, adjusted for PEY (Raltegravir=395)

3.3 0

PEY = Patient exposure years

36

Malignancy: Summary

• Identified malignancies expected in this heavily-treatment experienced population

• No clear pattern to types of malignancies observed

• Initial imbalance diminished with longer follow up

37

AIDS Defining Conditions (ADCs)• Determined by blinded external adjudicator in Phase 3 studies• 32 subjects with 40 ADCs

– 15 presumptive, 25 definitive– Majority during double-blind treatment period (N=34)

Raltegravir 400 mg bidN=462

PlaceboN=237

n % n %

All ADCs 19 4.1% 15 6.3%Esophageal candidiasis 4 0.9% 6 2.5%

Lymphoma 3 0.6% 0 -Cytomegalovirus 2 0.4% 3 1.3%Herpes simplex 2 0.4% 0 -

Kaposi’s sarcoma 2 0.4% 0 -Cryptococcal meningitis 2 0.4% 0 -

MAC 1 0.2% 2 0.8%Encephalopathy 1 0.2% 0 -Microsporidiosis 1 0.2% 0 -

Recurrent pneumonia 1 0.2% 1 0.4%Cryptosporidiosis 0 - 2 0.8%

Salmonella bacteremia 0 - 1 0.4%

38

Rash Events: Phase 1

• 17/334 (5.1%) reported rash

• Mild intensity

• Discontinuations for rash only occurred in setting of DRV/r co-administration

Raltegravir - DRV/r interaction study– 2 period study: raltegravir alone → raltegravir + DRV/r– Healthy adults– 4 discontinuations due to rash, one SAE

• All taking raltegravir + DRV/r for ≥ 9 days at rash onset

39

Rash Events: Phase 2 and 3

• 71 subjects with 73 rash events, double-blind period

• No study discontinuations due to rash– 4 subjects interrupted study therapy (3 raltegravir,1

placebo), all resumed

• Raltegravir-treated subjects: – Median (mean) onset 45 days (78 days)– Median (mean) resolution 20 days (41 days)

RaltegravirN=755

ControlN=320

n % n %

Subjects with >1 Rash AE 54 7.2% 17 5.3%

40

Rash Events: Phase 2 and 3• 1 “severe” rash in raltegravir-treated subject

– OBT: abacavir, EFV, 3TC – Rash resolved w/o drug interruption

• 27 rashes assessed as drug-related: – 2.4% (N=17) raltegravir vs 3.1% (N=10) control– 3 in raltegravir arm resolved with discontinuation of OBT

component (abacavir, fosamprenavir, ENF)

• Open-Label– 1 rash 16 days after starting raltegravir with unchanged

OBT – Rash resolved w/o drug interruption

41

Hypersensitivity

• 14 hypersensitivity events in 10 subjects, double-blind period

• 2 SAEs: both in raltegravir-treated subjects– Resolution after discontinuation of darunavir; resumed raltegravir– Multiple hypersensitivity episodes and treatment interruptions with

discontinuation of darunavir, ENF, and TMP/SMX; back on raltegravir as of Day 180

RaltegravirN=755

ControlN=320

n % n %

Subjects with >1 Hypersensitivity AE 6 0.8% 4 1.3%

42

Rash AEs: Summary

• Majority of rash events in raltegravir-treated subjects were mild to moderate in intensity

• No rash event resulted in study discontinuation in the Phase 2 and 3 development program

• Clear pattern of rash has not been established and most are self-limited

• Many of the rash events confounded by use of concomitant medications associated with rash:– Darunavir, abacavir– All reported rashes in drug-drug interaction Protocol 029, for

example, occurred after darunavir was added to raltegravir

43

Hepatic Events: Phase 2 and 3

• No dose-response relationship observed• 5 SAEs

– Raltegravir (N=4) • Hepatocellular carcinoma • Portal HTN/varices• Hepatitis in setting of IRS and treatment for thyrotoxicosis • Pneumonia w/ elevated hepatic enzymes on DRV/r

– Placebo (N=1) • Hepatitis due to TPV/r

Raltegravir Control

n % n %

Total 144 19.1% 45 14.1%

44

Hepatic Events: Lab DataLaboratory Parameter Limit Treatment Arm

RaltegravirN=755

ControlN=320

% %

Serum ALT (IU/L)

Grade 2 2.6-5.0 x ULN 5.8 7.5

Grade 3 5.1-10.0 x ULN 2.0 1.9

Grade 4 >10.0 x ULN 0.4 0.3

Serum AST (IU/L)

Grade 2 2.6-5.0 x ULN 7.0 5.3

Grade 3 5.1-10.0 x ULN 1.3 2.2

Grade 4 >10.0 x ULN 0.7 0.3

Serum Alkaline Phosphatase (IU/L)

Grade 2 2.6-5.0 x ULN 1.6 0.4

Grade 3 5.1-10.0 x ULN 0.4 0.9

Grade 4 >10.0 x ULN 0.3 0.4

Total Serum Bilirubin (mg/dL)

Grade 2 1.6-2.5 x ULN 6.0 5.6

Grade 3 2.6-5.0 x ULN 3.0 2.2

Grade 4 >5.0 x ULN 0.7 0

45

Hy’s Law

46

Screening for Hy’s Law Cases

• Definition for potential Hy’s Law cases– AST and/or ALT > 3x ULN– Total bilirubin > 2x ULN– No evidence of obstruction (~normal Alk phos)– No evidence of another cause

• Phase 2 and 3 SUR datasets examined– 6 subjects meeting initial laboratory screening

criteria

47

Evaluation of Hy’s Law: No Cases1. Protocol 005 200 mg raltegravir Double Blind Continued study therapy

OBT: Atazanavir/r, ddI, 3TCHx ↑bilirubin, transaminases 2003; splenomegaly, steatosis 2000

2. Protocol 005 200 mg raltegravir OLPVF Continued study therapyOBT: Atazanavir, LPV/r, abacavir, 3TCHx hyperbilirubinemia 2004

3. Protocol 018 400 mg raltegravir Double Blind Continued study therapyOBT: DRV/r, abacavir, TDF(+)HCV -> transient reactivation

4. Protocol 018 400 mg raltegravir Double Blind, Post-Tx Interrupted Day 32 - 66OBT: DRV/r, indinavir, 3TC, AZT(+)Grade 2 Alkaline PhosphataseOccurred in setting of acute thyrotoxicosis tx with PTU (Day 36); bronchopneumonia (Day 102)

5. Protocol 019 400 mg raltegravir Double Blind Interrupted Day 168 - 174OBT: DRV/r, TDF + FTC (*discontinuation on Day 33)(+)HBV ->reactivation with HBV DNA 84,000,000 IU/mL

6. Protocol 019 400 mg raltegravir Double Blind Continued study therapyOBT: Atazanavir, DRV/r, TDF + FTC(+)HBV, baseline bilirubin 3.4

48

Creatine Kinase (CK)

• 63 subjects experienced Grade 2 - Grade 4 CK elevations

CK Grade Limit RaltegravirN=755

ControlN=320

n % n %

Grade 2 6.0–9.9 x ULN 18 2.4% 5 1.6%

Grade 3 10.0–19.9 x ULN 16 2.1% 5 1.6%

Grade 4 >20.0 x ULN 16 2.1% 3 0.9%

All Grades2-4

50 6.6% 13 4.1%

49

CK AEs

• Elevations were transient and resolved without drug interruption

• No SAEs or study discontinuations were associated with elevated CK levels

• No apparent association with concomitant use of lipid-lowering agents/PIs and increased CK

50

Renal AEs: Phase 2 and 3

• 22 Renal AEs occurred in 18 subjects

Preferred Term RaltegravirN=755 n (%)

ControlN=320n (%)

Renal failure 3 (0.4%) 3 (0.9%)

Nephropathy 2 (0.3%) 1 (0.3%)

Nephrolithiasis 2 (0.3%) 4 (1.3%)

Nephrotic syndrome 2 (0.3%) 0 (0)

Focal glomerulosclerosis 2 (0.3%) 0 (0)

Renal tubular necrosis 1 (0.1%) 0 (0)

Renal impairment 1 (0.1%) 0 (0)

Urinary calculus 1 (0.1%) 0 (0)

Total 14 (1.9%) 8 (2.5%)

51

Renal SAEs9 Renal SAEs, all double-blind period

• Calculi, nephrolithiasis 1 raltegravir, 1 placebo– Raltegravir (+)hx kidney stones– Placebo (+)indinavir

• Nephrotic syndrome 1 raltegravirFocal glomerulosclerosis– (+)HCV, HTN, Proteinuria

• Renal failure 3 raltegravir, 2 placebo– Raltegravir:

• 1 (+)HBV/HCV, hx renal insufficiency, (+) tenofovir - discontinued• 1 (+)HTN, DM, tenofovir. Occurred in setting of clinical dx c. difficile, CHF• 1 (+)tenofovir. Death attributed to suspected sepsis.

• Nephropathy 1 raltegravir– (+)tenofovir – discontinued

52

AEs in Subjects with OBT (+)Atazanavir• 116 subjects received atazanavir

– 78 raltegravir, 38 placebo

• AEs >5% raltegravir-treated subjects on atazanavir

Raltegravir-Treated Subjects

Preferred Term OBT with ATV

N=78 (%)

All Phase 3 and Protocol 005

N=595 (%)

↑Bilirubin 12 (15.4) 14 (2.4)

Headache 6 (7.7) 58 (9.7)

Nausea 6 (7.7) 63 (10.6)

Cough 4 (5.1) 32 (5.4)

Diarrhea 4 (5.1) 99 (16.6)

Fatigue 4 (5.1) 48 (8.1)

Hyperbilirubinaemia 4 (5.1) 4 (0.7)

Lymphadenopathy 4 (5.1) 23 (3.9)

Nasopharyngitis 4 (5.1) 38 (6.4)

Night sweats 4 (5.1) 13 (2.2)

Ocular icterus 4 (5.1) 4 (0.7)

Vomiting 4 (5.1) 41 (6.9)

53

HBV/HCV Co-Infected SubjectsRaltegravir-Treated Subjects Placebo-Treated Subjects

Laboratory Parameter

HBV/HCV

Co-infected

N=78 (%)

All Phase 3

N=462 (%)

HBV/HCV

Co-infected

N=36 (%)

All Phase 3

N=237 (%)

Serum AST

Grade 2 17 (21.8) 42 (9.1) 3 (8.3) 12 (5.1)

Grade 3 5 (6.4) 8 (1.7) 0 (0) 6 (2.5)

Grade 4 2 (2.6) 2 (0.4) 0 (0) 1 (0.4)

Serum ALT

Grade 2 13 (16.7) 31 (6.7) 4 (11.1) 21 (8.9)

Grade 3 6 (7.7) 13 (2.8) 2 (5.6) 4 (1.7)

Grade 4 2 (2.6) 3 (0.6) 0 (0) 1 (0.4)

Total Bilirubin

Grade 2 6 (7.7) 22 (4.8) 2 (5.6) 10 (4.2)

Grade 3 3 (3.8) 11 (2.4) 1 (2.8) 4 (1.7)

No study discontinuations due to ↑AST/ALT or bilirubin

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AEs associated with higher (top 10%) raltegravir plasma concentration

AE preferred term Subjects within top 10% of plasma concentration

All raltegravir treated subjects

N=462

All placebo treated subjects

N=237

Cough 3 22 (4.8%) 7 (3.0%)

Lymphadenopathy 3 14 (3.0%) 6 (2.5%)

Rash 2 27 (5.8%) 6 (2.5%)

• Selected AEs within +/- 2 days of higher raltegravir level

• No SAEs, no study discontinuations

• No temporal correlation between AEs and higher raltegravir plasma concentration

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Conclusion

56

Conclusion of Raltegravir Review

• Robust antiviral activity with no safety signals identified

• Relatively few subjects discontinued due to AEs

• Malignancy: Initial imbalance diminished with longer follow up

• Safety database limited by small population, short follow up– Longer term (48+ weeks) follow up with smaller

Phase 2 studies

57