Raltegravir NDA 22-145

1
RaltegravirNDA 22-145

• Sarah M. Connelly, MD
• Division 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 RNAgt1,000 copies/mL
• Resistant to gt 1 drug from each NNRTI, NRTI, PIs
• 21 randomization
• Primary Efficacy Endpoint
• Week 16 subjects with HIV-1 RNA lt 400 copies/mL
• Virologic failure gt 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 gt 5,000 copies/mL
• CD4 gt 50 cells/mm3
• Resistant to gt 1 drug from each NNRTI, NRTI, PIs
• Duration At least 24 weeks double-blind

7
Efficacy Demographics
Protocol 018 Protocol 018 Protocol 019 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 Characteristics
Protocol 018 Protocol 018 Protocol 019 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) lt50 - 156 (140) 30 153 (105) 34 146 (102) 34 163 (132) 32
HIV-1 RNA (log10 copies/mL) Mean (Median) gt100,000 - 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 Characteristics
Protocol 018 Protocol 018 Protocol 019 Protocol 019
Raltegravir Placebo Raltegravir Placebo
Subjects randomized and treated 232 118 230 119
Phenotypic Sensitivity Score (PSS) 0 1 2 gt 3 19 29 29 19 18 33 28 18 10 34 33 18 19 27 28 23
Genotypic Sensitivity Score (GSS) 0 1 2 gt 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 018 Protocol 019 Protocol 019
Raltegravir N232 Placebo N118 Raltegravir N230 Placebo N119
lt400 copies/mL n () 179 (77) 49 (42) 180 (78) 51 (43)
lt50 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 lt0.001 for both protocols
11
Efficacy Week 24 Analysis
Protocol 018 Protocol 018 Protocol 019 Protocol 019
Raltegravir N232 Placebo N118 Raltegravir N230 Placebo N119
Subjects with Week 24 Data n () 158 (68) 81 (69) 128 (56) 69 (58)
lt400 copies/mL n () 120 (76) 33 (41) 97 (76) 27 (39)
lt50 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 (lt1) 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 lt50
copies/mL at Week 16
Protocol 018 Protocol 018 Protocol 019 Protocol 019 Total Total
Responders/ Evaluable () Raltegravir N232 Placebo N118 Raltegravir N230 Placebo N119 Raltegravir N462 Placebo N237
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 lt50
copies/mL at Week 16
87

• Raltegravir
• Placebo

72
70
69
60
52
49
23
ENF/DRV ENF/-DRV -ENF/DRV -ENF/-DRV
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)
ENF enfuvirtide, DRV darunavir
14
Efficacy Summary

• Raltegravir OBT displays significantly greater
  antiviral activity as compared to OBT alone in
  treatment-experienced subjects
• Week 16 HIV-1 RNA lt400 copies/mL
• Supported by
• Week 16 HIV-1 RNA lt50 copies/mL
• ? 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 gt
  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

Raltegravir N595 Placebo N282
Protocol 005 4 0
Protocol 018 4 3
Protocol 019 5 0
Total 13 (2.2) 3 (1.1)
21
Mortality
Raltegravir Dose or Placebo Cause of Death Total Days On Tx Days Post-Tx to Death
Protocol 005 Protocol 005 Protocol 005 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 Protocol 018 Protocol 018 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 Protocol 019 Protocol 019 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 N13 Deaths on Placebo N3 All Other Subjects N861
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 lt50 - 46 100 26
Last CD4 Mean (Median) 136 (108) 7 (7) 270 (234)
23
Mortality Similar to Salvage Trials
Week 24 Mortality per 100 Patient-Yrs in Trt-Exp
Subjects As Treated
Raltegravir (N595) Placebo (N282)
By Week 24 By Week 24 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 Other
Clinical Trials
ENF Mortality at Wk 24 Analysis of TORO trials ENF Mortality at Wk 24 Analysis of TORO trials TPV/r Mortality at Wk 24 Analysis of RESIST trials TPV/r Mortality at Wk 24 Analysis of RESIST trials DRV/r Mortality at Wk 24 Analysis of POWER 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 Memorandum ENF
enfuvirtide OBR optimized background regimen
TPV/r tipranavir/ritonavir CPI/r comparator
protease inhibitor/ritonavir DRV/r
darunavir/ritonavir
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 Protocol 004 Protocols 005, 018, 019 Protocols 005, 018, 019
Raltegravir N 160 () EFV N 38 () Raltegravir N595 () Placebo N282 ()
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 AEs
Protocol Raltegravir Control
004 ?AST/ALT
005 Laceration/Suicide Sepsis/Bradycardia/Cardiorespiratory arrest Lipoatrophy
005 ?AST/ALT Lipoatrophy
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 N8 (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 gt 1
  AE
• Majority mild to moderate in intensity
• Most common AEs occurring in gt 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

Raltegravir 400 mg bid N507 Raltegravir 400 mg bid N507 Placebo N282 Placebo N282
n n
Subjects with gt 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
Malignancy

• 21 malignancies in 20 subjects through SUR
• No malignancies observed in placebo-treated
  subjects at time of SUR

Raltegravir
Control
20 malignancies in 19 subjects 1 switched
placebo?open-label raltegravir 2 subjects from
EAP

• 1 squamous cell ca of vocal cord
• EFV arm Protocol 004

32
Malignancy - July Update

• 36 malignancies in 31 subjects

Raltegravir
Control
30 malignancies in 26 subjects 2 placebo
switched?open-label raltegravir Double Blind
22 in 19 subjects
6 malignancies in 5 subjects 2 in 1 EFV-treated
subject 4 in placebo-treated subjects
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 N7
• Anal (N3)
• Carcinoma in situ (N4)
• Squamous cell carcinoma skin N6
• Kaposis sarcoma N5
• Lymphoma N4
• Basal cell carcinoma N3
• Hodgkins disease N2
• Rectal cancer N1
• Hepatocellular carcinoma N1
• Squamous cell carcinoma other N1
• Onset 25 557 days

• Control subjects
• Squamous cell carcinoma anogenital N2
• Anal (N2)
• Lymphoma N1
• Basal cell carcinoma N1
• Squamous cell carcinoma other N1
• Metastatic neoplasm N1
• Onset gt200 days

34
Malignancy July UpdatePhase 2 and 3 Double
Blind Phase
Raltegravir N755 PEY824 Control N320 PEY262
Malignancies 22 6
Subjects with gt1 Malignancy 19 5
Recurrences 8 2
Time to Onset, days - Median 98 285
Subjects with gt1 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 N595 PEY539 Placebo N282 PEY195
Malignancies 18 4
Subjects with gt1 Malignancy 16 4
Recurrences 6 1
Time to Onset, days - Median 73 285
Subjects with gt1 Malignancy 2.7 1.4
Malignancy Rate, adjusted for PEY 3.0 2.1
Prior SUR Malignancy Rate, adjusted for PEY (Raltegravir395) 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
  (N34)

Raltegravir 400 mg bid N462 Raltegravir 400 mg bid N462 Placebo N237 Placebo N237
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 -
Kaposis 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)

Raltegravir N755 Raltegravir N755 Control N320 Control N320
n n
Subjects with gt1 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 (N17) raltegravir vs 3.1 (N10) 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

Raltegravir N755 Raltegravir N755 Control N320 Control N320
n n
Subjects with gt1 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
Raltegravir Raltegravir Control Control
n n
Total 144 19.1 45 14.1

• No dose-response relationship observed
• 5 SAEs
• Raltegravir (N4)
• Hepatocellular carcinoma
• Portal HTN/varices
• Hepatitis in setting of IRS and treatment for
  thyrotoxicosis
• Pneumonia w/ elevated hepatic enzymes on DRV/r
• Placebo (N1)
• Hepatitis due to TPV/r

44
Hepatic Events Lab Data
Laboratory Parameter Limit Treatment Arm Treatment Arm
Raltegravir N755 Control N320

Serum ALT (IU/L) Serum ALT (IU/L) Serum ALT (IU/L) 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 gt10.0 x ULN 0.4 0.3
Serum AST (IU/L) Serum AST (IU/L) Serum AST (IU/L) 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 gt10.0 x ULN 0.7 0.3
Serum Alkaline Phosphatase (IU/L) Serum Alkaline Phosphatase (IU/L) Serum Alkaline Phosphatase (IU/L) 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 gt10.0 x ULN 0.3 0.4
Total Serum Bilirubin (mg/dL) Total Serum Bilirubin (mg/dL) Total Serum Bilirubin (mg/dL) 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 gt5.0 x ULN 0.7 0
45
Hys Law
46
Screening for Hys Law Cases

• Definition for potential Hys Law cases
• AST and/or ALT gt 3x ULN
• Total bilirubin gt 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 Hys Law No Cases

• 1. Protocol 005 200 mg raltegravir Double
  Blind Continued study therapy
• OBT Atazanavir/r, ddI, 3TC
• Hx ?bilirubin, transaminases 2003 splenomegaly,
  steatosis 2000
• 2. Protocol 005 200 mg raltegravir OLPVF
  Continued study therapy
• OBT Atazanavir, LPV/r, abacavir, 3TC
• Hx hyperbilirubinemia 2004
• 3. Protocol 018 400 mg raltegravir Double Blind
  Continued study therapy
• OBT DRV/r, abacavir, TDF
• ()HCV -gt transient reactivation
• 4. Protocol 018 400 mg raltegravir Double Blind,
  Post-Tx Interrupted Day 32 - 66
• OBT DRV/r, indinavir, 3TC, AZT
• ()Grade 2 Alkaline Phosphatase
• Occurred in setting of acute thyrotoxicosis tx
  with PTU (Day 36) bronchopneumonia (Day 102)
• 5. Protocol 019 400 mg raltegravir Double
  Blind Interrupted Day 168 - 174
• OBT DRV/r, TDF FTC (discontinuation on Day
  33)

48
Creatine Kinase (CK)

• 63 subjects experienced Grade 2 - Grade 4 CK
  elevations

CK Grade Limit Raltegravir N755 Raltegravir N755 Control N320 Control N320
n n
Grade 2 6.09.9 x ULN 18 2.4 5 1.6
Grade 3 10.019.9 x ULN 16 2.1 5 1.6
Grade 4 gt20.0 x ULN 16 2.1 3 0.9
All Grades 2-4 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 Raltegravir N755 n () Control N320 n ()
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 SAEs

• 9 Renal SAEs, all double-blind period
• Calculi, nephrolithiasis 1 raltegravir, 1
  placebo
• Raltegravir ()hx kidney stones
• Placebo ()indinavir
• Nephrotic syndrome 1 raltegravir
• Focal 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 gt5 raltegravir-treated subjects on
  atazanavir

Raltegravir-Treated Subjects Raltegravir-Treated Subjects
Preferred Term OBT with ATV N78 () All Phase 3 and Protocol 005 N595 ()
?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 Subjects
Raltegravir-Treated Subjects Raltegravir-Treated Subjects Placebo-Treated Subjects Placebo-Treated Subjects
Laboratory Parameter HBV/HCV Co-infected N78 () All Phase 3 N462 () HBV/HCV Co-infected N36 () All Phase 3 N237 ()
Serum AST Serum AST 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 Serum ALT 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 Total Bilirubin 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 N462 All placebo treated subjects N237
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
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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

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