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
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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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