# Presentation: 675816

## RaltegravirNDA 22-145

- Sarah M. Connelly, MD
- Division of Antiviral Products
- Advisory Committee Meeting
- September 5, 2007

## Raltegravir: Overview

- Efficacy review
- Resistance data
- Safety review
- Conclusions

## Efficacy Review

## 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

## Efficacy: Phase 3 Trial DesignProtocols 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

## Efficacy: Phase 2 Dose FindingProtocol 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

## Efficacy: Demographics

|  | Protocol 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) |

## Efficacy: Baseline Characteristics

|  | Protocol 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 |

## Efficacy: Baseline Characteristics

|  | Protocol 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 |

## 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

## 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) |

## Efficacy: Subgroup AnalysesHIV-1 RNA <50 copies/mL at Week 16

|  | Protocol 018 |  | Protocol 019 |  | Total |  |
| --- | --- | --- | --- | --- | --- | --- |
| Responders/ 
Evaluable (%) | Raltegravir
N=232 | Placebo 
N=118 | Raltegravir
N=230 | Placebo 
N=119 | Raltegravir
N=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

## Efficacy: Subgroup AnalysesHIV-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) |

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

**87**

**70**

** ****72**

**52**

** ****69**

**49**

** ****60**

**23**

-  **Raltegravir**
** ****Placebo**

## 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

## Resistance Data

## Microbiology Resistance DataProtocols 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

## 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

## Safety Review

## 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

## 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
N=595 | Placebo
N=282 |
| --- | --- | --- |
| Protocol 005 | 4 | 0 |
| Protocol 018 | 4 | 3 |
| Protocol 019 | 5 | 0 |
| Total | 13 
(2.2%) | 3 
(1.1%) |

## Mortality

| Raltegravir
Dose or Placebo | Cause of Death | Total Days
On Tx | Days Post-Tx
to 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 |

## 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 CD4
Mean (Median) | 
136 (108) | 
7 (7) |  | 
270 (234) |

## 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 Memorandum
- ENF = 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**

## 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

## Study Discontinuations

|  | Protocol 004 |  |  | Protocols 005, 018, 019 |  |
| --- | --- | --- | --- | --- | --- |
|  | Raltegravir
N= 160 (%) | EFV 
N= 38 (%) |  | Raltegravir
N=595 (%) | Placebo
N=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%) |

## Study Discontinuations Associated with AEs

| Protocol | 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 |  |

## 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%)

## 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

## Common AEs

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

|  | Raltegravir
400 mg bid
N=507 |  | Placebo
N=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% |

## Focused Analyses of AEs of Interest

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

## Malignancy

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

**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**

**Raltegravir**

**Control**

## Malignancy - July Update

- 36 malignancies in 31 subjects

**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**

**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 |

## 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: anogenital			N=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_

## Malignancy: July UpdatePhase 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

## Malignancy: July UpdateTreatment-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

## 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

## 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 bid
N=462 |  | Placebo
N=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% |

## 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

## 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
N=755 |  | Control
N=320 |  |
| --- | --- | --- | --- | --- |
|  | n | % | n | % |
| Subjects with >1 Rash AE | 54 | 7.2% | 17 | 5.3% |

## 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

## 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
N=755 |  | Control
N=320 |  |
| --- | --- | --- | --- | --- |
|  | n | % | n | % |
| Subjects with >1 Hypersensitivity AE | 6 | 0.8% | 4 | 1.3% |

## 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

## 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% |

## Hepatic Events: Lab Data

| Laboratory Parameter | Limit | Treatment Arm |  |
| --- | --- | --- | --- |
|  |  | Raltegravir
N=755 | Control
N=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 |

## Hy’s Law

## 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

## Evaluation of Hy’s 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 -> 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)**
**	**_**(+)HBV ->reactivation**_** with HBV DNA 84,000,000 IU/mL**
**6.****	****Protocol 019****	****400 mg raltegravir****	****Double Blind****	****	****Continued study therapy**
**	****OBT: **_**Atazanavir**_**, DRV/r, TDF + FTC**
**	****(+)HBV, baseline bilirubin 3.4**

## Creatine Kinase (CK)

**63 subjects experienced Grade 2 - Grade 4 CK elevations**

| CK Grade | Limit | Raltegravir
N=755 |  | Control
N=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 Grades
2-4 |  | 50 | 6.6% | 13 | 4.1% |

## 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

## Renal AEs: Phase 2 and 3

- 22 Renal AEs occurred in 18 subjects

| Preferred Term | Raltegravir
N=755 
n (%) | Control
N=320
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%)	 |

## 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

## 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) |

## HBV/HCV Co-Infected Subjects

|  | Raltegravir-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_

## 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_

## Conclusion

## 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