1	Raltegravir NDA 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 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
6	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
7	Efficacy: Demographics
8	Efficacy: Baseline Characteristics
9	Efficacy: Baseline Characteristics
10	Efficacy: Week 16 Analysis
11	Efficacy: Week 24 Analysis*
12	Efficacy: Subgroup Analyses HIV-1 RNA <50 copies/mL at Week 16
13	Efficacy: Subgroup Analyses HIV-1 RNA <50 copies/mL at Week 16
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 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
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
21	Mortality
22	Mortality Analysis of Baseline Characteristics Subjects who died were more advanced at baseline
23	Mortality: Similar to Salvage Trials
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
26	Study Discontinuations Associated with AEs
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
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
32	Malignancy - July Update 36 malignancies in 31 subjects
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: 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
34	Malignancy: July Update Phase 2 and 3: Double Blind Phase
35	Malignancy: July Update Treatment-Experienced Protocols
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)
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)
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
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
44	Hepatic Events: Lab Data
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 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
48	Creatine Kinase (CK) 63 subjects experienced Grade 2 - Grade 4 CK elevations
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
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 >5% raltegravir-treated subjects on atazanavir
53	HBV/HCV Co-Infected Subjects No study discontinuations due to ↑AST/ALT or bilirubin
54	AEs associated with higher (top 10%) raltegravir plasma concentration Selected AEs within +/- 2 days of higher raltegravir level No SAEs, no study discontinuations No temporal correlation between AEs and higher raltegravir plasma concentration
55	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
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