Safety and Efficacy of RaltegravirBased Versus Efavirenz-Based Combination Therapy in TreatmentNaïve HIV-1 Infected Patients STARTMRK Protocol 021 Jeffrey Lennox, Edwin DeJesus, Adriano Lazzarin, Richard.

Transcript Safety and Efficacy of RaltegravirBased Versus Efavirenz-Based Combination Therapy in TreatmentNaïve HIV-1 Infected Patients STARTMRK Protocol 021 Jeffrey Lennox, Edwin DeJesus, Adriano Lazzarin, Richard.

Safety and Efficacy of Raltegravir Based Versus Efavirenz-Based Combination Therapy in Treatment Naïve HIV-1 Infected Patients STARTMRK Protocol 021

Jeffrey Lennox, Edwin DeJesus, Adriano Lazzarin, Richard Pollard, Jose Valdez Ramalho Madruga, Jing Zhao, Xia Xu, Angela Williams-Diaz, Anthony Rodgers, Mark DiNubile, Bach-Yen Nguyen, Randi Leavitt, and Peter Sklar

For the STARTMRK Investigators

STARTMRK – Design (1)

● ● Double-blind, randomized (1:1), active-controlled study Raltegravir (RAL) 400 mg b.i.d. vs efavirenz (EFV) 600 mg q.h.s. both in combination with tenofovir/emtricitabine (TDF/FTC) ● Key inclusion criteria – No prior ART – – HIV RNA >5000 copies/mL Susceptible to EFV, TDF, and FTC ● Endpoints – Efficacy: HIV RNA, CD4 counts – Safety/tolerability: Adverse experiences (AEs); Central Nervous System (CNS) events; lipid changes from baseline 2008 ICAAC-IDSA Abstract H-896a Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved 2

STARTMRK – Design (2)

● Hypotheses (at Week 48) In treatment naïve, HIV-infected patients: – RAL + TDF/FTC will have non-inferior (12% bound) efficacy compared to EFV + TDF/FTC • Efficacy defined as % of patients with HIV RNA <50 copies/mL at Week 48 • Primary analysis: Non-Completer = Failure Approach – RAL + TDF/FTC will be generally safe and well tolerated • RAL + TDF/FTC will be superior to EFV + TDF/FTC in terms of CNS adverse events up to Week 8 2008 ICAAC-IDSA Abstract H-896a Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved 3

STARTMRK - Patient Disposition

Randomized 1:1 to RAL or EFV arms 281 Treated with RAL* 24 (8.5%) Discontinued due to: 8- Adverse events 4- Lack of efficacy 3- Lost to follow-up 9- Other events 282 Treated with EFV* 257 (91.5%) Completed 48 weeks

247 (87.6%) Completed 48 weeks 35 (12.4%) Discontinued due to: 17- Adverse events 2- Lack of efficacy 7- Lost to follow-up 9- Other events

*In combination with TDF/FTC 4

STARTMRK – Baseline Characteristics

# Patients Treated Age (mean, years) % Male % Non-White vRNA copies/mL (geometric mean) % with vRNA >10 5 copies/mL Mean CD4 count (cells/ μl) % with CD4 ≤200 cells/μl % Hepatitis B or C % Non-Clade B RAL* N = 281 38 81 59 103,205 55 219 47 7 21

EFV* N = 282 37 82 56 106,215 51 217 48 7 17

*In combination with TDF/FTC 5

Results

STARTMRK – Percent of Patients With HIV RNA <50 copies/mL (95% CI)

(Non-Completer = Failure)

100

86%

82%

60 40

Non-inferiority p-Value<0.001

20 0 0 2 4 8 12 16

Number of Contributing Patients

Raltegravir 400 mg b.i.d.* Efavirenz 600 mg q.h.s.* 281 279 281 279 281 282 282 282 282 281 24

Weeks

STARTMRK – Time to Virologic Response

(HIV RNA <50 copies/mL)

100 80 60

Log-Rank p-Value<0.001

40 20 0 0 2 4 8 12 16

Number of Patients at Risk

Raltegravir 400 mg b.i.d.* 281 214 134 71 Efavirenz 600 mg q.h.s.* 42 282 267 229 158 95 24 23 44 32

Weeks

STARTMRK – Change From Baseline in CD4 Cell Count (95% CI)

(Observed Failure) 189

200 150 100 50 0 0 2 4 8 12 16 24

Weeks Number of Contributing Patients

Raltegravir 400 mg b.i.d.* Efavirenz 600 mg q.h.s.* 281 281 274 272 277 272 272 268 270 269 266 266 2008 ICAAC-IDSA Abstract H-896a Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved 32 260 260 40

163 ∆ (95% CI) = 26 (4, 47)

48 259 254 258 251 *In combination with TDF/FTC 9

STARTMRK - Resistance by Week 48 in Patients with Virologic Failure*

RAL Failures vRNA >400c/mL N=12 VL Failures N=27 RAL N=39 EFV EFV Failures vRNA >400c/mL N=8 No known RAL resistance mutation N=5 4 Sens to TDF/FTC, 1 not tested Known RAL IN gene could not be amplified resistance mutation N=4 3 Res to FTC, 1 not tested N=3 No known EFV resistance mutation N=3 3 Sens to TDF/FTC RT gene no data N=2 Known EFV resistance mutation N=3 1 Res to FTC IN Mutations: N=1 N=2 G140S+Q148H/R Y143H+L74M+E92Q+T97A N=1 Y143R *Virologic failure

: Non-responder: (1) HIV RNA >50 copies/mL at the time of discontinuation or (2) HIV RNA >50 copies/mL at Week 24 Virologic rebound: HIV RNA >50 copies/mL (on 2 consecutive measurements at least 1 week apart) after initial response 2008 ICAAC-IDSA Abstract H-896a Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved 10

STARTMRK – 48-Week Safety Summary

● RAL group had significantly fewer drug-related clinical adverse experiences (AEs) compared to EFV* – Clinical AEs – RAL 90.0% vs EFV 96.5% Drug Related Clinical AEs p=0.002

All intensities: RAL 44.1% vs EFV 77.0% p<0.001

● Moderate/Severe: RAL 16.0% vs EFV 31.9% p<0.001

Serious Clinical AEs: – RAL 10.0% vs EFV 9.6% p=0.888

Deaths: 2 (0.7%) for RAL vs 0 (0%) for EFV Malignancies: 1 (0.4%) for RAL vs 9 (3.2%) for EFV – 7 KS, 1 B-cell NHL, 1 anal cancer, 1 bone cancer 2008 ICAAC-IDSA Abstract H-896a Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved *RAL and EFV were administered in combination with TDF/FTC 11

STARTMRK – Most Common

‡

Drug-Related

Clinical Adverse Events of Moderate or Severe Intensity

RAL* N = 281 EFV* N = 282 Headache Dizziness Insomnia n (%) 11 (3.9) 4 (1.4) 10 (3.6) n (%) 13 (4.6) 18 (6.4) 9 (3.2) Nausea Fatigue Diarrhea Rash 8 (2.8) 4 (1.4) 3 (1.1) 0 (0.0) 10 (3.5) 8 (2.8) 8 (2.8) 8 (2.8) Rash maculo-papular 0 (0.0) 7 (2.5)

‡ Present in ≥2% of either treatment group ¥ Determined by investigator to be possibly, probably, or definitely related to any drug in the treatment regimen *In combination with TDF/FTC 2008 ICAAC-IDSA Abstract H-896a Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved 12

STARTMRK – CNS Adverse Events Accumulated Up to Week 8

% with CNS Adverse Events RAL* EFV* 10.3

17.7

p-value 0.015

●

CNS terms compared at Week 8

– – – – – – Depression Major depression Nightmare Abnormal dreams Suicide Suicide attempt – – – – Nervous system disorder Psychotic disorder Acute psychosis Confusional state or ideation – – – – Delirium Depressed level of consciousness Hallucination Auditory hallucination ●

Cumulative differences persisted through Week 48

STARTMRK – Grade 3/4

‡

Abnormalities Laboratory

Laboratory Blood Test Absolute neutrophil count Hemoglobin Platelet count Fasting LDL cholesterol Fasting total cholesterol Fasting triglycerides Fasting glucose Total bilirubin Alkaline phosphatase Aspartate aminotransferase Alanine aminotransferase Toxicity Criteria ‡ <750 cells/µL <7.5 gm/dL <50 k/µL ≥190 mg/dL >300 mg/dL >750 mg/dL >250 mg/dL >2.5 x ULN >5 x ULN >5 x ULN >5 x ULN

RAL* N = 281 EFV* N = 282 n (%) n (%) 5 (1.8) 2 (0.7) 0 (0.0) 3 (1.1) 0 (0.0) 1 (0.4) 1 (0.4) 2 (0.7) 3 (1.1) 2 (0.7) 1 (0.4) 10 (3.6) 7 (2.5) 3 (1.1) 0 (0.0) 0 (0.0) 0 (0.0) 6 (2.1) 2 (0.8) 5 (1.8) 5 (1.8) 6 (2.1)

‡ Grades 3/4 by DAIDS criteria *In combination with TDF/FTC 14

STARTMRK – Change From Baseline in Fasting Serum Lipids Week 48

40 30

‡

33 ‡ p<0.001

‡

37 * * RAL EFV 20

‡

16 10 10

‡

4 10 0 T CHOL -10 Lipid-Lowering Rx HDL-C 6 LDL-C Added Rx Increased Rx

-3 TG RAL* # (%) 3 (1) 4 (1) T CHOL/HDL

p = 0.292

-1

EFV * # (%) 11 (4) 4 (1)

*In combination with TDF/FTC 15

STARTMRK – Conclusions

In treatment naïve patients given 48 weeks of TDF/FTC, the integrase inhibitor raltegravir: ● ● Had potent, durable antiviral efficacy that was statistically non-inferior to efavirenz − − 86% (RAL) versus 82% (EFV) <50 copies/mL at Week 48 Achieved faster vRNA suppression <50 copies/mL Had greater immunological effect than efavirenz, measured by increases in CD4 cell counts − 189 (RAL) versus 163 (EFV) cells/mm 3 at Week 48 ● Was better tolerated than efavirenz − − Significantly fewer overall and drug-related clinical adverse events Significantly lower percentages of patients with CNS adverse experiences • Had minimal effects on serum lipids 2008 ICAAC-IDSA Abstract H-896a Copyright © 2008 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights Reserved 16

Acknowledgements STARTMRK Protocol 021 Study Team

Investigators Dr. D. Berger Dr. E. DeJesus Dr. T. Friel Dr. C. Hicks Dr. M. Kozal Dr. P. Kumar Dr. J. Lennox Dr. R. Liporace Dr. S. Little Dr. J. Morales-Ramirez Dr. P.M. Girard Dr. D. Cooper Dr. C. Beltran Dr. A. Afani Dr. J. Perez Godoy Dr. J. Santamaria Jauregui Dr. J. Portilla Sogorb Dr. A. Rivero-Roman Dr. F. Smaill Dr. S. Sungkanuparph Dr. G. Reyes Dr. C. Viscoli Dr. A. Lazzarin Dr. A. Chiranni Dr. R. Esposito Dr. C. Kovacs Dr. J.G. Baril Dr. R. Zajdenverg Dr. J. Madruga Dr. E. Martins Netto Dr. R. Novak Dr. R. Pollard Dr. M. Saag Dr. S. Santiago Dr. S. Schneider Dr. R. Steigbigel Dr. W. Towner Dr. D. Wright Dr. G. Pialoux Dr. A. Vibhagool Dr. W. Manosuthi Dr. K. Supparatpinyo Dr. S. Esser Dr. G. Fatkenheuer Dr. J. Rockstroh Dr. H.J. Stellbrink Dr. R. Schmidt Dr. J. Sierra Dr. J. Velez Dr. J. Tamara Dr. A. Arango Dr. M. Angela Dr. R. Salazar Dr. E. Gotuzzo Dr. R. Cabello Dr. J. Lama Dr. O. Srivastava Dr. Y. Yazdanpanah Dr. L. Cotte Dr. J. Andrade Dr. N. Quintero Perez Dr. J. Rajendran Dr. A. Pazare Dr. D. Salmon Ceron Dr. I. Torres Dr. M. Dinaker Dr. G. Carosi

Merck Research Laboratories P. Sklar R. Leavitt B.-Y. Nguyen J. Zhao X. Xu A. Rodgers A. Williams-Diaz R. Isaacs K. Gottesdiener C. Gilbert M. Cahill S. Foley T. Finn L. Wenning M. Miller R. Barnard D. Hazuda M. DiNubile