XIX International AIDS Conference 2012 Washington DC, USA, 22-27 July, 2012

1. XIX International AIDS Conference 2012 Washington DC, USA, 22-27 July, 2012 B40: Clinical trials and antiretroviral therapy in children and adolescents IMPAACT P1066: Raltegravir (RAL) safety and efficacy in HIV infected (+) youth 2 to 18 years of age through week 48 1SUNY Stony Brook, Pediatrics, Stony Brook, United States; 2University of Alabama at Birmingham, Birmingham, United States; 3Harvard School of Public Health, Boston, United States; 4Merck, North Wales, United States; 5Division of AIDS, NIAID, NIH, Bethesda, United States; 6Natl Inst of Child Hlth and Human Devt, Bethesda, United States; 7Frontier Science Inc, Buffalo, United States; 8Baystate Medical Center, Springfield, United States; 9Social and Scientific Systems, Durham, United States; 10Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, United States S. Nachman1, E. Acosta2, N. Zheng3, H. Teppler4, B. Homony4, X. Xu4, C. Alvero3, E. Handelsman5, C. Worrell6, B. Graham7, M. Toye8, E. Petzold9, A. Wiznia10, and the P1066 Group

2. Background New antiretrovirals are needed for HIV+ children. IMPAACT P1066 is an international Phase I/II open label multicenter trial to evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of multiple RAL formulations in treatment experienced HIV+ youth

3. Study Design (1) • Open label, multi-center study conducted in US, South Africa, Botswana, Brazil, Argentina • Population: HIV+ youth who failed ≥ one ART regimen with HIV RNA >1000 • < 2yrs may have failed only PMTCT • 2-stage study: • Stage 1 performed intensive PK for dose finding/safety • Stage 2 enrolled additional patients at selected (final) dose • Dose selection based on intensive PK and safety data: • RAL film-coated (adult) tabs: 400 mg BID for 6-18 yrs and ≥ 25kg • RAL chewable: weight-based dosing at ~6mg/kg (75-300mg) BID for 2 -<12 yrs • RAL oral granules for suspension (< 2yrs) ongoing • RAL was given with an optimized background regimen • Subjects were enrolled sequentially in 5 age cohorts

4. Study Design (2)Formulation Summary Chewables available in 25 mg and 100 mg (scored), orange banana flavor Granules in sachets of 100 mg, reconstitute in 5mL water, banana flavor

5. Study Design (3) Endpoints: • Safety: Grade 3+ or serious adverse events (AE) • Efficacy: • Primary: vRNA < 400c/mL or ≥1 log reduction • Secondary: vRNA < 50c/mL, change in CD4 count (%) • Used Observed Failure missing data approach • Time points: • Primary: 24 wk • Secondary: 48 wk Analysis Populations: • Primary : subjects who received only the final selected dose • ITT population: all treated subjects • Here we present demographics and 48 week safety and efficacy data in 96 subjects 2-18yr (Cohorts I-III) who received RAL only at the final selected dose

6. Subject Baseline Characteristics (Final Dose) Cohort I (12-18 yrs) Cohort IIA (6-<12 yrs) Cohort IIB (6-<12 yrs) Cohort III (2-<6 yrs) Total (2-18 yrs) N=59 N=4 N=13 N=20 N=96 Film coated tablet Chewable tablet Median Age (yrs) 15 10.5 9 3 13 Male Gender 51% 75% 54% 35% 49% Black Race 59% 75% 54% 60% 59% vRNA (log 10 c/mL), mean [range] 4.3 [3.1-6] 4.4 [3.5-4.9] 4.3 [3.5-5.2] 4.3 [2.7-5.3] 4.3 [2.7-6] CD4 cells/mm3, median 397 807 529 1087 481 CDC HIV category B or C 76% 25% 23% 40% 59% Prior NNRTI 86% 75% 85% 50% 78% Prior PI 97% 75% 62% 60% 83%

7. Safety At Week 48 • Grade 3 + AEs • 15 subjects had Grade 3+ clinical AEs • 1 subject with drug related [DR] psychomotor hyperactivity, abnormal behavior and insomnia • 16 subjects with Grade 3+ laboratory AEs (1 with DR AST and ALT) • Serious AEs • 14 subjects with serious clinical AEs (1 with DR rash) • 2 subjects with serious laboratory AEs (1 with DR transaminase increased) • No discontinuations due to AEs and no deaths

8. Efficacy: Percent of Patients (95% CI) with vRNA<400 c/mL or 1 Log10 Decline from Baseline (Final Dose)

9. Efficacy: Percent of Patients (95% CI) with vRNA<400 c/mL or 1 Log10 Decline from Baseline (All Treated)

10. Efficacy: Percent of Patients (95% CI) with vRNA<50 c/mL (Final Dose)

11. Efficacy: Change From Baseline in CD4 cells/mm3 (Final Dose)

12. Conclusions Two RAL formulations were studied in HIV infected youth ages 2 to 18 years; PK targets were met forboth formulations At the selected final doses RAL was well-tolerated and showed favorable virologic and immunologic responses through 48 weeks of treatment Data from All Treated subjects (who received other than Final Dose, N=126) were consistent

13. Conclusions (2) • Data from this study has been used in obtaining US FDA approval for use of raltegravir in HIV+ youth ages 2-18 yrs • RAL film-coated tablet: 400 mg BID • Ages 12 to 18 yrs • Ages 6 to <12 yrs, weight ≥ 25kg • RAL chewable tablet • Ages 2 to <12 yrs, weight ≥10kg: weight based dosing (75-300mg) BID

14. Recommended Dose for Raltegravir (ISENTRESS) Chewable Tablets in Pediatric Patients 2 to Less Than 12 Years of Age – From US Product Circular • The weight based dosing recommendation for the chewable tables is based on approximately 6 mg/kg/dose twice daily • *The 100 mg chewable tablet is scored and can be divided into equal halves

15. The study team would like to thank the sponsors, sites and families who participated in this study NIAID: Ed Handelsman NICHD: Carol Worrell Merck: Hedy Teppler Merck: Brenda Homony Merck: Xia Xu Merck: Matthew Rizk Merck: Larissa Wenning Merck: Elizabeth Rhee SDAC: Terrence Fenton SDAC: Nan Zheng SDAC: Carmelita Alvero SSS: Kim Hudgens and Liz Petzold FSTRF: Bobbie Graham Pharmacist: Lynette Purdue Pharmacologist: Edward Acosta Virologist: Lisa Frenkel Immunologist: Steve Douglas Lab Technologist: Nancy Tustin Lab Manager: Carrie Fry Investigators: Steve Spector IMPAACT domestic and international site staff and investigators

16. Backups

17. Background: New antiretrovirals are needed for HIV+ children. IMPAACT P1066 is a Phase I/II open label multicenter trial to evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of multiple RAL formulations in treatment experienced HIV+ youth. RAL was given with an optimized background regimen. Dose selection was based upon intensive PK and safety data: 400 mg BID of RAL film-coated tablet (6-18 years) and weight-based dosing (~6mg/kg BID) of RAL chewable tablet (2 to < 12 years). Here we present safety and efficacy results at 24 and 48 weeks in the 96 subjects who received the selected RAL dose. Methods: Subjects were stratified sequentially in 3 age cohorts (I, 12-18 years; II, 6-< 12 years; III, 2-< 6 years); Cohort I enrolled first. Safety data through Week 48 was assessed. Grade 3+ or serious adverse events (AE) were summarized. Primary virologic endpoint was vRNA < 400c/mL or ≥1 log reduction. Secondary endpoints were vRNA < 50c/mL, and change in CD4 count (%). Efficacy analyses used Observed Failure missing data approach. Results: Baseline characteristics, virologic and immunologic responses at weeks 24 and 48 for 96 subjects are in tables. Overall, virologic response was observed in 78.9%, RNA < 50c/mL in 56.7%, with mean CD4 increase 155.7 cells/uL. Through Week 48, there were 15 subjects with Grade 3+ clinical AEs (1 subject with drug related [DR] psychomotor hyperactivity, abnormal behavior and insomnia); 16 subjects with Grade 3+ laboratory AEs (1 with DR AST and ALT); 15 subjects with serious clinical AEs (1 with DR rash); 2 subjects with serious laboratory AEs (1 with DR transaminase increased); no discontinuations due to AEs and no deaths. Conclusions: Two RAL formulations were studied in HIV infected youth ages 2 to 18 years. At the selected doses, both formulations were well-tolerated and showed favorable virologic and immunologic responses.

18. Efficacy Outcomes at Week 24 and 48 (Final Dose, Observed Failure Approach)

19. P1066: Raltegravir Steady State PK Parameters Following Administration of Recommended Dose(from US Product Circular)