IMPAACT P1066: Raltegravir (RAL) safety and efficacy in HIV infected (+) youth 2 to 18 years of age through week 48 S. Nachman 1, E. Acosta 2, N. Zheng 3, H. Teppler 4, B. Homony 4, X. Xu 4, C. Alvero 3, E. Handelsman 5, C. Worrell 6, B. Graham 7, M. Toye 8, E. Petzold 9, A. Wiznia 10, and the P1066 Group XIX International AIDS Conference 2012 Washington DC, USA, July, 2012 B40: Clinical trials and antiretroviral therapy in children and adolescents 1 SUNY Stony Brook, Pediatrics, Stony Brook, United States; 2 University of Alabama at Birmingham, Birmingham, United States; 3 Harvard School of Public Health, Boston, United States; 4 Merck, North Wales, United States; 5 Division of AIDS, NIAID, NIH, Bethesda, United States; 6 Natl Inst of Child Hlth and Human Devt, Bethesda, United States; 7 Frontier Science Inc, Buffalo, United States; 8 Baystate Medical Center, Springfield, United States; 9 Social and Scientific Systems, Durham, United States; 10 Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, United States

Background New antiretrovirals are needed for HIV+ children. 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 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

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

Study Design (2) Formulation Summary CohortAgeFormulation I12-18 yrsAdult IIA6-11 yrsAdult IIB6-11 yrsChewable III2-5 yrsChewable IV6mos – 2 yrsGranules for Susp V4wks – 6mosGranules for Susp Chewables available in 25 mg and 100 mg (scored), orange banana flavor Granules in sachets of 100 mg, reconstitute in 5mL water, banana flavor

Study Design (3) Endpoints: Safety: Grade 3+ or serious adverse events (AE) Safety: Grade 3+ or serious adverse events (AE) Efficacy: Efficacy: Primary: vRNA < 400c/mL or ≥1 log reduction Primary: vRNA < 400c/mL or ≥1 log reduction Secondary: vRNA < 50c/mL, change in CD4 count (%) Secondary: vRNA < 50c/mL, change in CD4 count (%) Used Observed Failure missing data approach Used Observed Failure missing data approach Time points: Time points: Primary: 24 wk Primary: 24 wk Secondary: 48 wk Secondary: 48 wk Analysis Populations: Primary : subjects who received only the final selected dose Primary : subjects who received only the final selected dose ITT population: all treated subjects 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 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

Total (2-18 yrs) Cohort III (2-<6 yrs) Cohort IIB (6-<12 yrs) Cohort IIA (6-<12 yrs) Cohort I (12-18 yrs) N=96N=20N=13N=4N=59 Film coated tabletChewable tablet Median Age (yrs) Male Gender51%75%54%35%49% Black Race59%75%54%60%59% vRNA (log 10 c/mL), mean [range] 4.3 [3.1-6]4.4 [ ]4.3 [ ]4.3 [ ]4.3 [2.7-6] CD4 cells/mm 3, median CDC HIV category B or C 76%25%23%40%59% Prior NNRTI86%75%85%50%78% Prior PI97%75%62%60%83% Subject Baseline Characteristics (Final Dose)

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

Efficacy: Percent of Patients (95% CI) with vRNA<400 c/mL or 1 Log 10 Decline from Baseline (Final Dose)

Efficacy: Percent of Patients (95% CI) with vRNA<400 c/mL or 1 Log 10 Decline from Baseline (All Treated)

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

Efficacy: Change From Baseline in CD4 cells/mm 3 (Final Dose)

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

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

Recommended Dose for Raltegravir (ISENTRESS) Chewable Tablets in Pediatric Patients 2 to Less Than 12 Years of Age – From US Product Circular Body weight (kg)DoseNumber of Chewable tablets 10 to <14 kg75 mg twice daily3 x 25 mg twice daily 14 to <20 kg100 mg twice daily1 x 100 mg twice daily 20 to <28 kg150 mg twice daily1.5 x 100* mg twice daily 28 to < 40 kg200 mg twice daily2 x 100 mg twice daily At least 40 kg300 mg twice daily3 x 100 twice daily 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

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

Backups

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, 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 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.

Cohort I (12-18yrs) Cohort IIA (6-<12yrs) Cohort IIB (6-<12yrs) Cohort III (2-<6yrs) Total (2-18 yr) N=59N=4N=13N=20N=96 WEEK 24 RESPONSE Achieved ≥1 log10 HIV RNA decline or <400 c/mL 72.4%50%76.9%70%71.6% Achieved HIV RNA <50 c/mL55.2%50%53.8%50%53.7% Mean CD4 change from baseline cells/mm3 (%) (4.1%) (2.2%) (0.8%) (5.3%) (3.8%) WEEK 48 RESPONSE Achieved ≥1 log10 HIV RNA decline or <400 c/mL 75% 90.9%84.2%78.9% Achieved HIV RNA <50 c/mL57.1%50%54.5%57.9%56.7% Mean CD4 change from baseline cells/mm3 (%) (5.2%) (6.0%) 76.8 (1.6%) (4.3%) (4.6%) Efficacy Outcomes at Week 24 and 48 (Final Dose, Observed Failure Approach)

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