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July 24, 2012

Phase 1/2, Multicenter, Open-label, Pharmacokinetic, Safety, Tolerability, and Antiviral Activity Study of Dolutegravir (DTG), a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children, and Adolescents: P1093. July 24, 2012.

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July 24, 2012

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  1. Phase 1/2, Multicenter, Open-label, Pharmacokinetic, Safety, Tolerability, and Antiviral Activity Study of Dolutegravir (DTG), a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 Infected Infants, Children, and Adolescents: P1093 July 24, 2012 Rohan Hazra, Rolando Viani, Edward Acosta, Nan Zheng, Carmelita Alvero, Ellen O’Gara, Elizabeth Petzold, Barb Heckman, Debra Steimers, Ivy Song, Steve Piscitelli, Andrew Wiznia, on behalf of the P1093 Study Team

  2. Key Characteristics of DTG • Once-daily, unboosted integrase inhibitor • Low to moderate PK variability1 • Few drug interactions requiring dose adjustment • Rapid and durable virologic response in adults2 • 10-50 mg DTG doses studied • 50 mg QD selected for phase 3, integrase inhibitor-naive subjects • Phase 3 treatment naïve adult data to be presented on Thursday (SPRING-2)3 1. Song et al. 13th International Workshop on Clinical Pharmacology of HIV Therapy 2012; Barcelona, Spain. Abstract O_07. 2. Stellbrink et al. CROI 2012; Seattle, WA. Abstract K-1002. 3. Raffi et al. IAC 2012; Washington, DC. Abstract LBB04.

  3. P1093 Study Design • Phase 1/2 multicenter, open-label, noncomparative study of HIV-1 infected infants, children, and adolescents aged ≥6 wk to <18 y, of DTG when administered both prior to starting and in combination with OBT • Cohort 1: 12 to <18 y • Cohort 2: 6 to <12 y • Cohort 3: 2 to <6 y • Cohort 4: 6 mo to <2 y • Cohort 5: 6 wk to <6 mo

  4. Enrollment Criteria • INI-naïve • HIV-1 RNA >1000 copies/mL • ARV treatment experienced • On ART • Unchanged, failing regimen at least 8 wk • Off ART • Off treatment 4 wk • Must have at least 1 fully active drug for the OBT

  5. P1093 Study Design Cohort 1: 12 to <18 y Intensive PK group n=10 Optimize therapy continuation phase 48 wk DTG + OBT Functional monotherapy or monotherapyphase Day 5-10 Intensive PK visit Day 1 Week 4 (PK and safety)

  6. Primary Objectives • Select DTG dose that achieves similar exposure as the adult dose (AUC(0-24) as primary endpoint and C24 as secondary endpoint) • Determine short- and long-term safety and tolerability • Evaluate steady-state PK of DTG in combination with other antiretrovirals (OBT)

  7. Baseline Characteristics

  8. Prior Antiretroviral Therapies To minimize the potential impact of drug-drug interactions on PK variability, use of ATV, NVP, ATV/r, EFV, FPV, FPV/r, and TPV/r was not allowed PRIOR to the initial PK evaluation but could be added as part of optimized background therapy

  9. P1093 Dosing Table for Cohort 1 (Tablet Formulation)

  10. PK Result: DTG Exposure in Cohort 1 (12 to <18 y) is Similar to Adults 5000 4500 4000 3500 3000 Mean (SD) plasma DTG concentration (ng/mL) 2500 2000 Adult 1500 1000 500 0 0 5 10 15 20 25 Time (h) Adult profile is based on pooled data from Study ING111521 and SPRING-1: Min et al. AIDS. 2011; 25(14): 1737-45. Stellbrink et al. CROI 2012; Seattle, WA. Abstract K-1002. van Lunzen et al. Lancet Infect Dis. 2012;12(2):111-118.

  11. PK Result: DTG Exposure in Cohort 1 (12 to <18 y) is Similar to Adults 5000 4500 4000 3500 3000 P1093 Cohort 1 Stage 1 Mean (SD) plasma DTG concentration (ng/mL) 2500 2000 Adult 1500 1000 500 0 0 5 10 15 20 25 Time (h) DTG exposure in Cohort 1 (12 to <18 y) achieved target exposure for both AUC(0-24)(37-67 µg*h/mL) and C24 (0.77-2.26 µg/mL) Adult profile is based on pooled data from Study ING111521 and SPRING-1: Min et al. AIDS. 2011; 25(14): 1737-45. Stellbrink et al. CROI 2012; Seattle, WA. Abstract K-1002. van Lunzen et al. Lancet Infect Dis. 2012;12(2):111-118.

  12. Safety at Week 4 • DTG was generally well tolerated • No discontinuations • No drug-related AEs • No grade 3 or 4 clinical or laboratory events • No trends in lab abnormalities

  13. HIV-1 RNA Results at Week 4 Median change from baseline was -2.8 log10 copies/mL (95% CI: -3.1, -2.6)

  14. Conclusions • DTG achieved mean AUC(0-24) and C24 within target range in children aged 12 to <18 y • PK/safety/tolerability data support dose selection of 50 mgin children aged 12 to <18 y weighing ≥40 kg • Supported further enrollment in remainder of this cohort (now n=22) • Data support further DTG initiation in the younger pediatric cohort (6 to <12 y) • DTG plus OBT was well tolerated and potent through Week 4 • Development of pediatric formulation is ongoing

  15. Acknowledgments P1093 Rolando M. Viani, MD, MTP Andrew Wiznia, MD Rohan Hazra, MD Paul Palumbo, MD Edward P. Acosta, PharmD Ellen Townley O'Gara, MSN, FNP Elizabeth Petzold, PhD Terence Fenton, EdD Carmelita Alvero, MS Nan Zheng, MA Barbara Heckman, BS Katherine Shin, PharmD Linda Barlow-Mosha, MD, MPH Mutsa Bwakura-Dangarembizi, MD Derek Weibel Jennifer Bryant, MPA Linda Lambrecht, MS Sherene Min, MD, MPH Debra McCarty-Steimers, BS Ivy Song, PhD Stephen Piscitelli, PharmD • Thanks to IMPAACT investigators and all of the participants and their families! • Sites: • UCSF • Chicago Children’s • Children’s Hospital of Boston • Jacobi Medical Center • Funding: • IMPAACT is funded by NIH, NIAID, NICHD, and NIMH • Shionogi-ViiV Healthcare LLC

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