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Phase 1/2, Multicenter, Open-label, Pharmacokinetic, Safety, Tolerability, and Antiviral Activity Study of Dolutegravir (DTG), a Novel Integrase Inhibitor,

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Presentation on theme: "Phase 1/2, Multicenter, Open-label, Pharmacokinetic, Safety, Tolerability, and Antiviral Activity Study of Dolutegravir (DTG), a Novel Integrase Inhibitor,"— Presentation transcript:

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 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 July 24, 2012

2 Key Characteristics of DTG Once-daily, unboosted integrase inhibitor Low to moderate PK variability 1 Few drug interactions requiring dose adjustment Rapid and durable virologic response in adults 2 –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_ Stellbrink et al. CROI 2012; Seattle, WA. Abstract K 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 Day 1 Week 4 (PK and safety) Day 5-10 Intensive PK visit Functional monotherapy or monotherapy phase Optimize therapy continuation phase 48 wk DTG + OBT Cohort 1: 12 to <18 y Intensive PK group n=10

6 Primary Objectives Select DTG dose that achieves similar exposure as the adult dose (AUC (0-24) as primary endpoint and C 24 as secondary endpoint) Determine short- and long-term safety and tolerability Evaluate steady-state PK of DTG in combination with other antiretrovirals (OBT) Protocol-Defined Targets AUC (0-24) (µg*h/mL)C 24 (µg/mL) Targets46960 Target range Lower limit25500 Upper limit92NA

7 Baseline Characteristics Cohort 1 (n=10) Age (y), median (range)13.5 (12-17) Gender, n (%) Male3 (30) Female7 (70) Race, n (%) Black or African American6 (60) White4 (40) Plasma HIV-1 RNA (copies/mL), n (%) 5000 to <10,0001 (10) 10,000 to <25,0003 (30) 25,000 to <50,0003 (30) 50,000 to <100,0001 (10) ≥100,0002 (20) CD4 + cell count (cells/mm 3 ), median543 CD4 + percent, median22 Time on prior ART (years), median12.8

8 Prior Antiretroviral Therapies ART class n (%) NRTI10 (100) PI9 (90) NNRTI4 (40) Triple class experienced4 (40) 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) Dose range Weight range (kg) Dose (mg)nDTG tablets taken DTG dose in mg/kg for lower- weight subjects DTG dose in mg/kg for upper- weight subjects 15 to <20200Two 10 mg tablets to <30250One 25 mg tablet to <40351One 10 mg tablet AND one 25 mg tablet ≥40509One 50 mg tablet 1.25≤1.25

10 Mean (SD) plasma DTG concentration (ng/mL) Adult Time (h) PK Result: DTG Exposure in Cohort 1 (12 to <18 y) is Similar to Adults Adult profile is based on pooled data from Study ING and SPRING-1: Min et al. AIDS. 2011; 25(14): Stellbrink et al. CROI 2012; Seattle, WA. Abstract K van Lunzen et al. Lancet Infect Dis. 2012;12(2):

11 DTG exposure in Cohort 1 (12 to <18 y) achieved target exposure for both AUC (0-24) (37-67 µg*h/mL) and C 24 ( µg/mL) PK Result: DTG Exposure in Cohort 1 (12 to <18 y) is Similar to Adults Mean (SD) plasma DTG concentration (ng/mL) Adult P1093 Cohort 1 Stage 1 Time (h) PK parameter, mean (CV%)Cohort 1 AUC (0-24) 46.0 µg*h/mL (43%) C µg/mL (58%) Adult profile is based on pooled data from Study ING and SPRING-1: Min et al. AIDS. 2011; 25(14): Stellbrink et al. CROI 2012; Seattle, WA. Abstract K van Lunzen et al. Lancet Infect Dis. 2012;12(2):

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 Outcomesn/NPercent (95% CI) HIV-1 RNA <40 copies/mL7/1070 (34.7, 93.3) HIV-1 RNA <400 copies/mL9/1090 (55.5, 99.8) Achieved at least 1 log 10 drop in HIV-1 RNA or HIV-1 RNA <400 copies/mL 10/10100 (69.1, 100) Median change from baseline was -2.8 log 10 copies/mL (95% CI: -3.1, -2.6)

14 Conclusions DTG achieved mean AUC (0-24) and C 24 within target range in children aged 12 to <18 y –PK/safety/tolerability data support dose selection of 50 mg in 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 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 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


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