Rolando M. Viani, MD, MTP UCSD School of Medicine

IMPAACT P1093: Ongoing Results & Next Steps
IMPAACT Treatment Scientific Committee Meeting
June 17, 2014
Rolando M. Viani, MD, MTP
UCSD School of Medicine
Background
• IMPAACT P1093 is an ongoing Phase I/II multicenter openlabel PK, safety, dose finding study of dolutegravir (DTG)
plus optimized background regimen (OBR) in children and
adolescents in age defined cohorts.
• Adequate pharmacokinetics (PK), safety and virologic
efficacy up to 24 weeks have been described in children
aged 12 to 18 years, leading to the recent FDA and EMA
indication.
• Here we report the 48 week results in cohort I, 24 week
results in cohort IIA and status of the study.
Study Design
• Inclusion Criteria
–
–
–
–
HIV-1 infected children and adolescents aged ≥ 4 weeks to < 18 yrs
INI-naïve
HIV-1 RNA > 1000 copies/mL
ART treatment experienced
• On ART, unchanged, failing regimen for at least 12 weeks or
• Off ART treatment for 4 weeks
– Must have at least 1 fully active drug for the OBR
• Age defined cohorts:
–
–
–
–
–
–
Cohort I: ≥12 < 18 years-Tablet formulation
Cohort IIA: ≥ 6 to < 12 years-Tablet formulation
Cohort IIB:≥ 6 to < 12 years-Granule formulation
Cohort III: :≥ 2 to < 6 years-Granule formulation
Cohort IV : :≥ 6 months to < 2 years-Granule formulation
-Cohort V: ≥ 4 weeks to < 6 months-Granule formulation
Study Design
Stage I
Intensive PK group n=10
Optimize therapy
continuation phase
48 wk
DTG + OBR
Functional monotherapy
or
monotherapy phase
Day 1
Day 5‐10
Intensive PK visit
Week 4 (PK and safety)
48 Week Safety & Efficacy
Stage II: Opens after dose/safety criteria met in Stage I; N=13
DTG + OBR from day 1
4
Baseline Characteristics
Cohort I (n=23)
Age (y), median (IQR)
15 (12,16)
Gender, n (%)
Male
5 (21.7)
Female
18 (78.3)
Race, n (%)
Black or African American
12 (52.2)
White
8 (34.8)
Asian
3 (13)
Ethnicity, n (%)
Hispanic or Latino
6 (26.1)
Not Hispanic or Latino
17 (73.9)
Plasma HIV-1 RNA Log10 copies/mL, median (IQR)
CD4+ cell count (cells/mm3), median (IQR)
CD4+ percent, median (IQR)
Time on prior ART (years), median (IQR)
4.3 (3.9, 4.6)
466 (297, 771)
22 (18, 29)
12.53 (10.8, 14.0)
Prior Antiretroviral Therapies
ART class
n (%)
NRTI
23 (100)
PI
18 (78.3)
NNRTI
12 (52.2)
Triple class experienced
8 (34.8)
Mean (SD) plasma DTG concentration (ng/mL)
PK Result: DTG Exposure in Cohort 1
(12 to <18 y) is Similar to Adults
5000
PK parameter,
mean (CV%)
4500
Cohort 1
AUC(0-24)
4000
46.0 µg*h/mL (43%)
C24
0.90 µg/mL (58%)
3500
3000
P1093 Cohort 1 Stage 1
2500
2000
Adult
1500
1000
500
0
0
5
10 Time (h) 15
20
25
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.
Optimized Background Regimen
ART
n (%)
Tenofovir DF, emtricitabine, darunavir/r
7 (30.4)
Abacavir, lamivudine, darunavir/r
3 (13)
Tenofovir, lamivudine, lopinavir/r
3 (13)
Tenofovir DF, emtricitabine, efavirenz
3 (13)
Tenofovir DF, emtricitabine
2 (8.7)
Tenofovir DF, emtricitabine, darunavir/r, etravirine
1 (4.3)
Tenofovir DF, atazanavir/r
1 (4.3)
Tenofovir DF, emtricitabine, atazanavir/r
1 (4.3)
Abacavir, lamivudine, atazanavir
1 (4.3)
Zidovudine, lamivudine, darunavir/r
1 (4.3)
________________________________________________________________
Total
23 (100)
Dose and Safety at Week 48
Dose
n=23
50 mg for ≥ 40 kg
19 (82.6%)
35 mg for 30-< 40 kg
4 (17.4%)
• DTG was generally well tolerated
– No discontinuations due to adverse events
– No DTG-related AE
– Two participants with unrelated grade 3 laboratory abnormality
• Unconjugated bilirubin elevation associated with atazanavir
• Asymptomatic lipase elevation
– No trends in lab abnormalities
Efficacy: Percent of Patients (95% CI) with
HIV RNA<400 c/mL or ≥1 Log10 Decline from
Baseline (Cohort I - All Treated): ITT Approach
74%
Efficacy: Percent of Patients (95% CI) with
HIV RNA < 50 c/mL
(Cohort I - All Treated): ITT Approach
61%
Baseline Characteristics (Cohort IIA)
Cohort IIA (n=11)
Age (y), median (IQR)
10 (8,11)
Gender, n (%)
Male
7 (63.6)
Female
4 (36.4)
Race, n (%)
Black or African American
4 (36.4)
White
3 (27.3)
Asian
2 (18.2)
Ethnicity, n (%)
Hispanic or Latino
4 (36.4)
Not Hispanic or Latino
7 (63.6)
Plasma HIV-1 RNA Log10 copies/mL, median (IQR)
CD4+ cell count (cells/mm3), median (IQR)
CD4+ percent, median (IQR)
Time on prior ART (years), median (IQR)
5.0 (3.5, 5.3)
645 (325, 732)
19 (14, 26)
9.30 (6.4, 10.4)
Prior Antiretroviral Therapies (Cohort IIA)
ART class
n (%)
NRTI
11 (100)
PI
11 (100)
NNRTI
6 (54.5)
Triple class experienced
6 (54.5)
Optimized Background Regimen
ART
n (%)
Tenofovir DF, emtricitabine,
2 (18)
Tenofovir DF, emtricitabine, atazanavir/r
2 (18)
Tenofovir DF, lamivudine, atazanavir/r
1 (9)
Zidovudine, lamivudine
1 (9)
Zidovudine, lamivudine, atazanavir/r
1 (9)
Zidovudine, lamivudine, indinavir/r
1 (9)
Zidovudine, abacavir, lopinavir/r
1 (9)
Stavudine, darunavir/r
1 (9)
Didanosine, emtricitabine, efavirenz
1 (9)
_
___________________________________________________________
Total
11(100)
PK Result: DTG Exposure in Cohort IIA
(6 to <12 years)
PK Parameter
Geometric Mean (CV %)
AUC24
50.46 µg*h/mL (63%)
C24
0.92 µg/mL (89%)
DTG dose (Cohort IIA) and Safety at
Week 24
DTG Dose
Weight range
n
50 mg
> 40 Kg
5
35 mg
30‐ < 40 Kg
2
25 mg
20‐ <30 Kg
4
• DTG was generally well tolerated
– No discontinuations
– No drug-related AEs
– Three participants had grade 3 unrelated events
• Two with unconjugated bilirubin elevation while on atazanavir
• One developed neutropenia, all resolved spontaneously
– There were no grade 4 clinical or laboratory events
– No trends in lab abnormalities
Efficacy: Percent of Patients (95% CI) with
HIV RNA<400 c/mL or ≥1 Log10 Decline from
Baseline (Cohort IIA - All Treated): ITT Approach
82%
Efficacy: Percent of Patients (95% CI) with
HIV RNA < 50 c/mL
(Cohort IIA - All Treated): ITT Approach
64%
P1093 Enrolled
• Cohort I: ≥ 12 to < 18 years Tablet formulation
– Stage 1 12 patients (completed)
– Stage 2  11 patients (completed)
• Cohort IIA: ≥ 6 to < 12 years
– Stage 1  11 patients (completed)
– Stage 2  10 patients (close to completion)
• Cohort IIB: ≥ 6 to < 12 years (granules): Granules
reconstituted with water to give a final concentration of
1.6mg/mL
– Stage 1  1 patient
• Screening: Cohort IIA stage 2 2 patients
• Screening Cohort IIB stage 1  1 patient
Granule formulation in suspension once-a-day
dose with target dose of ~0.64 mg/kg
Granule Dose in Weight Granule Dose Suspension mg/kg for Dose in mg/kg for upper Taken
lower weight weight subjects
Range (kg)
subjects
(mg)
(mL)
8 ‐ <15
6.4
4
0.80
0.43
15 ‐ <20
12.8
8
0.85
0.64
20 ‐ <30
16.0
10
0.80
0.53
30 ‐ <40
22.4
14
0.75
0.56
≥40
32.0
20
0.80
≤0.80
Acknowledgments
P1093
•
Thanks to IMPAACT
investigators and all of the
participants and their families!
•
IMPAACT Sites
•
Funding:
– IMPAACT is funded by NIH,
NIAID, NICHD, and NIMH
– ViiV Healthcare LLC
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Rolando M. Viani, MD, MTP, Protocol Chair
Andrew Wiznia, MD, Protocol Co-Chair
Rohan Hazra, MD
Edward P. Acosta, PharmD
Ellen Townley O'Gara, MSN, FNP
Kathy George
Terence Fenton, EdD
Carmelita Alvero, MS
Bobbie Graham
Paul Palumbo, MD
Thucuma Sise, 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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