Post on 30-Dec-2015
Phase 2 of new ARVs
Fostemsavir, prodrug of temsavir (attachment inhibitor)– AI438011 Study
TAF (TFV prodrug)– Study 292-0102– Study 299-0102
Doravirine (non nucleoside reverse transcriptase inhibitor)– MK1439007 Study
Cabotegravir (integrase inhibitor)– LATTE Study
BMS-955176 (maturation inhibitor)– AI468002 Study
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
DOR 25 mg qd + TDF/FTC
DOR 50 mg qd + TDF/FTC
DOR 100 mg qd + TDF/FTC
DOR 200 mg qd + TDF/FTC
EFV 600 mg qd + TDF/FTC
Phase IIb,
part 1
Design Randomisation*1 : 1 : 1 : 1 : 1Double-blind
ARV-naïve HIV RNA > 1,000
c/mLCD4 ≥ 100/mm3
W24 W96
Open-label
W36
DOR 100 mg + TDF/FTC
Objective– Primary endpoints
• % HIV-1 RNA < 40 c/mL at W24 (estimation comparisons for DOR dose selection), ITT, NC=F
• Safety : general at W24, pre-specified CNS AEs by W8 and W24
* Randomisation stratified on HIV RNA (> or ≤ 100,000 c/mL)
Morales-Ramirez JO, CROI 2014, Abs. 92LB
DOR 100 mg + TDF/FTC
DOR 100 mg + TDF/FTC
MK1439007 Study
Double blind
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
DOR 100 mg qd + TDF/FTC
EFV 600 mg qd + TDF/FTC
Phase IIb,part 2
DesignRandomisation
1 : 1Double-blind
ARV-naïve HIV RNA > 1,000
c/mLCD4 ≥ 100/mm3
W96
Objective– CNS adverse events analysis, W8
• Parts 1 and 2 combined (DOR 100 mg vs EFV)
– Efficacy and safety analyses, W48 : part 1 only, W96 : parts 1 and 2• % with HIV RNA < 40 c/mL, < 200 c/mL, NC=F approach for missing data• Change from baseline in CD4 cell count, observed failure approach• Safety endpoints : adverse events, laboratory parameters
N = 66
N = 66
MK1439007 Study Gatell JM. HIV Drug Therapy 2014, Abs. O434
DOR qd EFV 600 mg25 mgN = 40
50 mgN = 43
100 mgN = 42
200 mgN = 41
N = 42
Median age Overall : 35 years
HIV RNA (log10 c/mL), median 4.5 4.8 4.5 4.5 4.5
HIV RNA > 100,000 c/mL 28% 30% 29% 29% 31%
CD4 cell count/mm3, median 385 431 352 403 383
B subtype 88% 79% 81% 88% 86%
Discontinuation by W24 9.8% 9.3% 4.8% 7.3% 16.3%
For adverse event* 1 2 1 0 2
Lost to follow-up 0 0 1 1 3
Withdrew consent 2 1 0 1 1
Medical decision 1 1 0 1 1
Discontinuation by W48 9.8% 18.6% 14.3% 12.2% 23.3%
For AE / lack of efficacy 1 / 0 3 / 1 2 / 0 0 / 1 2 / 1
LTFU / withdrew consent / other 0 / 2 / 1 0 / 2 / 1 1 / 1 / 2 2 / 1 /1 3 / 2 /1
Baseline characteristics and patient disposition (Part 1)
* DOR 25 mg : stupor (n = 1), DOR 50 mg: abdominal pain/nausea/insomnia (n = 1), sleep disorder (n = 1), DOR 100 mg : hallucinations (n = 1), EFV : right-sided dysesthesia (n = 1), hallucinations (n = 1)
Morales-Ramirez JO, CROI 2014, Abs. 92LB, Gatell JM. HIV Drug Therapy 2014, Abs. O434
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
MK1439007 Study
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
DOR 100 mg, N = 108 EFV 600 mg, N = 108Median age, years ; female, % 35 ; 8% 34 ; 6%
HIV RNA (log10 c/mL), median 4.6 4.6
HIV RNA > 100,000 c/mL 35% 37%
CD4 cell count/mm3, median 402 430
CNS events at W8, all causality (Parts 1 and 2)
Baseline characteristics (Parts 1 and 2)
DOR 100 mg EFV 600 mgDizziness 9.3% 27.8%
Insomnia 2.8% 6.5%
Abnormal dreams / Nightmares 16.7% / 8.3% 5.6% / 5.6%
Hallucinations 2.8% 0.9%
Depression 1.9% 0.9%
Somnolence 0 0.9%
Attention disturbance 2.8% 0
Suicidal ideation 0.9% 0
% patients with ≥ 1 CNS event
DOR 100 mgN = 108
EFV 600 mgN = 108
22.2% 43.5%
D (95% CI) : - 21.3 (- 33.2 to - 8.8)
MK1439007 Study Gatell JM. HIV Drug Therapy 2014, Abs. O434
Response to treatment, HIV RNA < 40 c/mL (ITT, NC = F)
Mean change in CD4/mm3 at W48– DOR all doses : + 168– EFV : + 179
Morales-Ramirez JO, CROI 2014, Abs. 92LB, Gatell JM. HIV Drug Therapy 2014, Abs. O434
MK1439007 Study
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
80.076.2
71.478.0
64.3
0
20
40
60
80
100
32/40 32/41 27/4232/42 30/40
72.572.1 76.2
82.9
71.4
29/40 34/41 30/4231/43 32/42
W24 W48
DOR25 mg
DOR50 mg
DOR100 mg
DOR200 mg
EFV DOR25 mg
DOR50 mg
DOR100 mg
DOR200 mg
EFV
%
≤ 100,000 c/mL > 100,000 c/mL0
20
40
60
80
10088
64
89
64
86
73
8592
87
737483
25 mg 50 mg 100 mg 200 mg All DOR EFV
HIV RNA < 40 c/mL (ITT, NC = F) at W48 by screening HIV RNA
MK1439007 Study
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
Gatell JM. HIV Drug Therapy 2014, Abs. O434
%
Virologic failure definition– Non-response : HIV RNA never < 40 c/mL by Week 24, or– Rebound : after initial response of HIV RNA < 40 c/mL, 2 consecutive
HIV RNA ≥ 40 c/mL at least 1 week apart, at or after Week 24
Criteria for resistance testing– HIV RNA > 500 c/mL
DOR all doses, N = 166 EFV, N = 42
Virologic failure ≥ 40 c/mL 27 (16.3%) 6 (14.3%)
Resistance testing performed 6 1
Emergent NNRTI mutations 1* 0
Emergent NRTI mutations 0 0
* K101K/E
Resistance data at virologic failure, W48
MK1439007 Study
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
Gatell JM. HIV Drug Therapy 2014, Abs. O434
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
DOR qdEFV 600 mg
N = 4225 mgN = 40
50 mgN = 43
100 mgN = 42
200 mgN = 41
Serious AE (none drug-related) 10% 2.3% 4.8% 2.4% 9.5%
Discontinued due to AE, n 1 4 2 0 2
Drug-related AE 40% 46.5% 16.7% 43.9% 57.1%
Dizziness, n 1 2 0 2 10
Abnormal dreams, n 3 9 2 3 4
Diarrhea, n 4 1 1 2 4
Nausea, n 1 4 4 4 1
Fatigue, n 2 4 1 5 2
Clinical adverse events at W48 (Part 1)
MK1439007 Study Gatell JM. HIV Drug Therapy 2014, Abs. O434
DOR qdEFV 600 mg
N = 4225 mgN = 40
50 mgN = 43
100 mgN = 42
200 mgN = 41
Platelet count, Grade 2 / Grade 3 0 / 0 0 / 0 1 / 0 0 / 1 0 / 0
LDL-cholesterol, Grade 1 / Grade 2 2 / 1 1 / 0 2 / 1 3 / 0 7 / 1
Total cholesterol, Grade 1 / Grade 2 3 / 0 1 / 1 2 / 0 4 / 0 10 / 3
Glucose, Grade 1 / Grade 2 2 / 1 5 / 2 1 / 1 2 / 1 5 / 1
Creatinine Grade 2 0 0 0 1 0
AST, Grade 1 / Grade 2 / Grade 3 5 / 0 / 1 1 / 2 / 1 3 / 0 / 0 3 / 2 / 0 6 / 2 / 0
ALT, Grade 1 / Grade 2 4 / 0 4 / 3 1 / 0 2 / 1 6 / 0
Alkaline phosphatase Grade 1 2 1 0 1 5
Lipase, Grade 1 / Grade 2 / Grade 3-4 3 / 5 / 1 2 / 2 / 1 7 / 2 / 2 2 / 4 / 0 7 / 5 / 0
Laboratory abnormalities at W48 (Part 1), N
MK1439007 Study
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
Gatell JM. HIV Drug Therapy 2014, Abs. O434
MK1439007 Study: doravirine (DOR) + TDF/FTC vs EFV + TDF/FTC
Conclusion
– In antiretroviral-naïve, HIV-1 infected subjects, DOR 100 mg qd + TDF/FTC had a lower rate of treatment-emergent CNS events by week 8 than EFV + TDF/FTC
– DOR 25 to 200 mg qd for 48 weeks• had simialr virologic and immunologic efficacy to EFV• with low rate of resistance mutation development• and good safety and tolerability profile
– DOR 100 mg qd dose was selected for further development
Gatell JM. HIV Drug Therapy 2014, Abs. O434MK1439007 Study