Phase 2 of new ARVs Fostemsavir, prodrug of temsavir (attachment inhibitor) –AI438011 Study TAF...

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




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



MK1439007 Study

Double blind



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


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)


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


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


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




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)


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




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

Phase 2 of new ARVs Fostemsavir, prodrug of temsavir (attachment inhibitor) –AI438011 Study TAF...

Documents

Transcript of Phase 2 of new ARVs Fostemsavir, prodrug of temsavir (attachment inhibitor) –AI438011 Study TAF...