Clinical development programmefor Second-Line treatment

Anton PozniakWorld AIDS Conference,

July 2014

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Current second-line treatment

WHO standard: 2 new NRTIs plus LPV/r or ATV/r

Efficacy of LPV/r + 2NRTIs in EARNEST and SECOND-LINE studies

? Use PI/r with Integrase

Issues:

– overlapping NRTI resistance

– pill count,

– twice daily (LPV/r),

– NRTI safety

– Cost versus first-line treatment

What do the patients look like?Baseline characteristics- Earnest(at randomisation / switch to second-line)

PI/NRTI PI/RAL PImono+ TotalRandomised 426 433 418 1277Female 264 (62%) 263 (61%) 215 (51%) 742 (58%)Age (years)

37 (31-43) 37 (30-43) 38 (32-44) 37 (31-44)Years since started ART

4.0(2.8-5.4)

4.0 (2.9-5.5)

3.9 (2.7-5.4)

4.0(2.8-5.4)

CD4 (cells/mm3) 72 (29-143) 70 (27-142) 70 (33-149) 71 (30-146)Pre-ART CD4 62 (23-144) 63 (23-135) 63 (22-152) 62 (23-145)VL (c/ml) 67515

(23065-175800)74500

(25004-205000)70874

(21584-210000)69782

(23183-194690)

VL ≥100,000 c/ml

168 (40%) 181 (41%) 181 (43%) 530 (42%)

3Note: n(%) or median (IQR)

VL suppression at 96 weeks

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PI/RAL vs PI/NRTI P=0.36 P=0.87 P=0.97 P=0.88

First-line to second Line

TDF/3TC/EFV400or NRTI /NNRTIs

First-line

DRV/r +DTG

Second-line

VFOption 1

TDF/3TC/DTG

First-line

PI/r+NNRTI

Second-line

VFOption 2

OPTION 1Pill A to Pill B – two single tablet regimens?

Pill A TDF/3TC/EFV400 $100

Pill B DRV400/r/DTG $250

Two pills, used in sequenceSimple treatment rule – task shiftingNo overlapping drug resistanceMass generic production for Universal AccessLow cost: $100 and $250 per person-year

Data for low dose DRV/r Phase 2 trials: %HIV RNA >1 log reduction

at Week 24, by dose and baseline DRV resistance

Katlama C et al AIDS 2007, 21: 395-402Haubrich et al AIDS 2007, 21: F11-F18

1 2 3 40

10

20

30

40

50

60

70

80

90

100

1 2 3 40

10

20

30

40

50

60

70

80

90

100DRV FC <4 (sensitive) DRV FC >4 (resistant)

400/100 800/100 400/100 600/100OD OD BID BID

400/100 800/100 400/100 600/100OD OD BID BID

DRV/r dose group DRV/r dose group

No PK/PD relationship ODIN trial: HIV RNA <50 copies/mL at Week 48, treatment experienced, DRV sensitive patients DRV/r

800/100 mg OD +2NRTIs, by DRV Cmin

1 2 3 40

20

40

60

80

100

84.687.5

83.6

66.1

Quartile of DRV Cmin

HIV RNA<50 c/mL(%)Week48

Kakuda et al, HIV11, Glasgow 2012 [abstr P072]

p=0.004, inverse correlation

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DRV/r 600/100 OD + 2NRTIs: 12 naïve patients ___________________________________________________________________________

Patient RNA BL RNA FU Time DRV Cmin

___________________________________________________________________________

Naïve 85,501 <50 20 months 2866

Naïve 115,853 <50 19 months 3140

Naïve 334,500 <50 10 months 3627

Naïve 154,000 <50 24 months 2553

Naïve 87,350 <50 18 months 3824

Naïve 88,110 <50 19 months 1700

Naïve 34,793 <50 12 months 1268

Naïve 4,526 <50 18 months 3732

Naïve 235,520 <50 20 months 2019

Naïve 7,251 <50 15 months 2818

Naïve 63,244 <50 16 months 4562

Naïve 397,932 <50 5 months no data

____________________________________________________________________

___________________________________________________________________

Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

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DRV/r 600/100 OD+2NRTIs: 7 pre-treated patients

___________________________________________________________________________

Prior ARV’s RNA BL RNA FU Time DRV Cmin

___________________________________________________________________________

TDF/FTC/FPV/r 33,250 <50 55 months 2143

ZDV/3TC/TDF 15,226 <50 55 months 4518

TDF/FTC/FPV/r 586 <50 43 months 844

TDF/FTC/ATV/r 8,450 <50 38 months no data

TDF/FTC/LPV/r 11,426 <50 38 months no data

TDF/FTC/FPV 119 <50 22 months no data

TDF/FTC/FPV/r 112 <50 20 months no data

____________________________________________________________________

___________________________________________________________________

Lanzafame et al, EACS, Brussels 2013 [abstr PE8/11]

Study endpoints– The proportion of patients with HIV-1 RNA <50 c/mL at w48 (ITT).

Non inferiority if lower limit of the 95% CI for d < -15%, 80% power– Changes in CD4+ T cell count

– Changes in DRV Ctrough in plasma

– The proportion of patients with AEs during follow-up– The economic cost derived from ARV drugs

DRV/r 800/100 mg QD+ 2 NRTIs

DRV/r 600/100 mg QD+ 2 NRTIs

Randomisation1 : 1

Open-label

100 HIV+ adultsOn 2 NRTIs + DRV 800mg qd > 4 weeks

HIV-1 RNA < 50 c/mL > 3 monthsNo history of prior virologic failure to

PI-based ARTN = 50

N = 50

W48

DRV600. Study Design

Results w48

0

20

40

60

80

100

% H

IV-1

RN

A <

50

cp

/mL

ITT Observed data

DRV800 DRV600

94%90%

96% 94%

Non inferiority of DRV/r 600/100 mg QD

0-15%

ITT

Observed data

50 50 49 48

95% CI for the difference

ITT -4.0 (-12.9; 4.9)

Observed data -2,2 (-9.6; 5.2)

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Clinical experience with DRV/r + DTG

There is no effect of DTG on DRV/r PK FDA label

DRV/r 600/100 BID lowers DTG Cmin by 38%. This is not considered clinically significant, given the 50mg OD dose of DTG used FDA label.

DRV/r + integrase proof of principle: NEAT (DRV/r + RAL vs DRV/r + TDF/FTC) CROI 2014

DRV/r + DTG was the most common combination used in the SAILING trial. Lancet 2013, 382, 700-708

In the SAILING trial, 72 patients treated with DRV/r + DTG + NRTIs with no primary PI mutations: HIV RNA <50 copies/mL at Week 48 in 69%, versus 70% for DRV/r + RAL + NRTIs.

Pill A, Pill B: Phase 2B-Dose ranging study

Treatment naive

SL2: Second-line, 2 drugsRandomised, 48 weeks24 week interim justifies progression of programme

TDF/FTC + DRV/r 800/100 OD

DTG + DRV/r 800/100 OD

DTG + DRV/r 400/100 OD

Pill A, Pill B: Phase 3 -pivotal study

NNRTI experienced

n=1050

(350 per arm)

Randomised, 96 weeksAfrica, Asia

2NRTI + PI/r (Control)

DTG + DRV/r 800/100 OD

DTG + DRV/r 400/100 OD

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Phase 3 study – design

Inclusion: HIV RNA >1000 on two visits while taking NNRTI based treatment

Primary endpoint: HIV RNA >1000 on two visits, 96 week follow up

Recruitment: Africa, SE Asia, E Europe

Statistics: powered to demonstrate non-inferiority for DRV/r + DTG versus control arm.

Clinical development programmefor Second-Line treatment

Need for FDC second line pill

Low dose Darunavir and DTG attractive option as no overlapping resistance Co formulated as STR so easy to takeComponents well toleratedCost savingsCan Task shift

Phase 2b into phase 3 for patient safety