Week 48 results of AMBER: A Phase 3, randomised, double-blind trial in antiretroviral treatment-naïve HIV-1-infected adults to evaluate the efficacy and safety of the once-daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) versus darunavir/cobicistat plus emtricitabine/tenofovir disoproxil fumarate

Joseph Eron1, Chloe Orkin2, Joel Gallant3, Jean-Michel Molina4, Eugenia Negredo5, Andrea Antinori6, Anthony Mills7, Jacques Reynes8, Erika Van Landuyt9, Erkki Lathouwers9, Veerle Hufkens9, John Jezorwski9, Magda Opsomer9, on behalf of the AMBER study group1The University of North Carolina School of Medicine, Chapel Hill, NC; 2Barts Health NHS Trust, London, UK; 3Southwest CARE Center, Santa Fe, New Mexico, USA; 4Department of Infectious Diseases, St-Louis Hospital, University of Paris Diderot, Paris, France; 5Germans Trias i PujolUniversity Hospital, Badalona, Spain; 6National Institute for Infectious Diseases, L. SpallanzaniIRCCS, Rome, Italy; 7Southern California Men's Medical Group, Los Angeles, CA, USA; 8Montpellier University Hospital, Montpellier, France; 9Janssen Pharmaceutica NV, Beerse, Belgium

Gallant C, et al. EACS 2017. Abstract PS8/2

*121 sites in USA, Canada, Belgium, France, Germany, Italy, Poland, Russia, Spain, UK†Lower limit of 95% CI of stratified Mantel-Haenszel difference between D/C/F/TAF and control >–10%

AMBER: Phase 3, Randomised, Double-blind, International,* Multicentre Trial

Primary objective: Assess non-inferiority of D/C/F/TAF vs D/C + F/TDF by proportion of patients with VL <50 c/mL at 48 weeks (NI margin 10%; FDA-Snapshot algorithm)†

Randomisation stratified by screening VL !/>100,000 c/mL and CD4+ </" 200 cells/mm3

2

AMBER (NCT02431247)

Treatment-naïve adults (N=725)

! Screening plasma VL "1,000 c/mL

! CD4+ >50 cells/mm3

! Genotypic susceptibility to DRV, FTC and TFV

! HBV/HCV negative

1:1

Baseline Week 48Primary endpoint

1:1

Baseline Week 96

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Baseline CharacteristicsD/C/F/TAF

N=362ControlN=363

TotalN=725

Median (IQR) age, years 34 (27–42) 34 (27–42) 34 (27–42)

Male, n (%) 318 (87.8) 322 (88.7) 640 (88.3)

Race, n (%)White 300 (82.9) 300 (82.6) 600 (82.8)Black/African-American 40 (11.0) 40 (11.0) 80 (11.0)Other races 22 (6.1) 23 (6.3) 45 (6.2)

Median (IQR) log10 VL, c/mL 4.4 (4.0–4.8) 4.6 (4.2–4.9) 4.5 (4.1–4.9)VL !100,000 c/mL, n (%) 60 (16.6) 70 (19.3) 130 (17.9)Median (IQR) CD4+ count, cells/mm3 461.5 (342–617) 440.0 (325–594) 453.0 (333–601)CD4+ count <200 cells/mm3 22 (6.1) 29 (8.0) 51 (7.0)Median (IQR) eGFRcr, mL/min (Cockcroft-Gault) 119 (105–135) 118 (103–138) 119 (104–136.5)

Genotype at screening N=361 N=362 N=723

!1 NNRTI RAMs 55 (15.2) 63 (17.4) 118 (16.3)!1 NRTI RAMs 18 (5.0) 16 (4.4) 34 (4.7)!1 primary PI RAMs 7 (1.9) 8 (2.2) 15 (2.1)

3

IQR, inter-quartile range

91.4%

4.4%(n=16)

4.1%(n=15)

88.4%

3.3%(n=12)

8.3%(n=30)

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VL !50 c/mL No virologic data

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-10 -8 -6 -4 -2 0 2 4 6 8 10

Virologic Outcome at Week 48 (FDA Snapshot; VL<50 c/mL) (ITT)

-1.6 7.1

D/C/F/TAF non-inferior to control Lower bound 95% CI >–10%

Favours control FavoursD/C/F/TAF

Percentage point difference

Stratified difference (95% CI) (D/C/F/TAF–control)

†p<0·0001

†p-value for non-inferiority at 10% NI margin

(n=331) (n=321)

4

Virologic Outcome Categories at Week 48 (FDA Snapshot; <50 c/mL) (ITT)

5

Outcomes, n (%)

D/C/F/TAFN=362

ControlN=363

Virologic response (VL <50 c/mL) 331 (91.4%) 321 (88.4%)

VL !50 c/mL 16 (4.4%) 12 (3.3%)

Last VL in week 48 window !50 c/mL 9 (2.5%) 9 (2.5%)

Discontinued for efficacy reasons 1 (0.3%)* 0

Discontinued due to other reasons("efficacy/AE/death) and last available VL !50 c/mL† 6 (1.7%) 3 (0.8%)

No VL data in week 48 window 15 (4.1%) 30 (8.3%)

Discontinued due to AE 8 (2.2%) 16 (4.4%)

Discontinued due to other reasons and last available VL <50 c/mL (or missing)¶ 4 (1.1%) 9 (2.5%)

Missing data during window but on study drug 3 (0.8%) 5 (1.4%)

*Patient reached a virologic endpoint (investigator’s assessment: withdrawal decision at week 36 with VL 168 c/mL; last VL on-treatment 31 c/mL)†Lost to follow-up (4 vs 2 patients), patient withdrew (1 vs 1), other reasons (1 vs 0)¶Lost to follow-up (0 vs 3), physician decision (2 vs 0), patient withdrew (1 vs 5), other reasons (1 vs 1)

Virologic responseDifference (95% CI)D/C/F/TAF

n/N (%)Control

n/N (%)

Age (years)

!50 299/326 (91·7) 293/331 (88·5) 3·2 (-1·4; 8·0)>50 32/36 (88·9) 28/32 (87·5) 1·4 (-15·5; 19·8)

Gender

Female 39/44 (88·6) 32/41 (78·0) 10·6 (-5·8; 28·0)Male 292/318 (91·8) 289/322 (89·8) 2·1 (-2·5; 6·7)

Race

White 276/300 (92·0) 267/300 (89·0) 3 (-1·8; 7·9)Black/African American 34/40 (85·0) 34/40 (85·0) 0 (-16·9; 16·9)Other 21/22 (95.5) 20/23 (87.0) 8.5 (-11.4; 29.2)

Baseline CD4+, cells/mm3

<200 16/22 (72·7) 25/29 (86·2) -13·5 (-37·8; 9·6)"200 315/340 (92·6) 296/334 (88·6) 4 (-0·4; 8·6)

Baseline VL, c/mL!100 000 278/303 (91·7) 265/293 (90·4) 1·3 (-3·4; 6·1)>100 000 53/59 (89·8) 56/70 (80·0) 9·8 (-3·3; 22·5)

-12 0 12or : 95% CI limit beyond x-axis range

Virologic Outcome by Subgroups at Week 48 (FDA Snapshot; <50 c/mL) (ITT)

Favours control FavoursD/C/F/TAF

Difference (95% CI) (D/C/F/TAF–control)

6

Resistance Analysis Through 48 Weeks

D/C/F/TAFN=362

ControlN=363

Virologic failures with paired screening andendpoint genotypes*, n 7 2

Patients developing mutations (IAS 2015) post-baseline, n

DRV RAMs 0 0

Primary PI RAMs 0 0

NRTI RAMs 1(M184I/V)† 0

NNRTI RAMs 0 0

*Post-baseline genotyping/phenotyping performed for patients who met the criteria for protocol-defined virologic failure (virologic non-response, virologic rebound, and/or viraemic at final timepoint) and who had VL !400 c/mL at failure (unconfirmed or confirmed failure) or at later time points

†Patient had K103N at screening, indicating transmitted NNRTI (efavirenz/nevirapine) resistance, and developed M184I/V, conferring resistance to FTC and 3TC

7

Incidence, n (%) D/C/F/TAFN=362

ControlN=363

≥1 AE, any grade 312 (86.2) 307 (84.6)≥1 grade 3–4 AE 19 (5.2) 22 (6.1)≥1 serious AE 17 (4.7) 21 (5.8)≥1 AE leading to permanent discontinuation 7 (1.9) 16 (4.4)

Deaths 0 0AEs at least possibly related to study drug

Any 126 (34.8) 151 (41.6)Most common (≥5% either arm)Diarrhoea† 31 (8.6) 40 (11.0)Rash 22 (6.1) 14 (3.9)Nausea 20 (5.5) 36 (9.9)

Adverse Events Through Week 48

8

• No grade 3 or 4 laboratory abnormalities occurred in ≥5% of patients in either treatment arm

†Most cases were mild: Grade 1: 24 (6.6%) vs 32 (8.8%); Grade 2: 7 (1.9%) vs 8 (2.2%)

No D/C/F/TAF discontinuations due to bone, renal, or CNS AEsCNS, central nervous

system

9

10

Mean Changes in eGFR Through 48 Weeks

aBased on serum levels and CKD-EPI formula*p value for difference estimated using ANCOVA, including treatment as a factor and baseline eGFR as a covariate

! Results are consistent with the known effect of cobicistat on inhibition of tubular secretion of creatinine

11

Estimated GFR based on Serum Creatininea

Estimated GFR based on Serum Cystatin Ca

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!3% decrease 27.1% 41.2% 12.5% 44.7%!3% increase 12.5% 4.7% 12.5% 2.4%

Mean % Changes in BMD Through 48 Weeks (DEXA Sub-study)

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! Through Week 48, D/C/F/TAF resulted in:

" High virologic suppression in treatment-naïve patients (91.4%; FDA Snapshot) that was non-inferior to DRV/C + F/TDF (88.4%)

" No development of DRV, primary PI or TDF/TAF RAMs

! One patient developed M184I/V (D/C/F/TAF arm)

" Few serious AEs, grade 3/4 AEs, or AE-related discontinuations

" No discontinuations due to bone, renal, or CNS AEs

" Bone, renal and lipid safety consistent with known profiles of TAF and cobicistat

D/C/F/TAF combines the efficacy and high genetic barrier to resistance of DRV with the safety advantages of TAF for

treatment-naïve, HIV-1-infected patients

AMBER Week 48 Analysis: Conclusions

13

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INSTIINSTI-INSTI-containingcontaining singlesingle-single-tablettablet regimenregimen size

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Methods

! Phase 1, randomised, open-label, crossover study of D/C/F/TAF (800/150/200/10 mg) – Enrolled 30 healthy adults,

18-55 years of age– A single D/C/F/TAF dose

was administered within 30 minutes after a standard breakfast

! Tablet preparation:– Swallowed whole

(reference)– Split with a tablet cutter

(both halves swallowed)– Crushed using a mortar

and pestle, mixed with applesauce

D, darunavir; C, cobicistat; F, emtricitabine; TAF, tenofovir alafenamide

Brown K, et al. EACS 2017. Number PS8/3

Whole tablet

Session 1

Split tablet

Session 2

Crushed tablet

Session 3

!7 day washout

!7 day washout

Sequence 1

(n = 5)

Sequence 2

(n = 5)

Sequence 3

(n = 5)

Sequence 4

(n = 5)

Sequence 5

(n = 5)

Sequence 6

(n = 5)

Whole tablet

Whole tablet

Whole tablet

Split tablet

Split tablet

Crushed tablet

Split tablet

Crushed tablet

Crushed tablet

Crushed tablet

Whole tablet

Split tablet

Crushed tablet

Split tablet

Whole tablet

Study design: 6-sequence, 3-period, 3-treatment, Williams design, crossover study

18

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Results: Plasma Concentration Over Time

Brown K, et al. EACS 2017. Number PS8/3

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8