Renal and Bone Safety of - PowerPoint Presentation

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Renal and Bone Safety of Tenofovir Alafenamide vs Tenofovir Disoproxil FumarateCombined Safety Results of Studies GS-US-292-0104 and GS-US-292-0111

Paul Sax

1

, Michael Saag

2

, Michael Yin

3

, Frank Post

4

, Shinichi Oka

5

,

Ellen Koenig

6

, Benoit Trottier

7

, Jaime Andrade-Villanueva

8

,

Huyen Cao

9

, Marshall Fordyce

9

1

Brigham and Women’s Hospital and Harvard Medical School, Boston, MA;

2

University of Alabama Birmingham, Birmingham, AL;

3

College of Physicians and Surgeons, Columbia University, New York, NY;

4

King’s College, London, UK;

5

National Center for Global Health and Medicine, Tokyo, Japan;

6

Dominican Institute for Virologic Studies, Santo Domingo, Dominican Republic;

7

Clinique

Medicale

L’Actuale

in Montreal, Montreal, Canada;

8

Unidad de VIH del Hospital Civil de Guadalajara, Guadalajara, Mexico;

9

Gilead Sciences, Foster City, CA

Abstract 143LB

Author DisclosuresDr. Sax has served as a consultant or Scientific Advisory Board member for Gilead Sciences, AbbVie, BMS, GSK/ViiV, Merck, and Janssen, and his institution, Harvard Medical School/Brigham and Women’s Hospital, has received support from Gilead Sciences, BMS, GSK/ViiV, and Merck 2

Tenofovir Alafenamide (TAF, GS-7340)Novel Prodrug of Tenofovir3Tenofovir alafenamide (TAF)Tenofovir disoproxil fumarate (TDF)

Tenofovir

(TFV)

Lymphoid Cell

Plasma

TFV-MP

TFV-DP

Gut

TFV

TFV

TAF

TDF

TFV

X

TFV

BackgroundAlthough potent and generally well tolerated, tenofovir disoproxil fumarate (TDF) may cause clinically significant renal and bone toxicity1-3Relative to TDF 300 mg, TAF 25 mg has 90% lower circulating plasma TFV, while maintaining high antiviral activity4 In a phase II comparative study, TAF associated with reduced renal and bone effects5 We sought to confirm these findings in fully powered clinical trials using extensive protocol-specified renal and bone endpointsVirologic efficacy of E/C/F/TAF non-inferior to E/C/F/TDF (Wohl # 113-LB)E/C/F, elvitegravir, cobicistat, emtricitabine.1. Mocroft AIDS. 2010 Jul 17;24(11):1667-78; 2. Morlat

PLoS

One.

2013;8:e66223; 3.

Mccomsey

J Infect Dis.

2011;203:1791-1801;

4.

Ruane P, et al. JAIDS 2013;

63:449-54; 5. Sax PE.. et al. JAIDS 2014;67:52-58

4

E/C/F/TAF QD

Study Design: Studies 104 and 111

5

Tx-Naïve Adults

HIV-1

RNA

≥

1000

c/mL

eGFR

≥50

mL/min

1:1

E/C/F/TDF QD (

Stribild

, STB)

n

=866n=867

Two Phase 3 randomized, double-blind,

double-dummy, active-controlled studiesStudy 104 (North America, EU, Asia), Study 111 (North America, EU, Latin America)Stratified by HIV-1 RNA, CD4 cell count, geographic regionPrimary endpoint: proportion of patients with HIV-1 RNA <50 copies/mL (Taqman 2.0)Non-inferiority (12% margin) based on Week 48 FDA snapshot analysisCombined efficacy analysis pre-specifiedPre-specified Week 48 safety endpoints: serum creatinine, proteinuria, hip BMD, spine BMD

Primary Endpoint

48

144

96

0

Week

Baseline CharacteristicsStudies 104 and 111: Week 48 Combined AnalysisE/C/F/TAF

n=866

E/C/F/TDF

n=867

Median age, year

33

35

Sex, %

Male

85

85

Female

15

15

Race/ethnicity, %

Black or African descent

26

25

Hispanic/Latino ethnicity

19

19

Median HIV-1 RNA, log

10

c/mL

4.58

4.58

% with HIV-1 RNA >100,000 c/mL23

23Median CD4 count, cells/μL

404406

% with CD4 count ≤200

13

14

Median estimated GFR*, mL/min

117

114

Dipstick proteinuria (any grade), %

10

10

*Cockcroft-

Gault

.

6

Plasma TFV and Intracellular TFV-DP LevelsStudies 104 and 111: Week 48 Combined Analysis 7

E/C/F/TDF

(n=14)

E/C/F/TAF

(n=21)

0

5

10

15

20

Geometric mean (95% CI)

4.1 X

X

Intracellular TFV-DP

Plasma TFV

E/C/F/TDF (n=29)

E/C/F/TAF (n=36)

Mean TFV Concentration, ng/mL (SD)

TFV Exposure

(

M

*h)

Time (h)

Steady State TFV PK

E/C/F/TDF

n=29

E/C/F/TAF

n=36

% Reduction

Mean

AUC

tau

, ng*h/mL (%CV)

3,410 (25)

297(20)

91

Change in

eGFR

(Cockcroft-

Gault

)

Studies 104 and 111: Week 48 Combined Analysis

8

*

Cockroft-Gault

(mL/min).

-

6.6

-11.2

p <0.001

Time (Weeks)

Mean (SD) Change

from Baseline

eGFR

*

n (%)

E/C/F/TAF

n=866

E/C/F/TDF

n=867

Events

Renal adverse events leading to discontinuation

0

4 (0.5)*

Tubulopathy

/

Fanconi

syndrome

0

0

Laboratory Abnormalities

Subclinical

tubulopathy

†

0

1 (0.1)

Serum creatinine (≥0.4 mg/dL increase)0

0

Hypophosphatemia (≥1 grade decrease)

3 (0.3)4 (0.5)

Normoglycemic

glycosuria (≥1 grade increase urine glucose; serum glucose ≤100 mg/dL)

02 (0.2)

Proteinuria (≥2 grade increase)2 (0.2)

2 (0.2)

Renal Adverse Events and

Tubulopathy

Studies 104 and 111: Week 48 Combined Analysis

*Renal failure (2), decreased GFR (1), nephropathy (1).

†

Confirmed abnormality in any 2 categories at 2 consecutive post-baseline visits.

9

Changes in Quantitative Proteinuria at Week 48Studies 104 and 111: Week 48 Combined Analysis 10Median % Change from Baseline (Q1, Q3)

Protein

(UPCR)

Albumin (UACR)

Retinol Binding Protein

Beta2-

microglobulin

E/C/F/TAF

E/C/F/TDF

p <0.001

f

or all

Urine [protein]:Creatinine Ratio

Baseline

44

mg/g

44

mg/g

5mg/g5mg/g

64μg/g 67μg/g 101μg/g

103μg/g 76133

16857

Changes in Spine and Hip BMD Through Week 48Studies 104 and 111: Week 48 Combined Analysis 11E/C/F/TAF, n845

E/C/F/TDF,

n

850

797

816

784

773

836

848

789

815

780

767

‒0.66

p

<0.001

‒2.95

‒1.30

p

<0.001

‒2.86

Hip

Spine

Mean (SD)

%

Change from Baseline

2448Week0

2448Week0

12E/C/F/TDF (N=850)E/C/F/TAF (N=845)

BMD Categorical Changes at Week 48

Studies 104 and 111: Week 48 Combined Analysis

≥3% gain

BMD Change

Hip

Spine

Gain or loss <3%

≥3% loss

Fasting Lipids at Week 48

Studies 104 and 111: Week 48 Combined Analysis

13

Total Cholesterol

LDL

HDL

Triglycerides

TC:HDL Ratio

Median Values (mg/

dL

)

Patients

initiating

lipid-modifying

medications:

3.6

% E/C/F/TAF vs 2.9% E/C/F/TDF (p=0.42). p <0.001 p <0.001 p <0.001 p=0.027 p=0.84

18917711510951

481083.71143.7

E/C/F/TAFBaseline

Week 48E/C/F/TDFBaseline

Week 48

ConclusionsStudies 104 and 111: Week 48 Combined Analysis In these two large randomized clinical trials, detailed protocol-specified renal and bone endpoints confirmed the favorable safety and tolerability profile of TAFCompared with TDF, TAF demonstrated:No discontinuations due to renal AEsSignificantly smaller decreases in eGFRSignificantly less proteinuria, albuminuria, and tubular proteinuria Significantly less impact on spine and hip BMDGreater increases in fasting lipids, TC:HDL sameThe most likely explanation for these findings is the 90% lower tenofovir plasma exposure with TAF vs TDF14

Additional DataStudy 104+111 primary results presented Feb 25th (Wohl, 113LB)E/C/F/TAF non-inferior to E/C/F/TDF at Week 48 (92.4% vs 90.4%)Treatment-emergent resistance <1% in both armsBoth drugs well tolerated through 48 weeksPatients with mild to moderate renal impairment (eGFR 30-69 mL/min) who switch to E/C/F/TAF improve BMD and markers of kidney function through 48 weeks (Pozniak, Poster #795)Complete results of Studies 104 and 111 submitted for peer-reviewed publicationHealth authority filings submitted and under review in multiple countries

15

AcknowledgmentsWe extend our thanks to the patients, their partners and families, and all participating Study 104 & 111 investigatorsC Achenbach, F Ajana, B Akil, H Albrecht, J Andrade Villanueva, J Angel, A Antela Lopez, J Arribas Lopez, A Avihingsanon, D Baker, J-G Baril, D Bell, N Bellos, P Benson, J Berenguer, I Bica, A Blaxhult, M Bloch, P Brachman, I Brar, K Brinkman, C Brinson, B Brown, J Brunetta, J Burack, T Campbell, M

Cavassini

, A

Cheret

, P

Chetchotisakd

, A Clarke, B

Clotet

,

N Clumeck, C Cohen, P Cook, L Cotte, D Coulston, M Crespo, C Creticos

, G Crofoot, F Cruickshank, J Cunha,

E Daar, E DeJesus, J De Wet, M Doroana, R

Dretler, M Dube, J Durant, H Edelstein, R Elion, J Fehr, R Finlayson, D Fish, J Flamm, S Follansbee, H Furrer, F

Garcia, J Gatell Artigas, J Gathe, S Gilroy, P-M Girard, J-C Goffard

, E Gordon, P Grant, R Grossberg, C Hare, T Hawkins, R Hengel, K Henry, A Hite, G Huhn, M Johnson, M Johnson, K Kasper, C

Katlama, S Kiertiburanakul, JM Kilby, C Kinder, D Klein, H Knobel, E Koenig, M Kozal, R Landovitz, J Larioza, A Lazzarin, R LeBlanc, B LeBouche, S Lewis, S Little, C Lucasti, C Martorell, C Mayer, C McDonald, J McGowan, M McKellar, G McLeod, A Mills, J-M Molina, G Moyle, M Mullen, C Mussini, R Nahass, C Newman, S Oka, H Olivet, C Orkin, P Ortolani, O Osiyemi, F Palella, P Palmieri, D Parks, A Petroll, G Pialoux, G Pierone, D Podzamczer Palter, C Polk, R Pollard, F Post, A Pozniak, D Prelutsky, A Rachlis, M Ramgopal

, B Rashbaum, W Ratanasuwan, R Redfield, G Reyes Teran, J Reynes, G Richmond, A Rieger, B Rijnders, W Robbins, A Roberts, J Ross, P Ruane, R Rubio Garcia, M Saag, J Santana-Bagur, L Santiago, R Sarmento e Castro, P Sax, B Schmied, T Schmidt, S Schrader, A Scribner, S Segal-Maurer, B Sha, P Shalit, D Shamblaw, C Shikuma, K Siripassorn, J Slim, L Sloan, D Smith, K Squires, D Stein, J Stephens, K Supparatpinyo, K Tashima, S Taylor, P Tebas, E Teofilo, A Thalme, M Thompson, W Towner, T Treadwell, B Trottier, T Vanig

, N Vetter, P Viale, G Voskuhl, B Wade, S Walmsley, D Ward, L Waters, D Wheeler, A Wilkin, T Wilkin, E Wilkins, T Wills, D Wohl, M Wohlfeiler, K Workowski, B Yangco, Y Yazdanpanah, G-P Yeni, M Yin, B Young, A Zolopa, C ZurawskiThis study was funded by Gilead Sciences, Inc.16