Adults with renal impairment switching from tenofovir disoproxil fumarate to tenofovir alafenamide have improved renal and bone safety through 144 weeks1

TAF/UK/17-08/MI/1037a September 2017

1. Podzamczer D et al. IAS Conference 2017, Paris, France. Poster MOPEB0288

Prescribing information for Genvoya can be found on the last page of this booklet

Prescribing Information

Consult the Summary of Product Characteristics before prescribing.

GENVOYA® elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/ tenofovir alafenamide 10mg film coated tablets.

Indication: Treatment of HIV-1 infection in adults & adolescents (aged 12 years & older weighing at least 35 kg) without any known mutations associated with resistance to the integrase inhibitor class, emtricitabine or tenofovir. Dosage: Adults & adolescents (aged ≥ 12 years, weighing at least 35 kg): One tablet, once daily, orally & whole with food. Children (< 12 years or weighing < 35kg): Safety & efficacy has not been established. Elderly: No dose adjustment is required. Renal: No dose adjustment is required in adult or adolescent patients (aged ≥ 12 years, weighing at least 35 kg) with estimated creatinine clearance (CrCl) ≥ 30 mL/min. In patients with CrCl < 30 mL/min: not recommended. Should be discontinued in patients whose CrCl declines to < 30 mL/min during treatment. Hepatic: Mild/moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Contraindications: Hypersensitivity to the active substances or to any excipients. Coadministration with alfuzosin, amiodarone, quinidine, carbamazepine, phenobarbital, phenytoin, rifampicin, dihydroergotamine, ergometrine, ergotamine, cisapride, St. John’s wort, lovastatin, simvastatin, pimozide, sildenafil for treatment of pulmonary arterial hypertension & oral midazolam & triazolam. Warnings & Precautions: Should not be co- administered with other antiretroviral products. Safety & efficacy in HCV co- infection has not been established. Tenofovir alafenamide is active against HBV. Co-infected HIV/HBV patients should be closely monitored for at least several months following discontinuation for symptoms of severe acute exacerbations of hepatitis. Should not be administered concomitantly with medicines containing tenofovir alafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil for treatment of HBV infection. Patients with galactose intolerance, Lapp lactase deficiency & glucose-galactose malabsorption should not take Genvoya. Women of childbearing potential should use either a hormonal contraceptive containing at least 30 μg ethinylestradiol & norgestimate as the progestagen or an alternative reliable method of contraception. Risks of mitochondrial dysfunction, immune reactivation syndrome, opportunistic infections, osteonecrosis with nucleoside analogues & CART therapy. Interactions: Co-administration with medicines that induce/inhibit CYP3A may affect the exposure of elvitegravir by decreasing its plasma concentrations leading to a reduced therapeutic effect of Genvoya. Cobicistat is an inhibitor of CYP3A & is a CYP3A substrate. Medicines highly dependent on CYP3A metabolism & have high first pass metabolism are most susceptible to large increases in exposure when co-administered with cobicistat. Medicines that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased plasma concentrations of cobicistat. Co- administration with medicines that are substrates of P-gp, BCRP, OATP1B1 & OATP1B3 may result in increased plasma concentrations of these products. Medicines that decrease renal function may increase concentrations of emtricitabine. Pregnancy & lactation: Should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. It should not be used during breast-feeding. Side effects: Refer to SPC for full information regarding side effects. Very common (≥1/10): Nausea. Common (≥1/100 to <1/10): Headache, dizziness, diarrhoea, vomiting, abdominal pain, flatulence, abnormal dreams, rash & fatigue. Uncommon (≥1/1000 to <1/100): anaemia, depression,

dyspepsia, angioedema & puritus. Legal Category: POM. Pack: Bottle of 30 film-coated tablets. Price: UK NHS List Price - £879.51; Éire/Ireland – POA. Marketing Authorisation Number: EU/1/15/1061/001 Further information is available from Gilead Sciences Ltd, 280 High Holborn, London, WC1V 7EE, UK; Telephone: +44 (0) 8000 113700. E-mail: ukmedinfo@gilead.com. Genvoya is a trademark. Date of approval: August 2017. Job Bag No: GNV/UK/17-08/MM/1271

This medicinal product is currently subject to additional monitoring. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse reactions to Genvoya should be reported to Gilead via email to safety_FC@gilead.com or by telephone +44 (0) 1223 897500.

For Ireland, suspected adverse reactions should be reported to the HPRA Pharmacovigilance using a Yellow Card obtained either from the HPRA, or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling +353 1 6764971.

Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard.

Introduction• Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (E/C/F/TAF; Genvoya )

were associated with high efficacy, and improved bone and renal safety in HIV-1-infected adults with mild to moderate renal impairment (creatinine clearance (CrCl) of 30–69 mL/min) at Weeks 48 and 96 (ClinicalTrials.gov NCT01818596)1,2

Adults With Renal Impairment Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Have Improved Renal and Bone Safety Through 144 Weeks

Daniel Podzamczer,1 Jose Arribas,2 Amanda Clarke,3 Laurent Cotte,4 Tatiana Mudrikova,5 Eugenia Negredo,6 William R. Short,7 Shuping Jiang,8 Andrew Cheng,8 Moupali Das8

1Hospital Universitari de Bellvitge, Barcelona, Spain; 2Hospital Universitario La Paz, Madrid, Spain; 3Brighton and Sussex University Hospitals NHS Trust, Brighton, UK; 4Hôpital de La Croix-Rousse, Rhône, France; 5Universitair Medisch Centrum Utrecht, the Netherlands; 6Hospital Germans Trias i Pujol, Barcelona, Spain; 7University of Pennsylvania, Philadelphia, USA; 8Gilead Sciences, Inc., Foster City, California, USA

Study Design

• We report efficacy (HIV-1 RNA <50 copies/mL; US Food and Drug Administration snapshot algorithm), and renal and bone safety endpoints stratified by preswitch TDF use

Results

Baseline Characteristics Preswitch TDF n=158

Without Preswitch TDF n=84*

Median age, y (range) 58 (24–77) 59 (41–82)Age ≥65 y, n (%) 35 (22) 28 (33)Female, n (%) 36 (23) 14 (17)Black or African descent, n (%) 34 (22) 10 (12)HIV-1 RNA <50 copies/mL, % 156 (99) 80 (95)Median CD4 count, cells/μL 661 585Hypertension, n (%) 54 (34) 41 (49)Diabetes, n (%) 21 (13) 12 (14)Median CrCl, mL/min† 58.3 53.0Median eGFRCKD-EPI,sCr, mL/min/1.73 m2‡ 55.8 50.2Median eGFRCKD-EPI,cysC, mL/min/1.73 m2§ 75.4 60.4Dipstick proteinuria, % 1+ 27 16 2–3+ 10 10Significant proteinuria (UPCR >22.6 mg/mmol), % 56 35Significant albuminuria (UACR ≥3.4 mg/mmol), % 64 41

*Of 84 participants without preswitch TDF use, 11 received abacavir (ABC); †Creatinine clearance (CrCl) by Cockcroft-Gault equation; ‡Estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease–Epidemiology Collaboration (CKD-EPI) equation using serum creatinine (sCr; adjusted for age, sex, and race); §eGFR by CKD-EPI equation using cystatin C (cysC; adjusted for age and sex). UACR, urinary albumin/creatinine ratio; UPCR, urine protein/creatinine ratio.

0.8 1 .0

0.8

2.0

2.7

3.2

-1

0

1

2

3

4

5

0 24 48 72 96 120 144

Hip*p <0.001

148 142

77 78

1 25

65

138

77

147

76

n=

n=

129

59

154

82

p=0.10

Week

0.9 0.81.2

3.1 3.1

3.6

-2

-1

0

1

2

3

4

5

0 24 48 72 96 120 144

Spine* p <0.001

147 145

79 78

128

66

140

76

146

76

n=

n=

132

62

154

82

p=0.03

Week

Preswitch TDF Without preswitch TDF

*p-values were for change relative to baseline and based on 2-sided Wilcoxon signed-rank test. BMD, bone mineral density; CI, confidence interval.

Mea

n %

Cha

nge

(95%

CI)

TDF TAF ABC TAF† Baseline

Week 144

00

1

2

3

4

5

6

1

2

3

4

5

Total Cholesterol

LDHLDL TotalCholesterol:

HDL

5.4

4.7

3.4

2.8

1.4 1.4

3.7

3.5

Triglycerides

1.62

5

5.1

3.23

1.41.8

3.6

3.7

*Arrows indicate direction of change from baseline; †n=52. HDL, high density lipoprotein; LDL, low density lipoprotein.

Med

ian

at W

eek

144

, mm

ol/

L*

Med

ian

at W

eek

144

*

β2M:Cr, β2-microglobulin/creatinine ratio; Q, quartile; RBP:Cr, retinol-binding protein/creatinine ratio.

Med

ian

RB

P:C

r, µ

g/m

mo

l (Q

1, Q

3)

Med

ian β2

m:C

r, µ

g/m

mo

l (Q

1, Q

3)Preswitch TDFWithout preswitch TDF

0

40

80

120

160

0 4 12 24 48

Week72 96 120 144

157 154 155 149 148 149 142 141 12683

n=n= 83 84 80 74 72 72 66 63

Normalrange 0

50

100

200

150

250

300

0 4 12 24 48

Week72 96 120 144

156 154 153 149 147 149 142 138 12681

n=n= 83 84 80 71 72 72 66 63

Normalrange

1,274 2,702

PreswitchTDF

Withoutpreswitch

TDFBaseline

Week 144

47

100

53

0

100

80

60

40

20

Resolved to<3.4 mg/mmol

Remained≥3.4 mg/mmol

n=960

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

n=45

n=51

BaselineUACR Week 144*196 participants had available UACR values at both baseline and Week 144.

Med

ian,

mg

/mm

ol

Res

olu

tio

n/N

onr

eso

luti

on

Rat

esA

mo

ng P

arti

cip

ants

Wit

h U

AC

R

≥3.4

mg

/mm

ol a

t B

asel

ine,

%*

4.6

1.1

3.4

2

1.9

92

17

88

210

83

2

15

197n= 222 214 55 233 17

Week 144Week 96Week 48

Par

tici

pan

ts, %

100

80

60

40

20

0Success Failure No Data

35

• For the entire study population, BMD increased significantly overall– Increases were greater for those on preswitch TDF (p<0.001)

• Spine BMD increased significantly for without preswitch TDF use (p=0.03)

Safety Summary• Upper respiratory tract infection (15%), diarrhoea (13%), and arthralgia (14%)

were the most common adverse events (AEs)• AEs, grades, and frequencies were generally similar in participants with baseline

CrCl < vs ≥50 mL/min• No participants discontinued study drug for AEs between Weeks 96 and 144

2

1

00

2

00

1

2

3

4

5

Dis

cont

inua

tio

ns D

ue t

oR

enal

–Uri

nary

AE

s, n

CrCl <50 mL/min (n=80)

CrCl ≥50 mL/min (n=162)

Baseline to Week 48 Week 48 to Week 96 Week 96 to Week 144

• No new participants discontinued study drug for renal AEs after Week 96• There were no cases of proximal renal tubulopathy or Fanconi syndrome through Week 144• 2 participants with medical history of TDF-associated Fanconi syndrome remained

on treatment with Genvoya with stable eGFR, and significant reductions in total and tubular proteinuria

• Of those participants with clinically significant albuminuria (UACR ≥3.4 mg/mmol) at baseline, 47% had resolution by Week 144

• Median (quartile [Q] 1, Q3) changes from baseline at Week 144 with preswitch TDF use:– eGFRCKD-EPI,sCr: 3.6 (-5.7, 11.4) mL/min/1.73 m2

– eGFRCKD-EPI,cysC: 3.7 (-3.4, 15.3) mL/min/1.73 m2

Conclusions• This is the first study of a single-tablet antiretroviral regimen in participants

with CrCl of 30–69 mL/min

• Through Week 144, HIV-infected adults with mild to moderate renal impairment who switched to Genvoya had high rates of virologic suppression, stable renal function, and statistically significant improvements in proteinuria and BMD (hip and spine), with benefits most notable for those with preswitch TDF use

• These long-term data support switching from TDF-containing regimens to Genvoya in patients with mild to moderate renal impairment (CrCl 30–69 mL/min)

References1. Post FA, et al. J Acquir Immune Defic Syndr. 2017;74:180-4. 2. Pozniak A, et al. J Acquir Immune Defic Syndr 2016;71:530-37.

AcknowledgmentsThe authors gratefully acknowledge the investigators, study staff, and all study participants. Study 112 investigators: J Andrade-Villanueva, J Arribas, A Avihingsanon, J Bartczak, P Benson, M Bloch, R Bolan, I Brar, F Bredeek, T Campbell, K Casey, P Chetchotisakd, A Clarke, C Cohen, L Cotte, G Crofoot, D Cunningham, C Dietz, R Dretler, C Fichtenbaum, D Fish, J Flamm, S Follansbee, F Garcia, J Gathe, R Grossberg, S Gupta, T Hawkins, K Henry, T Jefferson, R Kalayjian, C Katlama, S Kerkar, A Khalsa, S Kiertiburanakul, D Klein, E Koenig, S Lewis, K Lichtenstein, C Martorell, C McDonald, J McGowan, J McMahon, A Mills, T Mudrikova, E Negredo, O Osiyemi, P Palmieri, D Podzamczer, F Post, A Pozniak, D Prelutsky, M Ramagopal, W Ratanasuwan, G Richmond, W Robbins, N Roth, P Ruane, A Scarsella, G Schembri, S Schneider, P Shalit, W Short, J Slim, L Sloan, D Stein, J Stephens, P Tebas, D Ward, T Wills. This study was funded by Gilead Sciences, Inc.

DisclosuresD. Podzamczer: Gilead, Janssen, MSD, ViiV.

Virologic Outcome – Snapshot Weeks 48, 96, and 144

Discontinuations Due to Renal AEs per Timepoint – Week 144

Lipids – Week 144

Hip and Spine BMD Changes Over Time in Renal Biomarkers

Resolution of Clinically Significant Albuminuria

Preswitch TDF n=158

Without preswitch TDF n=84

Genvoya qd

Week 0 24 48 96 144

Primary Endpoint

Key Inclusion Criteria• CD4 cell count ≥50 cells/µL• No chronic hepatitis B/C virus infection• HIV-1-suppressed participants: HIV-1 RNA <50 copies/mL for ≥6 mo

*Genvoya met its primary endpoint and demonstrated no statistically significant changes from baseline in glomerular filtration rate (measured using the Cockcroft-Gault formula (eGFRCG) in all patients, and at four time points, including baseline) at Weeks 24, 961 and 144.TDF, tenofovir disoproxil fumarate

Adapted from Podzamczer D et al. IAS Conference 2017, Paris, France. Poster MOPEB0288.

• Primary endpoint: Change from baseline in CrCl at Week 24*