fixed-dose combination (fdc) is non-inferior to … · kelly et al. drugs. 2016;76:523-531. 2. cahn...

10th IAS Conference on HIV Science; July 21–24, 2019; Mexico City, Mexico

For Healthcare Professionals Only

SWITCHING TO DTG/3TC▼ FIXED-DOSE

COMBINATION (FDC) IS NON-INFERIOR TO

CONTINUING A TAF-BASED REGIMEN IN

MAINTAINING VIROLOGIC SUPPRESSION

THROUGH 48 WEEKS (TANGO STUDY)

1ViiV Healthcare, Brentford, UK; 2Centre Hospitalier de Tourcoing, Tourcoing, France; 3Holdsworth House Medical Brisbane, Queensland, Australia; 4CHU Saint-Pierre, Brussels, Belgium; 5Triple O Research Institute PA, West Palm Beach, FL, USA; 6Hospital General Universitario de Alicante, Alicante, Spain; 7McGill University Health Centre, Montreal, QC, Canada; 8Praxis am Ebertplatz, Cologne, Germany; 9ViiV Healthcare, Research Triangle Park, NC, USA; 10GlaxoSmithKline, Stockley Park, UK

J van Wyk,1 F Ajana,2 F Bisshop,3 S DeWit,4 O Osiyemi,5 J Portilla,6 JP Routy,7 C Wyen,8M Ait-Khaled,1 M-C Nascimento,1 KA Pappa,9 R Wang,9 J Wright,10 AR Tenorio,9 B Wynne,9M Aboud,1 MJ Gartland,9 KY Smith9

Date of preparation: August 2019 PM-IE-DLM-PPT-190006Adverse Event and Prescribing Information can be found at the end of the presentation



2van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB.

DISCLOSURES

• Jean van Wyk, Global Medical Lead for Dolutegravir, is an employee of ViiV Healthcare



• Two-drug regimens (2DRs) reduce drug exposure for PLWHIV who need lifelong ART1

• In the Week 48 primary analysis of the GEMINI studies, DTG + 3TC was non-inferior to DTG + TDF/FTC in HIV-1–infected treatment-naive adults2

• The results led to the marketing authorization of DTG/3TC (DOVATO▼*), as a once-daily, single-tablet 2DR by the US Food and Drug Administration and the European Medicines Agency

• TANGO is an ongoing phase III, non-inferiority trial evaluating efficacy and safety of a switch to DTG/3TC FDC in HIV-1–infected adults with virologic suppression on a 3- or 4-drug TAF-based regimen

• The Week 48 primary analysis results from TANGO are presented here

3

BACKGROUND

1. Kelly et al. Drugs. 2016;76:523-531. 2. Cahn et al. Lancet. 2019;393:143-155.

van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB.

*DOVATO is indicated for the treatment of HIV-1 in adults and adolescents above 12 years weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine.



4

aStratified by baseline third agent class (PI, INI, or NNRTI). bTwo patients excluded who were randomized but not exposed to study drug. cParticipants with initial TDF treatment who switched to TAF ≥3 months before screening, with no changes to other drugs in their regimen, were also eligible. d4% non-inferiority margin. eIncludesparticipants who changed a background therapy component or discontinued study treatment for lack of efficacy before Week 48, or who had HIV-1 RNA ≥50 c/mL in the 48-week window.

TANGO PHASE III STUDY DESIGN

Randomized, open-label, multicenter, parallel-group, non-inferiority study

DTG/3TC (N=369)b

Day 1

Screening

TAF-based regimen (N=372)

DTG/3TC

Week48

Early-switch phase Late-switch phase

Continuation phase

Week144

Week 24

Week96

•Adults, virologicallysuppressed (HIV-1 RNA<50 c/mL) for >6 months

•Stable TAF-based regimen

Randomizationa

1:1

Week 148

Week196

DTG/3TC DTG/3TC

Primary endpointc: participantswith virologic failure per

FDA Snapshot (ITT-E)d

Eligibility criteria•≥2 documented HIV-1 RNA measurements <50 c/mL

•No HBV infection or need for HCV therapy

•No prior VF and no documented NRTI or INSTI resistance

•TAF/FTC + PI or INI or NNRTI as initial regimenc

AustraliaBelgiumCanadaFrance

GermanyJapanNetherlandsSpain

United KingdomUnited States

Countries




5

DEMOGRAPHICS AND BASELINE CHARACTERISTICS: ITT-E POPULATION

Characteristic, n (%)DTG/3TC

(N=369)TAF-based regimen

(N=372)

Age, median (range), y≥50 y

40 (20-74)79 (21)

39 (18-73)92 (25)

Female 25 (7) 33 (9)

RaceAfrican American/African HeritageAsianWhiteOther

51 (14)13 (4)

296 (80)9 (2)

58 (16)13 (3)

289 (78)12 (3)

EthnicityHispanic or LatinoNot Hispanic or Latino

70 (19)299 (81)

66 (18)306 (82)




6

DEMOGRAPHICS AND BASELINE CHARACTERISTICS: ITT-E POPULATION (cont)

Characteristic, n (%)DTG/3TC


(N=372)

Median CD4+ cell count (range), cells/mm3 682 (133-1904) 720 (119-1810)

CD4+ cell count, cells/mm3

<350≥350

35 (9)334 (91)

30 (8)342 (92)

Baseline third agent classINI

EVG/c289 (78)243 (66)

296 (80)249 (67)

NNRTIRPV

51 (14)43 (12)

48 (13)45 (12)

PIbDRV

29 (8)25 (7)

28 (8)27 (7)

Duration of ART before Day 1, median (range), mo 33.8 (7.1-201.2) 35.1 (7.0-160.8)




7

aPrimary endpoint (Snapshot virologic non-response, ITT-E). bBased on Cochran-Mantel-Haenszel stratified analysis adjusting for baseline third agent class.

DTG/3TC IS NON-INFERIOR TO TAF-BASED REGIMEN AT WEEK 48

• In the per-protocol population, 0/352 participants in the DTG/3TC group and 2/358 participants in the TAF-based regimen group had HIV-1 RNA ≥50 c/mL at Week 48 (adjusted difference, −0.6; 95% CI, −1.3 to 0.2)b

0.3

93.2

6.50.5

93.0

6.5

0

20

40

60

80

100

HIV-1 RNA ≥50 c/mL

HIV-1 RNA<50 c/mL

No virologicdata

Pro

po

rtio

n o

f p

art

icip

an

ts, %

DTG/3TC(N=369)

TAF-based regimen(N=372)

Virologic outcomes Adjusted treatment difference (95% CI)b

0.2

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

-3.4 3.9

Difference, %

-0.3

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

-1.2 0.7

TAF-based regimen

Primary endpoint:

DTG/3TC non-inferior to

TAF-based regimen

(≥50 c/mL) at Week 48

Key secondary endpoint:

DTG/3TC non-inferior to

TAF-based regimen

(<50 c/mL) at Week 48

a

DTG/3TC

TAF-based regimen DTG/3TC

4% non-

inferiority

margin

-8% non-

inferiority margin




8

aOne fatal AE occurred (homicide).

SNAPSHOT OUTCOMES AT WEEK 48: ITT-E POPULATION

DTG/3TC (N=369)


HIV-1 RNA <50 c/mL, n (%) 344 (93.2) 346 (93.0)

HIV-1 RNA ≥50 c/mL, n (%) 1 (0.3) 2 (0.5)

Data in window and HIV-1 RNA ≥50 c/mL 0 0

Discontinued for lack of efficacy 0 2 (0.5)

Discontinued for other reason and HIV-1 RNA ≥50 c/mL 1 (0.3) 0

No virologic data, n (%) 24 (6.5) 24 (6.5)

Discontinued because of AE or deatha 12 (3.3) 1 (0.3)

Discontinued for other reasons 12 (3.3) 22 (5.9)

Missing data during window but on study 0 1 (0.3)




9

aOne assessment with HIV-1 RNA ≥200 c/mL after Day 1 with an immediately prior HIV-1 RNA ≥50 c/mL. bTreatment interrupted before suspected virologic withdrawal (VL, 38,042 c/mL) and resumed 3 weeks before VL retest (297 c/mL). cPlasma HIV-1 RNA resistance genotype at failure is compared with baseline PBMC pro-viral resistance genotype.

NO CONFIRMED VIROLOGIC WITHDRAWALS WITH DTG/3TC THROUGH WEEK 48

n (%)DTG/3TC


(N=372)

Confirmed virologic withdrawal (CVW)a 0 1 (<1)b

Observed resistance mutation at failurec 0 0




10

SAE, serious adverse event.aAll drug-related AEs were of grade 2. bOne fatal AE occurred (homicide). cNo SAEs were drug related.

ADVERSE EVENTS

n (%)DTG/3TC


(N=371)Any AE

NasopharyngitisUpper respiratory tract infectionDiarrheaHeadacheSyphilisBack painFatigueBronchitis

295 (80)43 (12)31 (8)30 (8)24 (7)24 (7)21 (6)20 (5)8 (2)

292 (79)41 (11)32 (9)26 (7)17 (5)13 (4)28 (8)3 (1)

20 (5)Any drug-related Grade 2-5 AE 17 (5) 3 (1)Drug-related Grade 2-5 AEs occurring in ≥0.5%a

InsomniaConstipationFlatulenceHeadache

4 (1)2 (1)2 (1)2 (1)

01 (<1)

00

AEs leading to withdrawal from the study 13 (4)b 2 (1)Drug-related AEs leading to withdrawal from the study 9 (2) 1 (<1)

Any SAEc 21 (6)b 16 (4)

• At Week 48, a similar adjusted mean increase from baseline in weight of 0.8 kg was observed in both treatment groups• Increased weight was reported as an AE in 3 (1%) participants treated with DTG/3TC and in 6 (2%) treated with a

TAF-based regimen




11

aParticipants may have had more than 1 AE leading to withdrawal. bAE not related to study treatment.

ADVERSE EVENTS LEADING TO WITHDRAWAL

n (%)aDTG + 3TC

(N=369)


Participants with AEs leading to withdrawal

13 (4) 2 (1)

Anxiety 3 (1) 0

Insomnia 3 (1) 0

Weight increased 2 (1) 1 (<1)

Fatigue 2 (1) 0

Abdominal discomfort 1 (<1) 0

Gastroesophageal reflux disease

1 (<1) 0

Hypoesthesia oral 1 (<1) 0

Nausea 1 (<1) 0

Paraesthesia oral 1 (<1) 0

Drug hypersensitivity 1 (<1) 0

Gunshot woundb 1 (<1) 0

n (%)aDTG + 3TC

(N=369)


Diffuse large B-cell lymphomab

1 (<1) 0

Lung adenocarcinomab 1 (<1) 0

Disturbance in attention 1 (<1) 0

Hypoesthesia 1 (<1) 0

Paraesthesia 1 (<1) 0

Depression 0 1 (<1)

Irritability 1 (<1) 0

Suicidal ideationb 1 (<1) 0

Suicide attemptb 0 1 (<1)

Genital hypoesthesia 1 (<1) 0

Genital paraesthesia 1 (<1) 0

Pruritus 1 (<1) 0




12

TC, total cholesterol; TGL, triglycerides.an = number of participants with non-missing fasting lipid data at Week 48, removing participants with lipid-modifying agent administered at baseline (lipid data collected after a lipid-modifying agent are censored and uses last on-treatment pre-modifying agent LOCF method). bNCEP categories at Week 48 vs baseline. cPurple shading indicates High for LDL.

CHANGE IN SERUM LIPIDS FROM BASELINE AT WEEK 48: SAFETY POPULATION

NA, NA, Borderline high, High, 4.4 to <5High, Low, Very high, Very high, ≥5Missing

Desirable, High, Optimal, Normal, <3.5Borderline high, Normal, Near/Above optimal, Borderline high, 3.5 to <4.4

0

25

50

75

100

TCb

BL W48

Pa

rtic

ipa

nts

, %

TAF-based regimen (n=277)a

HDLb LDLb,c TGLb TC/HDL TCb HDLb LDLb,c TGLb TC/HDL

BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48

DTG/3TC (n=291)a




13

aEstimated mean change from baseline at Week 48 in each group calculated from MMRM model adjusting for treatment, visit, baseline third agent class, CD4+ cell count (continuous), age (continuous), sex, race, BMI (continuous), presence of diabetes mellitus, presence of hypertension, baseline biomarker (continuous), treatment-by-visit interaction, and baseline value-by-visit interaction, with visit as the repeated factor. bBased on estimated geometric means ratio of Week 48 vs baseline. Based on the same model as plasma/serum markers except adjusting for loge-transformed baseline biomarker (continuous).

CHANGE IN RENAL BIOMARKERS AT WEEK 48

-2.9

6.3

-2.7

1.6

6.7

-7.8

-20

-15

-10

-5

0

5

10

15

20

Ch

an

ge

fro

m b

ase

line

, %

b

6.67

-7.8

0.1

2.19

-3.0-1.6

-10

-5

0

5

10

Ad

juste

d m

ea

n c

ha

ng

e

fro

m b

ase

line

a

eGFR from

creatinine,

CKD-EPI

(mL/min/1.73 m2)

Creatinine

(µmol/L)

Protein/

Creatinine

(g/mol)

Retinol-binding

protein/

Creatinine

(µg/mmol)

Beta-2

microglobulin/

Creatinine

(mg/mmol)

DTG/3TC (N=369) TAF-based regimen (N=371)

*P<0.001

*

*

Plasma/Serum markers Urine markers

eGFR from cystatin C,

CKD-EPI

(mL/min/1.73 m2)




14

aEstimated mean change from baseline at Week 48 in each group calculated from MMRM model adjusting for treatment, visit, baseline third agent class, CD4+ cell count (continuous), age (continuous), sex, race, BMI (continuous), smoking status, vitamin D use, baseline biomarker (continuous), treatment-by-visit interaction, and baseline value-by-visit interaction, with visit as the repeated factor.

CHANGE IN BONE BIOMARKERS AT WEEK 48

-0.03-1.15

9.3

0.0602

-0.34

0.69

6.4

0.0310

-4

-2

0

2

4

6

8

10

12

14

Serum bone-specificalkaline phosphatase

Serumosteocalcin

Serum procollagen 1N-terminal propeptide

Serum type 1 collagenC-telopeptide

Adju

ste

d m

ean c

hange

from

baselin

e, µ

g/L

a

DTG/3TC (N=369)

**P<0.001*P<0.05

*

*

**

TAF-based regimen (N=371)




• Switching to DTG/3TC FDC was non-inferior to remaining on a TAF-based regimen through Week 48 in ART-experienced, virologically suppressed adults

• No confirmed virologic withdrawals in the DTG/3TC group

• Zero resistance development in the DTG/3TC group

• The safety profile of DTG/3TC FDC was consistent with the DTG and 3TC labels

• These data support the use of DTG/3TC as a new robust switch option without increased risk of virologic failure or resistance and with reduced ART exposure

15

CONCLUSIONS




• We thank the study participants; their families and caregivers; investigators and site staff who participated in the study; and the ViiV Healthcare, GlaxoSmithKline, Pharmaceutical Product Development, and Phastar study team members

16

ACKNOWLEDGMENTS

AustraliaBakerBisshopBlochMcMahonMoorePellRothSchmidtSmithWoolley

Belgium De Wit FlorenceLacorVandekerckhoveVandercam

CanadaKasperLeBlancRoutySassevilleWalmsley

France AjanaBonnetGirardKatlamaPhilibertPuglieseYazdanpanah

Germany ArastehBognerDegen

Germany (cont)JägerKrznaricLutzPostelScholtenSpinnerStellbrink StollWyen

JapanAdachiIgariYokomaku

NetherlandsRijnders

Spain Angel-MorenoAntelaArribas LopezBernal MorellBravo UrbietaCrusells CanalesDeig ComermaDomingo ForceGalinda PuertoGil AnguitaGórgolasMartinez ChamorroMasia CanutoMerino MunozMontero-AlonsoOcampo HermidaPasquau LianoPérez EliasPerez Stachowski

Spain (cont)PinedaPodzamczer PalterPortilla SogorbRubioSantos FernandezSantos GonzalezSanz MorenoVera MendezVergas GarciaViciana

United KingdomArumainayagamChapondaClarkeGompelsPettRossUstianowski

USAAlozieBatraBensonBerheBolivarBrennanBrinsonCrofootCruickshankCunninghamDaarDeJesusEdelsteinFarabiFelizartaFlammGoldsteinGupta

USA (cont)HaginsHenryJohnsonKatnerKinderMartorellMayerMcDonaldMcKellarMeltonMillsMounzerOrtizOsiyemiParkPatelPrelutskyRamgopal

USA (cont)RaviReddyRodriguezRuaneScarsellaSchneiderSchraderSchreibmanSimonSimsSinclairSteinThedingerTownerVanigWohlfeilerWurapaZane




17

Prescribing InformationTivicay (dolutegravir 50mg) / Epivir (lamivudine 300mg) tabletsSee Summary of Product Characteristics (SmPC) before prescribing

Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellowcard in the Google Play or Apple App store. Adverse events should also be reported to GlaxoSmithKline on 0800 221441.

Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: +353 1 676 4971,[email protected]. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

DOVATO is owned by or licenced to the ViiV Healthcare group of companies.©2019 ViiV Healthcare group of companies or its licensor.

References: van Wyk et al. IAS 2019; Mexico City, Mexico. WEAB0403LB.

http://www.mhra.gov.uk/yellowcard

mailto:[email protected]

fixed-dose combination (fdc) is non-inferior to … · kelly et al. drugs. 2016;76:523-531. 2. cahn...

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