7th IAS Conference on HIV Pathogenesis, Treatment and PreventionJune 30-July 3, 2013; Kuala Lumpur, Malaysia

Dolutegravir (DTG) is Superior to Raltegravir (RAL) in ART-Experienced, Integrase-Naive Subjects: Week 48 Results From SAILING

(ING111762)Pedro Cahn,1 Anton Pozniak,2 Horacio Mingrone,3 Carlos Brites,4 Jaime Federico

Andrade-Villanueva,5 Jan Fourie,6 Moti Ramgopal,7 Debbie Hagins,8 Jose Madruga,9 Tamara Newman,10 John Lombaard,11 David Dorey,12 Mark Underwood,13 Sandy Griffith,13

Sherene Min,13 on behalf of the extended SAILING study team1Fundación Huésped, Buenos Aires, Argentina; 2Chelsea and Westminster Hospital NHS Foundation Trust, London, UK;

3Fundación IDEAA, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina; 4Complexo Hospitalar Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil; 5Hospital Civil de Guadalajara “Fray Antonio Alcalde,” CUCS, Universidad de

Guadalajara, Guadalajara, Mexico; 6Fourie Medical Centre, Dundee, South Africa; 7Midway Immunology and Research Center, Fort Pierce, FL, USA; 8Chatham CARE Center, Savannah, GA, USA; 9Centro de Referencia e Treinamento DST/AIDS, São Paulo,

Brazil; 10Instituto de Infectologia Emílio Ribas, São Paulo, Brazil; 11JOSHA Research, Bloemfontein, South Africa; 12-13GlaxoSmithKline, 12Mississauga, ON, Canada; 13Research Triangle Park, NC, USA

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

Study Rationale

•Dolutegravir has been shown to be effective in antiretroviral (ART)-naive (SPRING-2 and SINGLE) and integrase inhibitor (INI)-resistant subjects (VIKING-3).

• SAILING was designed to test the efficacy and safety of DTG versus RAL when used with a background regimen of 2 antiretrovirals (1 of which must have been fully active) in ART-experienced, INI-naive subjects with at least 2-class drug resistance.

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

SAILING (ING111762) Study Design

Week 48primary analysis

Randomization Week 24planned interim

a At Screening and a second consecutive test >400 c/mL within 4 months prior to Screening (if Screening HIV-1 RNA >1000 c/mL, no additional HIV-1 RNA assessment was needed). PBO, placebo; BR, background regimen comprising at least 1 and no more than 2 active agents.

HIV ART-experienced, INI-naive

HIV-1 RNA >400 c/mLa

1:1 Randomizationstratified by HIV-1 RNA

(≤ or >50,000), DRV/r use and # of fully

active drugs

DTG 50 mg QD + RAL PBO + BR

RAL 400 mg BID + DTG PBO + BR

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

DTG 50 mg QD(n=354)

RAL 400 mg BID(n=361)

Age, median (y) 42 43Gender, female 30% 34%Race, white 50% 49%

African American/African heritage 41% 44%HIV-1 RNA, median (log10 c/mL) 4.17 4.21

>50,000 c/mL 30% 29%CD4+ count, median (cells/mm3) 205 193

<200 cells/mm3 49% 51%HBV/HCV coinfection 14% 18%Duration prior ART, median (y) 6.7 6.0≥3 Class resistance 47% 51%DRV/r in background regimenDRV/r use without primary PI mutations 72 (20%) 77 (21%)No DRV/r use or DRV/r use with primary PI mutations

282 (80%) 284 (79%)

Baseline Characteristics

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

Subject Accountability Patients screenedN=1441

Not randomizedN=717

Randomized phasePatients randomized

N=724

Patients randomizedto DTG 50 mg QD

N=360

Patients randomizedto RAL 400 mg BID

N=364

Not treatedN=3

Treated (ITT-E)N=357

Patients excluded at site 083523

N=3

Treated (ITT-E)N=362

Not treatedN=2

Patients excluded at site 083523

N=1

Completion status at Week 48299 (84%) completed

55 (16%) withdrew4 adverse event

20 lack of efficacy9 protocol deviation

5 stopping criteria5 lost to follow-up

1 investigator discretion11 withdrew consent

Completion status at Week 48283 (78%) completed

78 (22%) withdrew11 adverse event

42 lack of efficacy6 protocol deviation

3 stopping criteria10 lost to follow-up

1 investigator discretion5 withdrew consent

mITT-EN=354

mITT-EN=361

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

Mean CD4+ change from Baseline was similar between arms: DTG: +162.4 cells/mm3 (n=294); RAL: +153.2 cells/mm3 (n=283).

71%64%

DTG 50 mg QDRAL 400 mg BID

100908070605040302010

0

BL 4 8 12 16 24 32 40 48Week

Prop

ortio

n (%

)

DTG 50 mg QD was statistically superior to RAL 400 mg BID at Week 48.

*Adjusted treatment difference (95% CI): 7.4% (0.7%, 14.2%); P=0.03

*Adjusted difference based on stratified analysis adjusting for Baseline HIV-1 RNA (≤50,000 c/mL vs >50,000 c/mL), DRV/r use without primary PI mutations and Baseline PSS (2 vs <2).

Proportion (95% CI) With HIV-1 RNA <50 c/mL (Snapshot, mITT-E)

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

Primary Endpoint: HIV-1 RNA <50 c/mL at Week 48

71

20

9

64

28

9

0

20

40

60

80

Virologic success Virologic non-response

No W48 data*

Perc

enta

ge o

f sub

ject

s (%

)

DTG 50 mg QD (n=354) RAL 400 mg BID (n=361)

95% CI for differenceFavors

RALFavors

DTG

-20% 0 20%

7.40.7 14.2

-12%

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

DTG RALno. with response/total no. (%)

Overall 251 (71) 230 (64)

Baseline plasma HIV-1 RNA ≤50,000 c/mL >50,000 c/mL

186/249 (75)65/105 (62)

180/254 (71)50/107 (47)

Baseline CD4+ cell count <200 cells/mm3

≥200 cells/mm3110/173 (64)141/181 (78)

106/184 (58)124/177 (70)

DRV/r with no primary PI mutations DRV/r use without primary PI mutations No DRV/r use or DRV/r use with primary PI mutations

50/72 (69)

201/282 (71)

54/77 (70)

176/284 (62)

Background regimen PSS = 2* PSS <2

181/250 (72)70/104 (67)

169/267 (63)61/94 (65)

*PSS based on full susceptibility, reported category “2” includes 2 subjects with PSS = 3.

Subgroup Response ratesDifference (DTG-RAL) and 95% CI

0-10-20-30 10 20 30

In favor of RAL In favor of DTG

Percentage of Subjects With HIV-1 RNA <50 c/mL by Subgroup

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

DTG 50 mg QD(n=354)

RAL 400 mg BID(n=361)

Difference (%, 95% CI)

Per protocol, HIV-1 RNA <50 c/mL 238/325 (73%) 225/340 (66%) 7.5% (0.6%, 14.3%) Kaplan-Meier proportion without failure, % (95% CI)

Treatment-related discontinuation = failurea 92.0 (88.5, 94.4) 85.1 (80.8, 88.4) 6.9 (2.1, 11.7)Efficacy-related discontinuation = failureb 93.7 (90.4, 95.8) 86.7 (82.6, 89.9) 6.9 (2.5, 11.4)

a Protocol-defined virologic failure or withdrawal because of drug-related adverse events, safety stopping criteria or lack of efficacy.b Protocol-defined virologic failure or withdrawal due to lack of efficacy.

Sensitivity Analyses

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

•Non-response• HIV-1 RNA <1 log10 c/mL decrease by Week 16, unless <400 c/mL

• HIV-1 RNA ≥400 c/mL on or after Week 24, through Week 48

•Rebound • HIV-1 RNA ≥400 c/mL after confirmed <400 c/mL • HIV-1 RNA >1 log10 c/mL above nadir (lowest prior value ≥400 c/mL)

Protocol-Defined Virologic Failure

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

• Fewer PDVFs for DTG versus RAL by Week 48

DTG50 mg QD(N=354)

RAL400 mg BID

(N=361)Week 16 10 (3%) 21 (6%)

Virologic non-response 0 13 (4%)Rebound 10 (3%) 8 (2%)

Week 24 15 (4%) 35 (10%)Virologic non-response 1 (<1%) 19 (5%)Rebound 14 (4%) 16 (4%)

Week 48 21 (6%) 45 (12%)Virologic non-response 2 (<1%) 19 (5%) Rebound 19 (5%) 26 (7%)

Protocol-Defined Virologic Failure

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

Supportive Analysis• Treatment-emergent resistance to background regimen was also

statistically significant.**• DTG 1% vs RAL 3%, adjusted difference (95% CI) of -2.2% (-4.3%, -0.1%)

Proportion of Subjects With INI Treatment-Emergent Genotypic/Phenotypic Resistance

TreatmentFailure with INI-r (n)/mITT-E population (N)

Adjusted difference inproportion

(95% CI)(DTG-RAL)

DTG 50 mg QD 4/354 (1%)

RAL 400 mg BID 17/361 (5%) -3.7% (-6.1%, -1.2%)*

*DTG was superior vs RAL at Week 48 (P=0.003), pre-specified and adjusted for multiple testing.

Treatment-Emergent Resistance to INI and to Background Regimen

Key Secondary Endpoint

**This analysis was pre-specified but was unadjusted for multiple testing.

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

Adverse EventsDTG

50 mg QD(N=357)

RAL 400 mg BID

(N=362) Discontinuations due to safety events 9 (3%) 14 (4%)Most commonly reported (≥10%) AEs in either arm

Diarrhea 71 (20%) 64 (18%)Upper respiratory tract infection 38 (11%) 29 (8%)

Drug-related (≥2% in either arm) 73 (20%) 85 (23%)Diarrhea 29 (8%) 21 (6%)Nausea 13 (4%) 16 (4%)Vomiting 8 (2%) 11 (3%)Headache 7 (2%) 7 (2%)Fatigue 4 (1%) 10 (3%)Rash 5 (1%) 6 (2%)Insomnia 0 6 (2%)Abdominal pain upper 6 (2%) 0

Drug-related Grade 2-4 28 (8%) 32 (9%)Drug-related Grade 4 1 (<1%) 1 (<1%) Serious – any event 33 (9%) 42 (12%)Serious drug-related – any event 2 (<1%)a 4 (1%)b

Fatal AEs 0 3 (<1%)c

a DTG: 1 hepatotoxicity, 1 myositis and acute renal failureb RAL: 1 oral mucosal blistering and rash pruritic, 1 pancreatitis, 1 hepatitis, 1 suicidal ideationc 1 adenocarcinoma, 1 acute hepatic and renal failure, 1 cervical carcinoma

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

DTG50 mg QD

RAL400 mg BID

Select treatment-emergent Grade 3-4 laboratory abnormalities

N=357 n (%)

N=362 n (%)

Creatine phosphokinase (CPK) 7 (2) 4 (1)Alanine aminotransferase (ALT) 9 (3) 7 (2)Lipase 4 (1) 7 (2)Total bilirubina 21 (6) 14 (4)Creatinine 1 (<1) 1 (<1)

Renal laboratory valuesChange from Baseline serum creatinine (μmol/L), mean (SD)

11.1 (15.53)b

(n=291)5.1 (12.23)

(n=283)

Change from Baseline urine albumin/creatinine ratio (mg/mmol), mean (SD)

-0.33 (27.51)(n= 260)

-0.56 (31.81)(n=253)

a 16/21 subjects in the DTG arm and 11/14 subjects in the RAL arm were receiving atazanavir or atazanavir/ritonavir.b As previously described, small non-progressive increase in serum creatinine due to OCT2 inhibition

Select Laboratory Abnormalities

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

• DTG once daily has higher virologic efficacy when compared with RAL twice daily in a treatment-experienced, INI-naive population.• 71% on DTG versus 64% on RAL had HIV-1 RNA <50 c/mL at Week 48.

• DTG 50 mg once daily had a similar tolerability and safety profile to RAL twice daily with a wide variety of background regimens in treatment-experienced subjects.• DTG statistical superiority was driven by fewer withdrawals due to

lack of efficacy, lower number of protocol defined virologic failures and lower treatment emergent resistance.

Conclusions

Cahn et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract WELBB03.

• We thank everyone who has contributed to the success of this study, including• All study participants and their families• The SAILING clinical investigators and their staff

• The GSK and ViiV Healthcare study team• This study was funded by ViiV Healthcare

Argentina: Chile: Mexico: South Africa: Taiwan: USA (cont): USA (cont):Belloso Afani Saud Andrade-Villanueva Fourie His-Hsun Lin Gupta RobbinsBenetucci Beltran Buendia Granados-Reyes Latiff Yu-Hui Lin Hagins RodriguezCesar Lasso Mosqueda-Gómez Lombaard Hung-Chin Tsai Hardy RuaneCassetti Perez Rosas-Dossetti Spain: Jen-Hsien Wang Henry SaagLupo Wolff Netherlands: Barros Wing-Wai Wong Hicks SamuelMingrone France: Hollander Boix Martínez UK: Hodder SandkovskyAustralia: Ajana Romania: Cano Sánchez Hay Huhn ScarsellaBloch De Truchis Duiculescu Castro Iglesias Kegg Jefferson SchneiderElliott Katlama Rugina Clotet Khoo M Johnson SchraderBelgium: Molina Streinu-Cercel de los Santos Gil Wilkins P Johnson ScribnerClumeck Pialoux Russia: Deig USA: Kozal ShalitFlorence Poizot-Martin Chernova Flores Akil Kumar SirajLegrand Quertainmont Khafizov Galindo Anstead McCurdy SlimMoutschen Teicher Kozyrev González García Bartczak McDonald SloanBrazil: Yeni Kulagin Górgolas Hernández-Mora Blick Meier SmallAndrade Neto Greece: Moshkovich Masia Brar Mildvan TashimaBahia Gargalianos-Kakolyris Nagimova Ribera Burack Murphy TebasCaseiro Gogos Pokrovsky Rodríguez Baño Casey Nahass VanigDiaz Paparizos Pronin Vera Méndez Eron, Jr. Newman WardGrinsztejn Italy: Rakhmanova Von Wichmann De Miguel Feinberg O’Keefe WarnerSchiavon Di Perri Ryamova Canada: Felizarta Osiyemi WheelerPereira Gori Shuldyakov Conway File Parks ZingmanReuter Lazzarin Sonin Logue Gathe JacobsTupinambas Piga Hungary: Smaill Goulston Richmond

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Acknowledgments