20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia DTG-Based Regimens Are Active in INI-Naive Patients With a History of NRTI Resistance

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia

DTG-Based Regimens Are Active in INI-Naive Patients With a History of NRTI Resistance

Jim Demarest,1 Mark Underwood,2 Marty St Clair,2 David Dorey,3 Steve Almond,3 Robert Cuffe,4

Dannae Brown,5 Garrett Nichols6 1ViiV Healthcare, Global R&D, Research Triangle Park, NC, USA; 2GlaxoSmithKline,

Clinical Virology, Research Triangle Park, NC, USA; 3GlaxoSmithKline, Clinical Statistics, Mississauga, Canada; 4ViiV Healthcare, Statistics, London, United Kingdom; 5ViiV Healthcare, Medical Affairs, Abbotsford, Australia; 6GlaxoSmithKline,

Infectious Disease R&D, Research Triangle Park, NC, USA


Introduction

Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.

1. Raffi et al. Lancet. 2013;381:735-743. 2. Walmsley et al. N Engl J Med. 2013;369:1807-1818. 3. Clotet et al. Lancet. 2014;383:2222-2231. 4. Cahn et al. Lancet. 2013;382:700-708.

• Dolutegravir (DTG, Tivicay) has exhibited potent antiviral efficacy in Phase 3 studies of more than 1800 integrase inhibitor (INI)-naive patients1-4

• All subjects were screened for resistance• Individuals with resistance were excluded from treatment naïve

studies

• Baseline resistance was used as inclusion criteria and to select background regimens in SAILING

• Here we present post-hoc analyses of virologic failure by background regimen and baseline resistance in SAILING


Potent and Durable Efficacy in Treatment-Naive Subjects Across the DTG Phase III Program


1. Raffi et al. Lancet Infect Dis. 2013;13:927-935. 2. Walmsley et al. CROI 2014, Boston, MA. Abstract 543. 3. Clotet et al. Lancet. 2014;383:2222-2231.

Study SPRING-2 (Wk 96)1 SINGLE (Wk 96)2 FLAMINGO (Wk 48)3

Regimen DTG +2 NRTI

RAL +2 NRTI

DTG +ABC/3TC

EFV/TDF/FTC DTG +2 NRTI

DRV/r +2 NRTI

<50 c/mL,a

n/N (%)332/411

(81%)314/411

(76%)331/414

(80%)302/419

(72%)217/242

(90%)200/242

(83%)PDVF,b

n (%)22 (5%) 29 (7%) 25 (6%) 25 (6%) 2 (<1%) 2 (<1%)

• DTG demonstrated statistical superiority in SINGLE and FLAMINGO in a pre-specified analysis

• In DTG treated individuals:• No treatment-emergent resistance through 96 weeks in SPRING-2 and

SINGLE • No treatment-emergent resistance through 48 weeks in FLAMINGO

aFDA Snapshot algorithm. bProtocol-defined virologic failure.


SAILING: DTG Superior to RAL in Treatment-Experienced, INI-Naive Adult Subjects


Cahn et al. Lancet. 2013;382(9893):700-708.

DTG 50 mg QD plus background regimen

(n=354)

RAL 400 mg BID plus background regimen

(n=361)

• HIV RNA ≥400 c/mL• Resistant to ≥2 classes

of ARVs• Background regimen =

1-2 agents, at least 1 fully active

71%

64%

Week 48<50 c/mL

P=0.03

• Significantly less resistance at PDVF with DTG vs RAL at Wk 48• Emergent genotypic/phenotypic resistance:

• INI: DTG (4/354, 1%) vs RAL (17/361, 5%) p=0.003• Background: DTG (4/354, 1%) vs RAL (12/361, 3%)

Protocol-defined virologic failure (PDVF), defined as plasma HIV-1 RNA decrease <1 log10 c/mL (unless <400 c/mL by week 16 or HIV-1 RNA ≥400 c/mL on or after week 24) or virological rebound (plasma HIV-1 RNA ≥400 c/mL after confirmed HIV-1 RNA <400 c/mL or >1 log10 c/mL increase above any nadir of ≥400 c/mL); BR, background regimen.

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.

Response by DRV/r Use: Baseline Strata(SAILING, Week 48 Analysis)

Cahn et al. Lancet. 2013;382:700-708. Supplemental Appendix.

Baseline Stratification

Virologic Response (<50 c/mL)Responders/Total n, (%)

DTG(n=354)

RAL(n=361)

Difference(95% CI)

DRV/r Use

No 143/214 (67%) 126/209 (60%) 6.5% (-2.6 to 15.7)

Yes, with primary PI mutations

58/68 (85%) 50/75 (67%) 18.6% (5.0 to 32.2)

Yes, withoutprimary PI mutations

50/72 (69%) 54/77 (70%) -0.7% (-15.4 to 14.1)


Protocol-Defined Virologic Failure in Subjects by Type of Background Regimen (SAILING, Week 48 Analysis)


a Protocol-defined virologic failure (PDFV), defined as plasma HIV-1 RNA decrease <1 log10 c/mL (unless <400 c/mL by week 16 or HIV-1 RNA ≥400 c/mL on or after week 24) or virological rebound (plasma HIV-1 RNA ≥400 c/mL after confirmed HIV-1 RNA <400 c/mL or >1 log10 c/mL increase above any nadir of ≥400 c/mL).

DTG n with PDVFa/N

(%)

RALn with PDVFa/N

(%)

Overall 21/354 (6) 45/361 (12)

NRTI-only background regimens* 0/32 7/32 (22)

PI-containing background regimens 18/300 (6) 36/305 (12)

Other background regimens 3/22 (14) 2/24 (8)

*All received 2 NRTI with exception of one subject on DTG (received only 1 NRTI)


No PDVF for DTG Subjects Receiving Only NRTIs Regardless of Number of Active NRTIs (SAILING, Week 48 Analysis)


a Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist).

DTG n with PDVF/N

RALn with PDVF/N (%)

NRTI-only background regimens 0/32 7/32 (22)

2 fully active NRTIsa 0/16 3/19

1 fully active NRTIs 0/12 4/13

0 fully active NRTIs 0/1 -

Missing phenotype 0/3 -


No PDVF for DTG Subjects with M184V Detected and Receiving 3TC or FTC Plus a Second NRTI (SAILING, Week 48 Analysis)


a Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist). TAM, thymidine analogue mutation.

DTG n with PDVF/N

RALn with PDVF/N

M184V patients who received 3TC/FTC plus a second NRTI

0/13 4/12

Activity of second NRTI by phenotypea

Fully active 0/10 4/12

Reduced susceptibility 0/1 NA

Missing phenotype 0/2 NA

In presence/absence of TAMs

0 TAMs 0/10 3/10

1 TAMs NA 1/1

≥2 TAMs 0/3 0/1


Lower PDVF Incidence for DTG Subjects with TAMs Than for Subjects on RAL (SAILING, Week 48 Analysis)


aFully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist). TAM, thymidine analogue mutation.

DTG n with PDVF/N (%)


All patients with TAMs 10/164 (6) 17/166 (10)

TAMs + less than fully active 2nd agent NRTI of ABC, TDF, AZT, or ddIa

3/24 1/19

+ third agent (PI) 2/19 1/15

+ third agent (MVC) 0/1 0/2

+ third agent (NNRTI) 1/3 0/2

+ third agent (NRTI) 0/1 -

NRTI = 3TC or FTC 0/1 -

NRTI = Other - -


Lower PDVF Incidence for Subjects Receiving DTG + PI/r Versus Those on RAL + PI/r (SAILING; Week 48 Analysis)


a Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if upper and lower exist). b DRV also determined as fully active by genotype (Stanford): 6/102 (6%) vs 11/126 (9%).

DTG n with PDVF/N (%)


PI-containing background regimensa 18/300 (6) 36/305 (12)1 fully active PI 18/289 (6) 32/295 (11) DRV/rb 6/130 (5) 12/145 (8) LPV/r 6/93 (6) 9/90 (10) Other 6/66 (9) 11/60 (18)0 fully active PI 0/7 3/8 Missing phenotype 0/4 1/2


Conclusions


• Treatment-naive subjects• No resistance detected to DTG or to the 2 NRTIs (ABC/3TC or

TDF/FTC) through 96-week (SPRING-2, SINGLE) or 48-week (FLAMINGO) follow-up

• Treatment-experienced, INI-naive subjects (SAILING; 48 Week)• No observed virologic failures in this limited set of subjects

receiving DTG + 2 NRTIs, even without full backbone activity• Further studies with larger numbers of subjects and longer

follow-up are required to confirm these findings

• The resistance profile for DTG will be defined further by use in clinical practice and additional clinical trials


Acknowledgments• Patients and their supporters

• DTG study investigators

• Study teams and colleagues at ViiV Healthcare and GSK

• These studies were sponsored by ViiV Healthcare



Backup


Resistance Testing in Phase III Studies of DTG


* The assay for RT/PRO and IN is only validated for HIV RNA >400 c/ml

• Ongoing studies will store samples to allow future analysis

Viral load at PDVF: SPRING-2

HIV RNA >50 c/mL HIV RNA >400 c/mL*

PDVF Detection

PDVFConfirmation

PDVF Detection

PDVFConfirmation

DTG 22/22 22/22 6/22 1/22

RAL 29/29 29/29 4/29 5/29

• Samples from baseline and PDVF detection were evaluated for resistance, regardless of plasma HIV-1 RNA (Monogram Biosciences)

• No plasma was stored from confirmatory (unscheduled) visit

• VL at confirmatory visit tends to decrease with adherence counselling

Documents

20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia DTG-Based Regimens Are Active in INI-Naive Patients With a History of NRTI Resistance