A Comprehensive Understandingof InSTI....stomach, preferably at bedtime. f ABC has been associated with increased CV risk, although conflicting data; use with caution in patients with

A Comprehensive

Understanding of InSTI. Clinical Efficacy and Barrier to Resistance

in HIV pre-treated patients

Emilio Fumero, MD, PhD

ViiV Global Medical Director

DISCLOSURE

Emilio Fumero is a full-time employee of ViiV healthcare.

AGENDA

Biology of HIV-1 Integrase

General considerations of DTG.

Understanding the clinical data and relevance of DTG

studies in HIV pre-treated and naive patients.

Addresing Unmet Clinical Needs. DDI aspects

Summary

DHHS1

(Dept. of Health and Human Services)

IAS-USA2

(International Antiviral Society USA Panel)

EACS3

(European AIDS Clinical Society)

NNRTI-based therapy

Now alternative

EFVe+ TDF/FTC

EFVe + ABCaf/3TCg

RPVh/TDF/FTC

RPVbcm + TDF/FTC

Ritonavir-boosted PI-based therapy

DRV/r + TDF/FTC or 3TC

ATV/r ij + TDF/FTC

ATV/r ij + ABCaf/3TCg

DRV/rj + TDF/FTC

DRV/rn + TDF/FTC

INI-based therapy

DTG + ABCa/3TC or FTC

DTG + TDF/FTC or 3TC

EVG/cobi/TDF/FTCd

RAL + TDF/FTC or 3TC

DTGk + ABCaf/3TC

DTGk + TDF/FTC

RALk + TDF/FTC

EVGk/cobi/TDF/FTC

EVG/cobi/TDF/FTCdo

DTG + TDF/FTC or ABC/3TCa

RAL + TDF/FTC

a Only if HLA-B*5701 negative. b only if VL<100,000 c/mL.c Only if CD4>200 cells/mm3. d Only for patients with pre-treatment CrCl>70ml/min. e Take on an empty

stomach, preferably at bedtime. f ABC has been associated with increased CV risk, although conflicting data; use with caution in patients with high CV risk. g

Combination of ABC/3TC less efficacious with baseline HIV-1 RNA >100,000 copies/mL than combination of TDF/FTC when given with EFV or ATV/r. h RPV

should not be given with proton pump inhibitors and should be taken consistently with a full meal. i Take with food. j avoid co-administration with H2-blockers

or proton pump inhibitors if possible and, if not, follow specific doses/dose separation schedules recommended in prescribing information. k Avoid simultaneous

administration with antacids or other divalent cations due to chelation of INI by the cation, thereby reducing absorption. l EFV not recommended to be initiated

in pregnant women or women with no reliable and consistent contraception; continuation is possible if EFV is already started before pregnancy; not active

against HIV-2 and HIV-1 group O strains. m PPI contraindicated, take H2 antagonists 12 hours before or 4 hours after RPV. n Co-administration with PPI is

contraindicated for treatment-experienced persons; if co-administration unavoidable, close clinical monitoring is recommended and doses of PPI comparable to

omeprazole 20mg should not be exceeded and must be taken approximately 12 hours prior to ATV/r. O Not to be initiated in persons with eGFR<70ml/min; not

to be initiated when eGRF<90ml/min unless the preferred treatment.1. DHHS Guidelines April 2015; 2. Gunthard HF et al. JAMA 2014;312:410–425; 3. EACS Guidelines version 8-0 November 2015.

Preferred Regimens for Treatment-Naive Patients Now Include Integrase Inhibitors (April 2015)

GESIDA 2015

Science 2000;287

8

Integrase Structure/FunctionPre-2010 limited structural information

D64 D116-(35)-E152 SH3H H C C

1 50 212 288

Zinc Finger Catalytic Core DNA Binding

“DDE” residues coordinate the essential active site metals(s). Conserved in all integrases and transposases.

Bujacz, G. et al. (1997) J. Biol. Chem. 272, 18161-18168

Screening for strand transfer inhibitors identified novel inhibitors of HIV-I integration

(Hazuda et. al Science 2000; 287, 646.)

N

F

O OH

O

OH

L-731988

Integrase Strand Transfer Inhibitors (InSTIs) define a functionally distinct mechanistic class

� Biochemical mechanism1: High-affinity binding to complex with (viral) donor DNA; compete with the (host cell) target DNA

� Molecular mechanism2: Essential pharmacophore binds/sequester divalent metals in the active site; specificity/affinity derived from the attached pendant groups

1. Espeseth AS. Proc Nat Acad Sci USA. 2000;97:11244-11249.

2. Grobler JA, et al. Proc Natl Acad Sci USA. 2002;99:6661-6666.

RO

O O

OH

Mg2+

2.0

2.02.7

2.9

3.6Mg2+

Proposed model of InSTI

binding

Catalytic

metals

Hydrophobic

pocket

11

A decade since the first InSTIs……

Nature advance online publication 31 January 2010

Retroviral intasome assembly and inhibition of DNA strand transfer

Stephen Hare, Saumya Shree Gupta, Eugene Valkov1, Alan Engelman, & Peter Cherepanov

Interacttion with two essential elements of the virus

Inactivation of intasome both by blocking critical active Mg

and dislocating the 3’ nucleotide of the vDNA

vDNAintegrase

F

F

NH

O

N

N

HO

O

OOH

O

F

HN

N N

O

O

O

OH

NH

N N

F

N

O

OHCI

O

O

OH

Dolutegravir

(DTG)

Raltegravir

(RAL)

Elvitegravir

(EVG)

Adapted from DeAnda F, et al. PLoS One 2013;8:1–12

STRUCTURES OF DOLUTEGRAVIR, RALTEGRAVIR AND ELVITEGRAVIR

Coloured boxes show similarities and differences across the antiretrovirals

HIV PROTEOMICS

RETROTRANSCRIPTASE

Error prone: 10 5- 106 pairs

Inhibition of γ-DNA mitochondrial polymerase†

PROTEASE

Functional and structural plasticity

High homology to signal proteins involved in lipid metabolism: CRABP-1,

LRP‡

INTEGRASE

Unique to Retroviruses

Highly efficient enzyme; viral DNA strand transferᶱ

†Brinkman, et al. Lancet 1999

‡Carr A, et al. Lancet 1998

ᶱ Bukrinsky, et al. Pro Nactl Acad Sci 1992

14

InSTI “single hit”mechanism of action

Bind after RT

Long dissociatecv half lifeIrreversible inhibition

VIROLOGIC RESPONSE AT WEEK 481

Results confirmed in per protocol analysis: 91% DTG versus 84% DRV/r

(difference [95% CI]: 7.4% [1.4–13.3])2

100

BL

Weeks

Proportion with HIV-1 RNA <50 c/mL 90

80

70

60

50

40

30

20

10

0

4 8 12 16 24 36 48

0% 20%–12%–20%

0.9 7.1 13.2

95% CI for difference*

Favours

DRV/r

Favours

DTG

DRV/r†: 83%

DTG†: 90%

Test for superiority: p=0.025

DTG 50 mg QD†

DRV/r 800/100 mg QD†

*Adjusted difference (DTG - DRV/r) based on Cochran-Mantel-Haenszel stratified analysis

adjusting for baseline HIV-1 RNA and background NRTI therapy; †plus 2 NRTIs

1. Adapted from Clotet B, et al. Lancet 2014;383:2222–31

2. Clotet B, et al. Lancet 2014;383:2222–31. Supplementary appendix

-Integrase; life cycle. Segadhat A, et al. PNAS 2008

-Active in

Monocyte/macrophages. Pollicita

M, et al. JAC 2014.

-Deeper phase I VL decay. Gilmore J. PloS comp biol 2013



(difference [95% CI]: 7.4% [1.4–13.3])2

100

BL

Weeks

Proportion with HIV-1 RNA <50 c/mL 90

80

70

60

50

40

30

20

10

0

4 8 12 16 24 36 48

0% 20%–12%–20%

0.9 7.1 13.2

95% CI for difference*

Favours

DRV/r

Favours

DTG

DRV/r†: 83%

DTG†: 90%


DTG 50 mg QD†


*Adjusted difference (DTG - DRV/r) based on Cochran-Mantel-Haenszel stratified analysis

adjusting for baseline HIV-1 RNA and background NRTI therapy; †plus 2 NRTIs



-VL>50c/mL W4: 70% of then

80% supressed by w96. Quercia

R. EACS 2015; Abs PE 1/10.

-Faster CD4/CD8 normalization

in VL<50c/mL w8. Tsoukas, et al.

CROI 2013.

-MDR-late pregnancy; surgical

urgency; PEP

AGENDA






Summary

DTG: IN VITRO DATA AND PHARMACOLOGICAL PROPERTIES

In-vitro characteristics of DTG

• In vitro, DTG is a broadly potent antiviral and is synergistic or additive with approved anti-HIV drugs1,2

• In vitro potency, PA-IC90 : 64ng/mL (150nM/mL)

• DTG exhibits broad potency across HIV sub-types1

• Most RAL- and EVG-resistant mutants are susceptible to DTG2,3

• DTG shows potential for a higher genetic barrier to resistance compared with RAL2,4

O

O

N

N

O

O

NH

O

F

FH

CH3

Na+

1. Johns BA, et al. CROI 2010. Abstract 55; 2. Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21

3. Sato A, et al. IAS 2009. Poster WEPEA097; 4. Seki T, et al. CROI 2010. Abstract 555

5. Min S, et al. AIDS 2011;25:1737–45

Pharmacological properties

DTG primarily metabolised via UGT1A1 with minor CYP3A4 component1,2

Renal elimination of unchanged DTG is low (<1% of dose)2

Plasma protein binding: ≥98.9%1

T1/2:13-15 hr

PROXIMAL RENAL TRANSPORTERS: EFFECT ON SERUM CREATININE

In addition to glomerular filtration, creatinine is

excreted into urine by active secretion (10–20%)

in the proximal renal tubules1

OCT2 on the basolateral membrane is

responsible for creatinine influx2

MATE1 on the apical membrane is responsible

for creatinine efflux2

DTG and RPV inhibit tubular secretion of

creatinine via inhibition of OCT23

Ritonavir and cobicistat inhibit tubular secretion

of creatinine via inhibition of MATE13

In vivo, DTG did not alter plasma concentrations

of TDF or PAH, substrates of OAT1 and OAT34

Creatinine

OAT1/3

OAT2

OATp4C1 MATE2/2K

MRP4

MRP2

BCRP

OCT

2MATE1MATE1

ApicalBasolateral

Blood Urine

Creatinine

Excretion

80–90%10–20%

Active

Tubular

Secretion

Glomerular

Filtration

Renal tubular call

1. Shemesh O et al. Kidney Int. 1985;28(5):830-838; 2. Sato T et al. Biochem Pharmacol.

2008;76(7):894-903; 3. Lepist EI, et al. 51st ICAAC 2011. Abstract A1-1724;

4. Tivicay US Prescribing Information. ViiV Healthcare, August 2015

IMPACT OF DTG ON CYP3A:STUDY WITH MDZ, A CYP3A SUBSTRATE1,2

16.3 15.4

0

5

10

15

20

GLS mean ratio (MDZ+DTG/MDZ alone): 0.945 (90% CI: 0.82–1.10)

Plasma MDZ AUC0–t was similar with MDZ + DTG 25 mg versus MDZ alone

Reduction in exposure of DTG with midazolam = 1–0.945 = 0.055 = 5.5%

AUC0–t, GLS m

ean

MDZ alone MDZ + DTG

DTG does not induce or inhibit the CYP3A isozyme in vivo

1. Min S, et al. Antimicrob Agents Chemother 2010;54:254–8

2. Min S, et al. IAS 2009. Abstract WEPEA099

PHARMACOKINETICS/PHARMACODINAMIC

A Phase IIIb study assessed the distribution of DTG in CSF3

DTG concentrations observed in CSF at both Week 2 and Week 16

exceeded the in-vitro IC50 against wild-type viruses (0.2 ng/mL)3 for all

subjects, suggesting that DTG was able to achieve therapeutic

concentrations in the CSF

DTG achieves suppressive concentrations (>IC50) in male4 and female5

genital tract.

No need for dose adjustment in patients with severe renal

impairment (CrCl<30ml/min).

No need for dose adjustment in patients with mild and moderate liver

impairment. (Child-Pugh A & B).

Tissue penetration / Patient Populations


2. Tivicay EU Summary of Product Characteristics, August 2015

3. Letendre S, et al. CROI 2013. Poster 178LB

4. Greener BN, et al. J Acquir Immune Defic Syndr 1999

5.Adams JL, et al. Antivir Ther. 2013

DTG DIFFERENTIATION VERSUS RAL:

MODELLING REPRESENTATIONSDTG1

Catalytic loop

1. Adapted from DeAnda F, et al. PLoS ONE 2013;8(10):e77448

2. Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552–9

Dissociation t1/2 (h) at 37° C2

Integrase DTG RAL

Wild type 71 8.8

N

ONN

H

O

O

OH

O

F

FH

N

OH

O

NH

O

N N

O

O

NH

FN

S/GSK1349572 RaltegravirDTG2 RAL2

DTG’s larger metal-chelating scaffold may more effectively delocalise positive charge when interacting with the metals1

DTG’s electron-deficient scaffold may interact favourably with the electron-rich A11

RAL’s oxadiazole proximity to Y143 at the top of the catalytic loop increases potential for mutations at Y143, Q148, and

N155 to disrupt binding1

Together, these properties may increase DTG binding affinity for integrase over RAL1

DTG DIFFERENTIATION VERSUS RAL:

MODELLING REPRESENTATIONSRAL1

Catalytic loop

Dissociation t1/2 (h) at 37° C2

Integrase DTG RAL

Wild type 71 8.8

N

ONN

H

O

O

OH

O

F

FH

N

OH

O

NH

O

N N

O

O

NH

FN

S/GSK1349572 RaltegravirDTG2 RAL2

DTG’s larger metal-chelating scaffold may more effectively delocalise positive charge when interacting with the metals1

DTG’s electron-deficient scaffold may interact favourably with the electron-rich A11

RAL’s oxadiazole proximity to Y143 at the top of the catalytic loop increases potential for mutations at Y143, Q148, and

N155 to disrupt binding1

Together, these properties may increase DTG binding affinity for integrase over RAL1

1. Adapted from DeAnda F, et al. PLoS ONE 2013;8(10):e77448

2. Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552–9

INI DISSOCIATION FROM WT INTEGRASE-DNA COMPLEX AT 37 C

Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9

INI koff (s-1)

Dissociation

t1/2 (h)

DTG 2.7 x 10-6 71

RAL 22 x 10-6 8.8

EVG 71 x 10-6 2.7

Koff , dissociation rate; t1/2h, half-life in hours

DTG dissociated more slowly from a WT IN-DNA complex at 37°C compared with RAL and EVG

DTG dissociation was eight times slower than RAL and 26 times slower than EVG

DTG

RAL

EVG

1.0

0.8

0.6

0.4

0.2

0.0

Relative binding

Time (h)

0 10 20 30 40 50 60

SUPPORTING DATA

DISSOCIATION T1/2 RATIO FOR DTG, RAL AND EVG BY INI-RELATED MUTATION

aND, not determined due to low signal with 3[H]EVG

DTG maintained

prolonged binding with

all IN mutants

The addition of a

second substitution to

either N155H or Q148

resulted in a decrease

in the dissociative t1/2

of DTG compared with

a single substitution

Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9

SUPPORTING DATA

DTG RAL EVG

INI-related

mutationt1/2 (h) at 37°°°°C

WT 71 8.8 2.7

E92Q 17 3.3 0.4

E138K 84 11 3.7

G140S 20 4.4 1.1

Y143C 60 2 2.1

Y143H 44 2.5 1.6

Y143R 42 1.1 1.7

Q148H 5.2 0.2 0.2

Q148K 11 0.3 NDa

Q148R 9.2 0.4 ND

N155H 9.6 0.6 0.4

E92Q/N155H 3.9 0.3 ND

E138K/Q148R 3.6 0.2 ND

G140S/Q148H 3.3 0.2 ND

EVG (56 days)1

T66I E92QT124A P145S Q148K Q148R

T66I/T124AT66K/T124AE92V/T124A

P145S/T124AQ146L/T124AQ148R/T124A

T66I/V72A/A128TT66I/E92Q/T124AT66I/T124A/Q146L

RAL (84 days)1,2

T124AQ148K*Q148R

E138K/Q148KE138K/Q148RG140S/Q148R

N17S/Q148K/G163RG140C/Q148K/G163RE138K/Q148K/G163R

E92Q/E138K/Q148K/M154IN155H/I204TV151I/N155H

T124A/V151I/N155H

DTG (112 days)2

T124AS153Y

T124A/S153YL101I/T124A/S153F

DTG (84 days)2

T124AS153Y

T124A/S153YL101I/T124A/S153F

DTG (56 days)2

T124AT124A/S153F

*Red text indicates substitutions seen in clinical trials

Maximum ~4 FC for DTG mutants selected in vitro

T124A and L101I are polymorphic and do not confer resistance to DTG or RAL

Preclinical data suggested DTG had potential for a higher barrier to resistance

FEWER SUBSTITUTIONS WERE DETECTED DURING PASSAGE WITH DTG COMPARED WITH RAL AND EVG

Adapted from: 1. Kobayashi M, et al. Antiviral Research 2008;80;213–22

2. Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21

SUBTYPE-SPECIFIC MUTATIONS SELECTED IN

VITRO WITH DOLUTEGRAVIR

HIV-1 subtypeMost common mutations selected with dolutegravir

B R263K, H51Y

C G118R, H51Y

Quashie, Mesplède et al., Journal of Virology, 2012

IN VITRO, MOST RAL- AND EVG-RESISTANT SINGLE MUTANTS WERE SUSCEPTIBLE TO DTG

Mean FC IC50

Viruses DTG RAL EVG

WT1,2 1 1 1

T66A1,2 0.26 0.61 4.1

T66I1,2 0.26 0.51 8.0

T66K1,2 2.3 9.6 84

E92I1,2 1.5 2.1 8.0

E92Q1,2 1.6 3.5 19

E92V1,2 1.3 1.4 8.3

G118S1,2 1.1 1.2 4.9

F121Y1,2 0.81 6.1 36

T124A1,2 0.95 0.82 1.2

E138K1,2 0.97 1 0.93

G140S1,2 0.86 1.1 2.7

Y143C1,2 0.95 3.2 1.5

Y143H1,2 0.89 1.8 1.5

Mean FC IC50

Viruses DTG RAL EVG

Y143R1,2 1.4 16 1.8

P145S1,2 0.49 0.87 >350

Q146R1,2 1.6 1.2 2.8

Q148H1,2 0.97 13 7.3

Q148K1,2 1.1 83 >1700

Q148R1,2 1.2 47 240

I151L1,2 3.6 8.4 29

S153F1,2 1.6 1.3 2.8

S153Y1,2 2.5 1.3 2.3

M154I ,2 0.93 0.82 1.1

N155H1,2 1.2 11 25

N155S1,2 1.4 6.2 68

N155T1,2 1.9 5.2 39

G193E2 1.3 1.3 1.3

RAL and EVG-related single mutation SDMs

(site directed mutants)

Adapted from :1. Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21

2. Seki T, et al. CROI 2010. Abstract 555

3 ≤ FC IC50 < 5 5 ≤ FC IC50 < 10 10 ≤ FC IC50

IN VITRO, MOST RAL- AND EVG-RESISTANT MULTIPLE MUTANTS WERE SUSCEPTIBLE TO

DTG

Adapted from Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21

Mean FC IC50

Viruses DTG RAL EVG

WT 1 1 1

T66I/L74M 0.35 2.0 14

T66I/E92Q 1.2 18 190

T66K/L74M 3.5 40 120

L74M/N155H 0.91 28 42

E92Q/N155H 2.5 >130 320

T97A/N155H 1.1 26 37

L101I/S153F 2.0 1.3 2.6

F121Y/T125K 0.98 11 34

E138A/Q148R 2.6 110 260

E138K/Q148H 0.89 17 6.7

E138K/Q148K 19 330 371

E138K/Q148R 4.0 110 460

Mean FC IC50

Viruses DTG RAL EVG

G140C/Q148R 4.9 200 485

G140S/Q148H 2.6 >130 >890

G140S/Q148K 1.5 3.7 94

G140S/Q148R 8.4 200 267

Y143H/N155H 1.7 38 16

Q148R/N155H 10 >140 390

N155H/G163K 1.4 23 35

N155H/G163R 1.1 17 35

N155H/D232N 1.4 20 36

V72I/F121Y/T125K 1.3 13 58

L101I/T124A/S153F 1.9 1.4 2.0

E138A/S147G/Q148R 1.9 27 130

V72I/F121Y/T125K/I151V 1.2 7.0 37

RAL and EVG-related single mutation SDMs

(site directed mutants)

3 ≤ FC IC50 < 5 5 ≤ FC IC50 < 10 10 ≤ FC IC50

DOSE-DEPENDENCY OF DTG EXPOSURE AND HALF-LIFE IN HEALTHY VOLUNTEERS

Single-dose study Multiple-dose (10 day) study

• t1/2 was 13–15 hours following single administration of DTG

• DTG was still detectable in plasma up to 72 hours after single dosing

• Tmax was 0.5–3 hours in both studies

0 10 20

Time (hours)

10

1

0.1

0.01

DTG plasma concentration (µg/mL)

0.00130 40 50 60 70 80 0 5 10

Time (hours)

100

10

1

0.1

DTG plasma concentration (µg/mL)

0.0115 20 25

100 mg

50 mg

25 mg

10 mg

5 mg

2 mg

PA-IC900.064 µg/mL

PA-IC90 0.064 µg/mL

50 mg QD

25 mg QD

10 mg QD

24hrs

Adapted from Min S, et al.

J Antimicrob Chemother 2010;54:254–8

ING111521: STUDY DESIGN

Adapted from Min S, et al. AIDS 2011;25:1737–45

Phase IIa multicentre, randomised, placebo-controlled, double-blind,*

parallel-group, dose-ranging study of DTG monotherapy

Primary endpoint: change from baseline in HIV-1 RNA on Day 11

*Subjects blinded within cohort to active versus placebo

• INI-naïve, treatment-

naïve or experienced

• CD4 cell count

≥100 cells/mm3

• HIV-1 RNA ≥5,000 c/mL

• No HIV treatment for

12 weeks

Randomisation

(Day 1)

Screening visit End of treatment

(Day 10)

Follow-up

(Day 21)

DTG 50 mg (N=10)

DTG 10 mg (N=9)

DTG 2 mg (N=9)

Placebo (N=7)

Follow-up

(11 days)

CHANGE IN HIV-1 RNA FROM BASELINE WITH DTG MONOTHERAPY (ING111521)

Min S, et al. AIDS 2011;25:1737–45

0.5

–0.5

–2.0

2 3 4 7 8 9 10 11 14 21

(follow-up)Day

0

–1.0

–1.5

–2.5

1

(BL)

Mean change from BL in HIV-1 RNA (log 10c/mL)

Dosing period Follow-up period

2 mg

10 mg

50 mg

Placebo

CHANGE IN HIV-1 RNA FROM BASELINE WITH DTG AND OTHER ARV MONOTHERAPIES

Adapted from Lalezari J, et al. IAS 2009. Abstract TUAB105

–2.03

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0

Change from BL in HIV-1 RNA (log 10)

50 mg QD + RTV

900 mg BID

100 mg BID

100 mg BID

400 mg BID + RTV

300 mg BID

300 mg BID

–1.7

–1.99–1.96 –1.85

–1.42

–1.19

–0.52

50 mg QD

400 mg BID

INIs OTHER ARVs

–2.46

It should be noted that there are inherent limitations of comparing data

across trials. Head-to-head studies with DTG have not been conducted.

Doses may differ from approved dose

RELATIONSHIP BETWEEN DTG TROUGH CONCENTRATION AND VIRAL LOAD REDUCTION

DTG is associated with a well characterised, predictable

exposure-response relationship

Phase IIa, dose-ranging, placebo-controlled, 10-day monotherapy study

Placebo

2 mg QD

10 mg QD

50 mg QD

Model fit: Emax = –2.6, IC50 – 0.036 µg/mL

Cτ (µg/mL)

Day 11 log 10viral load change from baseline –3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0

0.5

1.0

0 0.4 0.6 0.8 1.0 1.4

Subjects with HIV-1 RNA

<50 c/mL are represented

by orange-bordered circles

Open circles with lines

denote mean SD

0.2 1.2

Adapted from Min S, et al. AIDS 2011;25:1737–45

DOSE-DEPENDENCY OF DTG EXPOSURE AND HALF-LIFE IN SUBJECTS WITH HIV

Phase IIa, dose-ranging, placebo-controlled, monotherapy study: Day 10 sampling1,2

Once-daily

dose

Cmax

(µg/mL)

AUC0–ττττ

(µg��h/mL)

Cττττ

(µg/mL)IQ*

2 mg1,2 0.22 (25) 2.56 (29) 0.04 (50) 0.6

10 mg1,2 0.80 (23) 10.1 (20) 0.19 (25) 3

50 mg1,2 3.34 (16) 43.4 (20) 0.83 (26) 13

Values shown are geometric means (CV%)

• PK variability was low-to-moderate (CV 25–50%)1,2

• Median Tmax was 1.5–2.5 hours and mean t1/2 was 11–12 hours after multiple doses1

0 5

Time (hours)

10

1

0.1

DTG concentration (µg/mL)

0.0110 15 20 25

50 mg QD2

10 mg QD2

2 mg QD2


*IQ is defined as Cτ/PA–IC90

1. Adapted from Min S, et al. AIDS 2011;25:1737–45

2. Adapted from Song I, et al.

IAS 2009. Abstract WEPEB250

SPRING-1: CONFIRMATION OF DOSE DEPENDENCY FOR DTG EXPOSUREDTG PK parameters at Week 2 by dose in the SPRING-1 Phase IIb trial1,2

Once-daily

dose

Cmax

(µg/mL)

AUC0–ττττ

(µg��h/mL)

Cττττ

(µg/mL)IQ*

10 mg1,2 1.10 (37) 16.0 (40) 0.30 (71) 4.7

25 mg1,2 1.71 (43) 23.1 (48) 0.54 (67) 8.4

50 mg1,2 3.40 (27) 48.1 (40) 1.20 (62) 19

• DTG showed low-to-moderate PK variability1,2

• All drug levels were well above the in-vitro PA-IC90 of 0.064 µg/mL1,2

Values shown are geometric means (CV%)0 5

Post-dose time (hours)

10

1

Mean DTG concentration (µg/mL)

0.1

10 15 20 25

10 mg QD2

25 mg QD2

50 mg QD2


*Inhibitory quotient is defined as Cτ/PA–IC90

1. Adapted from van Lunzen J, et al. Lancet Infect Dis 2012;12:111–8

2. Adapted from Rockstroh J, et al. HIV10 2010. Abstract O50

RATIONALE FOR BOUNDARIES OF CLINICALLY SIGNIFICANT ALTERATIONS IN DTG EXPOSURE

SPRING-1: Phase IIb, dose-ranging study in INI-naïve subjects1–3

Once-daily

doseN2,3

HIV-1 RNA

<50 c/mL at

Week 96 (%)2,3

Cττττ

(µg/mL)1,3IQ*,1,3

EFV 600 mg 50 72 – –

DTG 10 mg 53 79 0.30 (71) 4.7

DTG 25 mg 51 78 0.54 (67) 8.4

DTG 50 mg 51 88 1.20 (62) 19

Lower boundary: in SPRING-1, a 75% reduction in DTG Cττττwith DTG 10 mg vs 50 mg QD (from 1.20 to 0.30) was not

deemed clinically significant based on efficacy at Week 96 and IQ3

Upper boundary (toxicity): no dose-limiting toxicities identified3

Cτvalues are geometric means (CV%) at Week 20 5

Post-dose time (hours)

10

1

Mean DTG concentration (µg/mL)

0.1

10 15 20 25

10 mg QD3

25 mg QD3

50 mg QD3


*Inhibitory quotient is defined as Cτ/PA-IC90

1. Adapted from van Lunzen J, et al. Lancet Infect Dis 2012;12:111–8

2. Adapted from Stellbrink H-J, et al. CROI 2012. Abstract 102LB

3. Adapted from Song I, et al. IWCP 2012. Abstract O07

1

10

100

1000

10000

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 208 216

Drug plasma concentrations up to 216h post dose

DTG (GM)

EVG (GM)

COBI (GM)

Time (h)

[Dru

g]

(ng

/mL)

Elliiot E, et al. 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. Washington DC. Abstract 13.

EVG plasma concentrations over time

Time (h)

45 ng/mL

1

10

100

1000

10000

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 208 216

48 h: GM 8.3 ng/ml (range from <LLQ-21.7 , 16/17 detectable but all below IC95)

36 h: GM 57 ng/ml (range from 11 to 296, above IC95 in 11/17)

EVG (GM 90%CI)

60 h: GM 2.5 ng/ml (range from LLQ to 8.4, 13/17 detectable but all below IC95)

72 h: GM 1.7 ng/ml (range from LLQ to 2.9, 9/17 detectable but all below IC95)

[EV

G]

(ng

/mL)

24 h: GM 419 ng/ml (range from 182 to 666, all above IC95)


1

10

100

1000

10000

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 208 216

DTG plasma concentrations over time

Time (h)

64 ng/mL

DTG (GM 90%CI)

96 h: GM 52.2ng/ml (range 6.9-153.0, above IC90 in 4/17)

[DT

G]

(ng

/mL)

72 h: GM 131 ng/ml (range 20-367, above IC90 in 16/17)

60 h: GM 240ng/ml (range 49-532, above IC90 in 16/17)

48 h: GM 427 ng/ml (range 109-791, all above IC90)

36 h: GM 711 ng/ml (range 230 to 1182, all above IC90)

24 h: GM 1324 ng/ml (range 624 to 1970, all above IC90)


• DTG showed low-to-moderate PK variability1,2

• All drug levels were well above the in vitro

PA-IC90 of 0.064 µg/mL1

Dose–exposure relationship for DTG and

residency time at receptor site

Values shown are geometric means (CV%).

AUC 0-τ, area under the curve from time zero to last dosing interval; Cmax, maximum serum concentration; Cτ, concentration at the end of the dosing

interval; CV%, coefficient of variation; DTG, dolutegravir; EVG, elvitegravir; INI, integrase inhibitor; IQ, inhibitory quotient (Cτ/PA–IC90); Koff, dissociation

rate; OD, once-daily; PA-IC90, protein-adjusted 90% inhibitory concentration; PK, pharmacokinetic; RAL, raltegravir; t½, half-life in hours; WT, wild type.

1. Adapted from van Lunzen J, et al. Lancet Infect Dis 2012;12:111–8; 2. Rockstroh J, et al. HIV10 2010. Abstract O50; 3. Adapted from Hightower KE,

et al. Antimicrob Agents Chemother 2011;55:4552–9.

INI koff (s-1

) t½ res (h)

DTG 2.7 x 10-6 71

RAL 22 x 10-6 8.8

EVG 71 x 10-6 2.7

OD dose

Cmax

(μg/mL)

AUC0–ττττ

(µg.h/mL)

Cττττ

(µg/mL) IQ

50 mg1

3.40 (27%)48.1

(40%)1.20 (62%) 19

• DTG dissociated more slowly from a WT INI-DNA

complex at 37 C compared with RAL and EVG3

• DTG dissociation was 8 times longer than RAL and

26 times longer than EVG3

AGENDA






Summary

DTG TRIALS IN TREATMENT-EXPERIENCED ADULT SUBJECTS WITH HIV

Phase III, open-label, single-arm, multicentre study of:

• DTG (50 mg BID) + OBR (not incl. RAL)

VIKING-33

INI-resistantN=183

Phase III, randomised, double-blind, active-controlled, parallel group,

non-inferiority, multicentre study of:

• DTG (50 mg QD) + BR

• RAL (400 mg BID) + BR

SAILING1

INI-naïveN=719

Phase IIb open-label, single-arm multicentre study

(Cohort I) of:

• DTG 50 mg QD + OBR (not incl. RAL)

VIKING2

(Cohort I)INI-resistant

N=27

Phase IIb open-label, single arm multicentre study (Cohort II) of:


• Subjects required to have ≥1 fully active ARV for

Day 11 optimisation (not required for Cohort I)

VIKING2

(Cohort II)INI-resistant

N=24

Phase III, open-label, placebo-controlled, multicentre study of:

• DTG 50 mg BID vs placebo (both plus current failing regimen)

• At Day 8, all subjects received DTG (50 mg BID) + OBR (containing

≥1 fully active ARV)

VIKING-44

INI-resistantN=30

1. Cahn P, et al. Lancet 2013;382:700–8; 2. Eron JJ, et al. J Infect Dis 2013;207:740–8

3. Castagna A, et al. J Infect Dis 2014;210:354–62

4. Akil B, et al. Antivir Ther 2015;20:343–8

VIKING (Cohort II; N=24)DTG 50 mg BID + OBR (not incl. RAL)

≥1 fully active ART for Day 11 optimisation

Results formed rationale for regimen of DTG to

be used in VIKING-3

VIKING (Cohort I; N=27)DTG 50 mg QD + OBR (not incl. RAL)

Results formed rationale for regimen of DTG to

be used in VIKING Cohort II and VIKING-3

VIKING (COHORTS I AND II): INVESTIGATING THE DOSE OF DTG IN RAL-RESISTANT SUBJECTS

VIKING (study number: ING112961)Adult subjects with HIV-1

Current or historic RAL failures with evidence of RAL resistance

Resistance to ≥2 other ART classes

ART optimised on Day 11 (OBR)

Efficacy and safety of DTG assessed at Week 24

Eron J, et al. J Infect Dis 2013;207:740–8

VIKING (COHORTS I AND II): STUDY DESIGN

Q148H/K/R + ≥1

secondary

resistance

mutations*

All other mutations

(including codon

148 single

mutation)†

Functional monotherapy phase

(replace RAL with DTG or add

DTG if RAL already stopped)

Continuation phase

(DTG + OBR)

In both cohorts,

subjects were

allocated to one

of two groups

based on

genotype at

screening to

ensure broad

sensitivity

range Day 1 Week 24Day 11

*Q148H/K/R plus changes in L74 and/or E138 and/or G140†N155H and Y143H pathways or Q148H/K/R single mutants Adapted from Eron J, et al. J Infect Dis 2013;207:740–8

VIROLOGIC RESPONSE ON DAY 11

78%1,2

96%1,2

33%2

100%2

0

20

40

60

80

100

Responders (%)

Cohort I(DTG 50 mg QD)

Cohort II (DTG 50 mg BID)

23/24

3/9

21/27

11/11

Achieved plasma

HIV-1 RNA <400 c/mL or

>0.7 log10 c/mL decline

at Day 11 (primary endpoint)

Responders with HIV with Q148

+ secondary mutations*

*Q148H/K/R + ≥1 Q148 associated mutations at L74, E138 or G140

1. Eron J, et al. J Infect Dis 2013;207:740–8

2. Eron J, et al. CROI 2011. Abstract 151LB

CORRELATION BETWEEN BASELINE SUSCEPTIBILITY TO DTG AND VIROLOGIC RESPONSE AT DAY 11

Q148 + 1Q148 + 2

MixtureN155 Other integrase mutations

Y143

Change from baseline

in HIV-1 RNA

Baseline DTG FC in IC50 relative to WT virus

0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

0

–0.5

–1.0

–1.5

–2.0

–2.5

–3.0

0.5 1 2 4 8 16 32

Change from baseline

in HIV-1 RNA

0.5 1 2 4 8 16 32

Baseline DTG FC in IC50 relative to WT virus

DTG 50 mg QD

DTG 50 mg BID

Adapted from Eron J, et al. CROI 2011. Abstract 151LB


41%

75%

52%

83%

0

20

40

60

80

100

Responders (%)

Cohort I(DTG 50 mg QD)

Cohort II (DTG 50 mg BID)18/24

14/27

11/27

20/24

<50 c/mL* <400 c/mL*

*TLOVR analysis

Note that a higher proportion of subjects in Cohort I versus Cohort II had an

optimised background PSS of 0: 67% versus 63%, respectively Eron J, et al. J Infect Dis 2013;207:740–8

VIKING-3: STUDY DESIGN (N=183)

OSS, overall susceptibility score, determined

by Monogram Biosciences net assessment

Main eligibility criteria:• HIV-1 RNA ≥500 c/mL

• Screening or documented historic

evidence of resistance to RAL

and/or EVG, and resistance to ≥2

ARV classes other than INIs

DTG 50 mg BID

+

OBR with OSS ≥1

DTG 50 mg BID

and continue

failing ART

regimen

Screening period

up to a maximum of 42 days

Functional

monotherapy phase

Screening visit ~Day -35 Day 1 Day 8 Week 24

analysis

Optimised phase

Week 48

analysis

Adapted from: Castagna A, et al. J Infect Dis 2014;210:354–62

VIROLOGIC RESPONSE (HIV-1 RNA <50 C/ML) AT WEEK 24 AND WEEK 48 (SNAPSHOT, ITT-E)

At Week 24,135/183 (74%) achieved HIV-1 RNA <400 c/mL3

At Week 48,125/183 (68%) achieved HIV-1 RNA <400 c/mL3

116/1833

(63%)

BLD8 4 8 12 2416 32 40 48

126/1831

(69%)

Subjects with

HIV-1 RNA <50 c/mL(%)

0

10

40

50

70

80

30

20

60

90

100

At Week 24, 126/183 (69%) were fully suppressed1

At Week 48, 116/183 (63%) were fully suppressed2

(HIV-1 RNA <50 c/mL) by Snapshot algorithm

Week

Day 8 efficacy: DTG was associated with significant reductions from baseline in HIV-1 RNA:

change from baseline: −1.43 log10 c/mL HIV-1 RNA (95% CI: −1.52 to −1.34; p<0.001)1,2

1. Adapted from Castagna A, et al. J Infect Dis 2014;210:354–62

2. Nichols G, et al. IAS 2013. Abstract TULBPE19; 3 Vavro CL, et al. EUDRW 2014. Abstract 0_10

DAY 8 AND WEEK 24 VIROLOGIC RESPONSE BY DERIVED MUTATIONAL GROUP

Day 8 response1Week 24

response1

IN mutation group N

Median decline in HIV-1 RNA

(log10 c/mL)

Full response,a

N (%) N<50 c/mL,

N (%)

No Q148 122 -1.65 112 (92%) 72 57 (79%)

Q148 + 1b 35 -1.10 25 (71%) 20 9 (45%)

Q148 + ≥2b 20 -0.74 9 (45%) 9 1 (11%)

Adapted from Vavro C, et al. IDRW 2013. Abstract 29aFull response: decline in HIV-1 RNA >1 log10 c/mL or <50 c/mL at Day 8bL74I, E138A/K/T and G140A/C/S

WEEK 24 AND WEEK 48 RESPONSE BY BASELINE INTEGRASE MUTATIONS*

Derived IN mutation group at BL N

HIV-1 RNA<50 c/mL

at Week 24,1 %

HIV-1 RNA<50 c/mL

at Week 48,2 %Total 183 69 63

No Q148 126 79 71

Q148 + 1 secondary mutation† 36 58 56

Q148 + ≥2 secondary mutations† 20 24 29

Adapted from:


2. Vavro CL, et al. EUDRW 2014. Abstract 0_10

*ITT-E, Snapshot algorithm†Key secondary mutations were G140A/C/S, L74I and E138A/K/T‡5 subjects became responders and 15 stopped being responders after Week 24;

4/15 subjects had HIV-1 RNA >50 c/mL at Week 48 and non-compliance; 11/15

subjects re-supressed after Week 48, discontinued for non-compliance, withdrew

consent while suppressed, or changed background ART while suppressed

Antiviral response was sustained through Week 482

Difference in response rates between Week 24 and Week 48 was primarily for non-virologic

reasons2‡

4/4(100%)

35/40(88%) 57/70

(81%)

96/114(84%)

2/2(100%)

8/12(67%) 10/17

(59%)

20/31(65%)

1/2(50%)

2/11(18%)

1/3(33%) 4/16

(25%)

0

20

40

60

80

100

OSS=0 OSS=1 OSS ≥2 Total

No Q148

Q148 + 1

Q148 + ≥2

WEEK 24 RESPONSE BY MUTATION CATEGORY AND OBR OSS

*Virus from the ≥2 primary mutations group was re-categorised to the Q148+ or No Q148 groups as appropriate; †Y143, N155, T66,

E92 or historical resistance evidence only; ‡G140A/C/S, E138A/K/T and L74I; FDA snapshot analysis; virologic outcome population

(N=161) used for baseline resistance analysis to minimise confounding factors of antiviral response

OBR PSS, optimised background regimen phenotypic sensitivity score:

sum of the phenotypic sensitivities of all the drugs in the OBR where 1 = sensitive, 0 = resistant

Su

bje

cts

wit

h H

IV-1

RN

A<

50 c

/mL

at

Wee

k 24

(%

)

*, †

*, ‡

*, ‡

Adapted from

Nichols G, et al. IAS 2013. Abstract TULBPE19

98/120(82%)

14/25(56%)

1/9(11%)

120/161(75%)

0

20

40

60

80

100

≤4 >4 to 10 >10 Total

WEEK 24 RESPONSE BY BASELINEDTG FC IC50 CATEGORY

*Virologic outcome population (N=161) used for baseline resistance

analysis to minimise confounding factors of antiviral response

Subjects with HIV-1 RNA

<50 c/mL at Week 24 (%)*1

1. Adapted from Nichols G, et al. IAS 2013. Abstract TULBPE19

2. Vavro C, et al. IDRW 2013. Abstract 29

DTG FC IC50 at baseline

• In a separate analysis to estimate DTG phenotypic cut-offs, DTG FCs in IC50 of <9.45, 9.45 to <25.99 and >25.99 were estimated as full, intermediate and no response cut-offs, respectively2

• 87% of subjects with baseline DTG FC IC50 <9.45 achieved full response at Day 8, and 69% of subjects with baseline DTG FC IC50 <9.45 had <50 c/mL at Week 24

2

• However, univariate response by baseline DTG phenotype grouping does not account for other factors and is not meant to represent definitive clinical susceptibility breakpoints for DTG1

PROTOCOL-DEFINED VIROLOGIC FAILURE

Cumulative number of PDVF*

DTG 50 mg BID

(N=183)

at Week 24, n (%)

DTG 50 mg BID

(N=183)

at Week 48, n (%)

All PDVF 36 (20) 41 (22)

Virologic non-response 21 (11) 21 (11)

Rebound 15 (8) 20 (11)

Five (2%) subjects experienced PDVF between Week 24 and Week 48

Four additional subjects met PDVF post-Week 48 (open-label extension phase): at Week 60

(n=2), 72 and 84

All subjects with PDVF were evaluated for treatment-emergent resistance (n=45)

*PDVF was defined as any HIV-1 RNA value >400 c/mL and meeting following criteria:

<0.5 log10 decrease at Day 8, confirmed decrease of <1 log10 c/mL by Week 16, confirmed

400 c/mL on or after Week 24, confirmed 400 c/mL after prior confirmed <400 c/mL or

confirmed >1 log10 c/mL above a nadir of 400 c/mL

Adapted from

Vavro CL, et al. EUDRW 2014. Abstract O_10

BASELINE INTEGRASE MUTATION CATEGORY OVERALL AND IN SUBJECTS WITH PDVF

ITT-E (N=183), n (%)

Subjects with PDVF (N=45), n (%)

Integrase mutation category Baseline PDVF

Q148 + ≥2 21 (11) 13 (29)

Q148 + 1 32 (17) 9 (20)

≥2 primary mutations 8 (4)* 2 (4)†

Y143 28 (15) 4 (9)

N155 33 (18) 4 (9)

T66 1 (<1) -

Primary not detected 60 (33) 13 (29)‡

67% (30/45) of subjects who met criteria for PDVF had Q148 mutations at baseline or

historically

*4 subjects with Q148 with T66 or Y143 mutations

†2 subjects with Q148 with Y143 or T66 mutations

‡6 subjects with only screening or historic evidence of Q148 mutations but not present at baseline Adapted from Vavro CL, et al. EUDRW 2014. Abstract 0_10

TREATMENT-EMERGENT MUTATIONS IN SUBJECTS WITH Q148 VIRUS PATHWAY

AT BASELINE OR HISTORIC*

Q148 + 1

N=7

Q148 + ≥2

N=6

Historic*

Q148

N=5

Q148H + G140S

Q148H + G140S + E138T/K/A

Q148H + G140S + E157Q

Q148H

Q148H + G140S + E138T/A + G193E

Q148H + G140G/S + E138E/K + T97T/A + E92E/Q

Q148H + G140S + E138A + T97T/A

Q148Q/H + G140S + E138E/K

Q148Q/H + G140S + N155H

Q148H + G140S + E138A + T97T/A

DTG Treatm

ent

Q148H + G140S + E138K

Q148H + G140S + E138K + E92E/Q

Q148H + G140S + E138E/A + T97A

Q148H + G140S + E138K + T97A

Q148H + G140S + E138T/K/A + E157E/Q

Q148H + G140S + E157Q + N155H

Q148Q/R/K + G140A + E138A + G193E

Q148H + G140S + E138T + T97A

Q148Q/H + G140G/S + E138T/A + G193E + L74L/M +

T97T/A

Q148H + G140S + E138T + N155H

Q148H + G140S + T97T/A (n=3)

Emergent mutations shown in bold

*Historic includes subjects with screening Q148 but not at baseline Vavro CL, et al. EUDRW 2014. Abstract O_10

DTG TRIALS IN TREATMENT-EXPERIENCED ADULT SUBJECTS WITH HIV

Phase III, open-label, single-arm, multicentre study of:


VIKING-33

INI-resistantN=183

Phase III, randomised, double-blind, active-controlled, parallel group,

non-inferiority, multicentre study of:

• DTG (50 mg QD) + BR

• RAL (400 mg BID) + BR

SAILING1

INI-naïveN=719

Phase IIb open-label, single-arm multicentre study

(Cohort I) of:

• DTG 50 mg QD + OBR (not incl. RAL)

VIKING2

(Cohort I)INI-resistant

N=27

Phase IIb open-label, single arm multicentre study (Cohort II) of:


• Subjects required to have ≥1 fully active ARV for

Day 11 optimisation (not required for Cohort I)

VIKING2

(Cohort II)INI-resistant

N=24

Phase III, open-label, placebo-controlled, multicentre study of:

• DTG 50 mg BID vs placebo (both plus current failing regimen)

• At Day 8, all subjects received DTG (50 mg BID) + OBR (containing

≥1 fully active ARV)

VIKING-44

INI-resistantN=30

1. Cahn P, et al. Lancet 2013;382:700–8; 2. Eron JJ, et al. J Infect Dis 2013;207:740–8


4. Akil B, et al. Antivir Ther 2015;20:343–8

MINOR VARIANTS IN HIV-1 INTEGRASEFOR SUBJECTS WITH ONLY HISTORICAL

EVIDENCE OF INI RESISTANCEBaseline samples with no primary INI mutation present were tested using 454 sequencing and

a detection threshold of 0.5%. Data were obtained for 52/60 baseline samples tested; these 52

had a median HIV-1 RNA of 4.46 log10 c/mL

Their documented historic resistance was as follows: N155H (N=17), Q148H/R (N=17),

Y143H/R (N=3), E92Q (N=2), RAL FC >1.5 (N=13)

10%Primary

INI Mutations

38%Only

Secondary INI

Mutations

52%No

Detection

Minor Variants Detected(N=52)

Time on RAL

(years)

Time off RAL

(years)

Overall 1.9 1.4

Primary or

secondary

mutations (A)

2.6 <1

No mutations (B) 1.7 1.7

P value (A vs B) 0.0084 0.0005

Adapted from Paredes R, et al. IDRW 2014. Abstract 15

DETECTION OF MINOR VARIANTS AT BASELINE FOR SUBJECTS EXPERIENCING PDVF*

N

Minor variant detection at

baseline, n/N (%)

Relative risk of VF

(95% CI)

Total 52 25/52 (48%) -

PDVF 12 8/12 (66%) RR = 2.16 (0.7, 6.3)

No PDVF 40 17/40 (43%) RR = 0.80 (0.6, 1.1)

There was no significant association between minor variants detected at baseline and PDVF

(p value = 0.193)

For the 12 subjects with PDVF and with minor variant detection at baseline:

2 had INI primary mutations

6 had INI secondary mutations only

*Subjects with evidence of historical INI resistance and baseline minor variant data available Adapted from Paredes R, et al. IDRW 2014. Abstract 15

DAY 8 RESPONSE BY BASELINE INI MUTATIONS: VIKING-4 AND VIKING-3 COMPARISON

Baseline INI mutation group

VIKING-4DTG 50 mg BID

VIKING-4PLACEBO

VIKING-3DTG 50 mg BID

n Meana (SE) n Meana (SE) n Mean

Overall 13b -1.06 (0.17) 16 -0.03 (0.26) 182 -1.43 (0.61)

n Mean (SD) n Mean (SD) n Mean (SD)

No Q148 5 -1.43 (0.75) 9 -0.03 (0.33) 126 -1.59 (0.51)

N155 2 -1.13 (0.97) 4 0.11 (0.36) 33 -1.43 (0.51)

Y143 2 -1.74 (0.95) 4 -0.01 (0.10) 28 -1.70 (0.42)

Q148 + 1c 6 -0.87 (0.59) 6 -0.05 (0.18) 36 -1.15 (0.54)

Q148 + ≥2c 3 -0.90 (0.76) 1 0.09 20 -0.92 (0.81)

Adapted from: Akil B, et al. EACS 2013. Abstract PE7/3

Akil B et al. Antivir Ther in press (doi: 10.3851/IMP2878)

aMean adjusted baseline plasma HIV-1 RNA, baseline DTG FC in IC50, OSS of failing regimen and the interaction between DTG FC in IC50 and

treatment. bOne out of 14 subjects in the DTG 50 mg BID arm had no result for baseline DTG FC in IC50 and was excluded from the calculation of the

mean adjusted change from baseline in plasma HIV-1 RNA. cG140A/C/S, E138A/K/T, L74I

As in VIKING-3, baseline INI mutations impacted on DTG antiviral response in VIKING-4

SAILING: PHASE III TRIAL IN TREATMENT-EXPERIENCED, INI-NAÏVE SUBJECTS

Primary endpoint: proportion of subjects with HIV-1 RNA <50 c/mL at Week 48

DTG 50 mg QD plus

background regimen

(N=354)

RAL 400 mg BID plus

background regimen

(N=361)

• ARV-experienced,

INI-naïve adults

• HIV-1 RNA ≥400 c/mL*

• Resistance to ≥2 classes of

ARVs (not incl. INIs)

• Stratified by HIV-1 RNA (≤ or

>50,000), DRV/r use and no. of

fully active drugs for

background

Screening period Randomised phase

Randomisation (Day 1) Interim analysis

Week 24

Analysis Week 48 Screening Visit

*With 2 consecutive HIV-1 RNA ≥400 c/mL, unless screening HIV-1 RNA >1,000 c/mL Cahn P, et al. Lancet 2013;382:700–8

BASELINE CHARACTERISTICSDTG 50 mg QD

(N=354)

RAL 400 mg BID

(N=361)

Age, median (years) 42 43

Gender, female 30% 34%

Race

White 49% 48%

African American or African heritage 40% 44%

HIV-1 RNA, median (log10 c/mL) 4.17 4.21

>50,000 c/mL 30% 30%

CD4+ count, median (cells/mm3) 205 193

HBV coinfection 5% 4%

HCV coinfection 9% 13%

Duration prior ART, median (months) 80 72

≥3 class resistance 47% 51%

Most common background regimens, n (%)

DRV/r, TDF 62 (18) 73 (20)

LPV/r, TDF 40 (11) 40 (11)

DRV/r, ETR 33 (9) 40 (11)

LPV/r 36 (10) 35 (10)

ATV/r, TDF 37 (10) 33 (9)

DRV/r, MVC 23 (6) 19 (5)

Adapted from Cahn P, et al. Lancet 2013;382:700–8

SUBJECT ACCOUNTABILITYSubjects screened

N=1441 Not randomised

N=717

Randomised phase Subjects randomised

N=724

Subjects randomised

to DTG 50 mg QD

N=360

Subjects randomised

to RAL 400 mg BID

N=364

Not treated

N=3

Treated

N=357

Subjects excluded at

site 083523

N=3

Treated

N=362

Not treated

N=2

Subjects excluded at

site 083523

N=1

Completion status at Week 48

299 (84%) completed

55 (16%) withdrew

4 adverse event

20 lack of efficacy

9 protocol deviation

5 stopping criteria

5 lost to follow-up

1 investigator discretion

11 withdrew consent

Completion status at Week 48

283 (78%) completed

78 (22%) withdrew

11 adverse event

42 lack of efficacy

6 protocol deviation

3 stopping criteria

10 lost to follow-up

1 investigator discretion

5 withdrew consent

mITT-E

N=354

mITT-E

N=361

mITT-E, modified intent-to-treat exposed analysis (primary analysis) Adapted from Cahn P, et al. Lancet 2013;382:700–8

PROPORTION OF SUBJECTS WITH HIV-1 RNA <50 C/ML (SNAPSHOT*)

Mean (SD) CD4+ change from baseline to Week 48 was similar between arms: DTG: +162 (151) cells/mm3;

RAL: +153 (144) cells/mm3

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

RAL (N=361): 64%

Week 48 adjusted difference† in response (95% CI):

+7.4 in favour of DTG (0.7%, 14.2%); P=0.03Proportion achieving


Week

DTG (N=354): 71%

Baseline 4 8 12 16 24 32 40 48

0

10

40

50

70

80

30

100

20

60

90

DTG 50 mg QD

RAL 400 mg BID

*Analysis based on all subjects randomised who received ≥1 dose of study drug, excluding

four subjects at one site with violations of good clinical practice; SD, standard deviation†Adjusted difference based on stratified analysis adjusting for BL 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)

Adapted from Cahn P, et al.

Lancet 2013;382:700–8

SAILING: Additional week 48 Efficacy

Analyses (Snapshot)

n/N (%)DTG 50 mg OD

(n=354)

RAL 400 mg BD

(n=361)

HIV-1 RNA <50 c/mL, n (%) 251 (71) 230 (64)

Virologic non-respondera 71 (20) 100 (28)

No virologic data at Week 48b 32 (9) 31 (9)

Per protocol, HIV-1 RNA <50 c/mL 238/325 (73) 225/340 (66)

Adjusted difference, % (95% confidence interval) 7.5% (0.6, 14.3)

a HIV-1 RNA not <50 c/mL in window; discontinued for lack of efficacy; discontinued for other reason while not <50 c/mL; change in ARTb Discontinued due to AE, death or for other reasons unrelated to safety; missing data but still on study

Adapted from Cahn P et al. Lancet

2013;382(9893):700-708

SAILING: Percentage of Subjects With

HIV-1 RNA <50 c/mL by baseline viral load

75

62

71

47

0

10

20

30

40

50

60

70

80

90

100

≤50,000 >50,000

Baseline plasma HIV-1 RNA, c/mL

RAL 400 mg BD (n=361)

DTG 50 mg OD (n=354)

186

249

65

105

180

254

50

107

Pe

rce

nta

ge

wit

h H

IV-1

RN

A <

50

c/m

L (%

)

30% of patients had baseline viral load >50,000 copies/mL

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

SAILING: Additional week 48 Efficacy

Analyses (Snapshot)

n/N (%)DTG 50 mg OD

(n=354)

RAL 400 mg BD

(n=361)

Response <50 c/mL by background regimen genotypic susceptibility score1

<2 155/216 (72) 129/192 (67)

2a 96/138 (70) 101/169 (60)

Response <50 c/mL by background regimen phenotypic susceptibility score2

<2 70/104 (67) 61/94 (65)

2b 181/250 (72) 169/267 (63)

Use of DRV without primary PI mutations2

Yes 50/72 (69) 54/77 (70)

No 201/282 (71) 176/284 (62)

a One subject with GSS=3 was included in the score=2 categorybTwo subjects with PSS=3 were included in the score=2 category

1. ViiV data on file

2. Adapted from Cahn P et al. Lancet 2013;382(9893):700-708.

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

DRV/r use without

primary PI mutations50/72 (69) 54/77 (70)

No DRV/r use or

DRV/r use with primary

PI mutations

201/282 (71) 176/284 (62)

No DRV/r use

DRV/r use with primary

PI mutationsa

143/214 (67)

58/68 (85)

126/209 (60)

50/75 (67)

SAILING: Percentage of Subjects WithHIV-1 RNA <50 c/mL by Background

Regimen Use of Darunavir

Difference (DTG-RAL) and 95% CIResponse rates

Subgroup In favour of RAL In favour of DTG

0-10-20-30 10 20 30

a The proportion of individuals who used fully active DRV/r (e.g. without phenotypic

resistance) was also balanced across treatment groups: DTG 58/65 (89%), RAL 68/74

(92%)Adapted from Hagins D, et al. ICAAC 2013. Abstract H-1460

PDVF AT WEEK 48 BY TYPE OF BACKGROUND REGIMEN

DTG

n with PDVF/N (%)

RAL

n with PDVF/N (%)

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

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

2 fully active NRTIs† 0/16 3/19

1 fully active NRTIs 0/12 4/13

0 fully active NRTIs 0/1 -

Missing phenotype 0/3 -

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

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

* All received 2 NRTIs with the exception of one subject on DTG (received only 1 NRTI)†Fully active based on phenotype as per Monogram Biosciences’ PhenoSense

assay (using lower cut-off if upper and lower exist) Demarest J, et al. IAC 2014. Abstract TUAB0104

PDVF AT WEEK 48 IN SUBJECTS WITH M184V RECEIVING 3TC OR FTC PLUS A SECOND NRTI

DTG

n with PDVF/N

RAL

n with PDVF/N

Subjects with M184V who received 3TC or

FTC plus a second NRTI

0/13 4/12

Activity of second NRTI by phenotype*

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

* Fully active based on phenotype as per Monogram Biosciences’ PhenoSense

assay (using lower cut-off if upper and lower exist) Demarest J, et al. IAC 2014. Abstract TUAB0104

Confidential and proprietary – internal use only Date of preparation: September 2015

Data on file. Studies ING201636, ING201637. ViiV Healthcare

DAWNING (200304)

Baseline 48 weeks24 weeks

Primary endpoint at

week 48: <50 copies/mL

(snapshot)†

ART-experienced,

open label,

randomised 1:1

N=306 per arm

Countries:

Argentina, Brazil, Chile, China,

Colombia, Kenya, Mexico, Peru,

Romania, Russia, South Africa,

Thailand, Ukraine

Assessments:

• Viral load <400 copies/mL

• Virological rebound

• CD4 cell count changes

• Development of resistance

• Clinical and laboratory safety

*Investigator-selected optimised NRTI backbone based

on local standard of care and resistance testing, with

the requirement of at least one active NRTI in backbone

†90% power based on 12% non-inferiority margin

(estimated response rate for comparator = 70%)

Inclusion criteria:

On first-line 2 NRTI +

NNRTI regimen for

>12 months, failing

virologically (HIV-1 RNA

>400 copies/mL)

LPV/RTV + 2 NRTI*

Primary objective: To demonstrate non-inferior antiviral activity

at 48 weeks of a DTG-containing regimen (DTG 50 mg QD + two

NRTIs) compared with a WHO-recommended standard-of-care

regimen for second-line treatment, LPV/RTV + two NRTIs, in HIV-1

infected patients with failing first-line therapy

DTG + 2 NRTI*

Interim analysis: <50 copies/mL

at 24 weeks of HIV therapy

PDVF AT WEEK 48 IN SUBJECTS RECEIVING PI-CONTAINING BACKGROUND REGIMENS

DTG

n with PDVF/N (%)

RAL

n with PDVF/N (%)

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

1 fully active PI 18/289 (6) 32/295 (11)

DRV/r† 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

* Fully active based on phenotype as per Monogram Biosciences’ PhenoSense

assay (using lower cut-off if upper and lower exist)† DRV also determined as fully active by genotype (Stanford): 6/102 (6%) vs 11/126 (9%) Demarest J, et al. IAC 2014. Abstract TUAB0104

Week 24 Week 48

n (%)

DTG

50 mg QD +

BR

(N=354)

RAL

400 mg BID +

BR

(N=361)

DTG

50 mg QD +

BR

(N=354)

RAL

400 mg BID +

BR

(N=361)

PDVF 14 (4) 34 (9) 21 (6) 45 (12)

INI mutations* present for patients with

determinable genotype/phenotype, n (%)2/9 (22)† 9/27 (33) 4/17 (24)‡ 16/38 (42)

PDVF SUBJECTS WITH TREATMENT-EMERGENT INTEGRASE SUBSTITUTIONS FROM BASELINE

*H51Y, T66A, T66I, T66K, L68V, L68I, L74I, L74M, L74R4, E92Q, E92V, Q95K, T97A, G118R,

E138A, E138K, E138T, G140A, G140C, G140S, Y143C, Y143H, Y143R, P145S, S147G, Q148H,

Q148K, Q148R, V151I, V151L, S153F, S153Y, N155H, E157Q, G163R, G163K, G193E, R263K.

Those in bold were defined from the Stanford database (http://hivdb6.stanford.edu) with a score of

>45. Other mutations are secondary mutations from the Stanford database detected during INI

clinical investigation, or were observed during other clinical investigation or in vitro studies with

DTG; †Mutation(s), DTG FC IC50: R263R/K, FC IC50 = 1.12; R263K, FC IC50 = 1.93; ‡Mutation(s),

DTG FC IC50: R263R/K, FC IC50 = 1.1; R263K, FC IC50 = 1.9; E138T/A and T97A, DTG FC IC50 >

max (baseline sample testing showed this patient enrolled with preexisting RAL resistance [Q148]

and FC IC50 > max for RAL and DTG); V151V/I, DTG FC IC50 = 0.92

Cahn P, et al. Lancet 2013;382:700–8.

Supplementary appendix

CUMULATIVE SUMMARY OF PDVFs BY VISIT (MITT-E POPULATION) THROUGH WEEK 24

Week, n (%)

DTG 50 mg QD + BR

N=354

RAL 400 mg BID + BR

N=361

Week 8 1 (<1) 1 (<1)

Rebound 1 (<1) 1 (<1)

Week 12 4 (1) 6 (2)

Rebound 4 (1) 6 (2)

Week 16 10 (3) 21 (6)

Virologic non-response 0 13 (4)

Rebound 10 (3) 8 (2)

Week 24 14 (4) 34 (9)

Virologic non-response 1 (<1) 19 (5)

Rebound 13 (4) 15 (4)

PDVF: virologic non-response - if plasma HIV-1 RNA levels had decreased <1 log10 c/mL

(unless <400 c/mL) by Week 16, or were ≥400 c/mL on or after Week 24; virologic rebound

- if plasma HIV-1 RNA levels increased to ≥400 c/mL following confirmed suppression to

<400 c/mL, or if >1 log10 c/mL above nadir (lowest value ≥400 c/mL). Suspected PDVF

required confirmatory testing; suspect time point was tested once confirmed.

Adapted from

Underwood MR, et al. IDRW 2013. Abstract 21

TREATMENT-EMERGENT RESISTANCE TO INI AND BACKGROUND REGIMEN

Treatment

Failure with INI-r (n)/

mITT-E population (N)

Adjusted difference in

proportion (95% CI)

(DTG-RAL)

DTG 50 mg QD 4/354 (1%)

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

The proportion of subjects with evidence of INI genotypic or phenotypic resistance was

significantly lower in the DTG arm than in the RAL arm

DTG: at PDVF, 2 subjects harboured virus with R263K (FC IC50 for both DTG and RAL <2). One subject

harboured virus with mutations E138T/A and T97A; one subject harboured virus with V151V/I mutations2

RAL: in subjects with genotypic resistance, high-level phenotypic resistance was present but cross-

resistance to DTG was limited1

The difference in treatment-emergent resistance to background regimen was also statistically significant*1

DTG 1% vs RAL 3%, adjusted difference (95% CI) of –2.2% (–4.3%, –0.1%)2

*DTG was superior vs RAL at Week 48 (P=0.003), pre-specified and adjusted for multiple testingThe analysis was pre-specified but was unadjusted for multiple testing1

1. Cahn P, et al. Lancet 2013;382:700–8

2. Cahn P, et al. Lancet 2013;382:700–8. Supplementary appendix

VIROLOGIC CHARACTERISTICS OF DTG SUBJECTS WITH EMERGENT R263K: SUBJECT 1

Selected relevant characteristics

• Fluctuating HIV-1 RNA despite DTG + potent BR

HIV-1 RNA (log10c/mL)

Week

PDVF Week 16: 6,446 c/mL

1

2

3

4

5

6

7

0 4 8 12 16 24 32 40 48 60 72

Treatment: DTG 50 mg QD – Subject 1

Plasma HIV-1 RNA Profile by Visit

Day 1 PDVF

IN mutation - R263R/K

DTG FC IC50 0.96 1.12

RAL FC IC50 1.02 0.94

IN RC 61% 33%

PDVF BR: No emergent IAS, nor increased FC IC50

aMean Week 4 + Week 24 C0 was 0.86 µg/mL

Adapted from

Underwood MR, et al. IDRW 2013. Abstract 21

Day 1: Clade B; PSS=2, GSS=2

Regimen (PSSDay 1): TDF(1) and EFV(1)

DTG C0a: Week 4=<0.57 µg/mL

VIROLOGIC CHARACTERISTICS OF DTG SUBJECTS WITH EMERGENT R263K: SUBJECT 2Day 1: Clade C; PSS=1, GSS=0.75

Regimen (PSSDay 1): TDF(0) and EFV(1)

DTG C0a: Week 4=<0.02 µg/mL (BLOD); Week 24=0.26 µg/mL

Selected relevant characteristics

• Background regimen: Day 1 TDF (PSS=0) + EFV active

• DTG trough level <0.02 µg/mL (BLOD) indicates dose ≥3 days prior

HIV-1 RNA (log10c/mL)

Week

PDVF Week 24: 9,367 c/mL

1

2

3

4

5

6

7

0 4 8 12 16 24 32 40 48 60 72

Treatment: DTG 50 mg QD – Subject 2

Plasma HIV-1 RNA Profile by Visit

Day 1 PDVF

IN mutation - V260I/R263K

DTG FC IC50 0.92 1.93

RAL FC IC50 1.11 1.12

IN RC 119% NR

PDVF BR: Emergent RT G190S; EFV FC IC50 increase

aMean Week 4 + Week 24 C0 was 0.86 µg/mL Adapted from Underwood MR, et al. IDRW 2013. Abstract 21

Selected relevant characteristics:

• In addition to R263K both A49G and S230R

were observed at Week 120 and Week 132.

Decreased RC with A49G,S230R,R263K

substitutions

VIROLOGIC CHARACTERISTICS OF DTG SUBJECTS WITH EMERGENT INI RESISTANCE: SUBJECT 3

79

Day 1: Clade B; PSS=2, GSS=2

Regimen (PSSDay 1): TDF (1) and FTC (1)

DTG C0a: Week 4=0.36 µg/mL, Week 24=0.22 µg/mL, Week 48=0.03 µg/mL

aGeometric mean Week 4 + Week 24 C0 0.86 µg/mL (CVb=140%); bCould not be determined

*Wildtype RC = 100%

Day 1 PDVF Confirm

HIV-1 RNA 733 622 1,054

IN mutation - A49G, S230R,

R263K

A49G, S230R,

R263K

DTG FC IC50 0.73 3.82 5.77

RAL FC IC50 0.54 2.39 2.62

IN RC* 20% 7.1% 12%

PDVF BR: No emergent resistance, and no NRTI resistance at any time points

Underwood MR et al. European HIV & Hepatitis Workshop 2015. Abstract 6

Week

0 144

10

10,000

100

12 24 36 48 60 72 84 96 108

1,000

Subject 3

386 c/mL

Confirm

Week 132

1,054 c/mLPDVF

Week 120

622 c/mL

HIV-1 RNA (log 10c/mL)

120 132

CLONAL ANALYSIS OF DTG SUBJECT WITH EMERGENT INI RESISTANCE: SUBJECT 3

80Underwood MR et al. European HIV & Hepatitis Workshop 2015. Abstract 6 Pop, population sequencing

IN Genotype FC IC50 vs WT

Time Source na Sequence na DTG EVGb RAL

Day 1 Pop - WT - 0.73 - 0.54

Clone 8 WT 4 0.87 1.10 0.75

Week 120 Pop - A49G, S230R, R263K - 3.82 - 2.39

Clone 8 A49G, S230R, R263K 4 5.80 7.65 2.67

Week 132 Pop - A49G, S230R, R263K - 5.77 - 2.62

Clone 4 A49G, S230Gc, R263K 2 4.07 3.77 1.71

Clone 4 A49G, S230R, R263K 2 5.66 8.13 2.80aClone data available, median is calculated if n>1; bEVGdata not available for population testing; cS230 to S230R and S230R to S230G substitutions

required two independent single nucleotide changes.

• DTG FC data for Week 120 clones was slightly higher than the population data (potential mixture

effect); EVG least susceptible

• Week 132 clones showed S230G present with A49G and R263K, though it was not present by

population sequence

• The S230G substitution showed less effect on FCs than S230R

DTG, RAL, AND EVG FOLD CHANGE IN IC50

VERSUS SITE-DIRECTED MUTANT HIV-1

Strain IN substitution / FC IC50 DTG RAL EVG

NL432a R263K 1.5 0.8 1.3

HXB2b

RVAV260I 1.0 0.7 5.3

R263K 2.1 0.6 10.6

V260I/R263K 2.0 0.5 6.3

DTG and RAL retained good activity against the R263K and V260I/R263K mutants

aHeLa-CD4 cells, 3-day assay, B-gal readout.bMT4 cells, 5-day assay, cell titer glow readout Underwood MR, et al. IDRW 2013. Abstract 21

The R263K mutation decreases

integrase activity in cell-free assays

B

0 5 10 15 20 250

5000

10000

15000

20000IN

INR263K

[Target DNA] (nM)

RF

U

Quashie, Mesplède et al., Journal of Virology, 2012


83

Day 1: Clade C; PSS=2, GSS=2

Regimen (PSSDay 1): TDF (1) and DRV/r (1)

DTG C0a: Week 4=1.78 µg/mL, Week 24=not evaluable, Week 48=1.23 µg/mL

aGeometric mean Week 4 + Week 24 C0 0.86 µg/mL (CVb=140%); bCould not be determined; DRV/r, darunavir/r; DTG, dolutegravir;

RC, replication capacity

Day 1 PDVF

HIV-1 RNA 84,313 27,050

IN mutation - I60L, T97A, N155H

DTG FC IC50 0.66 2.4

RAL FC IC50 0.52 113

IN RC NRb NR

PDVF BR: No emergent resistance, loss of RT M184V and

PI L10F, M36I, M46I, I54V, V82A.

Week

0 96

10

1,000,000


100

12 24 36 48 60 72 84

1,000

10,000

Subject 4

PDVF

Week 72

27,050 c/mL

Confirm

Week 84

132,100 c/mL

Underwood MR et al. European HIV & Hepatitis Workshop 2015. Abstract 6


• Subject non-adherent (protocol deviation), likely

contributed to VF and emergent INI resistance

100,000

9,870 c/mL


84Underwood MR et al. European HIV & Hepatitis Workshop 2015. Abstract 6

Day 1: Clade A; PSS=2, GSS=0.5

Regimen (PSSDay 1): ABC (1) and 3TC (1)

DTG C0a: Week 4=1.14 µg/mL; Week 24=<0.02 µg/mL (BLOD); Week 48=1.60 µg/mL

aGeometric mean Week 4 + Week 24 C0 0.86 µg/mL (CVb=140%);bCould not be determined

Day 1 PDVF

HIV-1 RNA 25,105 3,895

IN mutation - N155H

DTG FC IC50 0.97 1.8

RAL FC IC50 1.18 12

IN RC NRb NR

PDVF BR: No emergent resistance, loss of M184M/V

Week

0 12 24 36 48 60 72 84 96 108 120

10

100,000

100

1,000

10,000

Subject 5PDVF

Week 108

3,895 c/mL

Confirm

Week 108 retest

407 c/mL



• DTG Week 24 trough BLOD, suggests non-

adherence, contributing to VF and emergent

INI resistance

AEs LEADING TO WITHDRAWAL: ANALYSIS BY GENDER, RACE AND AGE

0 1 2 3 4 5 6 7 8 9 10

≥50 years

<50 years

African American/African heritage

Non-white

White

Male

Female

Overall

DTG 50 mg QD

RAL 400 mg BID

n/N (%)

13/361 (4)7/354 (2)

0/108 (0)6/124 (5)

7/249 (3)7/238 (3)

2/181 (1)7/176 (4)

5/175 (3)6/185 (3)

2/143 (1)5/160 (3)

4/272 (1)11/278 (4)

3/85 (4)2/84 (2)

Percentage of subjects with AEs leading to withdrawal

Hagins D, et al. ICAAC 2013. Abstract H-1460

MEAN ( SD) CHANGE FROM BASELINE IN CREATININE (µMOL/L) OVER TIME

30

20

10

0

W2 W4 W8 W12 W16 W24 W32 W40 W48

Week

Mean change from baseline in

creatinine(µmol/L)*

–10

DTG 50 mg QD

RAL 400 mg BID

Number of subjects

DTG 50 mg QD 314 340 339 333 325 323 309 299 291

RAL 400 mg BID 316 351 340 342 333 327 309 291 283

*10 µmol/L=0.11mg/dL Cahn P, et al. Lancet 2013;382:700–8

DTG TRIALS IN TREATMENT-NAÏVE ADULT SUBJECTS WITH HIV

Phase IIb dose-ranging, randomised, partially blinded

study of:

•DTG 10 mg, 25 mg, 50 mg versus EFV 600 mg + 2 NRTIsSPRING-11 N=205

Phase III non-inferiority, randomised, double-blind,

double-dummy, multicentre study of:

•DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs•RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs

SPRING-22 N=822

Phase III non-inferiority, randomised, double-blind,

double-dummy, multicentre study of:

•DTG (50 mg QD) with ABC/3TC FDC plus EFV/TDF/FTC placebo

•EFV/TDF/FTC (QD) plus DTG and ABC/3TC FDC placebos

SINGLE3 N=833

Phase IIIb non-inferiority, randomised, active-controlled,

multicentre, open-label study of:

•DTG (50 mg QD) + 2 NRTIs•DRV/r (800/100 mg QD) + 2 NRTIs

FLAMINGO4 N=484

1. Stellbrink H-J, et al. AIDS 2013;27:1771–8

2. Raffi F, et al. Lancet 2013;381:735–43

3. Walmsley S, et al. N Engl J Med 2013;369:1807–18

4. Clotet B, et al. Lancet 2014;383:2222–31


Week

BL 2 4 8 12 16 24 32 40 480

10

20

30

40

50

60

70

80

90

100DTG + ABC/3TC: 88%

EFV/TDF/FTC: 81%

Week 48 adjusted difference in response (95% CI):

+7.4% (+2.5% to +12.3%)*; p=0.003

Pro

po

rtio

n w

ith

HIV

-1 R

NA

<50

c/m

L

DTG was statistically superior to EFV/TDF/FTC at Week 48Subjects receiving DTG achieved faster virologic suppression than EFV/TDF/FTC

(p<0.001)

*-10% non-inferiority margin with pre-specified tests for

superiorityWalmsley S, et al. N Engl J Med 2013;369:1807–18

DTG 50 mg + ABC/3TC FDC QDEFV/TDF/FTC QD

VIROLOGIC RESPONSE THROUGH TO WEEK 144

DTG + ABC/3TC remained statistically superior to EFV/TDF/FTC through to Weeks 961 and 1442

1. Walmsley S, et al. CROI 2014. Abstract 543

2. Adapted from Pappa K, et al. ICAAC 2014. Abstract H-647a

Week

0

10

20

30

40

50

60

70

80

90

100

Pro

po

rtio

n w

ith

HIV

-1 R

NA

<50

c/m

L

BL 4 81216 24 32 40 14448 60 72 84 96 108 120 132

71%

63%

DTG 50 mg + ABC/3TC FDC QDEFV/TDF/FTC QD

Week 144 adjusted difference in response (95% CI):

+8.3% (+2.0% to +14.6%); p=0.0102

88%

81%

80%

72%

Adapted from Pappa K, et al. ICAAC 2014. Abstract H-647a

-0.2

-0.1

0

0.1

0.2

0.3

Mea

n c

han

ge

fro

m b

asel

ine

(SD

)in

ser

um

cre

atin

ine,

mg

/dL

No. of patientsDTG + ABC/3TC

EFV/TDF/FTC

BL4 32 40

399390

399390

391375

387363

379352

367345

369342

359330

355317

350311

344308

336300

332288

322282

312267

Week12 24 48 60 72 84 10896 120 132 144

DTG + ABC/3TC QD EFV/TDF/FTC QD

Parameter Week 48 Week 96Week 144 Week 48 Week 96

Week 144

Urine albumin/creatinine ratio

(mg/mmol)

0 0 0 0.05 0.05 0.10

Median change (IQR) (-0.3, -0.3) (-0.3, 0.2) (-0.4, 0.2) (-0.2, 0.3) (-0.2, 0.3) (-0.2, 0.4)

EFV/TDF/FTC QD

DTG 50 mg + ABC/3TC QD

CHANGE FROM BASELINE TO 144 WEEKS IN RENAL PARAMETERS


Treatment

Number of responders/

total assessed, n (%)

Adjusted difference in

proportion (95% CI)

(DTG - RAL)

DTG 50 mg QD* 332/411 (81) 4.5% (–1.1%, 10.0%)

RAL 400 mg BID* 314/411 (76)

Error bars indicate 95% CI

*plus 2 NRTIs Adapted from Raffi F, et al. Lancet Infect Dis 2013;13:927–35

• The lower end of the 95% CI (–1.1%) remains greater than –10%, indicating that

DTG remains non-inferior to RAL at 96 weeks

100

90

80

70

60

50

40

30

20

10

0

Proportion of subjects with


BL 4 8 12 16 24 32 40 48 60 72 84 96

RAL* 85%

RAL* 76%

DTG* 88%DTG* 81%

DTG 50 mg QD*

RAL 400 mg BID*

Week

FavoursRAL

DTG 50 mg QDn (%)

RAL 400 mg BID

n (%)Overall

≤100,000 c/mL

>100,000 c/mL

ABC/3TC

TDF/FTC

≤100,000 c/mL; ABC/3TC≤100,000 c/mL; TDF/FTC

>100,000 c/mL; ABC/3TC

>100,000 c/mL; TDF/FTC

332/411 (81) 314/411 (76)

89/114 (78)

243/297 (82) 241/295 (82)

73/116 (63)

125/169 (74) 124/164 (76)

207/242 (86) 190/247 (77)

98/132 (74)145/165 (88)

27/37 (73)

62/77 (81)

98/125 (78)143/170 (84)

26/39 (67)

47/77 (61)

Favours DTG

706050403020100–10–20

VIROLOGIC RESPONSE BY BASELINE VIRAL LOAD AND NRTI BACKBONE AT WEEK 961,2

The proportion of DTG subjects achieving HIV-1 RNA <50 c/mL was more pronounced in subjects with high baseline viral load, and in subjects receiving TDF/FTC. However, it was not statistically significantly different by use of ABC/3TC vs TDF/FTC1

— the subject numbers were small and confidence intervals wide and overlapping1

— responses varied due to differences in discontinuations for ‘other reasons while <50 c/mL’*1Difference in proportion (DTG – RAL; unadjusted). Error bars indicate

95% CI

*Part of this difference is due to the closure of one site, where all

subjects were receiving ABC/3TC and most had baseline HIV-1 RNA

<100,000 c/mL

1. Raffi F, et al. Lancet Infect Dis 2013;13:927–35

2. Raffi F, et al. IAS 2013. Abstract TULBPE17

MEAN (± SD) CHANGE FROM BASELINE TO WEEK 48 IN CREATININE (µMOL/L)

IN SPRING-2 AND SINGLE

Curtis LD, et al. IAS 2013. Poster TUPE282

Mea

n c

han

ge

fro

m b

asel

ine

in

crea

tin

ine

(µm

ol/L

)

Week2 4 8 12 16 24 32 40 48

–10

–5

5

10

15

20

DTG 50 mg QD + 2 NRTIs RAL 400 mg BID + 2 NRTIs

DTG 50 mg + ABC/3TC QD EFV/TDF/FTC QD

0

25

+12.3

+4.7



(difference [95% CI]: 7.4% [1.4–13.3])2

100

BL

Weeks

Pro

po

rtio

n w

ith

HIV

-1 R

NA

<5

0 c

/mL

90

80

70

60

50

40

30

20

10

0

4 8 12 16 24 36 48

0% 20%–12%–20%

0.9 7.1 13.2

95% CI for difference*FavoursDRV/r

FavoursDTG

DRV/r†: 83%

DTG†: 90%


DTG 50 mg QD†


*Adjusted difference (DTG - DRV/r) based on Cochran-Mantel-Haenszel

stratified analysis adjusting for baseline HIV-1 RNA and background NRTI

therapy; †plus 2 NRTIs




Adapted from Molina JM, et al. The Lancet HIV 2015. Epub ahead of print

Pro

port

ion w

ith H

IV-1

RN

A <

50

c/m

L (

%)

DTG†: 80%

DRV/r†: 68%

B

L

4 8 12 16 3624 4

89

6Week

Test for superiority: p=0.0020% 25%–12%

4.7 12.4 20.2

95% CI for differenceFavoursDRV/r

FavoursDTG

†plus 2 NRTIs

DTG 50 mg QD†

Differences largely driven by lower virologic failure rate and fewer withdrawals due to AEs

in the DTG arm


100

90

80

70

60

50

40

30

20

10

0

DTG 50 mg QD (%)

DRV/r800/100 mg QD (%)

Overall N=484 90 83

Baseline HIV-1 RNA≤100,000 c/mL>100,000 c/mL

n=362n=122

8893

8770

Background dual NRTIABC/3TCTDF/FTC

n=159n=325

9090

8581

Baseline CD4+<350 cells/mm3

≥350 cells/mm3n=171n=313

8891

8084

SexFemaleMale

n=72n=412

8491

7385

Age<50 years≥50 years

n=420n=64

9089

8192

RaceWhiteAfrican American/ African heritage

n=349n=113

9185

8477

SNAPSHOT BY SUBGROUP AT WEEK 48Favours

DRV/rFavours

DTG

Clotet B, et al. EACS 2013. Abstract LBPS4/6

Differences in response were observed in subjects with HIV-1 RNA >100,000 but this was not associated to

the NRTI backbone

–20–15–10 –5 0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

70

80

90

100

87%90% 90% 89%

83%

DTG +

ABC/3TC

253/280

ATRIPLA®

238/288

DTG 50 mg QD

+ 2NRTIs

160/181

DRV/r 800

mg/ 100

mg + 2

NRTIs

157/181

DTG

50 mg QD

+ 2NRTIs

267/297

RAL 400 mg

BID + 2 NRTIs

264/295

SINGLE† FLAMINGO‡ SPRING-2§

88%

Baseline viral load ≤100,000 copies/mL Baseline viral load >100,000 copies/mL

RAL 400 mg

BID + 2 NRTIs

87/116

Pro

po

rtio

n (

%)

of

pa

tie

nts

wit

h H

IV-1

RN

A <

50

co

pie

s/m

L

0

10

20

30

40

50

60

70

80

90

100

DTG +

ABC/3TC

113/134

ATRIPLA®

100/131

DTG 50 mg QD

+ 2NRTIs

57/61

DRV/r 800

mg/ 100

mg + 2

NRTIs

43/61

DTG

50 mg QD

+ 2NRTIs

94/114

SINGLE† FLAMINGO‡ SPRING-2§

83%

76%

93%

70%

82%

75%

† 32% of treatment-naïve patients had a baseline viral load > 100,000 copies/mL‡ 25% of treatment-naïve patients had a baseline viral load > 100,000 copies/mL§ 28% of treatment-naïve patients had a baseline viral load > 100,000 copies/mL

Pro

po

rtio

n (

%)

of

pa

tie

nts

wit

h H

IV-1

RN

A <

50

co

pie

s/m

L

Adapted from Walmsley S et al. 52nd ICAAC. 9-12 Sept 2012. Abstract H-556b

TIVICAY (dolutegravir) Summary of Product Characteristics, 06/2014

Adapted from Walmsley S et al. N Engl J Med 2013; 369:1807-18

Adapted from Walmsley S et al. N Engl J Med 2013; 369:1807-18 (appendix)

Adapted from Clotet B et al. Lancet 2014;383:2222-31

Adapted from Clotet B et al. Lancet 2014;383:2222-31(Supplementary Appendix)

Adapted from Raffi F et al. Lancet 2013;381:735–43

Week 48 snapshot analysis

DOLUTEGRAVIR . POST HOC ANALYSIS BASED ON BASELINE VIRAL LOAD

96-WEEK SNAPSHOT RESPONSE (HIV-1 RNA <50 C/ML) IN SUBJECTS WITH HIGH BL VL AND LOW BL CD4

HIV-1 RNA <50

c/mL (Snapshot),

n/N (%)

SPRING-2 SINGLE FLAMINGO

DTG RAL DTG EFV/TDF/

FTC

DTG DRV/r

Overall 332/411

(81%)

314/411

(76%)

332/414

(80%)

303/419

(72%)

194/242

(80%)

164/242

(68%)

Individuals with high baseline VL (>100,000 c/mL) by background regimen

ABC/3TC 27/37

(73%)

26/39

(67%)

95/134

(71%)

- 11/13

(85%)

7/12

(58%)

TDF/FTC 62/77

(81%)

47/77

(61%)

- 94/131

(72%)

39/48

(81%)

25/49

(51%)

Individuals with low baseline CD4

<200 cells/mm3 39/55

(71%)

28/50

(56%)

39/57

(68%)

45/62

(73%)

18/23

(78%)

14/24

(58%)

200 to

<350 cells/mm3

116/144

(81%)

103/139

(74%)

135/163

(83%)

113/159

(71%)

60/73

(82%)

36/51

(71%)

98Granier C et al. CROI 2015. Poster 550

4%

2%3%

14%

2%

6%

0

10

20

Pro

po

rtio

n (

%)

of

pa

tie

nts

wit

h A

E

lea

din

g t

o d

isco

nti

nu

ati

on SINGLE

up to 144 weeks

SPRING-2

up to 96 weeks

FLAMINGO

up to 96 weeks

ATRIPLA®

QD

(n=419)

DTG 50 mg

QD

(n=411)

RAL 400 mg

BID

(n=411)

DTG 50 mg

(n=242)

DTG 50 mg

+ABC/3TC

QD

(n=414)

DRV/r

800/100 mg

QD

(n=242)

Adapted from Pappa K, et al. Presented at: 54th ICAAC 2014. H-647a

Walmsley S et al. Poster presented at: 21st CROI 2014. Poster 543

Raffi F et al. Lancet Infect Dis 2013; 13:927-35

Molina J-M et al. J Int AIDS Soc. 2014;17(suppl 3):19490

Dolutegravir-based regimens demonstrate a good benefit-to-risk profile

ATRIPLA at 144 weeks in the SINGLE study (P=0.010)

Dolutegravir-based regimens demonstrate a good benefit-to-risk profile

• Dolutegravir-based regimens demonstrated statistically greater efficacy versus

ATRIPLA® at 144 weeks in the SINGLE study (P=0.010)

DOLUTEGRAVIR –OVERALL SAFETY IN HIV NAÏVE PATIENTS

MUTATIONS DETECTED IN SUBJECTS DURING SPRING-2 AND SINGLE OVER 96 WEEKS

SPRING-21 SINGLE2

n (%)

DTG50 mg QD(N=411)

RAL400 mg BID(N=411)

DTG 50 mg+ABC/3TC QD

(N=414)

EFV/TDF/FTCQD

(N=419)

Subjects with PDVF 22 (5) 29 (7) 25 (6) 25 (6)

IN genotypic results at baseline and time of PDVF

10 19 133 103

INI-resistant mutations 0 1 (6)* 0¶ 0

RT genotypic results at baseline and time of PDVF

14 20 173 123

NRTI-resistant mutations 0 4 (21)*† 0 1 (K65R)

NNRTI-resistant mutations – – 06 (K101E,

K103N, G190A)‡

*One subject had INI-resistance mutations (T97T/A, E138E/D, V151V/I, N155H) and

NRTI-resistance mutations (A62A/V, K65K/R, K70K/E, M184V)†M184M/I, A62A/V, M184M/V (each n=1)¶E157Q/P polymorphism detected with no significant change in phenotypic susceptibility; ‡K101E (n=1), K103N (n=1), K103K/N (n=2), G190A (n=1) and K103N + G190A (n=1)

(defined as two consecutive plasma HIV-1 RNA values of ≥50 c/mL on or after Week 24)

Adapted from

1. Raffi F, et al. Lancet Infect Dis 2013;13:927–35

2. Walmsley S, et al. CROI 2014. Abstract 543

3. ViiV data on file (SINGLE 96-week Clinical Study Report)

PDVF AND TREATMENT-EMERGENT RESISTANCE THROUGH 96 WEEKS

*Confirmed HIV-1 RNA >200 c/mL on or after Week 24 1. Molina JM, et al. HIV Drug Therapy Glasgow 2014. Abstract O153

2. Molina JM, et al. The Lancet HIV 2015. Epub ahead of print

PDVF*Treatment-emergent

primary mutations

Visit

DTG 50 mg QD

(N=242)

DRV/r

800/100 mg QD

(N=242)

DTG 50 mg QD

(N=242)

DRV/r

800/100 mg QD

(N=242)

Any time 2 (<1%) 4 (2%) 0 0

Week 24 2 (<1%) 0 0 0

Week 36 0 1 (<1%) 0 0

Week 48 0 1 (<1%) 0 0

Week 72 0 1 (<1%) 0 0

Week 84 0 1 (<1%) 0 0

Week 96 0 0 0 0

GESIDA 2015. Adherencia

AGENDA






Summary

Key Characteristics of Integrase

inhibitors

104US Package Insert: Isentress, Stribild, Tivicay

RALTEGRAVIR ELVITEGRAVIR/c DOLUTEGRAVIR

Dosing 400mg BD In single tablet OD with

TDF/FTC/c

50mg OD & in single

tablet OD with

ABC/3TC

Food Regardless With food Regardless

Metabolism UGT1A CYP3A, induces 2C9

/c inhibits 3A & 2D6, P-

gp, BCRP, OAT1,

MATE1

UGT1A1 > CYP3A.

Substrate of UGT1A3,

UGT1A9, BCRP, and P-

gp in vitro

Drug Interaction

Potential

Low High via P-gp, CYP and

MATE1

Low, OCT2 inhbitor

PK variability High Moderate-High Low

Renal effects No Raised creatinine via

MATE1 inhibition.

Renal DC

(tubulopathy)

Raised creatinine via

OCT2 inhibition. NO

Renal DC

DOSING RECOMMENDATIONS FOR DTG

Population Recommended dose

Adults

Treatment-naïve or treatment-experienced INI-naïve 50 mg QD

Treatment-naïve or treatment-experienced INI-naïve when co-administered

with certain UGT1A or CYP3A inhibitors50 mg BID

INI-experienced with certain INI-associated resistance substitutions or

clinically-suspected INI resistance*50 mg BID

Paediatric patients aged ≥12 years and weighing ≥40kg

Treatment-naive or treatment-experienced INI-naïve 50 mg QD

Treatment-naive or treatment-experienced INI-naïve when co-administered

with certain UGT1A or CYP3A inhibitors50 mg BID

DTG is an HIV-1 INI indicated in combination with other ARVs for the treatment of HIV-1 infection in

adults and children aged ≥12 years and weighing ≥40kg at the following doses:

Tivicay US Prescribing Information. ViiV Healthcare, August 2015

*Alternative combinations that do not include metabolic inhibitors should be considered where possible

SUMMARY OF THE IMPACT OF PROTEASE INHIBITORS ON DTG EXPOSURE

PIn

DTG dose

studied

DTG CττττGLS mean

ratio (90% CI)

Ratio of 1 = no impact

Recommendation1

ATV 400 mg QD2 12 30 mg QD 2.80 (2.52–3.11) No DTG dose adjustment required

ATV/r 300/100 mg QD2 12 30 mg QD 2.21 (1.97–2.47) No DTG dose adjustment required

DRV/r 600/100 mg BID3 15 30 mg QD 0.62 (0.56–0.69) No DTG dose adjustment required

LPV/r 400/100 mg BID3 15 30 mg QD 1.02 (0.88–1.17) No DTG dose adjustment required

NFV – – – No DTG dose adjustment required*

SQV/r – – – No DTG dose adjustment required*

FPV/r 700/100 mg BID4 12 50 mg QD 0.51 (0.41–0.63) DTG 50 mg BID should be given†

TPV/r 500/200 mg BID5 16 50 mg QD 0.24 (0.21–0.27) DTG 50 mg BID should be given†

*Anticipated based on metabolism pathway, no study conducted†INI-naive patients; alternative combinations that do not include metabolic inducers

should be considered where possible for INI-experienced patients with certain INI-

associated resistance substitutions or clinically suspected INI resistance


2. Song I, et al. Br J Pharmacol 2011;72:103–8

3. Song I, et al. J Clin Pharmacol 2011;51:237–42

4. Song I, et al. ICAAC 2011. Abstract A1-1727

5. Song I, et al. IWCP 2011. Abstract 002

SUMMARY OF THE IMPACT OF OTHER ARVs ON DTG EXPOSURE

ARV(s)n

DTG dose studied

DTG CττττGLS mean ratio

(90% CI)

Ratio of 1 = no impact

Recommendation1

NRTIs

TDF 300 mg QD2 16 50 mg QD 0.92 (0.82–1.04) No DTG dose adjustment required

Other NRTIs – – – No DTG dose adjustment required

NNRTIs

EFV 600 mg QD3 12 50 mg QD 0.25 (0.18–0.34) DTG 50 mg BID should be given*

NVP 400 mg QD4 10 50 mg QD –Co-administration with NVP should

be avoided (insufficient data)

ETR 200 mg BID5 16 50 mg QD 0.12 (0.09–0.16)DTG should not be given with ETR without

co-administration of ATV/r, DRV/r or LPV/r

ETR 200 mg + DRV/r 600/100 mg BID5 9 50 mg QD 0.63 (0.52–0.76) No DTG dose adjustment required

ETR 200 mg + LPV/r 400/100 mg BID5 8 50 mg QD 1.28 (1.13–1.45) No DTG dose adjustment required

RPV 25 mg QD6 16 50 mg QD 1.22 (1.15–1.30) No DTG dose adjustment required

Other ARVs

MVC – – – No DTG dose adjustment required


2. Song I, et al. J Acquir Immune Defic Syndr 2010;55:365–7

3. Song I, et al. IWCP 2011. Abstract 002; 4. Dailly E, et al. IWCPHIV 2015. Abstract 64

5. Song I, et al. Antimicrob Agents Chemother 2011;55:3517–21

6. Ford SL, et al. Antimicrob Agents Chemother 2013;57:5472–7

*INI-naive patients; alternative combinations that do not include metabolic inducers

should be considered where possible for INI-experienced patients with certain INI-

associated resistance substitutions or clinically suspected INI resistance

DTG MAY INCREASE PLASMA CONCENTRATIONS OF DRUGS ELIMINATED VIA OCT21,2

Co-administered drugEffect on concentration of co-administered drug

Recommendation1

Dofetilide1 Potential increase

Co-administration of DTG with dofetilide is contraindicated due to the potential for

increased dofetilide concentrations and the risk for serious and/or life-threatening events

Metformin2

DTG 50 mg q24h

DTG 50 mg q12h

↑ 66%*

↑ 111%*

Metformin dose reductions may be

considered when co-administered with DTG

Levels of the OCT2 transporter substrates may increase upon co-administration with the OCT2 inhibitor DTG.

Dofetilide/DTG co-administration is contraindicated and metformin dose reductions may be considered when

co-administered with DTG

*Cmax Geometric Mean ratio (90% CI) metformin + DTG vs metformin alone


2. Zong J, et al. HIV Drug Therapy Glasgow 2014. Abstract P052

STUDY OF THE EFFECT OF DTG ON METFORMIN IN HEALTHY SUBJECTS

Plasma exposures of metformin were increased when co-administered with DTG.

Dose adjustment of metformin may be required1,2

Regimen Cmax (µg/mL)1 AUC0–ττττ

(µg��h/mL)1 t1/2 (hr)1

Metformin + DTG (50 mg q24h) vs

metformin alone1.66 (1.53, 1.81) 1.79 (1.65, 1.93) 1.09 (0.954, 1.24)

Metformin + DTG (50 mg q12h) vs

metformin alone2.11 (1.91, 2.33) 2.45 (2.25, 2.66) 1.14 (1.00, 1.29)

0.1

1.0

10.0

0 4 8 12

Mean metform

in concentration, µ

g/mL

Time, h

Metformin Alone, Period 1

Metformin + DTG 50 mg q24h


0.1

1.0

10.0

0 4 8 12Mean metform

in concentration, µ

g/mL

Time, h


Metformin + DTG 50 mg q12h


Values shown are GLS mean ratio (90% CI)

1. Zong J, et al. HIV Drug Therapy Glasgow 2014. Abstract P052


Age Distribution of HIV-Positive People in

the United States

• By 2015, the proportion of persons older than 50 yrs of age living with

HIV/AIDS in the US will increase by 50% compared with 2010[1,2]

1. CDC HIV Surveillance Report 2004 and 2011. 2. Luther VP, et al. Clin Geriatr Med. 2007;23:567-583.

0%

10%

15%

20%

25%

5%

20012010

2011

Slide 115

SUMMARYDTG provides potent HIV virologic activity and was generally well tolerated.

– small, non-progressive increases in creatinine were consistent with inhibition of renal transporter OCT2. Analysis of AEs and laboratory data do not suggest that DTG has an adverse effect on renal function. No Renal DC drug related.

– AE related DC very low, range: 2-4%.

In the separate studies (snapshot responder analysis: HIV-1 RNA <50 c/mL):

– DTG administered once daily with 2 NRTIs showed non-inferiority to RAL, superiority to DRV/r up to Week 96 and superiority to EFV/TDF/FTC to Week 144

In-vitro and clinical data support the potential for DTG to have a higher barrier to resistance when compared to RAL and EVG.

No treatment-emergent mutations leading to drug resistance have been detected with DTG 50 mg QD in any clinical trial to date in treatment-naivesubjects up to 144 weeks.

SUMMARY (II)In treatment-experienced, INI-naive subjects (SAILING), DTG was superior

than RAL on a optimized regimen with lower rates of INI and resistance to

the background regimen agents-

In treatment-experienced, INI-resistant subjects

in VIKING-3, IN genotypic groups were derived based on differential

impact on DTG antiviral response: “No Q148”, “Q148 + 1” and “Q148 + ≥2”

– the best antiviral responses were seen in the “No Q148” group.

– in subjects harbouring virus with Q148, a decreased response was

observed with increasing numbers of mutations of G140A/C/S, L74I and

E138A/K/T

– treatment-emergent INI resistance was noted in 56% of subjects with

PDVF over 48 weeks

DTG has a limited DDI profile and may address most frequent aging clinical

needs

Muchas gracias

BACK UP Slides

DTG HAS SHOWN LESSER IMPACT ON LIPID PROFILE

THAN EFV & DRV/R

Quercia R et al. Clin Drug Invest 2015;35:211

Documents

A Comprehensive Understandingof InSTI....stomach, preferably at bedtime. f ABC has been associated with increased CV risk, although conflicting data; use with caution in patients with