xviii international aids conference 18-23 july 2010, vienna, austria shionogi-viiv healthcare llc...

XVIII International AIDS Conference18-23 July 2010, Vienna, Austria

Shionogi-ViiV Healthcare LLC

Activity of Next Generation Integrase Inhibitor (INI) S/GSK1349572 in Subjects with HIV Exhibiting Raltegravir Resistance: Initial Results of VIKING Study (ING112961)J. Eron 1, J. Durant2, I. Poizot-Martin3, J Reynes4, V Soriano5, P Kumar6, G Richmond7, D Vittecoq8, T Fujiwara9, M Ait-Khaled10, S Min11, D Thomas11, R Cuffe10, J Yeo10

1Center for AIDS Research Clinical Core, UNC School of Medicine, NC; 2Hôpital l'Archet, Nice; 3Hôpital Sainte Marguerite, Marseille; 4Hôpital Guide Chauliac, Montpellier; 5Hospital Carlos III, Madrid; 6Georgetown Univ, Washington; 7Fort Lauderdale; 8Hôpital Paul Brousse, Villejuif; 9Shionogi & Co., Ltd., Osaka, Japan; 10GlaxoSmithKline, London; 11GlaxoSmithKline, Research Triangle Park, NC

XVIII International AIDS Conference, 18-23 July 2010, Vienna, Austria

Background

● Virologic failure occurred in 23% of treatment experienced subjects receiving raltegravir (RAL) in BENCHMRK-1 and 2– 70% harbored virus with RAL-resistance signature mutations

– 3 RAL-resistance pathways – Y143, Q148 and N155

– Additional substitutions increase resistance and/or fitness

● In vitro susceptibility to S/GSK1349572, suggested two RAL-resistant viral populations:– Variable increase in fold-change (FC) to S/GSK1349572 (Q148 plus

secondary mutations)

– No or minimal increase in FC to S/GSK1349572 (N155 pathway, Y143 pathway, Q148 single mutants)

● The clinical evaluation of S/GSK1349572 in subjects with RAL-resistant virus is warranted


VIKING Study Design Cohort I

● Current or historic RAL-failures with evidence of RAL-resistance● At least 3 ART-class resistant (includes INI)● All subjects receive S/GSK1349572 50mg QD

Allocated to one of two groups based on genotype at screen to ensure broad sensitivity range

Functional Monotherapy Phase

Replace RAL with S/GSK1349572 or

add, if RAL already stopped

Continuation Phase

S/GSK1349572 + OBR

Day 1 Day 11 Week 24

*Q148H/K/R plus changes in L74 and/or E138 and/or G140**N155H and Y143H pathways or Q148H/K/R single mutants

Q148H/K/R + one or more secondary resistance mutations*

N~ 15

All other mutations (including codon 148 single mutation)**

N~ 15


VIKING Objectives and End-points

● Primary Objective– To assess the short-term antiviral activity of S/GSK1349572

+ failing background regimen

● Primary End-point– Proportion of subjects with Day 11 plasma HIV-1 RNA <400c/mL

or at least 0.7 log10 c/mL below their Baseline value

● Secondary End-points– Includes measures of safety, antiviral response, INI-resistance

emergence and pharmacokinetic parameters at Day 11 and over time


Baseline Characteristics

Enrolled, (N) 27

Age in years, median (range) 48 (19-61)

Males : females 25 : 2

CD4+ cells/mm3, median (IQ) 110 (40, 230)

CD4+ <50 cells/mm3, n (%) 7 (26%)

Plasma HIV-1 RNA log10 c/mL, median (IQ) 4.47 (3.9, 4.9)

Plasma HIV-1 RNA >50,000 c/mL, n (%) 9 (33%)

CDC class C, n (%) 16 (59%)

Current RAL failure 21 (78%)

Historic RAL failure 6 (22%)

Duration of prior ART in years, median (range) 14 (4-21)

Number of prior ART, median (range) 17 (6-24)

Prior ART exposure:

Etravirine, n (%) Enfuvirtide, n (%) Darunavir/r, n (%) Maraviroc, n (%)

19 (70%)22 (81%)23 (85%)10 (37%)


Baseline (Day 1) Viral IN Mutation Pathways and Phenotypic Susceptibility to S/GSK1349572

● More advanced Q148 pathway genotypes exhibit higher fold change to S/GSK1349572

Bas

elin

e 57

2 F

old

Ch

an

ge

Baseline Mutation Pathway

Q148+2n=3

Q148+1n=4

N155n=4

Mixturen=2

Other IN mutationsn=2

Y143n=12

Fold Change, median (range):RAL 161 (0.6 - >166)S/GSK1349572 1.5 (0.6 - 35)

Mixtures: n=1 Q148H + G140S / Y143Hn=1 Q148H+ E138A+G140S / Y143HOthers:n=1 E92Q (screen: E92Q, N155H)n=1 none (screen: G140G/S, Q148H/Q)

20

10

6

4

2

1

0.6


Plasma HIV-RNA Response at DAY 11 by Viral IN Baseline Genotypic Profile

PrimaryEnd-point

HIV-1 RNA <400c/mL or ≥0.7 log10c/mL decline in HIV-1 RNA

n/N (%)

SecondaryEnd-point

HIV-1 RNA log10c/mL change from baseline

Mean (SD)

All subjects 21/27(78%)

-1.45(SD 0.76)

Q148H/K/R + ≥1 Q148 associated mutations at L74, E138 or G140 (n=9)

3/9*(33%)

-0.72(SD 0.63)

All other genotypes from N155H and Y143H pathways (n=18)

18/18(100%)

-1.82(SD 0.53)

* Halted enrollment early in this group due to less robust virologic response


Virologic Response at DAY 11: Correlation with Baseline Fold Change (FC) in Susceptibility to S/GSK1349572

Mixtures: N=1 Q148H + G140S / Y143HN=1 Q148H+ E138A+G140S / Y143HOthers:N=1 E92Q (screen: E92Q, N155H)N=1 none (screen: G140G/S, Q148H/Q)

Strong correlation between baseline FC and Day 11 response (r=0.79, p value <0.001)

0.5 1.0 2.0 5.0 10.0 20.0

-2.5

-2.0

-1.5

-1.0

-0.5

Day 1 S/GSK1349572 Fold Change

Day

11

VL

Ch

an

ge

Fro

m B

ase

lin

e (l

og

10 c

/mL

)

Y143N155

Other

Q148 + 2Q148 + 1Mixture


HIV IN Genotypic and Phenotypic Changes at Day 11

● 18* paired viral isolates (Day 1 & Day 11) were evaluated● No signature RAL mutations emerged on therapy ● 17 paired isolates: susceptibility change was <2 fold ● 1 paired isolate: susceptibility change was ~6-fold ● Detailed resistance data presented by Clotet B et al.

TUPE0130 IAC 2010

*Viral load too low to analyze genotype and phenotype in remaining isolates at Day 11


Adverse Events

● Most common clinical AEs (>1 subject): Diarrhea & insomnia (3/27 subjects, 11%)● Grade 3/4 clinical AEs: 3 (11%) subjects

– Grade 3: syncope & vertigo (n=1), hypercholesterolaemia (n=1)– Grade 4: neurosyphilis (n=1)

● Drug related AEs: 4 (15%) subjects– Grade 1: diarrhoea & nausea (n=1), anaemia (n=1)– Grade 2: fatigue & insomnia (n=1), diarrhoea (n=1)

● Grade 3 laboratory toxicities: 6 (22%) subjects– 1 amylase increase– 1 total cholesterol increase– 2 lipase increase– 2 phosphorus decrease

● No Grade 4 laboratory toxicities● Serious Adverse Events: 2 (7%) subjects, neither considered related to S/GSK1349572

– 1 neurosyphilis ~ Wk 1– 1 brain mass ~ Wk 6

Median (min, max) exposure: 56 (28, 87) days


VIKING Study Conclusions

● Baseline isolates exhibited high FC in susceptibility to RAL (median 161) with substantially lower FC in susceptibility to S/GSK1349572 (median 1.5).– A broad spectrum of susceptibility to S/GSK1349572 ranging from 0.6

to 35 was observed

● 21/27 (78%) subjects achieved the primary end-point (<400c/mL or a ≥0.7log10c/mL decline in plasma HIV-1 RNA) at Day 11– 18/18 subjects with isolates exhibiting the N155H, Y143H pathways

achieved the primary end-point

● A strong correlation was observed between change from baseline in plasma HIV-1 RNA and baseline fold change in susceptibility to S/GSK1349572

● S/GSK1349572 was generally well tolerated in this advanced HIV-1 infected population


Acknowledgments

● All SUBJECTS who participated in VIKING in the screening or treatment phases

● VIKING Investigators:– France: Jacques Reynes, Isabelle Poizot-Martin, Jacques

Durant, Philippe Morlat, Daniel Vittecoq, Christine Katlama, Jean-Michel Livrozet

– Italy: Adriano Lazzarin– Spain: Bonaventura Clotet, Vincente Soriano– USA: Edwin DeJesus, Joseph J. Eron Jr., Trevor Hawkins,

Princy Kumar, Jacob P Lalezari, Anthony LaMarca, Gary J Richmond, Louis A Sloan, Benjamin Young

● Contributors from GSK, SHIONOGI and ViiV HC

XVIII International AIDS Conference18-23 July 2010, Vienna, Austria

Shionogi-ViiV Healthcare LLC

Backups

13


S/GSK1349572 Day 10 PK Parameters

AUC(0-), ug*h/mL Cmax, ug/mL C, ug/mL

50mg QD (n=25) 36.5 (53%) 3.04 (38%) 0.69 (91%)

Geometric Mean (95% Confidence Interval)

GSK1349572 PK observed in VIKING is consistent with accumulated PK data in humans.

xviii international aids conference 18-23 july 2010, vienna, austria shionogi-viiv healthcare llc...

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