1-4 April 2014, Arena and Convention Centre Liverpool

THIRD JOINT CONFERENCE

OF BHIVA AND BASHH 2014

Dr Max LatailladeBristol-Myers Squibb Pharmaceuticals

BHIVA 2014

(Abstract O2)

HIV-1 Attachment Inhibitor Prodrug in

Antiretroviral-Experienced Subjects: Week 24 Analysis

AI438011: A Phase IIb, Randomized, Controlled,

Partially-Blinded Trial to Investigate the Safety,

Efficacy and Dose-response of BMS-663068 in

Treatment-Experienced HIV-1-positive Subjects

Lalezari J, Latiff GH, Brinson C, Echevarría J, Treviño-Pérez S,

Bogner JR, Stock D, Joshi SR, Hanna GJ, and Lataillade M

for the AI438011 study team

Financial Disclosures

This study was funded by Bristol-Myers Squibb

Max Lataillade , DO MPH, Bristol-Myers Squibb, Wallingford,

CT

Executive Director, HIV Drug Development

Employee and shareholder of Bristol Myers-Squibb

BMS-663068 Overview

Prodrug metabolized to BMS-626529, a first-in-class

attachment inhibitor that binds to HIV-1 gp120,

preventing initial viral attachment and entry into

the host CD4+ T cell1,2

In vitro activity against HIV-1 viruses, with the

exception of subtype AE and Group O, irrespective

of co-receptor tropism3

Unique resistance profile with no in vitro cross-

resistance to other classes of antiretrovirals4

In the POC study, substantial declines in plasma HIV-

1 RNA (1.21–1.73 log10 c/mL) in treatment-naïve and

–experienced subjects after 8 days of monotherapy5

Generally well tolerated in clinical studies5

1. Brown J et al. J Pharm Sci 2013: 102(6):1742–512; 2. Langley DL et al. Manuscript in development; 3. Nowicka Sans Bet al. AAC 2012: 56:3498–507; 4. Li Z et al. AAC 2013: 57(9):4172–80; 5. Nettles R et al. J Infect Dis 2013: 206:1002–11.

Conversion of BMS-663068

to BMS-626529

BMS-626529 Attachment Inhibitor:

Proposed Mechanism of Action

1. Langley DL et al. Manuscript in development.

gp120

gp41

Conformational

changes

CD4 binding

Blocked

No drug BMS-626529

Conformational

changes inhibited

gp120

gp41

BMS-626529 binding

CD4 binding site

CD4 receptor

CD4 binding

CCR5

co-receptorCell surface

AI438011: Key Inclusion Criteria

Antiretroviral treatment-experienced (defined as current or

previous exposure to ≥ 1 antiretroviral for ≥ 1 week)

Plasma HIV-1 RNA ≥1000 c/mL

CD4+ T-cell count >50 cells/mm3

Susceptibility to RAL, TDF and ATV

BMS-626529 IC50 <0.1 μM (100 nM) as determined by screening

Phenosense® entry assay (Monogram Biosciences – LabCorp)

AI438011: Study Design

BMS-663068 Monotherapy Substudy: 10 patients per study arm

BMS-663068

400 mg BID

+ RAL + TDF

N=50

BMS-663068

800 mg BID

+ RAL + TDF

N=50

BMS-663068

600 mg QD

+ RAL + TDF

N=50

BMS-663068

1200 mg QD

+ RAL + TDF

N=50

ATV/r

300/100 mg QD

+ RAL + TDF

N=50

Part

ial Blind

Day 1 Primary study - start of combination therapy

Week 8 Data monitoring committee assessment

Week 24 Primary endpoint

Week

48/96Long-term follow-up through Week 48/96

AI438011: Baseline Characteristics

BMS-663068 + TDF + RAL ATV/r +TDF + RAL

400 mg BID

N=50

800 mg BID

N=49

600 mg QD

N=51

1200 mg QD

N=50

300 mg/100 mg QD

N= 51

Median age, years 38.1 38.4 40.1 39.2 39.6

Male, % 62.0 57.1 56.9 68.0 56.9

Non-white, % 60.0 61.2 66.7 68.0 55.0

HIV subtype, %

B

C

Other

70.0

16.0

14.0

59.2

24.5

16.2

68.6

21.6

9.9

64.0

20.0

16.0

66.7

17.6

15.6

HIV-1 RNA

mean, log10 c/mL

>100,000 c/mL, %

4.76

46.0%

4.85

51.0%

4.95

45.1%

4.65

36.0%

4.69

35.3%

CD4+ T-cell count

mean cells/µL

<200 cells/µL, %

252.9

38.0%

264.3

32.6%

241.5

41.2%

247.7

42.0%

265.4

37.3%

BMS-626529 IC50 median, nM 0.68 0.65 0.43 0.82 0.73

• Baseline Resistance (N=251): M184V/I, 29%; K103N, 29%; TAMS, 13%; Major PI mutations, 2%.

AI438011: Subject Disposition*

*581 patients screened

BMS-663068

400 mg BID

+ RAL + TDF

BMS-663068

800 mg BID

+ RAL + TDF

BMS-663068

600 mg QD

+ RAL + TDF

BMS-663068

1200 mg QD

+ RAL + TDF

ATV/r

300/100 mg QD

+ RAL + TDF

52Randomized

Treated

Discontinued

50 (96.2%)

6 (11.5%)

1 AE

1 consent

withdrawal

2 lost to FU

1 poor/ non-

compliance

1 other

49

49 (98.0%)

51

51 (100%)

7 (13.7%)

1 pregnancy

1 lost to FU

2 no longer met

study criteria

2 poor/ non-

compliance

1 other

50

50 (100%)

8 (16.0%)

1 AE

1 consent

withdrawal

3 lost to FU

1 subject request

1 no longer met

study criteria

1 lack of efficacy

51

51 (100%)

9 (17.6%)

2 AEs

3 consent

withdrawals

2 pregnancies

1 admin-related

1 poor/ non-

compliance

11 (22.0%)

2 AEs

2 consent

withdrawals

2 pregnancies

1 no longer met

study criteria

3 lack of efficacy

1 poor/ non-

compliance

AI438011: BMS-663068 Monotherapy Substudy:

Mean Change in HIV-1 RNA from Baseline*

*Error bars represent standard error of the mean.

AI438011: Proportion of Subjects Achieving

HIV-1 RNA <50 or < 400 c/mL

(Week 24 Snapshot): mITT

mITT population: all subjects receiving ≥1 dose of study drug

BMS-663068 + TDF + RAL ATV/r + TDF + RAL

400 mg BID

N=50

800 mg BID

N=49

600 mg QD

N=51

1200 mg QD

N=50

300 mg/100 mg QD

N=51

HIV-1 RNA <50 c/mL, % 80.0% 69.4% 76.5% 72.0% 74.5%

HIV-1 RNA ≥50 c/mL, % 16.0% 20.4% 21.6% 26.0% 17.6%

No virologic data at Week 24

Discontinued due to AE or

death, n (%) 1 (2.0%) 2 (4.1%) 0 1 (2.0%) 2 (3.9%)

Discontinued for other

reasons, n (%) 1 (2.0%) 3 (6.1%) 1 (2.0%) 0 2 (3.9%)

Missing data during window

but on-study, n (%) 0 0 0 0 0

HIV-1 RNA <400 c/mL, % 92% 80% 90% 80% 82%

AI438011: Proportion of Subjects Achieving

HIV-1 RNA <50 or <400 c/mL

(Week 24 Window): Observed

Observed population: subjects receiving ≥1 dose of study drug and with plasma HIV RNA data within the Week 24 window

BMS-663068 + TDF + RAL ATV/r + TDF + RAL

Observed (data

within Week 24

window)

400 mg BID

N=46

800 mg BID

N=42

600 mg QD

N=50

1200 mg QD

N=43

300 mg/100 mg QD

N=44

HIV-1 RNA

<50 c/mL, %87% 81% 78% 84% 86%

HIV-1 RNA

<400 c/mL, %100% 93% 92% 93% 96%

AI438011: Proportion of Subjects Achieving

HIV-1 RNA <50 c/mL by Baseline BMS-626529

IC50 Category: Observed

BMS-663068 + TDF + RAL ATV/r +TDF + RAL

Subgroup 400 mg BID

N=46

800 mg BID

N=42

600 mg QD

N=50

1200 mg QD

N=43

300 mg/100 mg QD

N=44

Baseline BMS-626529 IC50 category, n (%)

<0.1 nM

≥0.1 nM

2/2 (100%)

38/44 (86%)

1/1 (100%)

33/41 (81%)

3/3 (100%)

36/47 (77%)

2/2 (100%)

34/41 (83%)

0

38/44 (86%)

<1.0 nM

≥1.0 nM

23/27 (85%)

17/19 (90%)

20/22 (91%)

14/20 (70%)

26/34 (77%)

13/16 (83%)

18/21 (86%)

18/22 (82%)

24/26 (92%)

14/18 (78%)

<10.0 nM

≥10.0 nM

32/38 (84%)

8/8 (100%)

31/36 (86%)

3/6 (50%)

33/43 (77%)

6/7 (86%)

31/37 (84%)

5/6 (83%)

36/40 (90%)

2/4 (50%)

AI438011: Safety Summary

BMS-663068:

13 subjects reported 15 SAEs, none related to BMS-663068

No BMS-663068-related AEs led to discontinuation

No trend for Grade 2-4 related clinical adverse events or laboratory abnormalities

4 AEs leading to discontinuation: 1 non-specific EKG changes*, 2 TB cases, 1 TDF ARF

ATV:

Grade 2–4 ATV/r-related AEs were mostly secondary to GI disorders

*Corrected as not related (drug abuser)

BMS-663068 + TDF + RAL ATV/r +TDF + RAL

Total number of

subjects

400 mg BID

N=50

800 mg BID

N=49

600 mg QD

N=51

1200 mg QD

N=50

300 mg/100 mg QD

N=51

SAEs, n (%) 4 (8.0%) 4 (8.2%) 3 (5.9%) 2 (4.0%) 5 (9.8%)

Grade 2–4 related AEs,

n (%)6 (12.0%) 3 (6.1%) 2 (3.9%) 6 (12.0%) 14 (27.5%)

AEs leading to

discontinuation, n (%)1 (2.0%) 2 (4.1%) 0 1 (2.0%) 2 (3.9%)

AI438011: Summary

Through week 24, response rates were similar across all BMS-663068 arms

and with ATV/r in treatment-experienced, HIV-positive subjects

69–80% on BMS-663068 and 75% on ATV/r had HIV-1 RNA <50 c/mL (mITT Snapshot

algorithm)

78-87% on BMS-663068 and 86% on ATV/r had HIV-1 RNA <50 c/mL (observed)

Seven days of monotherapy resulted in mean decreases in plasma HIV-1 RNA

of 0.7–1.47 log10 c/mL across BMS-663068 doses

Response rates were comparable regardless of BMS-626529 IC50 category

BMS-663068 was generally well tolerated across all arms without any dose–

response safety signal

These results support the continued development of BMS-663068

Author Affiliations

Jacob Lalezari, Quest Clinical Research, San Francisco, CA, USA

Gulam H Latiff, Maxwell Clinic, Durban, South Africa

Cynthia Brinson, Central Texas Clinical Research, Austin, TX, USA

Juan Echevarría, Hospital Nacional Cayetano Heredia, Lima, Peru

Sandra Treviño-Pérez, Mexico Centre for Clinical Research, Mexico City, Mexico

Johannes Bogner, Hospital of the University of Munich, Munich, Germany

Max Lataillade, Samit R Joshi, David Stock, Bristol-Myers Squibb, Wallingford, CT, USA

George J Hanna, Bristol-Myers Squibb, Princeton, NJ, USA

Acknowledgments

We would like to thank all of the AI438011 clinical trial participants and their families

AI438011 Investigators: JD Altclas, PE Cahn, SH Lupo, MD Martins, AI Arango-Duque,

OA Sussmann-Pena, G Amaya-Tapia, JF Andrade-Villanueva, ER Granados-Reyes, J G Sierra-Madero,

SC Trevino-Perez, WM Casapia-Morales, JI Echevarria , JR Lama-Valdivia, MY Leon-Paredes,

FC Mendo-Urbina, Y Pinedo-Ramirez, MR Salazar-Castro, R Bardinas-Rodriguez, C Brinson,

E Dejesus, R Elion, J Ernst, J Feinberg, S Hassler, C Hicks, J Lalezari, AR Scribner, L Sloan,

M Thompson, K Arastéh, J Bogner, J Rockstroh A Stoehr, IG Diaconescu, LJ Prisacariu, S Rugina,

OA Tsybakova, EE Voronin, AA Yakovlev, NG Zakharova, J Fourie, D Johnson, R Kaplan, G Latiff,

B Clotet

Bristol-Myers Squibb: Anna Rightmire, Michelle DeGrosky, John Coumbis, Neela Ray, Nancy Cusack,

Mark Krystal, Carey Hwang and Todd Correll

Other: Peter Lill and John Riefler (ICON CRO)

Professional medical writing and editorial assistance was provided by Anna Shirazi at MediTech

Media and was funded by Bristol-Myers Squibb

Questions?

Back up slides

AI438011: Proportion of Subjects Achieving

HIV-1 RNA <50 c/mL by Baseline Viral Load:

Observed

AI438011: Mean Change in CD4+ T-cell Counts

from Baseline through Week 24: Observed*

*Error bars represent standard error of the mean.