Uproleselan (GMI-1271), an E-selectin antagonist, improves efficacy and safety of chemotherapy in R/R and newly diagnosed older patients with AML:

final, correlative, and subgroup analysesDaniel J. DeAngelo, Brian A. Jonas, Jane L. Liesveld, Dale L. Bixby, Anjali S. Advani, Paula Marlton, Michael E. O’Dwyer, William E. Fogler, Curt D. Wolfgang, John L.

Magnani, Helen M. Thackray, Pamela S. Becker

American Society of Hematology Annual Meeting, San Diego, CA USA, 2 Dec 2018

Dana-Farber Cancer Institute, Boston, MA; UC Davis Comprehensive Cancer Center, Sacramento, CA; U of Rochester School of Medicine and Dentistry, Rochester, NY; University of Michigan, Ann Arbor, MI; Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; Princess Alexandra Hospital, University of Queensland School of Medicine, Brisbane, Australia; National University of Ireland Galway, Galway, Ireland; GlycoMimetics, Rockville, MD;

University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA

Uproleselan (GMI-1271), an E-selectin Antagonist, Disrupts the Relationship Between Tumor Cells and Bone Marrow Microenvironment

E-selectin –

• Constitutively expressed in the bone marrow microvasculature

• Binds to the E-selectin ligands on AML cells• Promotes environment-mediated drug

resistance (EMDR) of leukemic cell

Uproleselan, an E-selectin antagonist –

• Inhibits activation of cancer survival pathways (e.g. NF-KB), disrupting EMDR within bone marrow

• Prolongs survival over chemotherapy alone in animal models

• Protects normal HSCs by enhancing quiescence and ability for self-renewal

• Reduces chemotherapy-associated mucositis

• Female NOD SCID mice injected iv with 5x106

human tumor cells (n=10-11/group)• Rx 3 days U937 injection

Treatment Survival (days)

% survival (day 120)

Saline 33 0

UproleselanIP 40 mg/kg bid x 10 days

26 0

AraC/DNR 71 20

Uproleselan+ AraC/DNR >120 55

• Clinical course may be predicted by expression of E-selectin ligand (sialyl Lex) on leukemic blasts‡• Addition of uproleselan to chemotherapy hypothesized to improve clinical outcomes, including survival

‡Aref S, et al. Hematology 2002, 7(2):83-87. Noguchi m, et al. Leuk Res. 2001, 25(10):847-853.*Winkler IG et al. Blood 2016, 128:2823. Chien S, et al. Blood 2012;120:4092.

Perc

ent S

urvi

val

Rx

0 20 40 60 80 100 1200

20

40

60

80

100

Days Post Tumor Implant

*p=0.03

Prolonged Survival Replicated in 4

Separate AML in vivo Models

(e.g. syngeneic, xenogeneic and

patient blasts)

Uproleselan in Combination with Chemotherapy Prolongs Survival in AML Tumor Models

0.4

0.6

0.8

1.0

5FU-treated

Saline

Untreated

Uproleselan

Sma

ll In

test

ine

Wei

ght

(g

)

0 20

5FU 5FU

†14 days

Up

role

sela

n

Salin

e

*Winkler et al. Blood. 2014;122:21.

F4/80 Macrophage Staining of Murine Small Intestine

Blockade of E-selectin significantly reduced intestinal mucositis and therapy-induced weight loss

Saline Uproleselan

Uproleselan Protects against Chemotherapy-Induced Mucosal Injury

Study Schema

*Amended to include up to 3 cycles of consolidation in Phase 2

• Eligible patients – Relapsed/refractory– ≥18 years old– Primary refractory AML, ≤2 prior inductions (one

with anthracyclines)– OR in first or second relapse– HSCT was allowed, >4 months prior (no GVHD)– Hemodynamically stable/adequate organ function

• Eligible patients – Newly diagnosed– Patients ≥60 years with newly diagnosed AML– Prior treatment for MDS, CMML was allowed– ECOG 0-2– Hemodynamically stable/adequate organ function

RP2D 10 mg/kg

Demographics – Relapsed/Refractory PatientsN=66

Age, median (range) 59 (26-84)Refractory, n (%) 22 (33)Relapsed, n (%) 44 (67)

Duration of prior remission <6 mos 22 (33)Prior Therapies

HSCT 11 (17)≥2 Induction Regimens 22 (33)

ELN Risk Category Intermediate 11 (17)Adverse 33 (50)Unknown 15 (23)

MutationsFLT3-ITD 3 (5)TP53 mutation; del (17p) 4 (6)

Grade 3/4 Adverse Events – Relapsed/Refractory Patients

Adverse Event TypeTotalN=66

RP2DN=54

Cardiac 6 (9) 5 (9)Colitis 2 (3) 1 (2)GI 7 (11) 4 (7)Hepatic 3 (5) 3 (6)Infectious 50 (76) 39 (72)

Bacteraemia 8 (12) 8 (15)

Febrile neutropenia 31 (47) 27 (50)

Sepsis 12 (18) 8 (15)

Oral Mucositis EventsGrades 1/2, n (%) 14 (21) 9 (17)

Grades 3/4, n (%) 2 (3) 1 (2)

Response Data – Relapsed/Refractory Patients

Outcomes, n (%)

Relapsed/RefractoryTotal (N=66) RP2D (N=54)

CR/CRi 26 (39) 22 (41)CR 22 (33) 19 (35)ORR (CR/CRi/MLFS/PR) 32 (48) 27 (50)Mortality, All-Cause

30 days 1 (2) 1 (2)60 days 6 (9) 5 (9)

Outcomes by Subgroup (CR/CRi Rate and %)Primary Refractory 8/22 (36) 5/17 (29)Relapsed (total) 18/44 (41) 17/37 (46)

Duration, prior remission <6 mos 5/22 (23) 5/19 (26)Duration, prior remission ≥12 mos 9/12 (75) 9/12 (75)

MRD RatesMRD Negative* (N=16 evaluable) 11 (69) 11 (69)Proceeded to SCT 17 (26) 16 (30)

*MRD negative = <10-3 leukemic cells at end of induction by local assessment using multicolor flow, RT-PCR, or NGS

• Median OS 8.8 mos (95% CI 5.7-11.4)– 28% censored at last follow-up– Median follow up 8.9 mos

• 1-year OS: – For all patients – 35%– For MRD negative – 73%

• 10 longest survivors (≥16 mos) all had either HSCT or MEC/uproleselanconsolidation − All were MRD negative

RP2D shown, N=54.

Survival Outcomes – Relapsed/Refractory Patients

# at risk 54 41 29 19 8 4 3 2 0

Subgroup Outcomes – Relapsed/Refractory Patients

• Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated- Primary refractory disease (N=22)

- Median OS 6.7 mos (3.1-13.8)- Early relapse

- Late relapse

Primary Refractory

Primary Refractory 22 16 10 9 2 0

Subgroup Outcomes – Relapsed/Refractory Patients

• Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated- Primary refractory disease (N=22)

- Median OS 6.7 mos (3.1-13.8)- Early relapse (<6 mo., N=22)

- Median OS 5.1 mos (3.2-9.4)- Late relapse

Primary RefractoryEarly Relapse

Primary Refractory 22 16 10 9 2 0Early Relapse 22 13 7 5 0

Subgroup Outcomes – Relapsed/Refractory Patients

• Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated- Primary refractory disease (N=22)

- Median OS 6.7 mos (3.1-13.8)- Early relapse (<6 mo., N=22)

- Median OS 5.1 mos (3.2-9.4)- Late relapse (>12 mo., N=12)

- Median OS NA (9.6-NA)

Primary RefractoryEarly RelapseLate Relapse

Primary Refractory 22 16 10 9 2 0Early Relapse 22 13 7 5 0Late Relapse 12 12 12 8 5 3 2 0

Subgroup Outcomes – Relapsed/Refractory Patients

• Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated- Adverse risk by ELN (N=39)

- Median OS 5.9 mos (3.4-9.4)- All other

Adverse 39 24 16 11 3 0

Adverse

Subgroup Outcomes – Relapsed/Refractory Patients

• Uproleselan with MEC resulted in promising survival outcomes for each subgroup evaluated- Adverse risk by ELN (N=39)

- Median OS 5.9 mos (3.4-9.4)- All other (N=27)

- Median OS 11.4 mos (5.8-NA)- p=0.018 by log rank, Kaplan-Meier

method

AdverseAll other

Adverse 39 24 16 11 3 0All other 27 24 17 12 6 5 4 2 0

• Higher E-sel ligand expression on blasts associated with poor prognosis – Chien et al, ASH 2018 abstract #1513

• E-sel ligand expression is detected in 100% of the trial population, and the majority of patients have E-sel ligand on >10% of leukemic blasts

• E-sel ligand expression on blast population correlates with LSC population

Relapsed/Refractory

E-selectin Ligand Detectable on Blasts in All PatientsRelapsed/Refractory

Overall Survival Based on E-selectin Ligand Expression• High expressers (E-sel ligand ≥10% of

LSCs or blasts) have poor prognosis (Chien abstract #1513)

• Addition of uproleselan to MEC reverses this: high expresser group survives longer than the low expresser group (E-sel ligand <10% of LSCs or blasts)

• Median OS 12.7 mos (8.3-NA) for ‘High expressers’

• Median OS 5.2 mos (2.3-9.4) ‘Low expressers’

• p=0.0056 by log rank, Kaplan-Meier method

• Data verify E-selectin/ligand as a target in AML

E-sel-L ≥10%E-sel-L <10%

E-sel-L ≥10% 22 20 17 12 6 3 2 0E-sel-L <10% 14 10 4 1 0

N=36 Evaluable for E-sel ligand at baseline

Demographics – Newly Diagnosed Patients

N=25Age, median (range) 67 (60-79)Newly diagnosed

de novo 12 (48)Secondary AML 13 (52)

ELN Risk CategoryFavorable 3 (12)Intermediate 7 (28)Adverse 12 (48)Unknown 3 (12)

Grade 3/4 Adverse Events – Newly Diagnosed Patients

Adverse Event Type N=25Colitis 3 (12)Infectious 19 (76)

Febrile neutropenia 17 (68)Sepsis 4 (16)Pneumonia 3 (12)

Respiratory 7 (28)Oral Mucositis Events

Grades 1/2, n (%) 5 (20)Grades 3/4, n (%) 0

Response Data – Newly Diagnosed PatientsOutcomes, n (%)

Newly DiagnosedN=25

CR/CRi 18 (72)CR 13 (52)ORR (CR/CRi/MLFS/PR) 20 (80)Mortality, All-Cause

30 days 2 (8)60 days 3 (12)

Outcomes by Subgroup (CR/CRi Rate and %)AML Type

de novo 9/12 (75)Secondary AML 9/13 (69)

MRD RatesMRD Negative* (N=9 evaluable) 5 (56)Proceeded to SCT 11 (44%)

*MRD negative = <10-3 leukemic cells at end of induction by local assessment using multicolor flow, RT-PCR, or NGS

Survival Outcomes – Newly Diagnosed Patients

• Median EFS 9.2 mos (3-12.6)– 16% censored at last follow-up

• Median OS 12.6 mos (9.9-NA)– Median follow up 13.0 mos

• 1-year OS: – All patients – 52%– MRD negative – 60%

All 25 16 14 9 5 3 0 All 25 20 18 12 7 3 0

All All

Subgroup Outcomes – Newly Diagnosed Patients

• Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated– All newly diagnosed (N=25): Median EFS 9.2 mos (3-12.6). Median OS 12.6 mos (9.9-NA).– sAML (N=13): Median EFS 7.7 mos (1.1-9.5). Median OS 10.5 (4.4-NA). – de novo AML

All 25 16 14 9 5 3 0

Secondary 13 8 6 2 0

All 25 20 18 12 7 3 0

Secondary 13 11 9 4 1 0

AllSecondary

AllSecondary

Subgroup Outcomes – Newly Diagnosed Patients

All 25 16 14 9 5 3 0

Secondary 13 8 6 2 0De Novo 12 8 8 7 5 3 0

AllSecondaryDe Novo

All 25 20 18 12 7 3 0

Secondary 13 11 9 4 1 0De Novo 12 9 9 8 6 3 0

AllSecondaryDe Novo

• Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated– All newly diagnosed (N=25): Median EFS 9.2 mos (3-12.6). Median OS 12.6 mos (9.9-NA).– sAML (N=13): Median EFS 7.7 mos (1.1-9.5). Median OS 10.5 (4.4-NA). – de novo AML (N=12): Median EFS 13.2 mos (0.8-NA). Median OS NA (0.8-NA).

Subgroup Outcomes – Newly Diagnosed Patients

• Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated– Adverse risk by ELN (N=8): Median EFS 3.1 mos (0.1-9.2). Median OS NA (0.1-NA). – All other

Adverse 8 4 3 2 1 1 1 0 Adverse 8 6 5 5 3 3 1 0

Adverse Adverse

Subgroup Outcomes – Newly Diagnosed Patients

• Uproleselan with 7+3 resulted in promising survival outcomes for each subgroup evaluated– Adverse risk by ELN (N=8): Median EFS 3.1 mos (0.1-9.2). Median OS NA (0.1-NA). – All other (N=17): Median EFS 11.3 mos (1.6-21.1). Median OS 12.6 (7.8-NA).

AdverseAll other

AdverseAll other

Adverse 8 4 3 2 1 1 1 0

All other 17 13 12 11 8 4 4 2 0

Adverse 8 6 5 5 3 3 1 0

All other 17 15 14 13 9 7 5 2 0

ConclusionsUproleselan, an E-selectin antagonist, can be safely added to chemotherapy ‒ MEC as well as standard 7+3

Selective disruption of the bone marrow niche with uproleselan is associated with:– Low rates of severe oral mucositis– Encouraging clinical outcomes• High remission rates (CR/CRi)– Relapsed/refractory and elderly newly diagnosed

• High rates of MRD negativity• Promising survival outcomes across all subgroups assessed

Correlative studies support biological and clinical rationale for targeting E-selectinConfirmatory trials underway in relapsed/refractory AML and frontline AML – Breakthrough Therapy Designation granted by FDA for R/R population– NCT03616470 (Relapsed/Refractory AML), NCT03701308 (Newly Diagnosed AML)

Acknowledgements• Patients and their families• Study Research Staff at our institutions

– Dana-Farber Cancer Institute, UC Davis Comprehensive Cancer Center, University of Rochester School of Medicine and Dentistry, University of Michigan Comprehensive Cancer Center, Taussig Cancer Center Cleveland Clinic, Princess Alexandra Hospital Brisbane, National University of Ireland Galway, University of Washington/Fred Hutchinson Cancer Research Center

• University of Washington Becker Lab – correlative biomarkers– Sylvia Chien, Jin Dai

• Rho, Inc. – Shane Rosanbalm, statistician

• GlycoMimetics, Inc. – Mary Chen, Martina Hemmer, Christine Nietubicz, Henry Flanner, Shanti Rodriguez,

Britney Brown• Novella Clinical

– Richard Gams, Rebecca Light