• Isocitrate dehydrogenase 1 mutations (IDH1m) produce 2-HG that blocks differentiation via inhibition of TET family enzymes and histone demethylases, yielding hypermethylated DNA and histones

• AZA, a hypomethylating agent (HMA), is a standard of care for MDS and for AML pts unfit for intensive therapy

• Superior clinical responses to HMAs have been reported in pts with IDH1m1

• IDH1m inhibitors + AZA showed synergistic effects on releasing differentiation block in IDH1m leukemia models in vitro2

• We present updated clinical data of FT-2102, an IDH1m inhibitor, in combination with AZA from the Phase 1 portion of the ongoing Phase 1/2 study of FT-2102 as a single agent and in combination with AZA in pts with IDH1m AML and MDS (CT.gov: NCT02719574)

FT-2102, an IDH1m Inhibitor, Combined with Azacitidine in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS): Results from a Phase 1 Study

Jorge E. Cortes1; Justin M. Watts2; Maria R. Baer3; Thomas Prebet4; Gary J. Schiller5; Sangmin Lee6; Jay Yang7; Eunice S. Wang8; Shira N. Dinner9; P. Brent Ferrell, Jr10; Will Donnellan11; Brian A. Jonas12; Pau Montessinos13; Montserrat Arnan Sangerman14; Patrick Kelly15; Julie Brevard15; Jennifer Sweeney15; Sanjeev Forsyth15; Patrick Henrick15; Hesham Mohamed15; Andrew Wei16

1MD Anderson Cancer Center, Houston, TX; 2University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; 3University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD; 4Yale University, New Haven, CT; 5David Geffen School of Medicine at UCLA, Los Angeles, CA; 6Cornell University, Ithaca, NY; 7Karmanos Cancer Center, Detroit, MI; 8Roswell Park Comprehensive Cancer Center, Buffalo, NY; 9Northwestern University, Chicago, IL; 10Vanderbilt University, Nashville, TN; 11Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 12UC Davis Comprehensive Cancer Center, Sacramento, CA; 13Hospital Universitari i Politècnic La Fe, Valencia, Spain;

14Institut Català d’Oncologia, Hospital Duran i Reynals, Barcelona, Spain; 15FORMA Therapeutics, Inc., Watertown, MA; 16The Alfred Hospital, Melbourne, Australia

Presented at the 24th Annual Congress of the European Hematology Association • Amsterdam, Netherlands • June 14, 2019

Demographics and Disease History Baseline Disease Characteristics

Characteristic FT-2102 + AZA (n = 46)

Age, median (range), years 67 (31 - 88)

Female, % 52

ECOG PS - 0 / 1 / 2, % 28 / 57 / 15

AML, n 39

Relapsed > 12 mo ≤ 12 mo

111 10

Refractory 15

Treatment-naïve 13

Secondary AML 15

t-AML 1

Prior regimens, median (range)* 3 (0 – 6)

HMA (azacitidine/decitabine) 9

IDHm inhibitor 4

Investigational 2

HSCT 3

MDS, n 7

Relapsed / Refractory 2

Treatment-naïve 5

Prior regimens, median (range)* 0 (0 – 4)

HMA (azacitidine/decitabine) 2* Not inclusive of all types; pt could have received more than one type

Disposition

Characteristic FT-2102 + AZA (n = 46)

Treatment Ongoing, n (%) 13 (28)

Treatment Discontinued, n (%) 33 (72)

Transplant (HSCT) 10 (22)

Disease Progression 7 (15)

Investigator Decision 5 (11)

Death 4 (9)

Adverse Event 4 (9)

Other* 3 (7)

Time on Treatment, months (median [range])

4.6 (< 1, 18)

* Reasons include treatment failure, hospice, and alternative therapy

FT-2102 + AZA TN AML (n = 13)

R/R AML (n = 26)

MDS (n = 7)

IDH1 mutation type*, n

R132C 8 13 2

R132H 1 9 4

R132S 2 2 0

R132G 2 2 0

Other** 0 0 1

Concurrent mutations*, n

FLT3 0 7 1

NPM1 0 6 0

CEBPA 0 1 1

TP53 0 2 0

IDH2 1 0 0

Cytogenetic Risk*, n

Favorable 0 0 3

Intermediate 6 15 0

Poor 3 5 1

Unknown 4 6 3* As reported by investigator per local tests

** One pt with a non-R132 mutation variant

Acknowledgements: We would like to acknowledge the participating institutions, their study investigators, and clinical staff for the successful conduct of the study. Most importantly, we sincerely thank our patients and their families for their participation.

Abbreviations: 2-HG = 2-hydroxyglutarate; AE = adverse event; AZA = azacitidine; BBB = Bundle Branch Block; BL = Baseline; C = cycle; Ceff = effective concentration; Css = steady state concentration; CR = complete remission; CRh = complete remission with partial hematological recovery; CRi = complete remission with incomplete hematologic recovery; D = day; HMA = hypomethylating agent; HSCT = hematopoietic stem cell transplantation; IDH-DS = IDH differentiation syndrome; MDS = myelodysplastic syndrome; MLFS = morphologic leukemia-free state; MTD = maximum tolerated dose; NE = not evaluable; NHP = non-human primate; ORR = overall response rate (CR + CRh + CRi + MLFS); PD = progressive disease; PK/PD = pharmacokinetics and pharmacodynamics; PR = partial response; RP2D = recommended Phase 2 dose; R/R = relapsed/refractory; SA = single agent; SD = stable disease; TEAE = treatment-emergent adverse event; TN = treatment-naïve

References: 1) Emadi et al. American Journal of Hematology, 90:5 May 2015. 2) DiNardo et al. Blood 2017 130:639.

EHA-3328

Phase 2 Study Open for Combination R/R AML & MDS (NCT02719574)

Phase 1 Study in IDH1m AML & MDS

Key Study Objectives

• Determine MTD/RP2D for FT-2102

• Evaluate safety

• Evaluate PK and PK/PD (2-HG) relationship

• Evaluate preliminary anti-leukemia activity

Background

Key Eligibility Criteria

• AML or MDS: documented IDH1-R132X mutation by local testing

• Adequate liver and renal function

• Baseline QTcF ≤ 450 msec (unless history of BBB)

• No exclusions for concomitant medications

• R/R to standard therapy or TN & eligible for AZA

• Prior IDH1m inhibitor or HMA allowed

* Pt with R100 mutation excluded from clinical response table

Dose Escalation (n = 15)

Dose Expansion (n = 31)

150 mg QD + AZA (n = 7)150 mg BID + AZA (n = 8)

R/R AML or MDS150 mg BID + AZA (n = 16)

TN AML or MDS150 mg BID + AZA (n = 15)

Data cutoff: 12 Apr 2019FT-2102 administered PO daily in 28-day cyclesAZA administered 75 mg/m2 IV or SC daily for 7 days of each 28-day cycle

Nucleus

Nucleo-some

Histonedemethylases

KDM2a

OH

TET1TET2

Me

MeMe

Epigenetic changes(e.g. hypermethylation)induce impaired cellulardifferentiation

Azacitidine, a hypomethylatingagent, reduces DNA methylationand induces cellular differentiation

2-HG induces dysregulationof epigenetic and geneexpression profiles

Cytoplasm

Endostatin

HIF1-αstabilization

Citrate

Isocitrate

IDH1

Tumor Cell

α-KGIDH1mut

HIF1-α

2-HG

Adapted from Presner and Chinnaiyan, Nature Medicine (2011)

R/R AML/MDS, < 60 y/o, naïve to HMA and IDH1m inhibitor

R/R AML/MDS, inadequate response or PD on HMA

R/R AML/MDS, failing IDH1m inhibitor

TN AML, candidates for AZA as first-line treatment

IDH1m AML/MDSFT-2102 150 mg BID

+ AZA

First ResponseOn treatmentOff treatmentTransplant (HSCT)ProgressionContinuing on study

FT-2102 is Well Tolerated in Combination with AZA

Hematologic: Preferred Term*

FT-2102 + AZA (n = 46)

All Gr. n (%)

Gr. 3/4 n (%)

Thrombocytopenia 18 (39) 15 (33)

Febrile neutropenia 15 (33) 13 (28)

Neutropenia 15 (33) 13 (28)

Anaemia 10 (22) 9 (20)

Leukocytosis 12 (26) 7 (15)

Leukopenia 8 (17) 6 (13)* Each hematologic term includes the associated PT

from the investigation SOC and hematologic SOC

Non-Hematologic: Preferred Term

FT-2102 + AZA (n = 46)

All Gr. n (%)

Gr. 3/4 n (%)

Nausea 32 (70) 4 (9)

Constipation 26 (57) 1 (2)

Diarrhoea 21 (46) 2 (4)

Fatigue 18 (39) 7 (15)

Cough 17 (37) 1 (2)

Vomiting 17 (37) 1 (2)

Hypokalaemia 16 (35) 3 (7)

Headache 14 (30) 1 (2)

Dyspnoea 12 (26) 2 (4)

Decreased Appetite 11 (24) 1 (2)

Dizziness 10 (22) 1 (2)

Abdominal Pain 9 (20) 1 (2)

Asthaenia 9 (20) 1 (2)

Insomnia 9 (20) 0

Pyrexia 9 (20) 0

Oedema Peripheral 8 (17) 0

Pneumonia 8 (17) 5 (11)

Pruritus 8 (17) 0

Arthralgia 7 (15) 0

Hypertension 7 (15) 6 (13)

Oropharyngeal Pain 7 (15) 0

Pain in Extremity 7 (15) 1 (2)

TEAEs ≥ 15% All Grades Regardless of Causality

Clinical Activity

Investigator-Assessed Response

Response TN AML (n = 13)

R/R AML (n = 26)

MDS (n = 6)*

ORR, n (%) [95% CI]

9 (69) [39, 91]

12 (46) [27, 67]

5 (83) [36, 100]

CR, n (%) 6 (46) 3 (12) 5 (83)

CRh, n (%) 0 1 (4) N/A

CRi, n (%) 3 (23) 6 (23) 0

MLFS, n (%) 0 2 (8) 0

SD, n (%) 2 (15) 11 (42) 1 (17)

PD, n (%) 0 1 (4) 0

NE, n (%) 2 (15) 2 (8) 0

ORR = overall response rate (CR + CRh + CRi + MLFS)

* One pt excluded from efficacy analysis due to the lack of an R132X mutation; pt continued on treatment and achieved a marrow CR

8070503010 6040200Weeks

CRCR

Marrow CRCRCRCRSD

*

Time on Treatment – FT-2102 + AZA: MDS

8070503010 6040200Weeks

CRCRi

MLFSCRiSDSDSD

CRiCRiCRSDCRCRiSD

MLFSSD

CRhSDPD

CRiSDSDSDSDNENE

Time on Treatment – FT-2102 + AZA: R/R AML

• 8/12 (67%) pts who achieved response discontinued for HSCT• Pts treated for a median of 3 months (range < 1, 7);

2 pts remain on treatment

• 5/6 (83%) pts achieved CR; 2 pts moved to transplant• Pts treated for a median of 5 months (range 4, 15); 4 pts remain on treatment

8070503010 6040200

CRCRCRCRiCRCRCRiSDCRCRiSDNENE

Weeks

Time on Treatment – FT-2102 + AZA: TN AML

• Response achieved in 69% of pts; mDOR = 8.3 months (range 3.7, 13.9)

• Pts treated for a median of 8 months (range < 1, 18); 9 pts remain on treatment

Pharmacokinetics and PharmacodynamicsFT-2102 150 mg BID Maintains Favorable PK Over Time

• Combination therapy of AZA plus FT-2102 150 mg BID maintained steady state concentrations of FT-2102 above the Ceff (effective concentration; resulting in 90% reduction in plasma 2-HG in mice) and below the FT-2102 levels predicted to pose a QT prolongation risk

• Azacitidine did not alter the pharmacokinetics of FT-2102, with consistent FT-2102 plasma concentrations observed over the treatment duration

FT-2102 RP2D Provides Sustained 2-HG Inhibition Over Time

• A significant (p < 0.0001) reduction in plasma 2-HG levels at the end of Cycle 1 was observed with the combination of FT-2102 (150 mg BID) and AZA and was sustained over the treatment duration

0

2000

4000

6000

8000

C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16C1D15

FT-2

102

Pla

sma

C

onc

ent

ratio

n (n

g/m

L)

Ceff (mouse model)

QTc Prolongation Potential (NHP)

10

100

1000

1E+04

BL C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16

Pla

sma

2-H

G

Co

nce

ntra

tion

(ng

/mL)

Median for wild-type IDH1AML patients

• FT-2102 in combination with AZA at 150 mg BID dose (RP2D) is well tolerated with a low risk of QT prolongation

• The combination of FT-2102 and AZA demonstrates clinical activity in a high-risk Phase 1 population of AML/MDS pts with an IDH1 mutation:

– In TN AML, 69% of pts achieved ORR with a mDOR of 8.3 months

– In R/R AML, 46% of pts achieved ORR, with 8/12 pts who responded proceeding to HSCT (censored, mDOR not calculated)

– In AML, durable disease control (> 6 months) was observed in the absence of IWG response

– In MDS, 83% of pts achieved a CR

Adverse Events of Interest

• IDH differentiation syndrome (IDH-DS): – 6 (13%) pts; all resolved with treatment interruption/reduction, dexamethasone, hydroxyurea, and supportive care, and then resumed treatment

– Best response in pts with IDH-DS (n = 6):

CR CRh CRi MLFS SD

3 1 0 1 1

• Low risk of QT prolongation: – 3 (7%) pts reported AEs of QT prolongation on study (G1, G2, and G3); all events were transient and pts resumed treatment

Study Conclusions