ACKNOWLEDGMENTS: We would like to acknowledge the participating institutions, study investigators, and clinical staff for the successful conduct of the study. Most importantly, we sincerely thank the patients and their families for their participation.ABBREVIATIONS: AE, adverse event; ATP, adenosine triphosphate; AUCinf, area under the concentration-time curve from time 0 extrapolated to infinity; Cmax, maximum plasma concentration; 2,3-DPG, 2,3-diphosphoglycerate; EI, elongation index; GeoCV%, geometric coefficient of variation; GeoMean, geometric mean; Hb, hemoglobin; HbF, fetal hemoglobin; HbS, hemoglobin S; HV, healthy volunteer; MAD, multiple ascending dose; ns, not significant; P50, partial pressure of O2 at which Hb O2 saturation of 50% is achieved; PD, pharmacodynamic; PEP, phosphoenolpyruvate; PK, pharmacokinetics; PKR, pyruvate kinase R; POS, point of sickling; PRBC, packed RBC; QD, once daily; RBC, red blood cell; SAD, single ascending dose; SCD, sickle cell disease; TEAE, treatment-emergent adverse event; t1/2, half life; Tmax, time to maximum plasma concentration; VOC, vaso-occlusive crisis; VOC rate, VOCs requiring hospitalization.REFERENCES: 1Poillon WN, Kim BC. Blood. 1990;76(5):1028-36; 2 Banerjee T, Kuypers FA. Br J Haematol. 2004;124(3):391-402;3 Kalfa TA, Kuypers FA, Telen MJ, et al. Blood. 2019;134(suppl 1) [abstract 616].

2000 4000 6000 800015

20

25

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35

2,3-DPG (µg/gHb)

P 50

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Hg)

HV Pre-dose

HV r2=0.68

SCD Post-dose SCD Pre-doseHV Post-dose

Placebo 700 mg Placebo 700 mg15

20

25

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P 50

(mm

Hg)

Pre-dose 24 h Post-dose

ns****

****

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HV SCD

RESULTS, contRESULTS

Jeremie H. Estepp1, Theodosia Kalfa2, Santosh Saraf3, Hyon Kim4, Lukasz Biernat5, Punam Malik2, Kimberly Cruz6, R. Clark Brown7, Rose Fessler2, Frans A. Kuypers8,Lindsey Wilson9, Maria Ribadeneira9, Sanjeev Forsyth9, Patricia Schroeder9, Eric Wu9, Patrick Kelly9, Marilyn J. Telen10

1St. Jude Children’s Research Hospital, Memphis, TN, USA; 2Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 3University of Illinois, Chicago, IL, USA; 4University of Cincinnati, Cincinnati, OH, USA; 5Medpace Clinical Pharmacology Unit, Cincinnati, OH , USA; 6Advanced Pharma, Miami, FL, USA; 7Children’s Healthcare of Atlanta, Atlanta, GA, USA; 8Children’s Hospital Oakland Research Institute, Oakland, CA, USA; 9Forma Therapeutics, Inc., Watertown, MA, USA; 10Duke University, Durham, NC, USA

INTRODUCTIONSICKLE CELL DISEASE• HbS polymerizes upon deoxygenation, resulting in RBC sickling and membrane damage, which lead to hemolysis

and vaso-occlusion• Sickle RBCs contain more 2,3-DPG1 than healthy RBCs, resulting in:

◦ Decreased (↓) Hb O2 affinity [ie, increased (↑) P50]◦ Early release of O2, leading to deoxygenation of HbS, polymerization, and sickling

• Sickle RBCs have insufficient energy (ATP)2 for membrane maintenance and repair, contributing to hemolysis and a reduced RBC lifespan

CONCLUSIONS• A single dose of FT-4202 has a favorable safety profile in patients with SCD• FT-4202 exhibited linear and time-independent PK, leading to decreased 2,3-DPG and increased ATP

levels ◦ These results confirm that the PKR enzyme is functional and responsive to PKR activation in

SCD RBCs• A single dose of FT-4202 resulted in the favorable biological effects of:

◦ Improved oxygen affinity, decreased point of sickling, and improved deformability ◦ Improved membrane function, demonstrated by an improved response to an osmotic gradient

• A single dose of FT-4202 resulted in improvements in hemoglobin, RBCs, and reticulocytes when maximum PD effects were observed ◦ Indicating a sustained 2,3-DPG reduction and increased ATP production may improve the

hemolytic anemia and reduce the frequency of VOCs that characterize SCD• Studies are ongoing to further evaluate the safety, PK/PD, and clinical activity of FT-4202 following

daily administration in patients with SCD

PATIENT BASELINE CHARACTERISTICS

STUDY DESIGNKEY STUDY OBJECTIVES• Evaluate the safety and tolerability of single and

multiple doses of FT-4202 in HVs and patients with SCD• Characterize FT-4202 PK• Evaluate the levels of 2,3-DPG and ATP in the

RBCs of HVs and patients with SCD after FT-4202 dosing

KEY ELIGIBILITY CRITERIA FOR PATIENTS WITH SCD• SCD (Hb SS, SC, Sβ0-thalassemia, or Sβ+-thalassemia) previously confirmed • Ages 12 to 65 years with ≤ 6 vaso-occlusive crises (VOCs) within the past 12 months • No PRBC transfusion within 30 days of dosing; concomitant hydroxyurea use allowed

STUDY STATUS (Figure 2)• Healthy volunteer studies completed (N = 90) and findings previously presented,3 including:

◦ Favorable safety profile: Grade 1 headache was the most reported AE◦ No effect on testosterone or estradiol levels

• Exhibited linear and time-independent PK with pharmacodynamic responses (↓ 2,3-DPG and ↑ ATP)◦ Biologic effect: ↓ reticulocytes (P < .0001) after 3 days of daily FT-4202 dosing with ↑ Hb (ns)◦ Modeling of PD response in HV RBCs indicated that doses ≥ 150 mg per day result in the maximum ATP response,

and ≥ 400 mg per day maximize the 2,3-DPG response (Figure 3)• Based on the safety and PK/PD profile in HV studies, a 700-mg single dose was evaluated in patients with SCD (N = 7)

We report results of the 700-mg, single-dose SCD cohort compared with a single 700-mg dose in the HV cohort (where relevant).

Phase 1 Single (SAD) and Multiple Ascending Dose (MAD) Study of the Safety, Pharmacokinetics (PK)and Pharmacodynamics (PD) of FT-4202, a PKR Activator, in Healthy and Sickle Cell Disease Subjects

Table 1. Baseline Characteristics of Patients With SCD Enrolled in the Single Dose Cohort (N = 7)

Age, years 34.7 (15, 48) Hb, g/dL 8.7 (7.1, 10.3)

Male 2 (29%) RBC, 1012/L 2.4 (1.8, 2.9)

Hb SS genotype 7 (100%) ARC, 109/L 196.0 (54.9, 350.3)

Hydroxyurea therapy 7 (100%) Total bilirubin, mg/dL 3.54 (2.0, 6.2)

12-month VOC rate 0 (0, 2 ) LDH, U/L 393.4 (317.0, 559.5)

Prior PRBC transfusion (> 30 days) 1 (14%)

Hemoglobin Electrophoresis 2,3-DPG, µg/gHb 5291 (4602, 6137)

% HbS 79.6 (69.1, 88.6) ATP, µg/gHb 1845 (1552, 2158)

% HbF 15.6 (7.9, 28.6) P50, p02 mm Hg 30.1 (26.1, 34.0)

• Figure 5A: In patients with SCD, 24 hours after a single 700-mg dose of FT-4202, ATP blood concentrations increased by 30% and 2,3-DPG blood concentrations decreased by 26%

• Figure 5B: ↑ Hb O2 affinity (↓ P50) was observed after a single 700-mg dose in both HVs and patients with SCD• Figure 5C: ↑ Hb O2 affinity correlated with a reduction in 2,3-DPG in both HVs and patients with SCD

Healthy Volunteers (Completed)

Patients with SCD

Randomization 6:2 vs. placebo

Single Ascending Dose (Completed)

Randomization 9:3 vs. placebo14 days treatment

700 mg 300 mg Daily

Randomization 6:2 vs. placebo

Randomization 9:3 vs. placebo14 days treatment

Single Dose (Completed) Multiple Ascending Dose (Enrolling)

DOSE 2 TBD

700 mg

400 mg

200 mg 100 mg BID

Multiple Ascending Dose (Completed)

200 mg BID

300 mg BID

12-week Open Label

1000 mg 400 mg Daily

FT-4202 (Figure 1)• FT-4202 is an oral activator of pyruvate kinase R (PKR)

◦ PKR activation results in ↓ 2,3-DPG and ↑ ATP in RBCsWe sought to test the following clinical hypotheses:• ↓ 2,3-DPG will result in an ↑ O2 affinity of HbS,

thereby reducing HbS polymerization and RBC sickling• ↑ ATP production will improve sickle RBC repair and

membrane health, reducing hemolysisProposed clinical outcome:• The multimodal action of FT-4202 may improve hemoglobin

levels and reduce the rate of vaso-occlusion in patientswith SCD

Figure 1. Multimodal Actions of PKR Agonism by FT-4202

• Maximal responses for ATP and 2,3-DPG are achieved atdoses of ≥ 150 and 400 mg QD, respectively, in HVs

• A potential exposure to the maximum PD response doserange to evaluate in patients with SCD was identified

• A single 700-mg dose of FT-4202 was selected to evaluatein patients with SCD to enable daily dosing cohorts at lower exposures

Single Dose (700 mg)

Cmax,ng/mL

AUCinf,h·ng/mL t1/2, h Tmax, h

HV (N = 6) 2204 (83.5) 6995 (30.3) 13.3 (34.3) 0.5 (0.5, 6.0)

SCD (N = 5) 2585 (59.9) 7300 (43.4) 14.9 (48.7) 2.0 (1.0, 4.0)

Parameter

HVs Patients With SCD

FT-4202 700 mg(N = 6)

Placebo(N = 2)

FT-4202 700 mg(N = 5)

Placebo(N = 2)

Any TEAE, n (%) 0 0 2 (40) 2 (100)Related to study drug, n (%) 0 0 1 (20) 0

All participants received a single dose of FT-4202 or placebo and were monitored for AEs for 7 days.• HV cohort: No TEAEs were reported in HVs receiving FT-4202 700 mg or placebo• SCD cohort: Six TEAEs were reported in 4 patients; all TEAEs were grade 1 and transient

◦ FT-4202 cohort (each in 1 patient): arthralgia, headache, palpitations One possibly related TEAE (palpitations) occurred ~ 8 hours post dose, no other symptoms, resolved in < 1 minute

◦ Placebo cohort (each in 1 patient): back pain, myalgia, pruritis• The single 700-mg dose of FT-4202 was considered tolerable and the first multiple dose SCD cohort (MAD 1)

was initiated (Figure 2)Figure 2. Study 4202-HVS-101

Figure 5. FT-4202 Results in ↓ 2,3-DPG, ↑ ATP, and ↑ Oxygen Affinity in Sickle RBCs

A CB

All patients had a Hb SS genotype and a mild VOC history but persistent anemia and ongoing hemolysis, despite hydroxyurea therapy

Table 3. Improved Deformability, Oxygen Affinity, and Osmotic Fragility in Sickle RBCs Under Deoxygenation and/or Shear Stress After a Single Dose of FT-4202

• FT-4202 decreased the deoxygenation HbS polymerization rate and improved sickle RBC deformability, as demonstrated by reductions in POS and increases in EImin

◦ This effect was observed in all participants receiving FT-4202 (Table 3)• FT-4202 ↑ O2 affinity (↓ P50) in all participants treated (Table 3)• FT-4202 improved sickle RBC membrane function, as demonstrated by improvements in Omin

and Ohyper (shifting toward normal; Table 3)• These effects were transient, returning to baseline 3 to 7 days after the single dose of FT-4202

(data not shown)

Values are GeoMean (GeoCV%) except for Tmax (median [range]).

0 24 48 72 96 120 144 1680

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2,3-DPG (FT-4202) 2,3-DPG (Placebo)ATP (FT-4202) ATP (Placebo)

ParameterFT-4202 (24 hours)

Pre-dose Post-dose P ValuePOS (Oxygenscan) 35.4 (27.3, 38.8) 24.0 (17.9, 31.8) .063EImin (Oxygenscan) 0.193 (0.16, 0.21) 0.296 (0.26, 0.38) .125EImax (Oxygenscan) 0.445 (0.41, 0.51) 0.451 (0.42, 0.52) .250P50 (Oxygen affinity curve) 29.4 (26.1, 32.3) 25.8 (23.3, 26.8) .063EImax (Osmoscan) 0.483 (0.46, 0.57) 0.478 (0.46, 0.57) .750Omin (Osmoscan) 108 (105, 121) 117 (106, 124) .063Ohyper (Osmoscan) 380 (371, 399) 400 (371, 412) .125

Values are median (range). P values based on the nonparametric Wilcoxon rank sum test for paired data.

Table 2. FT-4202 is Well Tolerated in HVs and Patients With SCD

Figure 4. Similar FT-4202 Plasma PK Profiles in HVs and Patients With SCD

P > .999 P = .095P = .095 P = .381 P = .190 P = .095P = .095 P = .571

P values based on the Wilcoxon rank sum test (exact)

FT-4202 (+ Mean)

Placebo (+ Mean)

• FT-4202–treated patients with SCD demonstrated improved hematologic parameters 24 hours after FT-4202 when maximum 2,3-DPG and ATP responses were observed (Figure 5A), returning to baseline after 72 hours◦ A single dose of FT-4202 resulted in an ↑ Hb of 0.5 g/dL (range: 0.3, 0.9) in FT-4202–treated participants vs.

a ↓ Hb of 0.4 g/dL (range: −0.5, −0.3) in placebo-treated participants (↓ Hb potentially due to phlebotomy)• ↓ LDH was also observed in FT-4202–treated participants 72 hours after FT-4202 dosing, indicating a

reduction in RBC turnover as the source of the improved RBC parameters• These results suggest that a sustained 2,3-DPG and ATP response may be required for optimal benefit

Figure 6. Improved Laboratory Parameters Following a Single Dose of FT-4202

Figure 7. FT-4202 Improves 02-dependent Deformability, Increases Oxygen Affinity and Improves Osmolality-dependent Membrane Function in Sickle RBCs

0 20 40 60 80 100 120 1400.0

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pO2 (mm Hg)

Elon

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Baseline Hb: 9.5 g/dL% HbS: 79.5% HbF: 17.7% F cells: 59.4

Pre PostPOS (mm Hg) 32 18EImin 0.19 0.32

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Baseline Hb: 7.05 g/dL% HbS: 88.5% HbF: 8.0% F cells: 33.3

Pre PostPOS (mm Hg) 39 40EImin 0.15 0.11

Normal RBCSCD RBC (pre) SCD RBC (post)

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Pre PostOmin 108 115Ohyper 380 400

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Pre PostOmin 113 118Ohyper 377 381

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Placebo Treated

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HV (700 mg)SCD (700 mg)

Presented at the 25th European Hematology Association Annual Congress, June 11-21, 2020.

EP1531

http://www.formatherapeutics.com/poster-4202-eha/

GLUCOSE

PEP

PYRUVATE

ADP

ATP

FT-4202 PKR

Hypothesis #2:PKR activation increases ATP, promotingRBC repair/health and reducing hemolysis

RBC membrane

integrity

Hypothesis #1:PKR activation decreases 2,3-DPG,

reducing HbS polymerization and sickling

Expected Clinical Outcome:Increased Hb levels

Decreased vaso-occlusion

HbS polymerization

Deoxy-Hb

2,3-DPG

Hb

**** P < .0001 based on Sidak’s multiple comparisons test

Values are mean (range) or n (%) except for 12-month VOC rate (median [range]).

Figure 3. Modeling of Predicted PD Response in HV RBCs Defines an Exposure:Response Threshold