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Phase 1 Single and Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects Theodosia A. Kalfa, MD,

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  1. Phase 1 Single and Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of FT-4202, an Allosteric Activator of Pyruvate Kinase-R, in Healthy and Sickle Cell Disease Subjects Theodosia A. Kalfa, MD, PhD, 1 Frans A Kuypers, PhD, 2 Marilyn J. Telen, MD, 3 Punam Malik, MD, 1 Diamantis G. Konstantinidis, PhD, 1 Jeremy H. Estepp, MD, 4 Hyon J. Kim, MD, PhD, 5 Santosh L. Saraf, MD, 6 Lindsey Wilson, MS, 7 Maria D Ribadeneira, PhD, 7 Sanjeev Forsyth, 7 Patricia Schroeder, 7 Adam Drake, PhD, 7 Olga Polyanskaya, MS, 7 Patrick Kelly, MD, 7 and Lukasz Biernat, MD 8 1 Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 2 Children's Hospital Oakland Research Institute, Oakland, CA; 3 Department of Medicine, Duke University Med. Ctr., Durham, NC; 4 St. Jude Children's Research Hospital, Memphis, TN; 5 University of Cincinnati College Medical Center, Cincinnati, OH; 6 University of Illinois at Chicago, Chicago, IL; 7 FORMA Therapeutics, Inc., Watertown, MA; 8 Medpace Clinical Pharmacology Unit, Cincinnati, OH Funded by FORMA Therapeutics, Inc. Clinicaltrials.gov identifier: NCT0381569.

  2. 2,3-DPG and ATP in Sickle Cell Disease (SCD) Hb Hemoglobin S (HbS) polymerizes upon deoxygenation, O2 resulting in red blood cell (RBC) sickling and membrane damage, Hb leading to hemolysis and vaso-occlusion. Deoxy-HbS O2 Hb Sickle RBCs contain: O2 • More 2,3-DPG than normal RBCs, resulting in decreased hemoglobin O 2 affinity (i.e, increased p50), ➢ Early release of O 2 leads to deoxygenation of HbS, polymerization and sickling, already initiated in arterioles (Charache et al, JCI 1970) HbA • ↑ 2,3-DPG Less ATP ➢ Insufficient energy for membrane maintenance and repair HbS Exacerbating the pathogenesis of SCD 2,3-DPG, 2,3-diphosphoglycerate; ATP, adenosine triphosphate;

  3. FT-4202 in Sickle Cell Disease (SCD) FT-4202 is an oral activator of the Pyruvate Kinase R (PKR) that decreases 2,3-DPG and increases ATP in erythrocytes In preclinical safety studies, FT-4202 • Had no effect on steroidogenesis, • Demonstrated low risk of drug-to-drug interactions, and • Was well tolerated in vivo at the maximum doses administered 2,3-DPG, 2,3-diphosphoglycerate; ATP, adenosine triphosphate;

  4. Multimodal Actions of PKR Agonism by FT-4202 Hypothesis #1: PKR activation decreases 2,3-DPG, GLUCOSE reducing HbS polymerization and sickling Hb HbS 2,3-DPG polymerization Deoxy- Hb PEP Expected Clinical Outcome: Increased Hb levels Decreased vaso-occlusion ADP FT-4202 PKR RBC ATP membrane integrity PYRUVATE Hypothesis #2: PKR activation increases ATP, promoting RBC repair/health and reducing hemolysis

  5. FT-4202 Increases Oxygen Affinity in vitro in HbA and HbS RBCs In vitro incubation with FT-4202 100 AA + DMSO AA + FT4202 HbA 80 • Increases oxygen affinity in HbA RBCs % HbO (Oxygenated Hemoglobin) 60 ✓ Consistent with clinical results in 40 studies with healthy volunteers 20 and 0 • Increases oxygen affinity in HbS RBCs 0 20 40 60 80 100 pO 2 (mm Hg) 100 SS + DMSO ➢ Indicating that the PKR enzyme in SS + FT4202 80 % HbO (Oxygenated Hemoglobin) HbS sickle RBCs is also responsive to a 60 PKR activator, and 40 ➢ The resulting decrease in 2,3-DPG 20 increases HbS-O 2 affinity 0 0 20 40 60 80 100 pO 2 (mm Hg)

  6. FT-4202 Increases Oxygen Affinity in vitro in HbA and HbS RBCs 100 AA + DMSO AA + FT4202 100 100 AA + DMSO SS + DMSO HbA 80 AA + FT4202 % HbO (Oxygenated Hemoglobin) SS + FT4202 60 80 80 % HbO (Oxygenated Hemoglobin) % HbO (Oxygenated Hemoglobin) 40 20 60 60 0 0 20 40 60 80 100 pO 2 (mm Hg) 100 SS + DMSO 40 40 SS + FT4202 80 % HbO (Oxygenated Hemoglobin) HbS 60 20 20 40 0 0 20 0 0 20 20 40 40 60 60 80 80 100 100 pO 2 (mm Hg) pO 2 (mm Hg) 0 0 20 40 60 80 100 pO 2 (mm Hg)

  7. FT-4202 improves deformability under de-oxygenation in vitro in HbS RBCs Oxygenscan (Oxygen Gradient Ektacytometry) ** EI max EI min p<0.05, n=6 **

  8. Study Objectives: 4202-HVS-101 (NCT0381569) • Primary • Safety and tolerability of single ascending dose (SAD) and multiple ascending dose (MAD) of FT-4202 in healthy volunteers (HV) and SCD subjects • FT-4202 pharmacokinetics • Secondary • 2,3-DPG and ATP levels in HV and SCD RBCs • Exploratory • Food effects on FT-4202 pharmacokinetics in HVs • Effects of FT-4202 on RBC hemoglobin-O 2 affinity and membrane mechanics • Effects of FT-4202 after multiple doses in SCD subjects on RBC metabolism, inflammation, and coagulation

  9. Study Design: 4202-HVS-101 Healthy Volunteers Multiple Ascending Dose Single Ascending Dose 400 mg daily 1000 mg Randomization Randomization 9:3 vs placebo 6:2 vs placebo 300 mg BID 14 days treatment 700 mg 200 mg BID 400 mg 100 mg BID 200 mg Subjects with SCD Single Dose Multiple Ascending Dose Randomization 700 mg DOSE 2 TBD Randomization 9:3 vs placebo 6:2 vs placebo 14 days treatment DOSE 1 TBD

  10. Healthy Volunteers: Demographics and Baseline Characteristics SAD Placebo SAD FT-4202 MAD Placebo MAD FT-4202 Characteristic N = 8 N = 24 N = 12 N = 36 Age, years (mean, SD) 41 (6) 45 (11) 45 (12) 45 (11) Male, n (%) 6 (75) 14 (58) 6 (50) 22 (61) Race, n (%) White 6 (75) 10 (42) 5 (42) 20 (56) Black 2 (25) 14 (58) 4 (33) 13 (36) Other/multiple 0 0 3 (25) 3 (8) Weight, kg, mean (SD) 79 (15) 81 (14) 73 (13) 80 (9) Height, cm, mean (SD) 171 (8) 173 (9) 170 (10) 173 (9) BMI, kg/m 2 , mean (SD) 27 (3) 27 (4) 25 (4) 27 (3)

  11. Healthy Volunteers: Treatment Emergent Adverse Events SAD Placebo SAD FT-4202 MAD Placebo MAD FT-4202 Characteristic N = 8 N = 24 N = 12 N = 36 Any TEAE, n (%) 1 (13) 5 (21) 3 (25) 15 (42) Any grade 3 or greater TEAE, n (%) 0 1 (4) 0 0 Drug interruption, reduction or 0 0 0 0 discontinuation due to TEAE, n (%) • Grade < 2 TEAE: related to FT-4202 • FT-4202: • SAD: headache (n=1) & transient ventricular tachycardia (n=1) --- each in different subject • MAD: headache (n=4), palpitations (n=1) & somnolence (n=1) --- each in different subject • Placebo: headache in 1 subject • One Grade 3 TEAE: unrelated to FT-4202 • Transient asymptomatic lipase elevation noted in one subject at the 1000 mg dose • Back-up sample was re-assessed independently, and no lipase elevation was detected

  12. Healthy Volunteers: FT-4202 Pharmacokinetics Plasma FT-4202 pharmacokinetics in healthy volunteers following a single dose 10000 Concentration (ng/mL) 200 mg 400 mg 1000 700 mg 1000 mg 100 10 • Linear pharmacokinetics (up to 700 mg): T 1/2 11-15 hrs 1 • No significant changes in 0 4 8 12 16 20 24 28 32 36 40 44 48 exposure after 14 days of dosing Time (h)

  13. FT-4202 Decreases 2,3-DPG and Increases ATP in RBCs (HV-MAD) 2,3-DPG ATP 14-day MAD 100 0 14-day MAD % Increase from Baseline % Decrease from Baseline 80 -20 60 -40 40 -60 20 0 -80 1 8 14 15 16 17 1 2 8 14 15 16 17 Day Day • 2,3-DPG levels decrease and are sustained for • ATP levels increase and are sustained for > 1 day post last dose > 3 days post last dose • PK/PD modelling predicts maximal 2,3-DPG response • PK/PD modelling predicts maximal ATP response at at doses ≥150 mg BID or ≥ 400 mg QD in HV RBCs doses ≥ 50 mg BID or ≥ 150 mg QD in HV RBCs

  14. Increased Oxygen Affinity Observed at All Doses Correlating with Reduction in 2,3-DPG in HVs Increased Hb O 2 affinity demonstrated Reduction in 2,3-DPG correlates at all doses tested with increased oxygen affinity ns **** 30 **** **** **** **** 30 25 p50 (mmHg) 20 25 P 50 (mmHg) 15 Pre-Dose 24 h Post dose (SAD)/Day 14 (MAD) 10 r 2 =0.64 Placebo 200 mg 400 mg 700 mg 1000 mg 400 mg QD 20 SAD MAD • Following either single or multiple doses, 15 all HVs receiving FT-4202 exhibit PD response associated 0.5 1.0 1.5 2.0 2.5 3.0 3.5 with decreased p50 (increased Hb oxygen affinity) 2,3-DPG (  mol/mL) 2,3-DPG (µmol/mL)

  15. Conclusions • FT-4202 has a favorable safety profile in healthy subjects • FT-4202 demonstrates linear and time-independent PK • Reduction in 2,3-DPG and increase in ATP levels in RBCs of healthy volunteers confirms PKR activation by FT-4202 • FT-4202 demonstrates proof of mechanism with increased Hb oxygen affinity in healthy volunteer RBCs • Consistent with observations from in vitro mixing studies in healthy and sickle RBCs • These initial results support further clinical development of FT-4202, a PKR activator, with the ongoing Phase I clinical trial in patients with SCD

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