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of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics - - PowerPoint PPT Presentation

Feb 25, 2023 346 likes •512 views

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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SLIDE 1

Phase 1 Single and Multiple Ascending Dose Study

  • f 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, MD8

Clinicaltrials.gov identifier: NCT0381569.

1Cincinnati Children's Hospital Medical Center, Cincinnati, OH; 2Children's Hospital Oakland Research Institute, Oakland, CA; 3Department of Medicine, Duke University Med. Ctr., Durham, NC; 4St. Jude Children's Research Hospital, Memphis, TN; 5University of Cincinnati College Medical Center, Cincinnati, OH; 6University of Illinois at Chicago, Chicago, IL; 7FORMA Therapeutics, Inc., Watertown, MA; 8Medpace Clinical Pharmacology Unit, Cincinnati, OH

Funded by FORMA Therapeutics, Inc.

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SLIDE 2

2,3-DPG and ATP in Sickle Cell Disease (SCD)

Hemoglobin S (HbS) polymerizes upon deoxygenation, resulting in red blood cell (RBC) sickling and membrane damage, leading to hemolysis and vaso-occlusion.

2,3-DPG, 2,3-diphosphoglycerate; ATP, adenosine triphosphate;

Hb O2 Hb O2

Sickle RBCs contain:

  • More 2,3-DPG than normal RBCs, resulting in

decreased hemoglobin O2 affinity (i.e, increased p50), ➢ Early release of O2 leads to deoxygenation of HbS, polymerization and sickling, already initiated in arterioles (Charache et al, JCI 1970)

  • Less ATP

➢ Insufficient energy for membrane maintenance and repair

Hb O2

Deoxy-HbS

↑ 2,3-DPG

HbS HbA Exacerbating the pathogenesis of SCD

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SLIDE 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;

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SLIDE 4

Multimodal Actions of PKR Agonism by FT-4202

Hb Deoxy- Hb

2,3-DPG

GLUCOSE PEP PYRUVATE

ADP ATP

FT-4202 PKR

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

RBC membrane integrity

Hypothesis #1: PKR activation decreases 2,3-DPG, reducing HbS polymerization and sickling

HbS polymerization

Expected Clinical Outcome: Increased Hb levels Decreased vaso-occlusion

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SLIDE 5

FT-4202 Increases Oxygen Affinity in vitro in HbA and HbS RBCs

20 40 60 80 100 20 40 60 80 100 pO2 (mm Hg) % HbO (Oxygenated Hemoglobin) AA + DMSO AA + FT4202

In vitro incubation with FT-4202

HbA

20 40 60 80 100 20 40 60 80 100 pO2 (mm Hg) % HbO (Oxygenated Hemoglobin) SS + DMSO SS + FT4202

HbS

  • Increases oxygen affinity in HbS RBCs

➢ Indicating that the PKR enzyme in sickle RBCs is also responsive to a PKR activator, and ➢ The resulting decrease in 2,3-DPG increases HbS-O2 affinity

  • Increases oxygen affinity in HbA RBCs

✓ Consistent with clinical results in studies with healthy volunteers and

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SLIDE 6

20 40 60 80 100 20 40 60 80 100 pO2 (mm Hg) % HbO (Oxygenated Hemoglobin) SS + DMSO SS + FT4202

FT-4202 Increases Oxygen Affinity in vitro in HbA and HbS RBCs

20 40 60 80 100 20 40 60 80 100 pO2 (mm Hg) % HbO (Oxygenated Hemoglobin) AA + DMSO AA + FT4202

HbA

20 40 60 80 100 20 40 60 80 100 pO2 (mm Hg) % HbO (Oxygenated Hemoglobin) SS + DMSO SS + FT4202

HbS

20 40 60 80 100 20 40 60 80 100 pO2 (mm Hg) % HbO (Oxygenated Hemoglobin) AA + DMSO AA + FT4202

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SLIDE 7

FT-4202 improves deformability under de-oxygenation in vitro in HbS RBCs

EI max

**

**

p<0.05, n=6 Oxygenscan (Oxygen Gradient Ektacytometry) EI min

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SLIDE 8
  • 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-O2 affinity and membrane mechanics
  • Effects of FT-4202 after multiple doses in SCD subjects on RBC metabolism,

inflammation, and coagulation

Study Objectives: 4202-HVS-101 (NCT0381569)

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SLIDE 9

Study Design: 4202-HVS-101

Randomization 6:2 vs placebo

Single Ascending Dose

1000 mg

Healthy Volunteers

Randomization 9:3 vs placebo 14 days treatment 700 mg DOSE 1 TBD

Subjects with SCD

Randomization 6:2 vs placebo Randomization 9:3 vs placebo 14 days treatment

Single Dose Multiple Ascending Dose

DOSE 2 TBD 700 mg 400 mg 200 mg 100 mg BID

Multiple Ascending Dose

200 mg BID 300 mg BID 400 mg daily

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SLIDE 10

Healthy Volunteers: Demographics and Baseline Characteristics

Characteristic SAD Placebo N = 8 SAD FT-4202 N = 24 MAD Placebo N = 12 MAD FT-4202 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 Black Other/multiple 6 (75) 2 (25) 10 (42) 14 (58) 5 (42) 4 (33) 3 (25) 20 (56) 13 (36) 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/m2, mean (SD) 27 (3) 27 (4) 25 (4) 27 (3)

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SLIDE 11

Healthy Volunteers: Treatment Emergent Adverse Events

  • 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

Characteristic SAD Placebo N = 8 SAD FT-4202 N = 24 MAD Placebo N = 12 MAD FT-4202 N = 36 Any TEAE, n (%) 1 (13) 5 (21) 3 (25) 15 (42) Any grade 3 or greater TEAE, n (%) 1 (4) Drug interruption, reduction or discontinuation due to TEAE, n (%)

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SLIDE 12

Healthy Volunteers: FT-4202 Pharmacokinetics

  • Linear pharmacokinetics

(up to 700 mg): T1/2 11-15 hrs

  • No significant changes in

exposure after 14 days of dosing

4 8 12 16 20 24 28 32 36 40 44 48 1 10 100 1000 10000

Time (h) Concentration (ng/mL) 200 mg 400 mg 700 mg 1000 mg

Plasma FT-4202 pharmacokinetics in healthy volunteers following a single dose

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SLIDE 13

FT-4202 Decreases 2,3-DPG and Increases ATP in RBCs (HV-MAD)

  • 2,3-DPG levels decrease and are sustained for

> 1 day post last dose

  • PK/PD modelling predicts maximal 2,3-DPG response

at doses ≥150 mg BID or ≥ 400 mg QD in HV RBCs

  • ATP levels increase and are sustained for

> 3 days post last dose

  • PK/PD modelling predicts maximal ATP response at

doses ≥ 50 mg BID or ≥ 150 mg QD in HV RBCs

2,3-DPG ATP

1 2

  • 80
  • 60
  • 40
  • 20

8 14 15 16 17 Day % Decrease from Baseline 14-day MAD 1 20 40 60 80 100 8 14 15 16 17 Day % Increase from Baseline 14-day MAD

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SLIDE 14

Increased Oxygen Affinity Observed at All Doses

Correlating with Reduction in 2,3-DPG in HVs

  • Following either single or multiple doses,

all HVs receiving FT-4202 exhibit PD response associated with decreased p50 (increased Hb oxygen affinity)

Increased Hb O2 affinity demonstrated at all doses tested

Placebo 200 mg 400 mg 700 mg 1000 mg 400 mg QD 10 15 20 25 30

p50 (mmHg) Pre-Dose 24 h Post dose (SAD)/Day 14 (MAD) ns **** **** **** **** **** SAD MAD

Reduction in 2,3-DPG correlates with increased oxygen affinity

0.5 1.0 1.5 2.0 2.5 3.0 3.5 15 20 25 30

2,3-DPG (mol/mL) P50 (mmHg) r2=0.64 2,3-DPG (µmol/mL)

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SLIDE 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