Pliant Therapeutics, Inc. · NASDAQ:PLRX
Pliant Therapeutics — 2022 New Directions in Biology and Disease of Skeletal Muscle Conference
25 slides from Pliant Therapeutics's conference presentation, November 2022
Slide 1: Increased Laminin Binding Through α7β1 Integrin Activation Protects Dystrophic Muscle
Increased Laminin Binding Through α7β1 Integrin Activation Protects Dystrophic Muscle 2022 NEW DIRECTIONS IN BIOLOGY AND DISEASE OF SKELETAL MUSCLE CONFERENCE Scott Turner, Ph.D. © 2022 PLIANT THERAPEUTICS
Slide 2: Disclaimers
Disclaimers This presentation has been prepared by Pliant Therapeutics, Inc. ("we," "us," "our," "Pliant" or the “Company”). The information set forth herein does not purport to be complete or to contain all of the information you may desire. Statements contained herein are made as of the date of th
Slide 3: About Pliant Therapeutics
About Pliant Therapeutics The Company Programs Targeting High Unmet Medical Need • Founded in 2015 • PLN-74809 in Phase 2a development in IPF and PSC • Based in South San Francisco − Topline data in IPF expected mid-2022 • 110 employees • IND submission in DMD expected by YE 2022 • June 2020 IPO (Na
Slide 4: Pliant Development Pipeline
Pliant Development Pipeline Clinical Anticipated Global Program Indication Preclinical Milestone Rights Phase I Phase II Phase III Phase 2a Idiopathic PLN-74809 INTEGRIS-IPF Enrollment Complete Topline Data Pulmonary Expected Fibrosis Mid-2022 Dual selective inhibitor WHOLLY OWNED of aVb 6/aVb1 Prim
Slide 5: The Integrin Family: Who, What, Where, When and How
The Integrin Family: Who, What, Where, When and How Who What Where How • Regulate the cell-matrix • Everywhere • Kinase signaling interaction • Cell type • Interaction with • Promote cell adhesion other integrin and migration • Organ pairs • Activate intracellular • Disease • Interaction with signal
Slide 6: The Integrin Family: Who, What, Where, When and How
The Integrin Family: Who, What, Where, When and How • Most integrins have 3 conformational states ⎼ Predominant state is the bent closed conformation ⎼ Extended open conformation can increase ligand binding up to 5000x • Inside-out signals through Talin and Kindlin induce conformation changes • Liga
Slide 7: α7β1: A Drug Target in Muscular Dystrophies
a7b1: A Drug Target in Muscular Dystrophies • Predominantly expressed in skeletal, heart and smooth muscle • a7b1 strong genetic modifier in MDX mice ⎼ Lack of a7b1 worsens disease phenotype ⎼ Over expression increases survival and improves function. • Pharmacological agents that increase expression
Slide 8: Antibody Activation of Muscle β1 Integrins
Antibody Activation of Muscle b1 Integrins • TS2/16 is an allosteric activating antibody of β1 integrins ⎼ Increases laminin binding of satellite cells ⎼ 4 main laminin binding integrins in muscle are a7b1, a6b1, a6b4, a3b1 • Intramuscular injections improve dystrophic muscle ⎼ Systemic activation o
Slide 9: Discovery of an α7 Integrin Specific Agonist Antibody
Discovery of an α7 Integrin Specific Agonist Antibody Antigen: human integrin 110 clones were picked as integrin α7β1 α7β1 ectodomain binders (from total of 9000 clones) Four agonist Abs: Two bind to β1; Two bind to α7 Multiple antagonist Abs Pre-clinical Model © 2022 PLIANT THERAPEUTICS 9
Slide 10: Discovery of an Integrin α7 Specific Agonist Antibody
Discovery of an Integrin α7 Specific Agonist Antibody • Epitope mapping identified Calf-2 as the • The a7 integrin subunits are expressed in two agonist antibody binding site cytoplasmic (a7A and a7B) and two • High homology across species extracellular splice variants (a7X1 and a7X2) ⎼ No differenc
Slide 11: Discovery of an α7 Integrin Specific Agonist Antibody
Discovery of an α7 Integrin Specific Agonist Antibody • Lead mAb increases healthy and DMD myoblast adhesion to laminin 211 • K562 cells expressing α7x2 adhere to laminin 211 which can be reversed by an α7 blocking antibody; ⎼ Both TS2/16 and α7 agonist can enhance the ligand binding Control Cell Ad
Slide 12: Discovery of an α7 Integrin Specific Agonist Antibody
Discovery of an α7 Integrin Specific Agonist Antibody Activation of α7b1 increases intracellular integrin signaling through phospho-FAK K562-hua7b1 Cells Human DMD Cells 0.4 Leukemia cells 0.6 0.3 0.4 pFAK(U)/FAK(ng) pFAK(U)/FAK(ng) 0.2 0.2 0.1 Stimulating time: 30 min Stimulating time: 30 min 0.0 0
Slide 13: Target Occupancy in the D2-mdx Model In Both GC Muscle and Heart
Target Occupancy in the D2-mdx Model In Both GC Muscle and Heart • D2-Mdx mice were dosed 2x IP/wk for 4wk • PLN-101325 tissue distribution was measured by anti-human IgG4 IHC. Tissue distribution vs Serum Concentration Low Low 10 GC Muscle Heart 8 IHC Score 6 4 Mid High Mid High 2 0 0 200 400 600 8
Slide 14: PLN-101325: An α7 Integrin Specific Agonist Antibody
PLN-101325: An α7 Integrin Specific Agonist Antibody • Single digit nm EC50 and Kd - more potent in human vs. mouse • IgG4 fully humanized antibody • 200h half-life in Cynomolgus monkeys (consistent with other IgG4 drugs) • No off target/non-specific binding • No internalization • Low immunogenicit
Slide 15: Evaluating the Effects of a Humanized α7β1 Integrin Antibody on DMD Muscle Cells
Evaluating the Effects of a Pliant Therapeutics Humanized a7b1 Integrin Antibody on DMD Muscle Cell Structure & Function in 3D Culture © 2022 PLIANT THERAPEUTICS 15
Slide 16: Integrin α7β1 Agonist Antibody Promotes Muscle Maturation
Integrin a7b1 Agonist Antibody Promotes Muscle Maturation • AB1071 hMMTs treated with 1 ug/ml or 10 ug/ml Pliant antibody contain myotubes with substantially improved Treatment Regime sarcomere organization that can withstand tetanic stimulation compared to IgG4 control. (+) “Exercise” IgG4 1 mg/ml
Slide 17: Effect of PLN-101325 in Ca2+ Homeostasis and Resting Membrane Potential
Effect of PLN-101325 in Ca2+ Homeostasis and Resting Membrane Potential of B10-mdx Myotubes Reduced intracellular resting calcium and hyperpolarization of the membrane potentially support improved plasmalemmal integrity by PLN-101325 Intracellular resting Ca2+ Resting membrane potential p, one-way A
Slide 18: Body Weight Improvement at 4 and 12 Weeks of Treatment
Body Weight Improvement at 4 and 12 Weeks of Treatment PLN-101325 3x/ wk IP 5-6 wk old D2-MDX mice 8 ± 3% Increase in 9 ± 1% Increase in 4-week Body Weight 12-week Body Weight Weight Increase 9 ± 1% Running test © 2022 PLIANT THERAPEUTICS 18
Slide 19: Improved Response to Post Eccentric Injury at 4 and 12 Weeks of Treatment
Improved Response to Post Eccentric Injury at 4 and 12 Weeks of Treatment Plantar flexion test • Gastrocnemius (GC): Premier mover muscle for plantar flexion. • GC only muscle to join both ankle and knee. Eccentric muscle injury protocol: A series of 20 tetanic stimulations (80Hz, 0.2ms pulse, 500ms
Slide 20: Diaphragm Force Significantly Improved at 4 Weeks
Diaphragm Force Significantly Improved at 4 weeks © 2022 PLIANT THERAPEUTICS 21
Slide 21: 277 Serum Proteins Differed Between MDX and Control Mice and Were Improved
277 Serum Proteins Differed Between MDX and Control Mice and Were Improved with PLN-101325 Treatment SOMAscan protein biomarker discovery assay 7,596 human proteins (not all detect mouse) • 277 proteins were different between MDX and DBA • PLN-101325 moved protein levels toward normal FDR <= 0.25 ab
Slide 22: Glycolysis and Gluconeogenesis Proteins
Glycolysis and Gluconeogenesis Proteins • PLN-101325 reduced circulating biomarkers of glycolysis and gluconeogenesis • May reflect reduced injury in glycolytic (fast) muscle fibers DBA PLN-101325 D2-MDX © 2022 PLIANT THERAPEUTICS 23
Slide 23: PLN-101325: A Novel Disease Modifying Approach in DMD
PLN-101325: A Novel Disease Modifying Approach in DMD • Increasing a7b1-laminin binding can compensate for loss of dystrophin in myofibers as well as satellite cells • Potential for clinical benefit in DMD in combination with current standard of care as well as gene targeted therapies. • Improvement
Slide 24: Thank you
Thank you © 2022 PLIANT THERAPEUTICS 25
Slide 25: Increased Laminin Binding Through α7β1 Integrin Activation Protects Dystrophic Muscle
Increased Laminin Binding Through α7β1 Integrin Activation Protects Dystrophic Muscle 2022 NEW DIRECTIONS IN BIOLOGY AND DISEASE OF SKELETAL MUSCLE CONFERENCE Scott Turner, Ph.D. © 2022 PLIANT THERAPEUTICS