PRECISION NEUROLOGY CORPORATE OVERVIEW MAY 2020
ESCAPE Develops Precisely Targeted Novel Therapies for Genetically Defined Neurodegenerative Diseases ✓ Diverse pipeline focused on genetically defined neurodegenerative diseases ✓ Selective therapies that overcome liabilities of non-selective approaches ✓ Clinical stage, selective S1P5 agonist and near-clinical, selective G2019S LRRK2 program and early state APOE4 program | 2
Diversified Pipeline of Precisely Targeted, Novel Small Molecules PATIENT PHASE 1 SAD / PHASE 1b/2a ANTICIPATED PROGRAM INDICATION DISCOVERY IND ENABLING SELECTION MAD BIOMARKERS MILESTONE Lysosomal Niemann- Ph1b/2a Storage Pick Biomarkers ESB1609 Disorders Type C MAD in Process S1P5 Selective Agonist Parkinson’s Ph1b/2a GBA PD Disease Biomarkers ESB5070 G2019S LRRK2 Parkinson’s LRRK2 G2019S IND Disease Kinase Carriers Inhibitor Structure Alzheimer’s ApoE4 Development Modulator Disease Carriers Candidate of ApoE4 | 3
ESB1609: S1P5 Selective Agonist | 4
ESCAPE’s S1P5 Selective Agonists Avoid the Limitations of Approved Non-selective Modulators Indication Phase S1P5 S1P1 S1P3 S1P4 Adverse Event Profile S1P5 Selective Agonists • No immune, CV or hepatotoxicity ESB1609 NPC, others Phase I observed preclinically • S1P5 primarily expressed in CNS Non-Selective Modulators RRMS Approved • Peripheral immune suppression SPMS Approved • Bradycardia, AV block, blood RRMS Approved pressure alteration • Hepatotoxicity • Bronchoconstriction Ponesimod MS Phase 3 Amiselimod MS, Crohns Phase 2 | 5 NPC: Niemann-Pick Type C; MS: multiple sclerosis; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis
Lysosomal Dysfunction is a Common Pathogenic Driver in Genetically Defined Neurodegenerative Diseases DISEASE PATHOGENIC MUTATION Lipid Dysmetabolism Neuronal & Glial cell dysfunction & inflammation Neurodegeneration Lyososomal enzyme Lysosomal Deficiencies Dysfunctional Altered lipid homeostasis Proteinopathies; Aggregation Aβ, ⍺ -synuclein, tau, mHTT | 6
S1P5 Agonism Consistently Restores Markers of Lysosomal Dysfunction, Neurodegeneration & Neurological Function Improved Improved Brain Lipid Disease Model Neurodegenerative Neurological Function Levels Biomarkers +++ +++ Explored in disease models Aged Rodent WT Senescence ↓ Aβ +++ +++ accelerated SAMP8 (age and dementia) Alzheimer’s Disease ↓ Aβ / ↓ Tau +++ Tg2576 / P301S (amyloid / tauopathy) ↑ CSF Aβ, Tau and pTau Niemann-Pick C BALB/cNctr- +++ +++ ↓ Aβ Npc 1 m1N /J Disease Parkinson’s Disease A53T Synuclein ++ In process Huntington’s Disease ↓ mutant Htt R 6/2 +++ Not reported | 7
S1P5 Agonism Improves Lysosomal & Neurodegenerative Biomarkers and Neurological Function in NPC* Null Mice Lysosomal NPC Biomarkers Neurodegenerative Biomarkers Treated Untreated • Untreated mice expected to have decreased Amyloid β 1 -40 soluble a myloid β and increased (Soluble) aggregated a myloid β • S1P5 agonism reverses trend in dose proportionate manner One-way ANOVA, post-hoc Dunnett * P < 0.05, ** P < 0.01 Neurological Function Grip Strength *NPC BALB/cNctr-Npc1 m1N /J Data from S1P5 agonist AV432 | 8
ESB1609: A Potent & Brain Penetrant S1P5 Selective Agonist with Excellent Clinical Safety and Tolerability ✓ Strong CNS product profile: • Highly potent and 1,000 fold selective for S1P5 • Excellent brain penetration (Brain/Plasma ratio 0.8) • Oral, once daily dosing with durable CNS exposure (CSF) ✓ Excellent safety & tolerability ✓ Manufacturing: Small molecule process; GMP batches produced ✓ Intellectual Property: Broad patent estate; coverage into 2030’s ✓ Clinical: Ph1 multiple-ascending dose underway → P1b 2020 ✓ Regulatory: Discussions ongoing for orphan indications | 9
ESB1609: Dose Dependent, Prolonged and Consistent Cerebral Spinal Fluid (CSF) Exposure in Single-Ascending Oral Dose Healthy Volunteer Phase 1 Study P1, Randomized, Placebo-Controlled, Safety, Tolerability and PK Single Ascending Dose Study of ESB1609 in Healthy Volunteers with a Continuous CSF Sampling Cohort 48 hr Plasma Concentration (ug/mL) 24 hr CSF Concentration (nM) | 10 73nM approximate EC50, 210nM 3x EC50 anticipated for clinical efficacy
MAD Study Design and Overview of Objectives Part 2: NPC Subjects Part 1: Healthy Volunteers (HVs) Open label Cohort 4 extension* ESB1609 (n=8) Cohort 3A or Placebo (n=4) ESB1609 (n=4) Cohort 2 or Placebo (n=4) - Safety, PK (Plasma and CSF) ESB1609 - CSF BMs in placebo and treated NPC Cohort 1 (n=6) or Cohort 3B CSF subjects to assess BM noise, variability in ESB1609 Placebo (n=3) ESB1609 (n=3) placebo (n=6) or or Placebo (n=3) - Time course of BMs in NPC subjects Placebo (n=3) - Gain experience in sample handling to translate to associated diseases of lipid - Safety, PK - Safety, PK (Plasma and CSF) dyshomeostasis (e.g. GBA PD) - CSF Biomarkers (BMs) in HVs | 11
ESB5070: G2019S Mutant LRRK2 Kinase Inhibitor | 12
LRRK2 is a Compelling Therapeutic Target for Genetic Parkinson’s Disease • G2019S is most common LRRK2 pathogenic 14-3-3 Auto- mutation, 1-3% of all PD phosphorylation binding pS935 pS1292 • Majority of patients with G2019S LRRK2 PD G2019S carry only 1 copy of the mutation, the second Kinase LRRK2/ARM ANK LRR ROC COR WD40 copy is normal Other substrates? Vesicle • Normal LRRK2 acts on downstream Rab trafficking GTPases, which orchestrate critical biological Rab phosphorylation functions Autophagy (Rab8a, Rab10 b10, Rab29, Rab35, others) • G2019S mutation elevates kinase activity via Lysosome autophosphorylation at pS1292 dysfunction • Program goal is to inhibit pathogenic Mitochondrial Rab dysfunction hyperphosphorylated kinase activity from G2019S mutation and spare normal LRRK2 Figure adapted from: function Science 360 (2018) 6384 Curr Opin Cell Biol. 63 (2020) 102 Clin Pharmacol 8 (2016) 117 • Ideal opportunity for precision medicine by targeting only G2019S LRRK2 | 13
ESCAPE Precisely Targets the Pathogenic Activity of G2019S LRRK2 • Denali, Biogen (ASO) & others inhibit BOTH mutant and wild type LRRK2 equally (non-selective) • Strong non-selective inhibition of LRRK2 produces pulmonary and renal histopathology similar to severe human pulmonary disease (e.g. pulmonary fibrosis, ARDS, COPD, vaping related lung injury) • Denali targeting 50% pS935 inhibition at trough to avoid safety concern, potentially compromising efficacy Selective Inhibition Maximizes G2019S Non-Selective On-Target Safety Limitation Inhibition Sparing WT LRRK2 Function • High ATP-competitive inhibition of LRRK2 – Renal and pulmonary histopathological toxicity Baseline WT G2019S – Reversible, but not monitorable Control Non-selective Inhibitor Non-Selective WT G2019S Inhibitors ESCAPE G2019S WT 90-95% Inhibition G2019S selective Inhibitor • Knockout/kinase dead TG mice show tox 0 20 40 60 80 100 – One wild type copy rescues toxicity Kinase activity (% phosphorylation at S1292) | 14 Bottom left: images from Escape Bio study in G2019S homozygous KI mice
ESCAPE Demonstrates G2019S Specific Inhibition Ex Vivo Sparing Healthy LRRK2 in Parkinson’s Patient Blood Cells pS935-LRRK2 pS935-LRRK2 pS935-LRRK2 • G2019S-selective inhibitor G2019S-selective Non-selective G2019S-selective Inhibitor Non-selective Inhibitor 120 120 % Vehicle Control % Vehicle Control 100 100 – Inhibited ~90% of pS935 & pRab10 in 80 80 homozygous G2019S carriers 60 60 120 120 % Vehicle Control – % Vehicle Control Only ~10% inhibition in non-carriers 40 40 100 100 20 20 – 100x selective tool compound 0 0 riers 19S 80 19S riers 019S 019S 80 Non- Non- HET HOM HET HOM carrier carrier pRab10 • Compared to non-selective inhibitor 60 60 G2019S-selective Non-selective 120 120 % Vehicle Control 40 % Vehicle Control 40 – Equal high inhibition across genotypes 100 100 20 20 80 80 60 60 0 0 40 40 Non-carriers HET G2019S HOM G2019S Non-carriers HET G2019S HOM G2019S 20 20 0 0 s S S riers 19S 19S Non- Non- r HET HOM HET HOM 9 9 e 1 1 i carrier carrier r PBMCs were isolated from whole blood and treated ex-vivo with tool molecules 3 HOM G2019S-LRRK2, 5 HET G2019S-LRRK2, 5 non-carriers | 15
ESCAPE Has Developed Potent, Mutant Selective and Brain Penetrant LRRK2 Inhibitors from Multiple Chemical Series • Screened ~800K compounds from 3 diverse libraries • Evolved a single HTS hit into 4 distinct, G2019S-selective, proprietary chemical series • Potency of compounds down to pM levels and selectivity > 1000-fold • Series follow iterative development of novel compounds combining good potency, selectivity, brain uptake, and bioavailability • Distinct chemotypes expanded to encompass 4 COM patents pending, 1 published 41126 Series 42156 Series 1 st patent 3 rd patent • • 42500 Series 44846 Series 2 nd patent 4 th patent • • | 16
Recommend
More recommend
