R&D Day May 17, 2021 NASDAQ: YMTX Exhibit 99.1
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Agenda for Today Introduction; Company Overview and Value Drivers Richard Peters, MD PhD Neurodegeneration Outlook Ajay Verma, MD PhD Overview of Parkinson’s Disease Landscape David Russell, MD PhD Discovery Engine and YTX-7739 Preclinical Development Daniel Tardiff, PhD Lead Clinical Program: YTX-7739 for Parkinson’s Disease Brigitte Robertson, MD Wrap Up Richard Peters, MD PhD Q&A All
A Future Free from Neurodegenerative Diseases Our Vision: Yumanity Therapeutics, Inc. 2021
Prolific Pipeline Novel targets discovered by Yumanity Goal of 1 new program into the clinic per year Opportunities for business development 1 7 20+
Accelerated discovery timelines Optimized clinical/ regulatory/payor outcomes Novel, relevant targets Yumanity Strategy to Transform Neuro Drug Development Unbiased Discovery Engine Rapid Validation in Human Models Leverage Biomarkers 1 2 3
Leveraging External Research Collaboration on 2 targets in ALS and FTD Supporting studies in proprietary Parkinson’s Disease animal models Emerging data in Glioblastoma
Discovery Target Validation Lead Optimization IND- enabling Phase 1 Anticipated Clinical Milestones Program 1: Parkinson’s Disease 3Q 2020 – Phase 1 SAD Data 2Q 2021 – Ph 1a MAD in Healthy Volunteers Mid-2021 – Ph 1b Patient Data 2022 – Phase 2 initiation Program 2: Dementia with Lewy Bodies 2Q 2020 – Start IND-enabling studies 2H 2021 – Phase 1 initiation Program 3: ALS/FTLD Program 4: ALS/FTLD Programs 5-15 PD, AD, ALS/FTLD YTX-7739 (SCD Inhibitor) Undisclosed Undisclosed Undisclosed YTX-9184 (SCD Inhibitor) Goal of 1 New Disease-Modifying Clinical Program Per Year Partnered with Prolific Discovery Engine Drives Rapidly Expanding Pipeline of Disease-Modifying Therapies SAD=single ascending dose; MAD = multiple ascending dose; IND=investigational new drug application
Differentiating Advantages Against Parkinson’s Disease Intervene upstream from α-synuclein pathology rather than downstream Advantages of small molecule pharmacology vs. large antibodies Potential to leverage treatment biomarker to individualize therapy and enrich for likely responders
Neurodegeneration Outlook Ajay Verma, MD, PhD Executive Vice President, Head of R&D
Neurodegeneration is Today’s Largest Therapeutic Challenge Alzheimer’s Parkinson’s ALS Aging is strongest risk factor Fastest rising population segment Huge Societal and economic impact 50 M+ affected by Alzheimer’s 10 M+ living with Parkinson’s >6000 ALS diagnosis each year High morbidity and mortality Symptomatic therapy only No treatment to stop progression Neurodegenerative Disease Has Become a Global Pandemic Hou, Nat Rev Neurol 2019 * “Dementia: A problem for our age”, Alison Abbott, Nature 475, S2–S4 (2011) Prevalence by Age Estimated Growth of Dementia*
Emerging Science and Rational Drug Development Alzheimer’s ALS Parkinson’s ALS Proteinopathy Synapse loss Inflammation Neurotoxicity Biomarker-tractable pathology Misfolded proteinopathy Ab, tau aSyn, TDP43 Others Intracellular dysfunction Mitochondria Lysosomes/autophagy Vesicle trafficking Extracellular progression CNS cell spread Neuroinflammation Impaired clearance (Imaging, CSF, Blood) Emerging Basic and Clinical Science of Neurodegenerative Diseases Slow Progression Offers Opportunity for Early Therapy Common Diseases Mechanisms
Injury Mechanisms Misfolded Proteinopathies are Central to Neurodegeneration Neurodegenerative Diseases Aggregation Prone Proteins Neurodegenerative Disease Ab aSyn Tau TDP43 Other Alzheimer’s disease ✔ ✔ ✔ ✔ Parkinson’s disease ✔ ✔ ✔ Lewy Body dementia ✔ ✔ ✔ ✔ Multiple systems atrophy ✔ Frontotemporal lobar dementia ✔ ✔ ✔ Corticobasal degeneration ✔ ✔ ✔ Progressive supranuclear palsy ✔ Amyotrophic lateral sclerosis ✔ ✔ ✔ Chronic traumatic encephalopathy ✔ ✔ ✔ b-amyloid plaques Tau tangles aSyn Lewy bodies TDP43 Lewy bodies Aggregation-prone Proteins Are Common Instigators of the Neurodegeneration Process Common CNS Proteinopathy Lesions Proteo-lipid aggregation Synaptic dysfunction Lysosomal dysfunction Mitochondrial dysfunction Axonal injury ER stress
Evolving Science of Synucleinopathy and Therapeutic Targets WT aSyn Mutated aSyn Excessive aSyn PRESYNAPTIC TERMINAL Clustering Assembly Fusion Endocytosis Secretory Endosome Autophagy Nucleus ER Golgi CELL BODY Physiological multimers Normal functions Normal a-Helix Coils a-State N C b-State P C N Disordered Lipid binding Aggregation Acidic 1 61 95 140 P a Synuclein protein N C Toxic oligomers/polymers Pathology hallmarks Abnormal b-Pleated Sheets FIBRILLAR LEWY BODY NON-FIBRILLAR LEWY BODY Fanning et al., Molecular Cell (2018); Vincent, Tardiff, et al., Cell Reports (2018); Maulik et al., Frontiers in Aging Neuroscience (2019); Soste et al., Cell Systems (2019) Modified from Fanning et. al.., Acta Neuropathologica (2021) SCD Unsaturated Fatty Acids Saturated Fatty Acids
Parkinson’s Disease Programs in Clinical Development 81 Total Programs Ph1 (26 trials, 32%) Ph3 (14 trials, 17%) Ph2 (41 trials, 51%) Active (51 trials, 63%) Complete (30 trials, 37%) Non- US/EU (14 trials, 17%) *Active development of Rotigone ph3 patch in China **These programs have likely been discontinued Note: Medtronic’s Activa PC+S, active in Neuromodulation, is not shown Disease Modification Symptomatic Neuraly NLY01 NON-DOPAMINERGIC 14 trials, 17% DOPAMINERGIC 23 trials, 28% REGENERATIVE 9 trials, 11% PROTEINOPATHY 14 trials, 17% NEUROPROTECTION 15 trials, 19% AstraZeneca MEDI1341 Biogen BIIB054** UCB Bio UCB7853 H. Lundbeck Lu AF82422 Vaxxinity UB-312 Aptuit anle138b Denali DNL151 Biogen BIIB094 Neuropore NPT520-34 Aptinyx NYX-458 Anavex ANAVEX2-73 Denali DNL201 Dong-A ST DA-9805 Alkahest GRF6021 Anavex ANAVEX2-73 B&A Tx Bumetanide Clene Nanomedicine CNM-Au8 Annovis Posiphen Genzyme GZ/SAR402671** Prevail PR001A Roche RO7046015 Sun Pharma K0706 UCB Bio UCB0599 Enterin ENT-01 Herantis CDNF Axovant Sciences OXB-102 Voyager VY-AADC02 Oxford BioMedica ProSavin NeuroGeneration Stem Cell ApoPharma Deferiprone Adamas ADS-5102 Impax Lab IPX203 Sunovion APL-130277 Pharma Two B P2B001 AbbVie ABT-SLV187 Cerevel Tavapadon Impel intranasal levodopa Eli Lilly LY3154207 Chase Tx CTC-413 Integrative Lab Mesdopetam AbbVie L/C intestinal gel AbbVie ABBV-951 Edison EPI-589 Sanofi Lixisenatide Novo Nordisk Liraglutide Alkahest AKST4290 Xoc XC130-A10H RaQualia RQ-00000010 Prexton PXT002331 Sunovion SEP-363856 Kyowa Kirin KW-6356 Takeda TAK-071 Cavion CX-8998 H. Lundbeck Droxidopa Theranexus THN102 ACADIA Pimavanserin Theravance Ampreloxetine Voyager VY-AADC01 Brain Neuro Bio AAV2-GDNF Bial - Portela Ongentys|BIA 9-1067 Alexza Apomorphine Luye Pharma LY03003 + Neupro Serina SER-214 Alexza Apomorphine Acorda CVT-301 Cerevel CVL-751 INFLAMMATION 6 trials, 7%
Overview of Parkinson’s Disease Landscape David Russell, MD PhD
Parkinson’s Disease (PD) Overview Epidemiology: PD is a rapidly growing, progressive, fatal disease that affects 7-10 million people worldwide Complex gene-environment interactions PD Patient journey Pathological hallmarks of PD Central role of alpha-synuclein in PD pathogenesis Biomarkers to track aSyn pathophysiology cascades in clinical studies Competitive landscape New directions, Emerging science – proteinopathy / lipidopathy
Parkinson’s disease (PD) is the second most common and fastest growing neurodegenerative disorder ~1 Million patients in US, ~7 million worldwide; Average onset Late 50s-Early 60s. From 1990 to 2015, the number of people with Parkinson disease doubled to over 7 million Projected to double again by 2040 Epidemiology: The Growing Pandemic of Parkinson’s Disease Parkinson’s Disease Prevalence *Number of individuals over 50 with PD from 2005 to 2030. Projected growth of Parkinson’s Disease* PD is a predominantly sporadic disease Aging is greatest risk factor Up to 10% of cases occur in a familial manner Both autosomal dominant and recessive Significant environmental component Hou Y, Nat Rev Neurol 2019
Genetics Complex Gene-Environment Interactions Underlie Parkinson’s Disease Progression Combination of Genetic, Environmental and Immune Factors Underlie Development of PD 5% genetic, 25% hereditary, 75% sporadic Dominant (SNCA, LRRK2) Recessive (PARK7, PINK1, PRKN) Environmental Pesticides Heavy metals (Manganese) Mitochondrial toxins Repetitive head trauma Chemical exposure Immunology Persistent inflammation Viral infections (post-pandemic) Microbiome-immune interface Progressive Stages of Parkinson’s Disease Chen H, J Parkinsons Dis 2018
Parkinson’s Disease: Clinical Journey Overview Cardinal motor symptoms of PD stem from the loss of substantia nigra (SN) dopaminergic neurons Progressive bradykinesia, muscular rigidity, resting tremor, and gait impairment Non-motor symptoms including autonomic and cognitive dysfunction involve non-dopaminergic neurons Low blood pressure, constipation, incontinence, sensory problems, sleep disorders, neuropsychiatric problems and dementia. Multiple neurotransmitters: Dopamine, Norepinephrine, Acetylcholine Resting tremor Difficulty with simple manual tasks Unilateral, masked face Bilateral, slow shuffling gait Pronounced gait and posture disturbance, falls Limited ambulation with assistance Bed or chair confinement Time MOTOR SYMPTOMS Tremor Rigidity Bradykinesia Postural Instability Gait difficulty NON-MOTOR SYMPTOMS Fatigue Cognitive Psychiatric Sleep Disorders and EDS Autonomic; Sensory Parkinson’s Symptoms Are Insidiously Progressive
Pathological Hallmarks of Parkinson’s Disease Neuropathological (BRAAK) Staging of PD Based on Topography of Lewy Bodies Dopaminergic Neuron Loss and Lewy Bodies Normal Substantia Nigra (SN) Loss of SN dopaminergic neurons Lewy body Lewy neurites FIBRILLAR LEWY BODY NON-FIBRILLAR LEWY BODY
The Role of α-Synuclein Proteinopathy in Parkinson’s Disease Modified from Irvin, JD, Nat Rev Neurol 2013 α-Synuclein (α-syn) Is Major Component of Lewy Bodies and Lewy Neurites Normal functions Abnormal functions Synaptic vesicle cycling Membrane lipid interaction Mitochondrial-ER communication Oxidative stress Protein sequestration Disruption of axonal transport Synaptic dysfunction Inhibition of UPS Mitochondrial dysfunction Lysosomal dysfunction Normal role in synaptic function SNCA missense mutations associated with familial forms of PD (A53T, A30P, A53E, E46K, G51D, H50Q) SNCA gene duplication / triplication is sufficient to cause PD Overexpression in cell culture and mice mimics important aspects of pathology Injection of a-syn aggregates into animal brains causes pathological changes resembling PD b-pleated sheet pathology
aSyn Pathology can Spread to Many Brain Cells: Involvement in Many Neurodegenerative Diseases Neurodegenerative Diseases Aggregation Prone Proteins Neurodegenerative Disease Ab aSyn Tau TDP43 Other Alzheimer’s disease ✔ ✔ ✔ ✔ Parkinson’s disease ✔ ✔ ✔ Lewy Body dementia ✔ ✔ ✔ ✔ Multiple systems atrophy ✔ Frontotemporal lobar dementia ✔ ✔ ✔ Corticobasal degeneration ✔ ✔ ✔ Progressive supranuclear palsy ✔ Amyotrophic lateral sclerosis ✔ ✔ ✔ Chronic traumatic encephalopathy ✔ ✔ ✔ b-pleated Toxic aSyn aggregates can spread to neuronal, glial and immune cells Extracellular aSyn injury cascade Extracellular aSyn Microglia Activation Oligodendrocytes Demyelination Astrocytes Activation Inflammation Neuron Inflammation
Biomarkers for Tracking Biological Impact of Synucleinopathies ` Lewy pathology DATscan TSPO Microgliosis fMRI EEG α-syn pathology Tractable molecular pathology Tractable brain circuit alterations αSyn Dopamine synapses α-syn spreading patterns Cortico-striatal-thalamic circuits Microgliosis
Potential Disease Modification Therapeutic Targets in PD Deplete αSyn ASO Prevent αSyn Misfolding Molecular chaperones Prevent/reverse DA neuron toxicity Growth factors (GDNF) Stem cells Promote immune clearance Reduce inflammation GLP-1 ligands Immunomodulators Prevent spreading pathology Anti-αSyn mABs Anti-αSyn Vaccines Restore αSyn function Current gap Inhibit αSyn toxicity Multiple modalities Microglia Macrophage Normal functions Abnormal functions Synaptic vesicle cycling Membrane lipid interaction Mitochondrial-ER communication Oxidative stress Protein sequestration Disruption of axonal transport Synaptic dysfunction Inhibition of UPS Mitochondrial dysfunction Lysosomal dysfunction Modified from Irvin, JD, Nat Rev Neurol 2013
Potential Novel Disease Modification Therapeutic Targets in PD Novel targets through unbiased screening Membrane/lipid-rich αSyn aggregation Deplete αSyn ASO Prevent αSyn Misfolding Molecular chaperones Prevent/reverse DA neuron toxicity Growth factors (GDNF) Stem cells Promote immune clearance Reduce inflammation GLP-1 ligands Immunomodulators Prevent spreading pathology Anti-αSyn mABs Anti-αSyn Vaccines Microglia Macrophage Modified from Irvin, JD, Nat Rev Neurol 2013
Yumanity Discovery Engine Daniel Tardiff, PhD Scientific Co-founder, Interim Head of Research
Yeast Models Predict Mechanisms of Human Disease HUMAN YEAST PATHOLOGY GENETICS Conserved Biology and Pathological Mechanisms Lewy Bodies Inclusions / Aggregates YPK9 YPT7 VPS35 TIF4631/2 INP53 PARK9 PARK16 PARK17 PARK18 PARK20 * Similar examples in ALS / FTLD (TDP-43), Alzheimer’s (Ab, APOe4) Example*: Parkinson’s Disease / Dementia with Lewy Bodies / Multiple Systems Atrophy
Discovery Engine Step 1: Unbiased Small Molecule Screening Live Cell Screening Human Cell Translation Target Identification 1 2 3 Identify compounds that enhance survival
Discovery Engine Step 2: Human Neuron Translation Live Cell Screening Human Cell Translation Target Identification 1 2 3 Translation of screening hits to diseased human cells iPSC Technology Parkinson’s Patient Diseased Neuron
Discovery Engine Step 3: Identify Small Molecule Targets Live Cell Screening Human Cell Translation Target Identification 1 2 3 Use of chemical genetics and informatics to uncover target Target
Key Outputs of Novel Discovery Engine Live Cell Screening Human Cell Translation Target Identification 1 2 3 Unbiased platform identifies novel targets 100% targets druggable with small molecules Access to intra-cellular targets Target identification reveals biomarkers
Yumanity’s Discovery Engine Has Generated 20+ Novel Targets To-Date Discovery Model Target Potential Indication Area of Biology α-Syn USP8-30 PD, LBD, MSA Ubiquitin/Proteasome system TDP43 DBR1 ALS, FTLD RNA Metabolism α-Syn FKBP12 PD, LBD, MSA Signaling α-syn, APOE, TDP-43 HDACs ALS, FTLD, PD, LDB, MSA Chromatin modification Discovery Model Target Potential Indication Novel Areas of Biology α-Syn SCD PD, LBD, MSA, AD Fatty acid desaturation Undisclosed Target A ALS, FTLD Undisclosed Undisclosed Target B ALS, FTLD Undisclosed α-Syn 10 targets PD, LBD, MSA Lipid metabolism Vesicle biology Energy metabolism Cofactor metabolism Ion channels Undisclosed TDP-43 6 targets ALS, FTLD C9ORF72 3 targets ALS, FTLD APOE4 11 targets AD, PD, CAA YTX-7739 Proprietary Merck Partnered Part of strategic collaboration eligible for milestones totaling $500M Empirical Validation of Previously Identified Targets Unbiased Identification of New Targets in Novel Areas of Biology
Discovery and Pre-clinical Development of Stearoyl-CoA Desaturase Inhibitor, YTX-7739
Biological Functions of Stearoyl-CoA Desaturase (SCD) Enzymes Reaction Target Biomarker Increases in desaturated fatty acid concentration lead to: Altered membrane structure Altered vesicle trafficking Enhanced a-synuclein aggregates FA-DI = Fatty Acid Desaturation Index (FA-DI) unsaturated saturated Unsaturated Fatty Acids Saturated Fatty Acids
SCD Inhibition Restores a-Synuclein Function SCD WT aSyn Mutated aSyn Excessive aSyn a-State N C b-State P C N Disordered YTX-7739 Secretory Endosome Autophagy Nucleus ER Golgi Physiological multimers Normal functions Toxic oligomers/polymers Pathology hallmarks
Novel Parkinson’s Disease Mouse Model Provides In Vivo Validation Mouse Model Recapitulates Key Disease Phenotype a-synuclein aggregation and pathology Loss of dopaminergic neurons Progressive motor deficits Responsive to L-DOPA Nuber et al., Neuron 2018 a-Synuclein Pathology L-DOPA-responsive Motor Deficits Wild Type a-Syn Mutant a-Syn
Nuber, Selkoe, et al, AD/PD 2019 Nuber et al., Annals in Neurology 2020 Parkinson’s mouse model SCD1 Knockout mouse (SKO) Parkinson’s cross with SCD1 knockout ~20% Reduction in Target Biomarker Genetic Validation of SCD in a Mutant a-Synuclein Mouse Model Heterozygous deletion of SCD1 improves all phenotypes in a-Synuclein Mice SKO NTG WT Mut SKO Mut SKO Significant Improvement in Pole Climbing Test Target Biomarker
… and Engages the Target YTX-7739 Target Engagement in Brain and Plasma YTX-7739 Crosses BBB into Brain… YTX-7739 YTX-7739 (ng/mL) Target Biomarker Target Biomarker Plasma Brain * FA-DI = Fatty Acid Desaturation Index Mutant a-Synuclein Mice - + - + YTX-7739
In Vivo Evidence Supporting YTX-7739 Activity: Protein Restoration of physiological a-Synuclein Multimer Decrease in pathological, phosphorylated a-Synuclein (hallmark of Parkinson’s disease) Protein Pathology Neuronal Survival Motor Function Multimer/ monomer Ratio Mutant aS WT aS WT – wild-type Mut - Mutant Phospho-Ser129 a-Syn Collab. with BWH, Nuber, Tardiff, et al., ADPD 2021 P Mut a-Syn Placebo Mut a-Syn YTX-7739 WT a-Syn Placebo - + YTX-7739 - Mutant aS WT aS - + YTX-7739 -
In Vivo Evidence Supporting YTX-7739 Activity: Survival Protein Pathology Neuronal Survival Motor Function TH Staining Intensity Enhanced survival of dopaminergic neurons Monitor neurons affected in Parkinson’s Disease Collab. with BWH, Nuber, Tardiff, et al., ADPD 2021 - + YTX-7739 - Mutant aS WT aS WT - Placebo Mut - Placebo Mut – YTX-7739 WT - Placebo Mut - Placebo Mut – YTX-7739 Nerve Terminals (Striatum) Cell Bodies (SNpc)
In Vivo Evidence Supporting YTX-7739 Activity: Motor Function Protein Pathology Neuronal Survival Motor Function SCD Inhibition by YTX-7739 prevents deficits in motor function caused by mutant a-synuclein Collab. with BWH, Nuber, Tardiff, et al., ADPD 2021 - + YTX-7739 - Mutant aS WT aS + - + YTX-7739 - Mutant aS WT aS + Pole climbing test Rotarod test
Cancer cell proliferation is dependent on SCD activity and lipid biosynthesis SCD inhibition Enhances Survival in Glioblastoma Mouse Model SCD Activity Linked to Cancer Evaluate YTX-7739, a brain-penetrant and clinical-stage SCD inhibitor, in GBM models in collaboration with MGH GBM Team K. Eyme – C. Badr., Targeting Fatty Acid Biosynthesis in Glioblastoma SNO/NCI Symposium 2021 Vehicle YTX-7739 Pinkham et al., 2019 Glioblastoma (GBM) is an aggressive brain cancer 12-18 month survival with standard of care SCD inhibition improves GBM mouse models Increased Survival in Aggressive Glioblastoma Stem Cell Model Target Biomarker Reduced in Tumor Tumor Target Biomarker
Clinical Development of YTX-7739, a Stearoyl-CoA Desaturase Inhibitor (SCDI) Brigitte Robertson, MD Chief Medical Officer
72 healthy volunteers Single and Multiple Ascending Doses Well tolerated Pharmacokinetics dose proportional in fed state Cerebral Spinal Fluid (CSF) Concentration dose-dependent Profile supports once-daily oral dosing Proof of biology achieved with target engagement biomarker (FA-DI) YTX-7739 Phase 1 Program Summary – Healthy Volunteers YTX-7739 is a novel, oral, brain-penetrant SCD inhibitor
Part A 10 mg – 400 mg Fasted YTX-7739 Well Tolerated Part B & C* 5 mg, 10 mg, 30 mg 250 mg and 400 mg Fed Cohort results: blinded safety assessment after every cohort for dose escalation or dose adjustment Double Blind Placebo Controlled N=56 N = 8 / cohort (6:2 ratio YTX-7739 to PBO)* Key Endpoints: Adverse Events, Safety labs, Vital Signs, ECGs, Pharmacokinetics (Plasma and CSF) Key Findings Broad dose range evaluated, single oral doses (5-400 mg) in both fasted and fed states No serious adverse events, subject withdrawals or deaths in the study. All adverse events (AEs) were mild except 6 that were moderate in severity. Headache, fatigue, gastro-intestinal and musculoskeletal complaints were the most frequently reported AEs No drug related safety concerns or trends observed in blood chemistry, haematology, urinalysis, vital signs or 12-lead electrocardiograms (ECG’s). Maximum tolerated dose not identified *Part C was conducted open label Phase 1 Single Ascending Dose (SAD) Study in Healthy Volunteers
YTX-7739 Pharmacokinetic Profile Supports Once-daily dosing Plasma and CSF Pharmacokinetics Dose dependent reduction in bioavailability was observed following single dose administration of YTX-7739 in the fasted state at high doses In fed state, dose proportionality and linearity in the dose-exposure relationship was observed following single dose administration in the 5–250 mg dose range (Cmax and AUC0-24h) Half life 47–72 hours Cerebral Spinal Fluid (CSF) Penetration: Geometric Mean CSF to Total Plasma Ratio 0.052 (CV% 18.45%) Concentrations for target engagement were achieved
YTX-7739 Well Tolerated Adverse Event Placebo N=4 All Active N=12 15 mg N=6 25 mg N=6 Number of subjects (%) in each dose group with at least one post dose TEAE 4 (100) 11 (91.7) 5 (83.3) 6 (100) Number of subjects (%) with at least one report of most frequent TEAE (≥2 reports on active treatment) Headache 0 8 3 5 Fatigue 0 6 1 5 Abdominal discomfort 0 4 2 2 Rhinorrhea 2 3 2 1 Dry eyes 1 3 1 2 Feeling cold/hot 0 3 1 2 Hyperbilirubinemia 1 2 0 2 Paresthesia 0 2 2 0 Anemia 0 2 0 2 Dry skin 0 2 2 0 Dry throat 0 2 2 0 25 mg 14-days dosing 15 mg 28-days dosing Double Blind Placebo Controlled N=16 N = 8 / cohort (6:2 ratio YTX-7739 to PBO)* Cohort results: blinded safety assessment after every cohort for dose escalation or dose adjustment Phase 1 Multiple Ascending Dose (MAD) Study in Healthy Volunteers Key Endpoints: Adverse Events, Safety labs, Vital Signs, ECGs, Pharmacokinetics (Plasma and CSF), Pharmacodynamics: FA-DI These results are preliminary as of May 8th and are subject to change as the final CSR has not been completed
YTX-7739 MAD HV Plasma and CSF Pharmacokinetics: Dose Proportional* Mean YTX-7739 Pharmacokinetic Parameters1 Maximal Concentration Median Time Max Concentration Occurs AUC24h DN Cmax DN AUC24h Accumulation Ratio (AUC) CSF: Plasma Ratio2 Dose (mg) Day (ng/mL) (hr) (ng*hr/mL) (ng/mL/mg) (ng*hr/mL/mg) 15 1 131.4 10.06 2332 8.76 155 NA 15 14 703.2 8 1030 46.88 1030 6.981 15 28 757.3 7 14320 50.49 955 6.302 0.047 25 1 278.7 6 4727 11.15 189 NA 25 14 1408 4 26144 56.34 1046 5.955 0.052 AUC24h: Area under concentration versus time curve from time 0 to 24 hours post dose, DN Cmax: Dose normalized maximal concentration, calculated by Cmax divided by dose, DN AUC24h: Dose normalized AUC24h, calculated by AUC24h divided by dose 1These results are preliminary as of May 8th and are subject to change as the final CSR has not been completed *Administered in fed state 2Geometric Mean CSF to total Plasma Ratio
YTX-7739 MAD Study Part A Healthy Volunteers: Baseline Biomarker Stability Across Treatment Groups MAD Placebo MAD 15 mg MAD 25 mg Mean 0.08 0.07 0.08 SD 0.014 0.016 0.015 CV% 16.2 23.6 18.3 Unsaturated Saturated Target Biomarker (FA-DI) = Biomarker: Fatty Acid Desaturation Index (FA-DI) Ratio decreases with SCD inhibition MAD Study results in healthy Volunteers align with phase 0 study suggesting the Biomarker findings in Healthy volunteers will translate to Patients with Parkinson’s Disease Baseline Biomarker (Plasma FA-DI)* Low Within and Between Subject Variability Changes in plasma levels of fatty acids (substrates and products) are an index of SCD enzyme inhibition *These results are preliminary as of May 8th and are subject to change as the final CSR has not been completed 1Patients with Parkinson’s Disease
YTX-7739 MAD Study: Proof of Biology Achieved with Biomarker of Target Engagement Proof of biology: dose dependent reduction in plasma biomarker Target engagement biomarker generally reaches maximal response by 14 days Some evidence of heterogeneity in response Effect appears to trend towards to baseline after drug discontinuation Findings consistent with drug effect Target engagement biomarker
YTX-7739 Proof of Biology in Patient Population: Data Expected Mid 2021 Dose 20 mg 28-days dosing Dose TBD 28-days dosing Double Blind Placebo Controlled N~30 N = 10 / cohort (8:2 ratio YTX-7739 to PBO)* Mild to Moderate symptoms (Hoehn and Yahr 1-3) Treatment Naïve or satisfactory control on L-Dopa Blinded safety assessment after every cohort for dose escalation or dose adjustment Key Endpoints Safety and Tolerability and Pharmacokinetics (plasma and CSF) Proof of biology: Target Engagement biomarker (plasma FA-DI) Biomarkers: Exploratory Drug effects in brain: EEG, MRI Parkinson’s Disease: Alpha synuclein, Fatty Acids related to Glucocerebrosidase and LRRK2 Clinical (e.g. motor, non motor [cognition, sleep]) Neurodegeneration: Neurofilament light chains Inflammation: C-reactive protein Phase 1 Multiple Ascending Dose (MAD) Study in Patients with Parkinson’s Disease *YTX-7739 being administered orally with low fat meal
Phase 1 Single Ascending Dose Study (SAD) and food Effect in Healthy Volunteers Phase 1 Multiple Ascending Dose Study (MAD) in Healthy Volunteers Phase 1b Multiple Dose Study (MAD) in Patients with Parkinson’s Disease YTX-7739 Clinical Program Advancing Rapidly Towards Phase 2 Mid- 2021 Safety, Tolerability, Pharmacokinetics and food effect à Dose Selection-Progression to Multiple Dose Study Steady State Safety, Tolerability, Pharmacokinetics à Dose Selection, Advancement to Patient Population Cerebral Spinal fluid à Blood Brain Barrier, CSF Drug Concentration Target Engagement (FA-DI) àProof of biology, Dose/Drug response Safety, Tolerability, Pharmacokinetics à Dose Selection, Advancement to Phase 2 Cerebral Spinal fluid à Blood Brain Barrier, CSF Drug Concentration Target Engagement (FA-DI) à Proof of biology, Dose / Drug response Early Evidence Effectiveness à Biomarkers Measures à Implications
Wrap Up
YTX-9184 start of Phase 1 for Dementia with Lewy Bodies Upcoming Catalysts Completed Reverse Merger NASDAQ: YMTX YTX-7739 Multiple Ascending Dose results in healthy volunteers YTX-7739 Phase 1b results in Parkinson’s patients 2Q 2021 Mid 2021 2H 2021 Goal of one new program into the clinic per year; Growing pipeline enables scalable business model Potential for $600M+ in future milestone payments plus royalties from Merck and Genentech Cash runway into 3Q 2022 Potential for multiple BD deals 4Q 2020
Discovery Target Validation Lead Optimization IND- enabling Phase 1 Anticipated Clinical Milestones Program 1: Parkinson’s Disease 3Q 2020 – Phase 1 SAD Data 2Q 2021 – Ph 1a MAD in Healthy Volunteers Mid-2021 – Ph 1b Patient Data 2022 – Phase 2 initiation Program 2: Dementia with Lewy Bodies 2Q 2020 – Start IND-enabling studies 2H 2021 – Phase 1 initiation Program 3: Glioblastoma Multiforme 1Q 2022- Window of opportunity study initiation Program 4: ALS/FTLD Program 5: ALS/FTLD Programs 6-16 PD, AD, ALS/FTLD YTX-7739 (SCD Inhibitor) Undisclosed Undisclosed Undisclosed YTX-9184 (SCD Inhibitor) Prolific Discovery Engine Drives Rapidly Expanding Pipeline of Disease-Modifying Therapies Partnered with SAD=single ascending dose; MAD = multiple ascending dose; IND=investigational new drug application SCD Inhibitor
Q & A