Ovid Therapeutics Inc. · NASDAQ:OVID

Ovid Therapeutics — Investor Day (November 2024)

87 slides from Ovid Therapeutics's investor day presentation, Nov 13, 2024

Slide 1: Welcome to Ovid Therapeutics
Welcome to Ovid Therapeutics Potassium chloride cotransporter 2 November 13, 2024
Slide 3: Forward looking statement
Forward looking statement This presentation contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 including, without limitation, statements regarding the timing and development of Ovid’s product candidate pipeline and achievement of expected
Slide 4: Our Brain Trust
Direct activator portfolio Ovid approach & OV350 Jeremy Levin, MB BChir, Zhong Zhong, Ph.D. CEO & Chairman Chief Scientific Officer Our KCC2 opportunity & strategy Clinical translation strategy Meg Alexander Amanda Banks, M.D. President & COO Chief Development Officer Brain Trust A fundamental targe
Slide 5: Ovid is a pioneer in this evolution
A new era in neurotherapeutics Biology identifying key pathophysiologic targets Novel mechanisms are required Highly specific, brain-penetrant small molecules are preferable to treat and ultimately, halt brain disease Ovid is a pioneer in this evolution CONFIDENTIAL – NOT FOR DISTRIBUTION © Copyrigh
Slide 6: Foundational biological targets, therapeutic opportunities, highly specific small molecules
Foundational biological targets Substantial therapeutic opportunities Implicated in neuronal hyperexcitability, Across neurological and neuropsychiatric neuroinflammation or neurovascular dysfunction conditions with deep unmet need Highly specific small molecules Cash balance of $62.7 million Harnes
Slide 7: A pipeline positioned to lead the era of neurotherapeutics
A pipeline positioned to lead the era of Proven developers of candidates to mitigate neuronal hyperexcitability neurotherapeutics Translators of ROCK2 inhibition in the brain Pioneers of KCC2 direct activation © Copyright 2024 Ovid Therapeutics 7
Slide 8: Differentiated pipeline, advancing in the clinic
Differentiated pipeline, advancing in the clinic Programs Indication Preclinical Phase 1 Phase 2 Phase 3 Anticipated Milestones OV329 • Conditions with Phase 1 estimated readout in 2025 neuronal Topline timing to be updated following discussions GABA-aminotransferase hyperexcitability with regulator
Slide 11: Many neurological & neuropsychiatric medicines are limited today
Many neurological & neuropsychiatric medicines are limited today Therapeutic zone Toxicities & tolerability bounds Tolerability limits efficacy Drug interactions Unclear underlying biological & root cause contra-indications © Copyright 2024 Ovid Therapeutics 11
Slide 12: What if there was a biological target in the brain that…
What if there was a biological underlies disease mechanisms across many target in the brain that… central nervous system conditions? is druggable with highly specific, small molecule medicines? minimizes side effects & toxicities associated with current CNS medicines? acts as a monotherapy & enhance
Slide 13: Neuronal hyperexcitability is at the biological root of many brain diseases
Neuronal hyperexcitability is at the biological root of many brain diseases that have no effective treatments today ©2024 OVID THERAPEUTICS INC. | ALL RIGHTS RESERVED 13
Slide 14: Directly activating KCC2 can restore neuronal balance
Directly activating KCC2 can restore neuronal inhibitory/excitatory balance to bring a hyperexcited neuron back into homeostasis ©2024 OVID THERAPEUTICS INC. | ALL RIGHTS RESERVED 14
Slide 15: Cracking a fundamental target can spark a therapeutic revolution
Metastatic Malignant Pleural Mesothelioma Cracking a fundamental target Metastatic Solid Tumors can “spark” a therapeutic revolution Gastroesophageal Junction Adenocarcinoma Recurrent Endometrial Carcinoma Unresectable Colorectal Cancer Advanced Endometrial Carcinoma Metastatic Biliary Tract Cancer
Slide 16: KCC2 holds similar breakthrough potential for the brain
KCC2 holds similar breakthrough potential for the brain Neuropsychiatric Neurodegenerative Psychosis in neuronal synuclein Psychosis disorders (Parkinson’s disease, Schizophrenia Lewy body dementia) Bipolar disorder Huntington’s disease Obsessive compulsive disorder Depression KCC2 direct Pain Anxie
Slide 17: Ovid's KCC2 direct activator portfolio
Ovid’s KCC2 direct activator portfolio Unique target Multiple compounds Differentiated potential & formulations target product profile Direct activator of KCC2 100+ unique compounds No sedation observed Key to regulating neuronal excitation Different pharmacologic properties Low risk of over modulat
Slide 18: Progress of our KCC2 portfolio
Progress of our KCC2 portfolio Screened 100+ 4 Phase 1 1.3 million active pharmaceutical characterized & in 1st-in-human for candidates for direct activators agents identified active development class in Q1 2025 Low EC50 activity against Ovid in-licensed library Formulation optimization OV350 intrav
Slide 19: KCC2 direct activator portfolio: Franchise of potential medicines
KCC2 direct activator portfolio: Franchise of potential medicines Program Potential indications Preclinical Phase 1 Phase 2 Phase 3 Anticipated milestones OV350 IV Predominant antipsychotic • Acute & sub-acute Phase 1 Q1 2025 activity, rapid acting conditions (e.g., psychosis, pain, others) Phase 1
Slide 20: KCC2 portfolio offers
KCC2 portfolio offers: Successive programs Strategic optionality to collaborate or out-license Substantial therapeutic opportunity in under-addressed indications © Copyright 2024 Ovid Therapeutics 20
Slide 21: KCC2: A fundamental target
KCC2: A fundamental target Jeffrey Noebels, M.D., Ph.D. Director, Developmental Neurogenetics Laboratory Cullen Chair in Neurogenetics Professor of Neurology, Neuroscience, and Molecular and Human Genetics Baylor College of Medicine, Houston © Copyright 2024 Ovid Therapeutics 21
Slide 23: Challenge of drug discovery in the era of precision neurology
Challenge of drug discovery in the era of precision neurology Hyperexcitability is a prominent feature of major clinical disorders Which are redundant, which are critical Cognitive impairment in disease network? Inflammation >> 1K disease genes Autism Ataxia Dyskinesia Even different variants Dyston
Slide 24: Targeting hyperexcitability by strengthening synaptic inhibition homeostasis
Key strategy: Targeting hyperexcitability by strengthening synaptic inhibition homeostasis Excitatory vs inhibitory balance Restoring balance I E Add more rocks Remove some rocks © Copyright 2024 Ovid Therapeutics 24
Slide 25: Targeting hyperexcitability by strengthening synaptic inhibition homeostasis
Key strategy: Targeting hyperexcitability by strengthening synaptic inhibition homeostasis Excitatory vs inhibitory balance Restoring balance I E Add more rocks Remove some rocks KCC2 KCC2 is a molecular fulcrum for a spectrum of excitability disorders © Copyright 2024 Ovid Therapeutics 25
Slide 26: Why we like KCC2 as a target
Why we like KCC2 as a target Precision mechanism of action to rebalance network hyperexcitability Targets the “final common pathway,” synaptic inhibition, downstream of many genetic and acquired causes of hyperexcitability Converges on a broad spectrum of neurodegenerative disorders where hyperexcit
Slide 28: KCC2 is the main regulator of GABA inhibition
What is it? KCC2 is the main regulator of GABA inhibition by maintaining neuronal chloride homeostasis Healthy Neuron Pathological Conditions Regulates chloride gradient Manages the passive inward entry of KCC2 KCC2 Cl− through activated GABA channels Cl- K-Cl K-Cl Cl- GABAAR GABAAR Na-Cl Na-Cl Main
Slide 29: KCC2 is the main regulator of GABA inhibition
What is it? KCC2 is the main regulator of GABA inhibition by maintaining neuronal chloride homeostasis Healthy Neuron Pathological Conditions Regulates chloride gradient Manages the passive inward entry of KCC2 KCC2 Cl− through activated GABA channels Cl- K-Cl K-Cl Cl- GABAAR GABAAR Na-Cl Na-Cl Main
Slide 30: KCC2 protein expression is uniquely confined to CNS neurons
Where is it? KCC2 protein expression is uniquely confined to CNS neurons Brain KCC2 expression vs. other potassium/chloride transporters mRNA NKCC1 KCC2 KCC3 KCC4 High Allen Brain Atlas Protein Low Markkanen, JCN 2013 • Isoform of the potassium chloride cotransporter family • KCC2 expression only in
Slide 31: Hyperexcitation can drive cascade of toxic neuro-inflammation & cell death
Hyperexcitation can drive cascade of toxic neuro-inflammation & cell death Release of Activating Activates inflammasomes Oxidative stress, Hyperexcitability pro-inflammatory Cell death microglia & reactive neuroinflammation cytokines oxygen species TNF-α IL-1β IL-6 Translational Psychiatry (2022) 12
Slide 32: Major clinical opportunities for KCC2 activation therapy
Major clinical opportunities for KCC2 activation therapy GABA/Glycine receptor hypofunction Neuropsychiatric (Low Chloride Gradient Syndromes) Epilepsies & seizure disorders Psychosis Cluster seizures Schizophrenia Treatment resistant seizures Bipolar disorder Obsessive compulsive disorder Pain Depr
Slide 33: Major clinical opportunities for KCC2 activation therapy
Major clinical opportunities for KCC2 activation therapy GABA/Glycine receptor hypofunction (Low Chloride Gradient Syndromes) Epilepsies & seizure disorders Cluster seizures Treatment resistant seizures KCC2 direct activation Restoring excitatory / inhibitory homeostasis © Copyright 2024 Ovid Therap
Slide 34: KCC2 loss of function mutation linked to multiple seizure types
KCC2 loss of function mutation linked to multiple seizure types Focal seizures Generalized epilepsy Developmental epileptic encephalopathies Adapted from Moore et al. Trends Neurosci. (2017) Solid genetic evidence that KCC2 is a precision target in the hyperexcitability disorder pathway © Copyright
Slide 35: KCC2 is downstream of the most common hyperexcitability pathway genes
KCC2 is downstream of the most common hyperexcitability pathway genes 40 epilepsy (DEE) genes impair GABA signaling Chloride gradient enhances inhibition Master switch to repair network brake defects Noebels, Nature Neuroscience 2015 © Copyright 2024 Ovid Therapeutics 35
Slide 36: KCC2 is downregulated in pain and neuroinflammation models
KCC2 is downregulated in pain and neuroinflammation models Gate Control Theory Sciatic nerve injury allodynia Dorsal Theiler’s viral-induced epilepsy KCC2 expression horn spinal cord KCC2 lowers hippocampal KCC2 Dorsal Root Entry zone Cervical Microglia Thoracic Hu, Molecular Pain, 2023 Patel, Front
Slide 37: EEG of genetic Alzheimer's mouse model confirms sub-clinical seizures
EEG of genetic Alzheimer’s mouse model confirms sub-clinical seizures Hippocampal electrodes in hAPP-J20 mouse Non-convulsive electrographic seizures with hippocampal involvement Palop J, Neuron, 2007 How was this overlooked for more than 100 years? © Copyright 2024 Ovid Therapeutics 37
Slide 38: Focal human hippocampal seizures are invisible to scalp EEG
Focal human hippocampal seizures are invisible to scalp EEG and ‘subclinical’ Frontal, Parietal, occipital Non-convulsive, scalp electrodes difficult to detect 1. Staring 2. No speech Lateral Temporal ` 3. Soliloquy, mumbling 4. Agitation Mesial Temporal Foramen 1 5. Fearful expression Ovale electro
Slide 40: Why stabilize hyperexcitability in Alzheimer's?
Why stabilize hyperexcitability in Alzheimer’s? Delay hippocampal neurodegeneration Subclinical (EEG spikes) hyperexcitability in 42% of 33 sporadic AD cases, more rapid dementia than those without* *Vossell et al, Ann Neurol. 2016 Epilepsy accelerates CA1 hippocampal neuronal loss in human presenil
Slide 41: Major clinical opportunities for KCC2 activation therapy
Major clinical opportunities for KCC2 activation therapy GABA/Glycine receptor hypofunction Neuropsychiatric (Low Chloride Gradient Syndromes) Epilepsies & seizure disorders Psychosis Cluster seizures Schizophrenia Treatment resistant seizures Bipolar disorder Obsessive compulsive disorder Pain Depr
Slide 42: The therapeutic goal: Arrest the enduring impact of hyperexcitability
The therapeutic goal: Arrest the enduring impact of hyperexcitability If neuronal decline & death can be prevented with KCC2 activation, we may discover novel medicines for neurological & neurodegenerative disease © Copyright 2024 Ovid Therapeutics 42
Slide 43: Direct activation matters
Direct activation matters Dr. Stephen Moss Director, Moss Lab for Neuropharmacology at Tufts University Professor of Molecular Pharmacology at University College London ©2024 Ovid Therapeutics | All Rights Reserved 43
Slide 44: Direct activation matters
Chemistry & phosphorylation challenge to achieve direct activation Direct activation matters Confirming direct activation of KCC2 co-transporter Relevance to potential therapeutic target product profile ©2024 Ovid Therapeutics | All Rights Reserved 44
Slide 45: Neuronal Cl- extrusion by KCC2 is a pre-requisite for GABAA inhibition
Neuronal Cl- extrusion by KCC2 is a pre-requisite for GABAA receptor dependent neuronal inhibition and the therapeutic efficacy of benzodiazepines, neurosteroids and barbiturates Extracellular GABAAR KCC2 Intracellular © Copyright 2024 Ovid Therapeutics 45
Slide 46: Therapeutic strategies to increase KCC2 activity
Therapeutic strategies to increase KCC2 activity Direct activation has significant advantages Direct pharmacological activation, by molecules for drug development, that bind to and increase KCC2 intrinsic activity as efficacy can be directly correlated with KCC2 activity Indirect activators that inc
Slide 47: Screening and deconvolution strategy to identify direct KCC2 activators
TI influx FLIPR assay in KCC2-HEK293 1.3 M compounds tested at 30 μM single point Hit reconfiguration and dose response Counterscreen assays TI influx FLIPR in overexpressed-HEK293 Screening and Dose response vs KCC3, KCC4, NKCC1 & UT-HEK deconvolution Focused Kinase Screening -kinase activators str
Slide 48: Click-chemistry and mass spectrometry identified amino acids mediating OV350 binding
Click-chemistry and mass spectrometry identified amino acids in KCC2 that mediate binding of OV350 © Copyright 2024 Ovid Therapeutics 48
Slide 49: OV350 increases KCC2 activity via binding to its cytoplasmic domain
OV350 increases KCC2 activity via binding to amino acids in its cytoplasmic domain SPECIFICITY KCC2 CRYO-EM KNOWN BINDING SITE A B A A B OV350 exhibits 100-1,000-fold higher potency for KCC2 compared to other peripheral K/Cs and NKCC1, limiting peripheral side effects seen with other NKCC1 inhibitor
Slide 50: The efficacy of GABAAR positive allosteric modulators is GABA-dependent
L-Glut GABA-AT inhibitors The efficacy of GABAAR positive allosteric Sabril® modulators is GABA-dependent OV329 Non-benzodiazepines Pre-synaptic Ganaxalone GABAergic neuron Allopregnalone Phenobarbital Diacomit® KCC2 has potential to act as: Topamax® • Monotherapy Benzodiazepines • Combination thera
Slide 51: Benefits of KCC2 direct activation
Benefits of KCC2 direct activation • Normalizes neuronal activity • Nearly impossible to “over-activate” transporter • Potential to work as a monotherapy • Restores GABA-ergic function for other GABA acting agents to be efficacious • Avoids sedation © Copyright 2024 Ovid Therapeutics 51
Slide 53: Direct activators with unique chemistry
Direct activators with unique chemistry High degree of specificity with lower risk of off-target effects 4 compounds in active development with Ovid’s portfolio of unique characteristics KCC2 direct activators Multiple formulation opportunities In vivo efficacy in disease models without sedation Pha
Slide 55: Potent, specific & brain-penetrant small molecules with electrophysiologic activity
Potent, specific & brain-penetrant small molecules with electrophysiologic activity • HT screen of 1.3 million compounds using an established thallium TI influx assay in HEK-293 cells overexpressing KCC2 POTENCY • Threshold of >30% potentiation of KCC2 activity at EC50 of <30 mM • All KCC2 leads hav
Slide 56: Four-tiered screen applied to identify next-generation compounds
Four-tiered screen applied to identify next-generation compounds Specificity Brain Therapeutic Disease model & potency penetrance reference screens screens In vitro activity Oral formulation Phenotypic screens Effect compared to (SmartCube®) reference compounds Direct, specific and BBB permeability
Slide 57: Franchise of KCC2 direct activators
Franchise of KCC2 direct activators OV4000 OV5000 OV350 OV4071 Series Series Anxiolytic Antipsychotic activity Antipsychotic Antipsychotic In discovery Attributes Rapid acting Increased potency Anticonvulsant activity Intravenous Oral, chronic Intramuscular injection Multiple compounds Multiple comp
Slide 59: OV350 is a first-in-class KCC2 direct activator
OV350 is a first-in-class KCC2 direct activator Specificity Penetrance Directly binds to KCC2 (surface plasmon Small molecule (MW<500) resonance and thermal shift assay) Excellent brain penetration No off-target effects on kinases regulating KCC2 activity (PKC, SPAK, WNK) Potential for biomarker OV3
Slide 60: Rapid, stable accumulation in the brain with a translatable biomarker
Rapid, stable accumulation in the brain with a potentially translatable pharmacodynamic biomarker in pathologic condition OV350 rapidly accumulates in rodent brain OV350 induces a shift in EEG high gamma via IV/IP dosing power spectrum (biomarker) Control OV350 Concentration (microM) Time (hours) Fr
Slide 61: OV350 shows anticonvulsant activity in nerve agent model in rats
OV350 shows anticonvulsant activity in nerve agent model in rats Seizure Seizure Termination Termination OV350 IV terminated seizures in a subset of animals exposed to the nerve agent Termination 0 100 Vehicle Standard of Care 50 mg/kg Reduction • Soman + standard medical care (atropine and 100 mg/k
Slide 62: OV350 elicits rapid antipsychotic-like effects
OV350 elicits rapid antipsychotic-like effects Potent, robust, rapid and reversible antipsychotic activities have been observed for OV350 • Behaves as atypical antipsychotic with a clean profile in SmartCube® • Elicits its in vivo effects within 15 minutes of administration • Effects are robust from
Slide 63: OV350 has dose-dependent effect greater than clozapine
Marked effect in PCP-perturbed model, underscoring activity only in disease state OV350 has dose-dependent effect greater than atypical antipsychotic clozapine PCP Rx N=10 mice/group © Copyright 2024 Ovid Therapeutics 63
Slide 64: OV350 IND-enabling studies show favorable toxicology profile
OV350 IND-enabling studies show favorable toxicology profile & dose- dependent exposure All IND-enabling studies completed Rat (QD) NOAEL identified in both species • Mild, reversible clinical tox observed with no Supportive of Phase 1 study macro/microscopic findings at target dose range • Cmax and
Slide 66: OV4000s display antipsychotic, anxiolytic and anticonvulsant activities
OV4000s display antipsychotic, anxiolytic and anticonvulsant activities Class Probability (%) Subclass Probability (%) 10 30 10 30 10 20 3 10 1 3 10 30 10 20 30 4035 4095 4050 4100 4071 4036 CLP mg/kg © Copyright 2024 Ovid Therapeutics 66
Slide 67: OV4071 showed a robust, dose dependent signal in schizophrenia psychosis model
OV4071 showed a robust, dose dependent signal in schizophrenia psychosis model Model considered to be a 5000 Vehicle + MK-801, 0.3mg/kg proxy for schizophrenia Locomotor activities (counts/5min) OV4071, a mg/kg + MK-801, 0.3mg/kg OV4071, b mg/kg + MK-801, 0.3mg/kg 4000 OV4071, c mg/kg + MK-801, 0.3m
Slide 68: OV4000 series exhibits anxiolytic effects comparable to diazepam
OV4000 series exhibits anxiolytic effects comparable to diazepam • Elevated plus maze (below) is a rodent model of anxiety in which animals naturally prefer the protected, closed arms relative to the open arm • Spending time in the open arms is indicative of an anxiolytic-like effect • 4000 series c
Slide 69: KCC2 programs moving forward from research to clinical studies
KCC2 programs moving forward from research to clinical studies Targeting KCC2 provides a unique and unprecedented opportunity to correct neuronal hyperexcitability • Direct activation to minimize off-target effects • Normalize chloride homeostasis in neurons • Restore the excitatory/Inhibitory balan
Slide 71: Clinical translation strategy: Matching biology to indications
Highly diverse library of compounds across chemistry, formulation and pharmacology Multiple candidates moving forward in parallel Clinical translation strategy: Matching biology Key is to align drug characteristics and biology with potential clinical applications to indications Potential for applica
Slide 72: Potential therapeutic indications for Ovid portfolio
Potential therapeutic indications for Ovid portfolio KCC2 Direct Activation Acute Sub-acute Chronic (IV & IM Formulations) (PO & IM Formulations) (PO & IM Formulations) • Acute psychosis • Seizures • Seizures • Traumatic brain injury • Psychosis • Psychosis • Spinal cord injury • Schizophrenia • Sch
Slide 73: Building a KCC2 franchise: Matching biology with target indications
Building a KCC2 franchise: Matching biology with target indications Anticonvulsant Antipsychotic • Epilepsy • Psychosis of Parkinson's disease • Neurodevelopmental disorders OV4071 • Psychosis of Lewy Body Dementia • Neurodegenerative diseases • Schizophrenia • Neurotrauma OV350 • Bipolar • Delirium
Slide 74: Potential for prolific franchise
Potential for prolific franchise Annual regulatory submissions from KCC2 direct activator platform 2025 2026 2027+ OV350 Phase 1 Phase 1 b OV350 Phase 1 Bridging study Phase 2 initiation OV4071 Phase 1 OV4071 Phase 1 OV4000 series Human study OV5000 series Human study © Copyright 2024 Ovid Therapeut
Slide 75: OV350 Phase 1 trial design with readout expected H1 2026
OV350 Phase 1 trial design with readout expected H1 2026 • Standard Phase 1 SAD/MAD design in healthy volunteers • Endpoints are safety, tolerability and PK over a range of doses • Creates full optionality to run one or more Phase 1b studies in patients • Given profile of OV350, we are considering a
Slide 76: Rationale for OV350 IV as first-in-human direct activator
Rationale for OV350 IV as first-in-human direct activator Attribute Rationale  First-in-human study using formulation less subject to absorption/metabolism variability First-in-class molecule  Drives learnings around PK parameters and safety, tolerability  Development ahead of PO formulations Mos
Slide 78: Restoring GABA's inhibitory tone via KCC2 activation
Restoring GABA’s inhibitory tone via KCC2 activation is a foundational approach to many CNS diseases Healthy Neuron Pathological Conditions KCC2 KCC2 Cl- K-Cl K-Cl Deficits in KCC2 activity have GABAAR GABAAR Cl- been linked to a variety of Na-Cl Na-Cl neurological disorders K-Cl K-Cl NKCC1 NKCC1 GA
Slide 79: Potential to address multiple diseases with little or no pharmacologic treatments
Potential to address multiple diseases with little or no pharmacologic treatments Neurodegenerative Psychosis in neuronal synuclein disorders (Parkinson’s disease, Lewy body dementia) Huntington’s disease KCC2 direct activation Restoring excitatory / inhibitory homeostasis © Copyright 2024 Ovid Ther
Slide 80: Potential development indication: Psychosis in Parkinson's disease & Lewy body dementia
Potential development indication: Psychosis in Parkinson’s disease & Lewy body dementia Parkinson’s disease psychosis and Lewy body dementia are both neuronal synuclein diseases (NSD) • Progressive clinical syndromes characterized clinically by movement disorders, cognitive impairment and sleep dysr
Slide 81: High unmet need
High unmet need Common manifestation Atypical antipsychotics Limited responders to only contra-indicated approved medicine ~30% of Parkinson’s patients Atypical antipsychotics can make Only approved drug for psychosis experience within 2 years of motor features worse, and carry in neurodegenerative
Slide 82: Psychosis associated with neuronal synuclein disorders (NSD)
Psychosis associated with neuronal synuclein disorders (NSD) Mechanistic rationale for KCC2 activation OV350 pharmacology and its antipsychotic effects suggests it may: KCC2 activity is lower in disease states Improve psychosis of NSD Regulation of chloride balance is lost and GABA inhibitory Withou
Slide 83: Psychosis as a core feature of many CNS diseases
Psychosis as a core feature of many CNS diseases Mechanistic grounding may be similar among them Current therapies limited by sedation, metabolic syndrome, QTC prolongation Large proportion of patients’ have uncontrolled symptoms requiring a new approach Broad application across psychotic symptoms a
Slide 84: Ovid franchise of KCC2 direct activators
Ovid franchise of KCC2 direct activators KCC2 Direct Activation Acute Sub-acute Chronic (IV & IM Formulations) (PO & IM Formulations) (PO & IM Formulations) • Acute psychosis • Seizures • Seizures • Traumatic brain injury • Psychosis • Psychosis • Spinal cord injury • Schizophrenia • Schizophrenia •
Slide 86: Ovid's Library of KCC2 Direct Activators
Platform of KCC2 direct activators Multiple drug compounds and formulations OVID’s Library of KCC2 Direct Activators Substantial and broad therapeutic opportunity OV350, Phase 1 and first-in-human in Q1 2025 Successive regulatory submissions for years to come © Copyright 2024 Ovid Therapeutics 86

Ovid Therapeutics — Investor Day (November 2024) on 6ix

Ovid Therapeutics — Investor Day (November 2024)

Slide 1: Welcome to Ovid Therapeutics

Slide 2: Welcome

Slide 3: Forward looking statement

Slide 4: Our Brain Trust

Slide 5: Ovid is a pioneer in this evolution

Slide 6: Foundational biological targets, therapeutic opportunities, highly specific small molecules

Slide 7: A pipeline positioned to lead the era of neurotherapeutics

Slide 8: Differentiated pipeline, advancing in the clinic

Slide 9: Restoring balance in the brain

Slide 10: KCC2 opportunity & strategy

Slide 11: Many neurological & neuropsychiatric medicines are limited today

Slide 12: What if there was a biological target in the brain that…

Slide 13: Neuronal hyperexcitability is at the biological root of many brain diseases

Slide 14: Directly activating KCC2 can restore neuronal balance

Slide 15: Cracking a fundamental target can spark a therapeutic revolution

Slide 16: KCC2 holds similar breakthrough potential for the brain

Slide 17: Ovid's KCC2 direct activator portfolio

Slide 18: Progress of our KCC2 portfolio

Slide 19: KCC2 direct activator portfolio: Franchise of potential medicines

Slide 20: KCC2 portfolio offers

Slide 21: KCC2: A fundamental target

Slide 22: Today's topics

Slide 23: Challenge of drug discovery in the era of precision neurology

Slide 24: Targeting hyperexcitability by strengthening synaptic inhibition homeostasis

Slide 25: Targeting hyperexcitability by strengthening synaptic inhibition homeostasis

Slide 26: Why we like KCC2 as a target

Slide 27: KCC2: What is it? Where is it? How does it modify disease?

Slide 28: KCC2 is the main regulator of GABA inhibition

Slide 29: KCC2 is the main regulator of GABA inhibition

Slide 30: KCC2 protein expression is uniquely confined to CNS neurons

Slide 31: Hyperexcitation can drive cascade of toxic neuro-inflammation & cell death

Slide 32: Major clinical opportunities for KCC2 activation therapy

Slide 33: Major clinical opportunities for KCC2 activation therapy

Slide 34: KCC2 loss of function mutation linked to multiple seizure types

Slide 35: KCC2 is downstream of the most common hyperexcitability pathway genes

Slide 36: KCC2 is downregulated in pain and neuroinflammation models

Slide 37: EEG of genetic Alzheimer's mouse model confirms sub-clinical seizures

Slide 38: Focal human hippocampal seizures are invisible to scalp EEG

Slide 39: Lam, Nat Med . 2017 © Copyright 2024 Ovid Therapeutics

Slide 40: Why stabilize hyperexcitability in Alzheimer's?

Slide 41: Major clinical opportunities for KCC2 activation therapy

Slide 42: The therapeutic goal: Arrest the enduring impact of hyperexcitability

Slide 43: Direct activation matters

Slide 44: Direct activation matters

Slide 45: Neuronal Cl- extrusion by KCC2 is a pre-requisite for GABAA inhibition

Slide 46: Therapeutic strategies to increase KCC2 activity

Slide 47: Screening and deconvolution strategy to identify direct KCC2 activators

Slide 48: Click-chemistry and mass spectrometry identified amino acids mediating OV350 binding

Slide 49: OV350 increases KCC2 activity via binding to its cytoplasmic domain

Slide 50: The efficacy of GABAAR positive allosteric modulators is GABA-dependent

Slide 51: Benefits of KCC2 direct activation

Slide 52: KCC2 direct activator portfolio & OV350

Slide 53: Direct activators with unique chemistry

Slide 54: KCC2 library overview

Slide 55: Potent, specific & brain-penetrant small molecules with electrophysiologic activity

Slide 56: Four-tiered screen applied to identify next-generation compounds

Slide 57: Franchise of KCC2 direct activators

Slide 58: OV350: First-in-human KCC2 direct activator

Slide 59: OV350 is a first-in-class KCC2 direct activator

Slide 60: Rapid, stable accumulation in the brain with a translatable biomarker

Slide 61: OV350 shows anticonvulsant activity in nerve agent model in rats

Slide 62: OV350 elicits rapid antipsychotic-like effects

Slide 63: OV350 has dose-dependent effect greater than clozapine

Slide 64: OV350 IND-enabling studies show favorable toxicology profile

Slide 65: OV4000 Series: Next generation compounds

Slide 66: OV4000s display antipsychotic, anxiolytic and anticonvulsant activities

Slide 67: OV4071 showed a robust, dose dependent signal in schizophrenia psychosis model

Slide 68: OV4000 series exhibits anxiolytic effects comparable to diazepam

Slide 69: KCC2 programs moving forward from research to clinical studies

Slide 70: Clinical translation strategy

Slide 71: Clinical translation strategy: Matching biology to indications

Slide 72: Potential therapeutic indications for Ovid portfolio

Slide 73: Building a KCC2 franchise: Matching biology with target indications

Slide 74: Potential for prolific franchise

Slide 75: OV350 Phase 1 trial design with readout expected H1 2026

Slide 76: Rationale for OV350 IV as first-in-human direct activator

Slide 77: Therapeutic opportunity

Slide 78: Restoring GABA's inhibitory tone via KCC2 activation

Slide 79: Potential to address multiple diseases with little or no pharmacologic treatments