Alto Neuroscience, Inc. · NYSE:ANRO
Alto Neuroscience — Investor Day (September 2024)
74 slides from Alto Neuroscience's investor day presentation, Sep 9, 2024
Slide 1: Investor Day, Sept. 9, 2024
NYSE: ANRO Investor Day, Sept. 9, 2024
Slide 2: Disclaimer & Forward-Looking Statements
Disclaimer & Forward-Looking Statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding the progress and timing of the clinical develo
Slide 3: Precision Medicine for the Brain is Here
Precision Medicine OUR VISION for the Brain is Here. To redefine the approach to psychiatric drug development which matches the right patient with the right Alto drug 3
Slide 4: Today’s participants
Today’s participants Alto executive management team External expert perspective Amit Etkin, MD PhD Adam Savitz, MD PhD Michael Hanley Chief Executive Officer Chief Medical Officer Chief Operating Officer Gerard Sanacora, PhD MD George D. and Esther S. Gross Professor of Psychiatry, Director of Yale
Slide 5: Today’s Agenda
Today’s Agenda • Alto Neuroscience Overview and Background – Amit Etkin, MD, PhD – Founder & CEO • Understanding Major Depressive Disorder (MDD) with Poor Memory - Amit Etkin, MD, PhD – Founder & CEO • Clinician Perspective - Dr. Gerard Sanacora • Mechanism of ALTO-100 & Link to Patient Population –
Slide 6: Alto by the numbers
Alto by the numbers Advancing a leading, clinical-stage precision medicine portfolio for the brain >800 25+ MILLION 5 2027 Into Patients Dosed Patient Impact Phase 2 Data Read Outs Cash Across completed and ongoing Opportunity Runway Expected in the next 2.5 years studies with Alto’s novel product a
Slide 7: A core problem in psychiatry: unguided treatments work poorly
A core problem in psychiatry: unguided treatments work poorly Small effects on average… due to large heterogeneity in patients’ biology = = Average Average Current Approach Alto's Precision Psychiatry Approach Differentiated drug profile Trial-and-error, mostly failures Broad utilization of pharmaco
Slide 8: Precision medicine has brought innovation to other areas, yet psychiatry is largely untapped
Precision medicine has brought substantial innovation to other areas, yet psychiatry is largely untapped Precision medicine citations since 1996 9000 • Precision oncology impact has increased exponentially since the early 2010s with 8000 psychiatry oncology the rise of immuno-oncology and scalable a
Slide 9: We leverage a suite of biomarkers to segment patients
We leverage a suite of biomarkers designed to segment patients and drive improved clinical outcomes Biomarker Likely Responder Heterogeneous Alto Biomarker Example Alto Characterized to Alto Product Clinical Populations Platform Biomarker Population Candidate 600 500 40 400 300 20 ALTO-100 200 0 Beh
Slide 10: Leveraging proprietary tools, anticipating commercial scale
Leveraging proprietary tools, anticipating commercial scale ALTO-100 biomarker is ALTO-300 biomarker cognitive test-based is EEG-based 10
Slide 11: First biomarker-driven pipeline for neuropsychiatric conditions
First biomarker-driven pipeline for neuropsychiatric conditions Advancing towards multiple near-term milestones across pipeline of independent programs leveraging our biomarker strategy to systemically reduce development risks Phase 1 Phase 2 Phase 3 Product Responder Candidate Lead Indication Safet
Slide 12: Addressing common investor questions
Addressing common investor questions ❑ How do I think about this novel MoA (i.e., not targeted by others)? ❑ What weight and interpretation do I give the original third-party all-comer Phase 2 study? ❑ How much does the single-arm Phase 2a trial with a prospectively replicated enrichment reduce deve
Slide 13: ALTO-100 could be a highly differentiated new treatment option
ALTO-100 could be a highly differentiated new treatment option in an underserved patient population 1. MDD with poor memory biomarker Target Population(s) 2. Bipolar depression with poor memory biomarker Potentially first-in-class oral small-molecule, MoA and Route of Administration enhancing hippoc
Slide 14: MDD with poor memory/cognition: Mechanistic insights into a depression subgroup
MDD with poor memory/cognition: Mechanistic insights into a depression subgroup with high unmet need
Slide 15: The neuroplasticity deficit framework for MDD has been a focus for over two decades
The neuroplasticity deficit framework for MDD has been a focus for over two decades Overview of this framework: Example early reviews: • Neuroplasticity: the brain's ability to adapt to changing external or internal stimuli; underlies functions like 2002 memory and cognition • Neuroplasticity defici
Slide 16: Extensive evidence behind the neuroplasticity framework, BDNF signaling, and neurogenesis
Extensive evidence behind the neuroplasticity framework, the role of BDNF signaling, and neurogenesis Healthy MDD with poor memory/cognition Humans, in vivo: • ↓ hippocampal volumes • ↓ memory (along with other aspects of cognition) • ↓ synaptic density (SV2A PET) • Relationship between memory/cogni
Slide 17: Hippocampus-dependent verbal memory biomarker
Hippocampus-dependent verbal memory biomarker The Rey Auditory Verbal Learning Test (RAVLT) is a long- Our adaptation (VM-REACT) in our proprietary cognitive established and very well-validated measure of hippocampal battery (Spectra) closely matches performance on the RAVLT function and neuroplasti
Slide 18: MDD with poor memory/cognition is a common and persistent form of depression
MDD with poor memory/cognition is a common and persistent form of depression 30-50% of MDD patients have poor memory/cognition In a study of N=1,008 MDD patients in an 8-week SSRI/SNRI treatment study and N=336 healthy individuals: Impaired cognition, regardless of treatment, is Symptomatic remissio
Slide 19: High unmet treatment need for MDD patients with poor memory/cognition
High unmet treatment need for MDD patients with poor memory/cognition Psychiatric hospitalization rates Poor memory predicts treatment resistance (N=229) greater for poor memory patients (HR 1.84, p=0.03; N=398) Poor memory has been shown to predict treatment resistance, leading to nearly twice the
Slide 20: MDD with poor memory/cognition is a disabling form of depression
MDD with poor memory/cognition is a disabling form of depression, independent of depressive symptoms Extensive literature has shown poor memory/cognition relates to disability and dysfunction in MDD Building on this we found: Poor cognition predicts both worse functional capacity Poor cognition is s
Slide 21: Genetic risk for MDD is associated with poor memory/cognition
Genetic risk for MDD is associated with poor memory/cognition Demonstrates relationship between cognition and core disease processes (e.g. polygenic MDD risk score) 21 Cullen et al., JAMA Psych, 2023
Slide 22: ALTO-100 potentially offers a novel therapeutic option by enhancing hippocampal neuroplasticity
ALTO-100 potentially offers a novel therapeutic option for MDD with poor memory/cognition by enhancing hippocampal neuroplasticity Post-treatment Healthy MDD with poor memory/cognition ALTO-100 BDNF GPCRs TrkB Akt MEK Reduction in hippocampal Transcription plasticity and neurogenesis (contributing t
Slide 23: ALTO-100 mechanism of action
ALTO-100 mechanism of action: Enhances hippocampal neuroplasticity across multiple time scales, leveraging BDNF signaling
Slide 24: ALTO-100: developed to enhance hippocampal neuroplasticity, and improve cognition and mood
ALTO-100: developed to enhance hippocampal neuroplasticity, and improve cognition and mood BDNF Glutamate Identified based on a Increased hippocampal synaptic neurogenesis functional plasticity and volume preclinically screen NMDAR TrkB GPCRs AMPAR Preclinically, increases synaptic and cellular plas
Slide 25: Motivation for ALTO-100’s Discovery and Preclinical Validation
Motivation for ALTO-100’s Discovery and Preclinical Validation Ablating hippocampal neurogenesis has been shown Motivated Neuralstem to screen >10,000 compounds to eliminate the effects of antidepressants in mice for pro-neurogenic capacity Objective: enhance hippocampal plasticity with an aim to im
Slide 26: ALTO-100 results in an immediate increase in BDNF release
ALTO-100 results in an immediate increase in BDNF release, with downstream effects dependent on BDNF signaling BDNF has been shown to increase hippocampal neuroplasticity, neurogenesis, and improve cognition and mood analogs – ALTO-100 leverages this pathway for its downstream effects ALTO-100 incre
Slide 27: ALTO-100 resulted in neurogenesis-dependent memory enhancement
ALTO-100 resulted in neurogenesis-dependent memory enhancement • Hippocampal neurogenesis drives Sham-Vehicle Sham-ALTO-100 pattern separation, which is impaired by stress in depressed patients • Pattern separation task: animal learns to distinguish between subtly different safe and dangerous contex
Slide 28: Work done to define the direct target for ALTO-100
Work done to define the direct target for ALTO-100: potentially first-in-class molecular mechanism Block downstream effects in neurons with: • Pharmacological inhibition using multiple different antagonists • Genetic knockout via CRISPR Endow sensitivity in non-neuronal cells via exogenous expressio
Slide 29: Poor memory ALTO-100 biomarker: Identification, prospective replications, and specificity
Poor memory ALTO-100 biomarker: Identification, prospective replications, and demonstration of specificity vs. placebo
Slide 30: Poor memory patients respond better to ALTO-100 and not placebo
Poor memory patients respond better to ALTO-100 and not placebo: two prospective, two retrospective, and two placebo datasets Phase 2a completed by Alto: prospective memory marker replication Discovery Data Set Prospective Test Data Set Prior to acquisition by Alto ee ee Retrospective analysis 0 0 2
Slide 31: Alto’s precision drug development approach
Alto’s precision dr g develop ent approac Phase 2A Phase 2B/3 01 02 03 Determine Biomarker Prospective Efficacy in Clinical Population Biomarker Validation Biomarker + is Biologically Test Data Heterogeneous bio + bio - Candidate Biomarker Identified Statistical Analysis Plan Enroll based on biomark
Slide 32: ALTO-100 Phase 2A study design and participant flow
ALTO-100 Phase 2A study design and participant flow Patient Population Cognition MDD Cohort Baseline Demographics • Adults 18- 65 years old Enrolled 243 Discovery Data Set Test Data Set • Moderate to severe MDD and/or PTSD 90 Bio- Bio+ Bio- Bio+ • Monotherapy or adjunctive Baseline PTSD Cohort N 13
Slide 33: ALTO-100 Phase 2A: prospective testing of memory/cognition biomarker
ALTO-100 Phase 2A: prospective testing of memory/cognition biomarker as predictive of response 01 02 Prospective Replication in Test Dataset Determine Prospective Week Biomarker Biomarker Validation 0 2 4 6 8 N=30 N=93 0 MADRS LSM Change From Baseline d=0.28 p=0.10 -4 d=0.42 p=0.04 d=0.58 d=0.61 -8
Slide 34: Poor memory/cognition patients derived greater benefit from ALTO-100
Poor memory/cognition patients derived greater benefit from ALTO-100 p=0.004 Clinical response to ALTO-100 60 Cognition Bio + (poor memory; n=59) Cognition Bio - (good memory; n=64) observed to be more robust in p=0.01 ≥ 50% AD I prove ent patients with poor memory 50 % of Patients Achieving • Poor
Slide 35: Poor memory did not predict higher placebo response
Poor memory did not predict higher placebo response Tested poor memory and placebo response in 2 separate third-party MDD monotherapy trials, possible because they used the same memory test On placebo, Placebo-treated Patients patients with poor Study #2: Study #1: memory did not Week Week 0 2 4 6 8
Slide 36: Pilot decentralized study of ALTO-100 in MDD demonstrates feasibility of at-home biomarker collection
Pilot decentralized study of ALTO-100 in MDD demonstrates feasibility of at-home biomarker collection and consistency of biomarker results Study Summary 0 Individual Patient MADRS Change from Baseline to Week 6 • 20 adult moderate to severe MDD MADRS Change From Baseline to Week 6 patients -10 • Sin
Slide 37: ALTO-100 has potential to demonstrate greater efficacy in less-responsive population
ALTO-100 has potential to demonstrate greater efficacy in mechanistically-distinct and less-responsive population 0.5 Meta-analytic all-comer effect sizes at primary endpoint timepoint across studies Comparison all-comer Drug-placebo effect size (Cohen's d) effects: 0.4 monotherapy adjunctive 0.3 Ef
Slide 38: ALTO-100 was well tolerated: Alto Phase 2A study
ALTO-100 was well tolerated: Alto Phase 2A study Overall Treatment Emergent Adverse Events (TEAEs) TEAEs or ≥5% o t e Pop lation Safety Analysis Set Safety Analysis Set N (%) N (%) Total Participants 243 At least one TEAE 146 (60.1) Headache 40 (16.5) No TEAE 97 (39.9) Abdominal discomfort 13 (5.4)
Slide 39: We systematically ruled out potential confounders
We systematically ruled out potential confounders • Similar enrichment for monotherapy vs. adjunctive Background medications • In adjunctive, SSRI vs. SNRI similar • Comorbidity (e.g., GAD) did not impact Clinical factors • Similar enrichment for treatment resistant patients • Self-reported cognitio
Slide 40: Phase 2b study: Design, rationale, and baseline data
Phase 2b study: Design, rationale, and baseline data* *Data presented are provisional as database lock has not yet been completed data remain blinded
Slide 41: ALTO-100 Phase 2B biomarker-guided trial in MDD
ALTO-100 Phase 2B biomarker-guided trial in MDD Enrollment completed – topline data expected Oct. 2024 Screening Period 6-Week Double-Blind 7-Week Open Label Treatment Period Extension 40 mg BID ALTO-100 N=301 40 mg BID ALTO-100 Wearable Behavior EEG 1:1 Randomization PRIMARY OUTCOME: MADRS change i
Slide 42: We have carefully thought through the overall study design
We have carefully thought through the overall study design to ensure high-quality data interpretation Design Decisions Rationale Enroll poor memory (powered analysis) & good Describe enrichment & mitigate expectation memory patients bias for patients and sites Placebo mitigation efforts: • 1:1 rando
Slide 43: Verbal memory biomarker thresholds for study inclusion
Verbal memory biomarker thresholds for study inclusion Phase 2a data: memory score (z) -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 5 • Continuous relationship between 0 memory impairment and better response MADRS change from baseline -5 -10 • Poor memory defined as z≤-0.5 • Targeted N=200 for powering
Slide 44: FDA interactions support Phase 2b study interpretation
FDA interactions support Phase 2b study interpretation • Early feedback on protocol led to an increase from N=200 to 266 to enable better powering of monotherapy (largest subgroup) • June 2024 Type C meeting, focusing on enrichment approach via memory test: • Outcome in line with expectations • Prov
Slide 45: Phase 2B study flow, enabled by robust biomarker collection
Phase 2B study flow, enabled by robust biomarker collection Enrolled Screening visit structure (key elements): (ITT sample) 301 1. Visit 1: • Severity and diagnosis (at site), PHQ • SAFER including MADRS (MGH)** mITT sample 2. Visit 2: 289 • Biomarker baseline (at site), PHQ (Site baseline MADRS≥20)
Slide 46: Phase 2b: poor and good memory patients are well-matched
Phase 2b: poor and good memory patients are well-matched • No difference in depression severity or any other demographic factor (e.g. age) • Overall severity in line with expectations, consistent visit-wise across MADRS and PHQ • Shows cognition is an independent facet of MDD not confounded by clini
Slide 47: Phase 2b: similar severity for mono vs. adjunctive (poor memory)
Phase 2b: similar severity for mono vs. adjunctive (poor memory) • Within poor memory group, similar clinical profile for monotherapy and adjunctive patients • No difference in years since first episode (mean: 19.3) or number of episodes • Racial difference may reflect difference in access to health
Slide 48: Importance of patient selection across studies
Importance of patient selection: underpins ability to consistently identify the same patient population across studies Rate of poor memory patients When selecting patients based on memory, Phase 2a d ring screening (z≤-0.5) and 2b populations are now highly similar • Well-matched on depression sever
Slide 49: Alto’s in-house clinical operations approach
Alto’s in-house clinical operations approach ✓ Direct Data Entry ✓ Real Time Data Review Individual ✓ Eligibility review ✓ Onsite/Remote RBM ✓ Independent, external raters confirm MDD Site Level Monitoring Progress 100 % 90% 80% ✓ Biweekly Cumulative Data Reviews 70% Cumulative ✓ Timely identificati
Slide 50: Statistical analysis plan for key outcomes
Statistical analysis plan for key outcomes Primary outcome • Analyses guided by trial design, unmet clinical need of poor memory MDD • mITT poor memory population • Powered at 80% for d=0.4 • Will also look at a more cognitively impaired mITT subpopulation that may further enhance enrichment Step-do
Slide 51: Summary of key factors for potential Phase 2b success
Summary of key factors for potential Phase 2b success Target population, drug MOA and memory-based enrichment all strongly theoretically motivated High unmet clinical need as poor memory/cognition patients more chronic and disabled, with worse response to standard of care Two prospective replication
Slide 52: Results from Spectra
=> ALTO NEUROSCIENCE Results from Spectra
Slide 53: Spectra participant system specifications and demographics
Location All Countries» ‘System Specifications Browser 0 Name ee @ Chrome 76.19% @ Edge 19.05% e @ Safari 2.38% @ Firefox 2.38% %e TD _ Laptop 100.0% Tablet 0.0% a DO Mobile 0.0% “ @ Spain @ United States Bisract @ United Arab Emirates: @ Germany * ‘@Canads @ United Kingdom 2) User Demographics Sess
Slide 54: Dashboard
Dashboard Memory Speed 20 20 10 10 ° = 0 & 2 275-25.225 2 475-18-125 1 -075-05-025 0 025 05 075 1 12518 175 2 225 25 275 a 9275-25-22 2 7515-125 -1 075-05 -025 0 025 05 075 1 12515 175 2 225 25.275 4 © Alto Investor Day Participants | — Existing Observations © Atto Investor Day Participants + — Exis
Slide 55: Commercial considerations: Unique opportunity afforded by the precision psychiatry approach
Commercial considerations: Unique opportunity afforded by the precision psychiatry approach
Slide 56: Patients with MDD and poor cognition represent a large, underserved population
Patients with MDD and poor cognition represent a large, underserved, and readily addressable population Patients with MDD and poor cognition represent an estimated Patients with 30-50% of the overall MDD population schizophrenia For reference, the number of patients with MDD and poor cognition is es
Slide 57: Prescribers recognize the need for targeted therapies with novel mechanisms
Prescribers recognize the need for targeted therapies with novel mechanisms and improved clinical profiles In recent market research, prescribers provided perspective on the management of MDD A ong ad lt patients wit DD… Top unmet needs 64% Mechanism of action New and targeted mechanisms estimated t
Slide 58: Readily scalable cognitive testing enables multiple routes to ALTO-100 utilization
Readily scalable cognitive testing enables multiple routes to ALTO-100 utilization and drives market penetration Patient self-identifies At-home test (e.g., DTC campaign with clear call-to-action) In-clinic test Current Patient sees Medication Outcome Prescriber prescribed assessed 58
Slide 59: The MDD market is ripe for a precision medicine approach
The MDD market is ripe for a precision medicine approach HCPs view Alto’s cognitive test as predictive, reliable, and easy to integrate into practice Physicians expressed a strong desire … and a strong willingness to for a biomarker-based treatment incorporate Alto’s cognitive approac … biomarker te
Slide 60: Prescribers view ALTO-100’s clinical profile very favorably
Prescribers view ALTO-100’s clinical pro ile very avora ly Perceived access restrictions represent the biggest barrier to early use HCPs view the ALTO-100 clinical profile as highly differentiated from current treatment options “I would test most patients that are referred to me. I just Clinical att
Slide 61: Payers recognize the economic and clinical rationale of a targeted biomarker approach
Payers recognize the potentially unique economic and clinical rationale resulting from a targeted biomarker approach and compelling clinical profile In recent market research, payers provided perspective on their management of MDD • While payers currently control the MDD “(There is) a good clinical
Slide 62: ALTO-100: A clear path to commercialization and significant commercial potential
ALTO-100: A clear path to commercialization and significant commercial potential Large and readily identifiable patient population Substantial unmet need due to the heterogeneity of disease, lack of diverse MOAs, and limited treatment effect among available therapies Strong receptivity to a cognitiv
Slide 63: Broader Alto pipeline: Multiple Phase 2 studies across drugs and populations
Broader Alto pipeline: Multiple Phase 2 studies across drugs and populations
Slide 64: First biomarker-driven pipeline for neuropsychiatric conditions
First biomarker-driven pipeline for neuropsychiatric conditions Advancing towards multiple near-term milestones across pipeline of independent programs leveraging our biomarker strategy to systemically reduce development risks Phase 1 Phase 2 Phase 3 Product Responder Candidate Lead Indication Safet
Slide 65: Expert perspective: Gerard Sanacora, MD PhD
Expert perspective: Gerard Sanacora, MD PhD George D. and Esther S. Gross Professor of Psychiatry Director, Yale Depression Research Program Yale University
Slide 66: External expert perspective
External expert perspective Gerard Sanacora, PhD MD George D. and Esther S. Gross Professor of Psychiatry, Director of Yale Depression Research Program, Yale University Dr. Sanacora’s work has focused largely on elucidating the pathophysiological mechanisms associated with mood and other neuropsychi
Slide 67: A Discussion of the Relevant Conceptualization and Clinical Treatment of MDD
A Discussion of the Relevant Conceptualization and Clinical Treatment of Major Depressive Disorder Gerard Sanacora M.D., Ph.D. George D. Gross and Esther S. Gross Professor of Psychiatry, Yale University School of Medicine Director Yale Depression Research Program Co-Director Yale New Haven Hospital
Slide 68: Death Rates for Coronary Heart Disease, United States, 1950–2004
Death Rates* for Coronary Heart Disease, United States, 1950– 2004 Actual Rate and Expected Rates if Rise had Continued or Reached a Plateau *Age-adjusted. National Institutes of Health. National Heart, Lung, and Blood Institute. www.nhlbi.nih.gov/about/factbook-06/chapter4.htm. Accessed September 1
Slide 69: Depression is the leading cause of disability worldwide
Depression is the leading cause of disability worldwide and is a major contributor to the overall global burden of disease US Suicide rates overall appear to be increasing A large percentage of patients do not receive an adequate response to current antidepressant medications Zisook S, et al. J Clin
Slide 70: Changing Theories of Mood Disorder Pathophysiology
Changing Theories of Mood Disorder Pathophysiology Historically Shift to cortical and limbic dominant pathology monoaminergic theory “If one viewed depression as a disorder of cortico-limbic function, then glutamatergic and GABAergic signaling would be implicated. This perspective shift led us to te
Slide 71: Typical Patient Journey
Typical Patient Journey 1. Symptom Recognition •Self-awareness: The patient or those close to them may notice symptoms and recognize that something is wrong. •Screening and Assessment: PCPs commonly use standardized screening tools like the PHQ-9 (Patient Health Questionnaire) to assess the severity
Slide 72: Treatment Planning
4. Treatment Planning •Collaborative Discussion: The patient and clinician discuss treatment options, which may include psychotherapy, medication, lifestyle changes, or a combination of these (largely based on clinician’s own expertise). •Lifestyle Modifications: Recommendations might include regula
Slide 73: Unsatisfactory response and long-term management
• Unsatisfactory response: Several options based on level of severity, prior response, and patient preference (Typically where Psychiatrist becomes involved). • Modify existing treatment: (i.e. increase/decrease dose, change timing of dosing) • Switch treatment: Consider other treatment choice (i.e.
Slide 74: Precision Medicine for the Brain is Here
Precision Medicine OUR VISION for the Brain is Here. To redefine the approach to psychiatric drug development which matches the right patient with the right Alto drug 74