Alto Neuroscience, Inc. · NYSE:ANRO
Alto Neuroscience — Investor Presentation (January 2026)
70 slides from Alto Neuroscience's investor presentation, January 2026
Slide 1: Alto Neuroscience, NYSE: ANRO, January 2026
NEUROSCIENCE SS ALTO NYSE: ANRO = January 2026
Slide 2: Disclaimer
Disclaimer 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 development of the programs across
Slide 3: Precision Medicine for the Brain is Here
Precision Medicine OUR MISSION for the Brain is Here. Redefining psychiatry by leveraging individuals’ neurobiology to develop personalized and highly effective medicines, helping patients get better faster. 3
Slide 4: Alto by the numbers
Alto by the numbers 6 Advancing a leading, clinical-stage precision medicine portfolio for the brain 25 + 4 Into >800 MILLION 2028 Patients Dosed Patient Impact Mid- to Late-Stage Expected Cash Across studies with Alto’s Opportunity Data Readouts Runway novel product candidates across the portfolio
Slide 5: CNS is the next frontier in precision medicine
CNS is the next frontier in precision medicine Oncology Cardiovascular / predictive biomarkers target specificity or genetics CNS / Alto is the only company taking a precision biomarker-based approach to patient identification aiming to drive better clinical outcomes in CNS 5
Slide 6: Unmet needs pervade mental health disorders
Unmet needs pervade mental health disorders Depression and 13% of U.S. $280B spent on schizophrenia are adults take mental health leading causes of antidepressants services in 2020 disability worldwide Brody, 2020 SAMHSA Lancet, 2017 6
Slide 7: Alto's strategy addresses a core problem in psychiatry
Alto’s strategy addresses a core problem in psychiatry Characterizing drug activity and identifying responsive patient populations before advancing Current approach Alto precision approach Unguided trial-and-error treatments in Differentiated drug profile in stratified patient heterogeneous populati
Slide 8: First biomarker-driven pipeline for mental health conditions
First biomarker-driven pipeline for mental health conditions Multiple independent programs leveraging our biomarker strategy to systematically reduce development risk; all programs remain on track to achieve upcoming milestones Phase 1 Phase 2 Phase 3 Product Safety & Brain Clinical Effect in Candid
Slide 9: Platform
ALTO NEUROSCIENCE
Slide 10: Alto's suite of biomarkers designed to segment patients
Alto’s suite of biomarkers designed to segment patients to drive improved 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 Behavior Cognitive P
Slide 11: 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 11
Slide 12: ALTO-207: Development for TRD
ALTO-207 Development for TRD
Slide 13: ALTO-207: D3/D2 agonist combined with 5-HT3 antagonist
ALTO-207: combining a dopamine D3-preferring D3/D2 agonist with demonstrated antidepressant effects and 5-HT3 antagonist designed to reduce dose-limiting AEs D2 receptor (similar effects in prefrontal and Dopamine limbic areas) Gut input ALTO-207 Neuron (D3/D2 agonist & 5HT3 antagonist) pramipexole
Slide 14: ALTO-207 is a novel, clinically validated product candidate
ALTO-207 (fka CTC-501) is a novel, clinically validated product candidate for a high need patient population Pramipexole has shown robust antidepressant effects but is limited by significant tolerability issues CTC-501 demonstrated clear safety benefits over pramipexole alone, achieving higher doses
Slide 15: The Lancet Psychiatry PAX-D study publication
Peer-reviewed publication of PAX-D study demonstrates robust clinical effects of pramipexole in TRD Pramipexole augmentation for the acute phase of treatment-resistant, unipolar depression: a placebo-controlled, double-blind, randomised trial in the UK A close-up of a document AI-generated content m
Slide 16: Pramipexole trials: antidepressant effect limited by titration and nausea
Pramipexole trials showed antidepressant effect, but speed of titration and max dosage limited by nausea/vomiting TRD study: aimed for 3mg/daily dose but only PAX-D TRD study (n=150): striking and sustained clinical efficacy, but high dropout due to AEs reached 1.35mg/day 20% stopped d=0.87* 30 pram
Slide 17: Pramipexole effects on anhedonia
Pramipexole has exhibited field-leading effects on anhedonia measures, demonstrating potential to address a critical need in the treatment of depression Comparative Effect Sizes on Anhedonia 0.7 New result under peer 0.62 0.63 review – pre-print 0.6 available Oct. 29 0.5 Cohen's D on Anhedonia (SHAP
Slide 18: Real world prescribing of pramipexole in MDD
Real world prescribing of pramipexole in MDD shows very slow titration and few get to a therapeutic dose level, limiting use Data drawn from NIH’s All of Us dataset (N=633,547), focusing on those with MDD (N=113,666) • 1.8% treated with pramipexole (N=2,093) • 23.7% achieved ≥1mg/day • 1.5% achieved
Slide 19: CTC-501 achieved higher pramipexole doses faster
CTC-501 (n.k.a. ALTO-207) combination approach achieved higher pramipexole doses faster and more consistently ≥2.5x increase in pramipexole tolerability Novel combination supported by Phase 1* safety data 100 6 Proportion tolerating dose (%) 80 5 Maximum tolerated dose (mg) • Achieved a 2.5-fold or
Slide 20: CTC-501 builds on strong evidence of antidepressant effects
CTC-501 (n.k.a. ALTO-207) development builds on strong clinical evidence of antidepressant effects Phase 2a: MDD randomized, placebo-controlled trial (N=32) • Rapid titration to avg of 4.1mg/d pramipexole in 8 days (77% reached max 5mg/d after initial dosing schedule change) • Moderate-severe MDD (b
Slide 21: Phase 2a of CTC-501 confirmed favorable safety and tolerability
Phase 2a trial of CTC-501 (n.k.a. ALTO-207) in MDD confirmed favorable safety and tolerability profile Nausea and vomiting were the most common AEs – all were mild to moderate Post-titration AEs* CTC-501 (N=13) Placebo (N=15) Related Unrelated Related Unrelated Nausea 2 (15%) 2 (15%) 0 (0%) 2 (13%)
Slide 22: ALTO-207 designed to achieve rapid antidepressant effect
ALTO-207 designed to achieve rapid antidepressant effect Until CTC-501, all pramipexole depression trials followed CTC-501 showed the largest clinical effect, with rapid the FDA-approved titration schedule onset due to faster titration with good tolerability Pramipexole targeted titration schedules
Slide 23: ALTO-207 positioned for potential Phase 2b/pivotal success
ALTO-207 positioned for potential Phase 2b/pivotal* success Highly compelling evidence for the clinical effect of pramipexole in TRD, with principal limitation being dose-related intolerability (which motivated development of CTC-501) Completed Phase 1 study demonstrated significantly improved toler
Slide 24: Intended regulatory strategy makes use of biomarkers
Intended regulatory strategy makes use of biomarkers Dopamine-related biomarker strategy Regulatory considerations • Will focus on both clinical effect and tolerability • Anticipate a regulatory path with broad TRD approval as well as potential for an enrichment • Biomarkers will be pre-specified ke
Slide 25: ALTO-207 attributes deter off-label generic substitution
Novel ALTO-207 product attributes and substantial patient risk deters off-label generic substitution Key attributes of ALTO-207 that mitigate Prescribing generic components introduces likelihood of generic substitution substantial patient & prescriber risk • Strong IP portfolio covering formulation
Slide 26: Recent success in psychiatry supports combination approach
Recent success in psychiatry strongly supports combination approach and novel mechanism Recent combination analogs demonstrate… Innovation Antagonistic combination to Synergistic combination of two • improved tolerability, mitigate AEs in schizophrenia (SZ) generic medications • larger effect size,
Slide 27: ALTO-300: Phase 2b development for MDD
ALTO-300 Phase 2b development for MDD
Slide 28: ALTO-300 proposed mechanism of action
ALTO-300 proposed mechanism of action: synergy between melatonergic agonism and 5-HT2C antagonism ALTO-300 is a multi-modal antidepressant with a broad ALTO-300 range of synergistic neurobiological effects that lead (agomelatine) to antidepressant activity and favorable tolerability MT1/MT2 5-HT2C M
Slide 29: Opportunity for ALTO-300 as adjunctive treatment in MDD
Unique opportunity for ALTO-300 (agomelatine) as an adjunctive treatment in MDD Well-tolerated and validated antidepressant with Ex-U.S. approval (NCE in U.S.) ready for enhancement with a biomarker Similar all-comer efficacy as other adjunctive treatments Favorable tolerability compared to other ad
Slide 30: Head-to-head data positions ALTO-300 favorably
Head-to-head clinical trial data positions ALTO-300 favorably even against SSRI/SNRIs, setting up case for adjunctive use ALTO-300 (agomelatine) consistently better-tolerated with fewer discontinuations ALTO-300 (agomelatine): superior versus SSRI/SSNRIs due to adverse events (pooled analysis of ran
Slide 31: ALTO-300 Phase 2a study design and participant flow
ALTO-300 Phase 2a study design and participant flow Patient Population EEG Baseline Demographics • Adults 18-74 years old Enrolled 239 Discovery data set Test data set • Moderate to severe MDD Bio- Bio+ Bio- Bio+ • Adjunctive (<50% response to current drug) Baseline N 29 31 21 24 Severity 194 • 45%
Slide 32: Alto's precision drug development approach
Alto’s precision drug development approach Phase 2A Phase 2B/3 01 02 03 Determine Biomarker Prospective Efficacy in Biomarker Validation Biomarker + Clinical Population is Biologically Test Data Heterogeneous bio + bio - Candidate Biomarker Identified Statistical Analysis Plan Enroll based on biomar
Slide 33: Identified a unique and scalable biomarker for ALTO-300
Identified a unique and scalable biomarker for ALTO-300 Using an EEG machine learning strategy validated for other treatment biomarkers (e.g., SSRIs), a unique resting-state EEG signal from a single electrode was identified and prospectively replicated as a predictor of ALTO-300 response Pretreatmen
Slide 34: Prospective replication of EEG biomarker
ALTO-300 Phase 2a: prospective replication of EEG biomarker as predictive of response 01 02 Prospective Replication in Test Dataset Determine Prospective Week Biomarker Biomarker Validation 0 2 4 6 8 N=60 N=45 0 MADRS LSM Change From Baseline d=0.32 -2 p=0.15 d=0.32 -4 p=0.10 d=0.40 p=0.05 -6 d=0.51
Slide 35: Biomarker positive patients derived greater benefit
Biomarker positive patients derived greater benefit from ALTO-300 EEG biomarker positive p=0.07 % of Patients Achieving ≥ 50% Improvement patients observed to 60 p=0.01 achieve more robust clinical 50 EEG Biomarker + (n=55) p=0.02 EEG Biomarker – (n=50) response to ALTO-300 40 p=0.07 • Response rate
Slide 36: ALTO-300 biomarker: reduced neural signaling stability
ALTO-300 biomarker: a measure of reduced neural signaling stability • Greater EEG irregularity (i.e., biomarker positivity) is associated with decreased neural connectivity • Across multiple independent datasets (N=784), biomarker positive patients demonstrated reduced medial prefrontal neural conne
Slide 37: Link between ALTO-300 mechanism and EEG biomarker
Human and preclinical data demonstrates the link between the mechanism of ALTO-300 and its EEG biomarker • The biomarker signal reflects increased neural variability, which dopamine acts to reduce • ALTO-300’s MOA includes 5-HT2C antagonism and leads to an increase in dopamine • Studies test mechani
Slide 38: EEG prediction is specific to ALTO-300
EEG model prediction is specific to ALTO-300 as it does not predict greater placebo or SSRI/SNRI response Apply the ALTO-300 EEG biomarker to: Placebo-Treated Patients SSRI/SNRI-Treated Patients Week Week 0 2 4 6 8 0 2 4 6 8 0 0 -1 d=-0.21 HDRS change from baseline HDRS change from baseline p=0.86 B
Slide 39: Estimated placebo-adjusted ALTO-300 response
Estimated placebo-adjusted ALTO-300 response: biomarker positive patients 0.8 Meta-analytic all-comer effect sizes at primary endpoint timepoint across studies 0.7 Cohen's d effect size (drug-placebo) 0.6 0.5 0.4 0.3 ALTO-300: Robust clinical response 0.2 observed in biomarker positive 0.1 patients
Slide 40: Agomelatine has favorable established tolerability profile
Agomelatine has a favorable established tolerability profile No unexpected AEs in the completed ALTO-300 study Overall Treatment Emergent Adverse Events (TEAEs) TEAEs for ≥5% of the Population Safety Analysis Set Safety Analysis Set N (%) N (%) Total Participants 239 Headache 35 (14.6) At least one
Slide 41: ALTO-300 at 25mg maintains efficacy while avoiding LFT elevation
ALTO-300 at 25mg maintains efficacy while avoiding LFT elevation We selected the 25mg dose as meta-analyses show similar efficacy as 50mg Placebo-like LFT rate for 25mg 25mg and 50mg approved in EU/Australia • Novartis US studies showed placebo- like LFT rate with 25 mg: • 25mg: 0.3% • Placebo: 0.3%
Slide 42: Real-world use shows low agomelatine LFT elevation
Large-scale and real-world use demonstrates agomelatine- induced LFT elevation is low and adaptive Acute studies using the 25mg dose (n=4,957) shows placebo-like LFT rate consistent with Alto’s LFT monitoring not expected Phase 2a results where no patient exceeded >3x ULN (even with baseline allowan
Slide 43: ALTO-300 Phase 2b biomarker-guided trial in MDD
ALTO-300 Phase 2b biomarker-guided trial in MDD Evaluating ALTO-300 as an adjunctive to an existing antidepressant with an insufficient response Screening Period 6-Week Double-Blind 8-Week Open Label Treatment Period Extension 25 mg QHS ALTO-300 1:1 Randomization 25 mg QHS ALTO-300 Wearable Behavior
Slide 44: Interim analysis informs final sample size
Interim analysis on ALTO-300 Phase 2b informs final sample size Outcome 171 Patients enrolled as of Dec. 17, 2024 interim cutoff Continue study with sample re- Patients prospectively excluded following detailed site and subject case review -- estimation: Enroll Bio + target N of 52 includes removal
Slide 45: ALTO-101: Development for CIAS
ALTO-101 Development for CIAS
Slide 46: ALTO-101, a novel PDE4 inhibitor, in development for CIAS
ALTO-101, a novel PDE4 inhibitor, in development for CIAS with a validated mechanism and demonstrated pro-cognitive activity PDE4i represents a historically validated Direct effects on best EEG ALTO-101 has demonstrated clear 1 mechanism to address cognition 2 biomarker of CIAS 3 pro-cognitive effec
Slide 47: Theta EEG response is the best index of CIAS pathophysiology
Theta EEG response is the best index of CIAS pathophysiology • EEG biomarkers indexing cognition-relevant neural circuitry have been extensively studied in schizophrenia • They provide a biological measure of the processes accounting for disorder pathophysiology • Alto put all established biomarkers
Slide 48: Theta response in the ALTO-101 POC study
Theta response in the ALTO-101 POC study: linking biology of CIAS to drug mechanism and clinical meaningfulness Cortical circuit disruptions in schizophrenia ALTO-101 impacts key cognitive circuitry PDE4 inhibition: ↑ cAMP SST ↑ interneuron activity, plasticity cortical response to inputs improves P
Slide 49: ALTO-101 improves theta response and cognition
ALTO-101 improves theta response, and with it, cognition ALTO-101 Phase 1 data (N=40, healthy volunteer, crossover) ALTO-101 preclinical data Dose-dependent increase in theta response and processing speed Dose-dependent increase in theta response mirrors humans veh 0.1 mg/kg Theta response (placebo
Slide 50: Additional evidence for PDE4 inhibition targeting cognition
Additional evidence for PDE4 inhibition targeting of cognition and its neural circuitry in humans (including CIAS) 8-day crossover in 18 patients w/ CIAS using roflumilast (PDE4i) ALTO-101 Phase 1 data (N=40, healthy volunteer, crossover) Demonstrated significant improvement in the mismatch negativi
Slide 51: Transdermal formulation: greater exposure, improved tolerability
Transdermal formulation: greater drug exposure and improved tolerability profile 35 ALTO-101 ORAL ALTO-101 TDS 30 • Goal of TDS formulation: Eliminate rapid Cmax Concentration (ng/mL) Mean (SEM) Plasma related AEs and maintain steady exposure 25 • Healthy Volunteer (age 40-64) PK and Tolerability 20
Slide 52: Phase 2 POC study in cognitive impairment in schizophrenia
Phase 2 POC study in cognitive impairment in schizophrenia Study Population: Adults 21-55 years old with a Treatment Period 1: Treatment Period 2: Safety Follow-up Visit diagnosis of schizophrenia for > 1 year • 2-way Cross-over, Double-blind, Placebo-controlled design and sufficient cognitive impai
Slide 53: PDE4 inhibition relevant across high-need therapeutic areas
PDE4 inhibition is relevant across numerous high-need therapeutic areas Available medications are non-brain penetrant and only approved outside CNS – both come with substantial tolerability and dosing limitations $2.2bn NON - CNS CNS INDICATIONS • Schizophrenia • Bipolar 2022 SALES • Plaque Psoriasi
Slide 54: ALTO-100: MDD and Bipolar Depression
ALTO-100 MDD and Bipolar Depression
Slide 55: ALTO-100 enhances hippocampal neuroplasticity
ALTO-100 offers a novel therapeutic option for depression with poor memory/cognition by enhancing hippocampal neuroplasticity Post-treatment Healthy Depression with poor memory/cognition ALTO-100 BDNF GPCRs TrkB Akt MEK Reduction in hippocampal Transcription plasticity and neurogenesis (contributing
Slide 56: ALTO-100: enhance 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 57: Rationale for ALTO-100 in bipolar depression
Rationale for ALTO-100 in poor memory/cognition patients with bipolar depression • Bipolar disorder long thought to involve reduced neuroplasticity in the hippocampus, similar to MDD • Reduced hippocampal volume • Memory and broader cognitive deficits (as or more frequent than MDD) • Cellular and mo
Slide 58: Completed ALTO-100 Phase 2b trial in MDD
Completed ALTO-100 Phase 2b biomarker-guided trial in MDD 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 in Placebo cognitive biomarker + population at
Slide 59: Phase 2B study flow
Phase 2B study flow Screening visit structure (key elements): Enrolled 1. Visit 1: (ITT sample) 301 • Severity and diagnosis (at site), PHQ • SAFER including MADRS (MGH)** mITT sample 2. Visit 2: 287 (Site baseline MADRS≥20) • Biomarker baseline (at site), PHQ 3. Visit 3: Good memory Poor memory • C
Slide 60: Summary of ALTO-100 Phase 2b MDD results
Summary of ALTO-100 Phase 2b MDD results Mean Baseline Week 6 LSM MADRS Sample Size (n) MADRS (SD) Change (SE) Analysis Population ALTO-100 Placebo ALTO-100 Placebo ALTO-100 Placebo Cohen’s d p All Bio + mITT 97 99 31.2 (5.4) 31.5 (5.4) -10.3 (1.0) -9.8 (1.0) 0.05 > 0.1 (Primary) Monotherapy Bio + m
Slide 61: Adjunctive population showed meaningful response and higher compliance
Adjunctive population demonstrated clinically meaningful response to ALTO-100 and had significantly higher compliance The study included Bio+ patients taking ALTO-100 as monotherapy (69%) and those taking it adjunctive to an antidepressant (31%) Compliance rate among monotherapy Clear drug effect in
Slide 62: Drug effect and biomarker enrichment in compliant population
Evidence of drug effect & biomarker enrichment observed in the compliant population in additional analyses Bio + confirmed compliant patients vs. all placebo Bio + vs. bio – in confirmed compliant patients 62 Retrospective analyses conducted within population with measurable PK levels of ALTO-100, i
Slide 63: ALTO-100 was well tolerated
ALTO-100 was well tolerated Overall Treatment Emergent TEAEs for ≥5% of the Population Adverse Events (TEAEs) Safety Analysis Set Safety Analysis Set ALTO-100 Placebo ALTO-100 Placebo N (%) N(%) (%) (%) Total Participants 149 150 Headache % (related %) 10% (6.7%) 12.7% (10%) At least one TEAE 66 (44
Slide 64: ALTO-100 Phase 2b trial in bipolar depression
ALTO-100 Phase 2b biomarker-guided trial in bipolar depression Evaluating ALTO-100 as an adjunctive treatment to an existing mood stabilizer (no antipsychotics) Screening Period 6-Week Double-Blind 7-Week Open Label Treatment Period Extension 40 mg BID ALTO-100 N ≈ 200 40 mg BID ALTO-100 Wearable Be
Slide 65: ALTO-203: Novel H3 inverse agonist
ALTO-203 Novel H3 inverse agonist
Slide 66: ALTO-203: H3 inverse agonist across neurotransmitter systems
ALTO-203: An investigational H3 inverse agonist with effects across multiple major neurotransmitter systems Main effect of enhancing release ALTO-203 (H3 inverse agonist) • Mood Dopamine • Reward Processing H3 • Sustained Attention Norepinephrine • Alertness ↑ neurotransmitter • Sustained Attention
Slide 67: ALTO-203 increases reward system dopamine unlike pitolisant
ALTO-203 showed ability to increase reward system dopamine, unlike the only approved H3 (pitolisant)* ALTO-203 increases dopamine release in the reward Pitolisant does not increase reward system system (nucleus accumbens) in a dose-related manner dopamine (modafinil used as a comparator) 180 ** % in
Slide 68: Positive pharmacodynamic effects from ALTO-203 POC study
Positive pharmacodynamic effects from exploratory proof-of-concept study of ALTO-203 Effects replicated key findings from completed Phase 1 study Study Population: Topline pre-specified results Patients with MDD with anhedonia and who were Identified an EEG biomarker predictive of patient response n
Slide 69: Biotech leadership team with late-stage precision psychiatry experience
Biotech leadership team with extensive late-stage precision psychiatry experience Executive management team Amit Etkin, MD PhD Michael Hanley Adam Savitz, MD PhD Jessica Powell Nick Smith Erin McQuade Chief Executive Officer Chief Operating Officer Chief Medical Officer Chief Development Officer Chi
Slide 70: Multiple near-term clinical milestones expected
Multiple near-term clinical milestones expected Capitalized through multiple clinical milestones: $184.2mm^ as of October 31, 2025→ Expected cash runway into 2028, now including expanded execution on ALTO-207 for TRD 2026 ALTO-207 Phase 2b Initiation (1H 2026) ALTO-300 Phase 2b MDD data (mid-2026) A
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