Slide 1: Neuroscience R&D Day
NASDAQ: BTAI ® Neuroscience R&D Day December 12, 2023 1:00-2:30 pm ET BioXcel Therapeutics | 555 Long Wharf Drive, 12th Floor | New Haven, CT 06511 | bioxceltherapeutics.com
Slide 2: Forward-Looking Statements
2 Forward-Looking Statements This presentation includes "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this presentation include but are not limited to: statements regarding BioXcel Therapeutics’ expected timing
Slide 3: Presentation Focus on Advancing Innovation and Expanding Our Neuroscience Pipeline
3 Presentation Focus on Advancing Innovation and Expanding Our Neuroscience Pipeline Driven by company’s unique AI-based approach Advancing Innovative Pipeline in Seeking to Address Opioid Crisis Alzheimer’s-Related Symptoms BXCL502 BXCL501 • Novel agent in development for treatment of • Demonstrate
Slide 4: Agenda and Speakers
4 Agenda and Speakers • Our Corporate Strategy: Vimal Mehta • Our R&D Strategy: Frank Yocca • BXCL502: A Novel Agent for Treatment of Chronic Agitation in Dementia: Mike De Vivo Vimal Mehta, Ph.D. Frank Yocca, Ph.D. Mike De Vivo, Ph.D. • The Neuropsychiatric Inventory: Measuring Founder & CEO Chief
Slide 5: Our Corporate Strategy
5 Our Corporate Strategy Vimal Mehta Founder and CEO ®
Slide 6: Corporate Growth Drivers
6 Corporate Growth Drivers Transformative drug re-innovation approach resulted in rapid approval of IGALMI™ Land Expand ● 2024 Focus 2024 & Beyond BXCL501 Potential At-Home Agitation Associated Expansion With Bipolar Agitation Associated With: Emerging Disorders or • Alzheimer’s Dementia Alzheimer's
Slide 7: Our R&D Strategy
7 Our R&D Strategy Frank Yocca Chief Scientific Officer ®
Slide 8: R&D Strategy: Build Pipeline Depth with Innovation and Expansion
8 R&D Strategy: Build Pipeline Depth with Innovation and Expansion Pipeline as of December 12, 2023 Compound Indication/Proposed Indication Preclinical Phase 1 Phase 2 Phase 3 Registration Marketed APPROVED APRIL 5, 2022 Acute treatment of agitation associated with schizophrenia or bipolar I or II d
Slide 9: Potential mechanistic pathways of BXCL501, BXCL502, BXCL503
BXCL503 * * BXCL501 BXCL502 * * Denotes potential mechanistic pathway Proprietary & Confidential
Slide 10: Behavioral and Psychological Symptoms in Alzheimer’s Disease
10 Behavioral and Psychological Symptoms in Alzheimer’s Disease Identifying targets and compounds designed to address unmet medical needs in dementia 42.3% BXCL501 - Norepinephrine BXCL502 - Serotonin BXCL503 - Dopamine Agitation/Aggression BXCL501/502 BXCL501/502 * 35.6% * 26.8% Sleep Disturbances
Slide 11: BXCL502: A Novel Agent for Treatment of Chronic Agitation in Dementia
11 BXCL502: A Novel Agent for Treatment of Chronic Agitation in Dementia Michael De Vivo Vice President, Neuroscience ®
Slide 12: Drug-Sensitive Neural Pathways for Treatment of Neuropsychiatric Symptoms
12 Drug-Sensitive Neural Pathways for Treatment of Neuropsychiatric Symptoms Novel Pathway: Compound: Raphe (5-HT) and Latrepirdine: Locus Coeruleus (NE) Clinical Candidate With Extensively Characterized Safety The safety and efficacy of investigational agents and/or investigational uses of approved
Slide 13: Neuropsychiatric Symptoms are a Serious Unmet Medical Need
13 Neuropsychiatric Symptoms are a Serious Unmet Medical Need Latrepirdine is a promising candidate that potentially could address this need • Neuropsychiatric symptoms occur early in patients with Prevalence of Neuropsychiatric Symptoms dementia • These symptoms have serious adverse consequences fo
Slide 14: Latrepirdine: Clinical Safety Results, Preclinical Confidence in Rationale, and Early Sign of Potential Efficacy
Latrepirdine: Clinical Safety Results, Preclinical Confidence in 14 Rationale, and Early Sign of Potential Efficacy all Support Further Development ● Over 1000 AD patients exposed for SAFETY RESULTS IN 26 weeks and 500 up to 52 weeks PATIENTS (Studies conducted by Pfizer and Medivation) VALUE PRECLI
Slide 15: Clinical Safety Results and Early Sign of Potential Efficacy from Published Studies
Clinical Safety Results and Early Sign of Potential Efficacy from 15 Published Studies Data support clinical development for chronic treatment of agitation in patients with Alzheimer’s disease NPI: 26 and 52 weeks CONCERT CONNECTION DOODY et al., 2008 P=0.01 ● NPI is a measure of neuropsychiatric ●
Slide 16: Pre-Clinical Confidence in Rationale
Pre-Clinical Confidence in Rationale 16 LC-mediated behaviors BioXcel Therapeutics Data LATREPIRDINE ANXIETY/ AGITATION MODEL • Showed activity in 5 preclinical ● Mice are agitated by administering yohimbine models of neuropsychiatric symptoms ● Latrepirdine increases exploration of open arms (reduc
Slide 17: Latrepirdine: Potential Mechanism of Action
17 Latrepirdine: Potential Mechanism of Action 5-HT7 receptor antagonist with high potency ● Potential mechanism of action of latrepirdine BioXcel Therapeutics Data previously not clear, many mechanisms were proposed (including 5-HT7 receptor antagonism) ● BioXcel results suggest that latrepirdine m
Slide 18: Preclinical Results Suggest Potential for Chronic Dosing
18 Preclinical Results Suggest Potential for Chronic Dosing Repeat-dose studies in mice • Chronic treatment requires: – Demonstration of persistent effect after repeat dosing – Able to washout quickly if needed (not irreversible) • Mice treated for 5 days using stress paradigm no longer attempted to
Slide 19: Recent Examples of Successful CNS Drug Re-Innovation
19 Recent Examples of Successful CNS Drug Re-Innovation DRUG CHALLENGE SOLUTION STATUS Dextromethorphan Metabolites cause Block metabolism with Successful clinical study/ (Axsome) unwanted side effects CYP2D6 inhibitor, bupropion depression Xanomeline Block peripheral effects with Successful clinica
Slide 20: BXCL502: Potential Chronic Once a Day Dosing for Agitation
20 BXCL502: Potential Chronic Once a Day Dosing for Agitation ● Metabolic instability limited clinical development of latrepirdine ● BioXcel screened metabolic enzyme inhibitors to identify potential compounds that could enable latrepirdine to be used as a chronic drug ● 3 inhibitors were chosen as
Slide 21: BXCL502 Presents a Compelling Value Proposition
21 BXCL502 Presents a Compelling Value Proposition Formulation studies are ongoing New Chemical Entity BXCL502 is a novel formulation of latrepirdine and a metabolic stabilizer Improved Potentially blocks excessive signaling mediated by 2 Understanding of neurotransmitters: serotonin and norepinephr
Slide 22: The Neuropsychiatric Inventory: Measuring Agitation Relief in Alzheimer’s Disease
22 The Neuropsychiatric Inventory: Measuring Agitation Relief in Alzheimer’s Disease Jeffrey Cummings, M.D., Sc.D.(HC) Chambers-Grundy Center for Transformative Neuroscience Department of Brain Health, School of Integrated Health Sciences University of Nevada Las Vegas (UNLV) Speaker is acting on be
Slide 23: Prevalence of Alzheimer’s Disease is Increasing
23 Prevalence of Alzheimer’s Disease is Negative Increasing Amyloid PET 2020/2023 2050 U.S. 6.5 million 19.5 million Global 57.4 million 152 million • Well-defined pathological entity (amyloid, tau, neurodegeneration [ATN]) • Advances in diagnosis: amyloid and tau PET, blood-based biomarkers • Advan
Slide 24: Agitation in Alzheimer’s Disease
24 Agitation in Alzheimer’s Disease Demography1,2 • 70% of Alzheimer dementia patients are agitated sometime in disease course • 40% in cross-sectional studies • 60% of agitated patients will receive pharmacotherapy • Antipsychotics 13-24.2%; antidepressants 24.2-44.2%; benzodiazepines 11.1-13% Etio
Slide 25: Defining Agitation in Alzheimer’s Disease
25 Defining Agitation in Alzheimer’s Disease • International Psychogeriatric Association (IPA) criteria for agitation in neurocognitive disorders: • Neurocognitive disorder present (e.g., Alzheimer’s disease) • One of 3 agitated behaviors present for past 2 weeks o Verbal aggression o Physical aggre
Slide 26: Neuropsychiatric Inventory (NPI)
26 Neuropsychiatric Inventory (NPI)1,2 • Most commonly used instrument to measure behavior in clinical trials of Alzheimer’s disease and other neurodegenerative disorders • 12 neuropsychiatric syndromes Agitation/aggression Apathy • Caregiver interview Hallucinations Depression • Past 1 month Delusi
Slide 27: Latrepirdine Produced Generally Consistent Results on the NPI
27 NCT00829374 • 611 patients on latrepirdine Latrepirdine Produced • NPI d/p change from BL = Generally Consistent 1.8 points Results on the NPI • Overall effect: p = 0.009 Cochrane Reviews are very rigorous • No meaningful effect observed on cognition or function NCT00675623 • Reproducible effect
Slide 28: Meta-Analysis Supports Potential NPI Effect Across Latrepirdine Alzheimer’s Disease Trials
28 Meta-Analysis Supports Potential NPI Effect Across Latrepirdine Alzheimer’s Disease Trials Statistical approach differed from that of MEAN DIFFERENCE: NPI Cochrane Analysis • 127 articles screened • 5 with trials • 3 with Alzheimer’s disease • No cognitive or functional benefit • NPI showed signi
Slide 29: Measurement of Agitation in Clinical Trials of Alzheimer’s Disease
29 Measurement of Agitation in Clinical Trials of Alzheimer’s Disease • Two primary tools to measure agitation in Alzheimer’s clinical trials • Cohen-Mansfield Agitation Inventory (CMAI)1 • 29 agitated behaviors (kicking, shouting, hitting, etc) • Neuropsychiatric Inventory (NPI)2 • 12 neuropsychiat
Slide 30: Agitation Trials: Risk Mitigation
30 Agitation Trials: Risk Mitigation • Planning can limit impact of challenges – Slow recruitment – Placebo response • Latrepirdine – Which items responded on NPI – Explore if response in population with variable agitation predicts response in population constructed around agitation
Slide 31: Summary
31 Summary • Alzheimer’s disease is common • Alzheimer’s disease with agitation is common • Treatment of agitation is a large unmet need (market) • Trial foundations are established – Definition of agitation – Clinical outcome assessments – Regulatory pathway • Preliminary latrepirdine NPI observati
Slide 32: BXCL503 for Dementia-Related Apathy
32 BXCL503 for Dementia- Related Apathy Friso Postma, Ph.D. VP, AI Drug Discovery ®
Slide 33: NovareAI: Ecosystem for Drug Discovery and Development
33 NovareAI: Ecosystem for Drug Discovery and Development Mid/Late-Stage AI AI Assets Pre-Clinical Opportunity Validation Prioritization Pre-Clinical Indications Platforms BTI Knowledge Graphs Compounds Targets BTI Re-Innovation Library Stress Axis AI AI
Slide 34: Targeting Selectivity Through Heteromeric Receptor Complexes
34 Targeting Selectivity Through Heteromeric Receptor Complexes Selected compounds are believed to modulate dopamine signaling ➢ Heteroreceptors through allosteric interactions may modify ligand affinity or stabilization of the receptor Heteromeric receptor examples include (but are not limited to):
Slide 35: Apathy in Alzheimer’s Disease is an Unmet Medical Need
35 Apathy in Alzheimer’s Disease is an Unmet Medical Need Concept BXCL503 holds potential to address this need ➢ Defined as a loss of initiative, interest and emotional expression/responsiveness. ➢ Apathy is a deficit in voluntary, goal-directed behavior ➢ Prevalence is high with ~ 5 million patient
Slide 36: Identifying Drug-Sensitive Neural Pathways for Treatment of Apathy
36 Identifying Drug-Sensitive Neural Pathways for Treatment of Apathy Dementia Related Neuropsychiatric Symptoms NovareAI DORSAL BXCL503 APATHY DOPAMINERGIC GANGLA MODULATION PRODUCT NovareAI CONCEPT NEURAL DRUG LATE STAGE PATHWAYS TARGETS CLINICAL COMPOUNDS NovareAI Predicted Target: Compound: Effi
Slide 37: BXCL503 May Increase Goal Directed Behavior
37 Concept BXCL503 May Increase Goal Directed Behavior Pre-clinical model of apathy: progressive ratio test • Progressive Ratio Test measures goal directed behavior Lever presses Not Depleted 600 Monoamine Depleted • Animals repeatedly press a lever * p <0.05 for a reward, the number of 500 * * pres
Slide 38: Pre-Clinical Confidence in Rationale
* SmartCube® by Psychogenics Inc. 38 Pre-Clinical Confidence in Rationale BioXcel Therapeutics Data BXCL503 • Demonstrated in vivo activity in behavioral phenotyping (SmartCube*) Class Probability • Potential BXCL503 (%) candidate is classified as a stimulant with activity in a dose- dependent manne
Slide 39: BXCL503 Product Concept
39 BXCL503 Product Concept Clinical safety results and preclinical confidence in rationale are favorable ● Shelved asset. Well tolerated in SAFETY RESULTS IN over 500 subjects exposed up to PATIENTS 26 weeks in two phase 2 trials VALUE PRECLINICAL CONFIDENCE IN ● Showed activity in 2 preclinical RAT
Slide 40: BXCL503 Product Concept Presents a Compelling Value Proposition
40 BXCL503 Product Concept Presents a Compelling Value Proposition Confidence in the approach and further studies ongoing Potential novel BXCL503 may modulate dopaminergic signaling in an mechanism of anatomically restricted manner to circuitry governing action goal directed behavior Prior safety da
Slide 41: BXCL501 for the Potential Treatment of Acute Opioid Withdrawal
41 BXCL501 (Sublingual Dexmedetomidine) for the Potential Treatment of Acute Opioid Withdrawal Sandra D Comer, Ph.D. Professor of Neurobiology (in Psychiatry) Columbia University Irving Medical Center New York State Psychiatric Institute Speaker is an independent investigator and is not a paid consu
Slide 42: Overview
42 Overview Public Health Emergency "Opioid Crisis" declared a Public Health Emergency in 2017 Emergent Threat Fentanyl adulterated or associated with xylazine (FAAX) declared an "Emergent Threat" in 2023 Treatment Gap No treatments for opioid withdrawal have been tested against fentanyl or xylazine
Slide 43: Majority of Opioid-related Overdose Deaths are due to Fentanyl
43 Majority of Opioid-related Overdose Deaths are due to Fentanyl As of Jun 2023, 106,842 drug- related overdose deaths in the previous 12 months (NCHS). Deaths involving synthetic opioids other than methadone (primarily fentanyl) continued to rise with 70,601 overdose deaths reported in 2021 (NCHS)
Slide 44: Introduction of Xylazine to Fentanyl Makes Opioids Even More Dangerous
Introduction of Xylazine to Fentanyl Makes Opioids Even More 44 Dangerous and has now Been Identified as an “Emerging Threat” Why are cartels producing fentanyl In addition to making fentanyl more lethal, associated or adulterated with xylazine xylazine is also damaging users’ bodies (FAAX)? • Repea
Slide 45: Use of Xylazine is Rapidly Growing Across the U.S.
45 And now the use of Xylazine is Rapidly Growing Across the U.S. *The Drug Enforcement Administration (DEA) reports that between 2020 and 2021, forensic laboratory identifications of xylazine rose in all four U.S. census regions, most notably in the South (193%) and the West (112%). - DEA Joint Int
Slide 46: BXCL501 Phase 1b/2 Study
46 BXCL501 Phase 1b/2 Study: Phase 1b Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study Jones et al., 2023 Am J Drug and Alcohol Abuse 49(1): 109- 122 https://doi.org/10.1080/00952990.2022.2144 743 The safety and efficacy of investigational agents and/or investigational uses of appr
Slide 47: BXCL501 Pilot Phase 1b/2 Study Design: Summary
47 BXCL501 Pilot Phase 1b/2 Study Design: Summary (June 2020 – January 2021) • Randomized, double-blind, placebo-controlled inpatient study • Evaluate the safety and tolerability of ascending doses of BXCL501 relative to placebo in participants with opioid use disorder who are physically dependent o
Slide 48: Phase 1b/2 Efficacy Results
48 Phase 1b/2 Efficacy Results 3 COWS Placebo 120µg BID BXCL501 2 180µg BID BXCL501 240µg BID BXCL501 Mean Change from Pre-Dose 1 • 120, 180, and 240mg BID BXCL501 reduced acute opioid withdrawal symptoms compared to placebo as measured by 0 ** the COWS with a 229% reduction in peak withdrawal and -
Slide 49: BXCL501 Pilot Phase 1b/2 Study Design
49 BXCL501 Pilot Phase 1b/2 Study Design Note: Urine drug screens in 76-92% of patients in each dose cohort were fentanyl-positive at screening (Jones et al., 2023) • In BioXcel’s 2020 Ph1b study, 40% of patients dropped out during the morphine stabilization phase, whereas in the 2001-2002 lofexidin
Slide 50: Phase 1b/2 Efficacy Results
50 Phase 1b/2 Efficacy Results SOWS “Insomnia/Problems Sleeping” (self-reported) 0.4 Placebo Mean Change from Pre-Dose 0.2 240µg BID BXCL501 0.0 • The 240mg BID BXCL501 dose significantly reduced both -0.2 subjective ratings of insomnia and clinician ratings of anxiety -0.4 P=0.07 or irritability (J
Slide 51: Phase 1b/2 Efficacy Results
51 Phase 1b/2 Efficacy Results Study Retention 100 Placebo 120µg BID BXCL501 • Higher study retention with all active 80 180µg BID BXCL501 doses of BXCL501 compared to placebo 240µg BID BXCL501 (Jones et., 2023) 60 • Results suggest potential to improve the % successful transition of patients onto 4
Slide 52: Potential Safety Review of BXCL501 vs. Lofexidine
52 Potential Safety Review of BXCL501 (Jones et al., 2023) vs. Lofexidine (Fishman et al., 2019) Placebo BXCL501 (Jones et al 2023) Lofexidine (Fishman et al 2019)* 120g BID 180g BID 240g BID 2.16mg 2.88mg Placebo Placebo Adverse BXCL501 BXCL501 BXCL501 Lofexidine Lofexidine (N=25) (N=151) Event
Slide 53: Current Ongoing Study Design
Current Ongoing Study Design 53 Just Added 4th site to Accelerate Enrollment Screening Days -30 to -1 Treatment Withdrawal: Study Days 1-7 #1 Placebo (n=40) #2 BXCL501 180g BID (n=40) Participant Pool (n=160) #3 BXCL501 240g BID n=40) #4 Lofexidine 0.72 mg QID (2.88 mg/day; n=40) Sublingual strips
Slide 54: Ongoing Trial Offers Opportunity to Evaluate Possible Opioid Withdrawal Treatment
54 Ongoing Trial Offers Opportunity to Evaluate Possible Opioid Withdrawal Treatment • BXCL501 reduced COWS and SOWS scores relative to placebo at doses that produced no serious or severe adverse events • BXCL501 improved patient-reported ratings of insomnia and clinician-reported ratings of anxiety
Slide 55: BXCL501 Could Potentially Address Several Clinical Scenarios
BXCL501, if Approved for Treatment of Opioid Withdrawal, Could 55 Potentially Address Several Clinical Scenarios Setting Possible Treatment • People who receive ED services after an overdose on opioids often experience severe opioid withdrawal • ED staff increasingly are directly transitioning patie
Slide 56: References
56 References 1. DEA Joint Intelligent Report. DEA-DCI-DIR-001-23. The Growing Threat of Xylazine and its Mixture with Illicit Drugs OCTOBER 2022. https://www.dea.gov/sites/default/files/2022- 12/The%20Growing%20Threat%20of%20Xylazine%20and%20its%20Mixture%20with%20Illicit%20Drugs.pdf 2. FDA EUAs. E
Slide 57: Q&A and Closing Remarks
57 Q&A and Closing Remarks Frank Yocca Chief Scientific Officer ®
Slide 58: R&D Strategy: Build Pipeline Depth with Innovation and Expansion
58 R&D Strategy: Build Pipeline Depth with Innovation and Expansion Pipeline as of December 12, 2023 Compound Indication/Proposed Indication Preclinical Phase 1 Phase 2 Phase 3 Registration Marketed APPROVED APRIL 5, 2022 Acute treatment of agitation associated with schizophrenia or bipolar I or II
Slide 59: Thank you!
59 Thank you! ® BioXcel Therapeutics | 555 Long Wharf Drive, 12th Floor | New Haven, CT 06511 | bioxceltherapeutics.com