GH001 Improves Illness Severity, Anxiety Symptoms, and Quality of Life in Patients with Treatment-Resistant Depression Michael E. Thase, MD Department of Psychiatry, University of Pennsylvania and Corporal Michael J. Cre

1 GH001 Improves Illness Severity, Anxiety Symptoms, and Quality of Life in

Patients with Treatment-Resistant Depression Michael E. Thase, MD Department of Psychiatry, University of Pennsylvania and Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA Co-authors: Bernhard T. Baune,

Narc s Cardoner, Kelly Doolin, Rosa Maria Due as Herrero, Lubo Jan , John R. Kelly, Rachael Maclsaac, Shane J. McInerney, Alexander Nawka, Tom P len ek, V ctor P rez Sola, Andreas Reif, Claire Sweeney, Madhukar H. Trivedi,

Velichka Valcheva, Eduard Vieta, Wies aw J. Cuba a

Author Disclosures Michael E. Thase Consultant - Axsome, Clexio Biosciences,

Gerson Lehrman Group, GH Research, Janssen, Johnson & Johnson, Lundbeck, Luye Pharma, Merck, Otsuka, Pfizer, Sage, Seelos Therapeutics, Sunovion, and Takeda. Grant Support - Acadia, Alkermes, Axsome, Intra-Cellular Therapies, Janssen,

Myriad, National Institute of Mental Health, Otsuka, Patient-Centered Outcomes Research Institute (PCORI), and Takeda. Royalties - American Psychiatric Press, Inc., Guilford Publications, Herald House, Wolters Kluwer, and W. W. Norton &

Company. Spouse's Employment - Dr. Diane Sloan is a Senior Vice President of OPEN Health, which does business with many companies Bernhard T. Baune Consultant - National Health and Medical Research Council (Australia). Honoraria - Angelini,

AstraZeneca, Biogen, BMS, Boehringer Ingelheim, Johnson & Johnson, LivaNova, Lundbeck, Medscape, Otsuka, Pfizer, Roche, Servier, Sumitomo Pharma, Sunovion, Teva, and Wyeth. Advisory Boards - Biogen, Boehringer Ingelheim, Janssen-Cilag,

LivaNova, Lundbeck, Medscape, Novartis, Otsuka, and Teva. Research Grants from Private Industries or Nonprofit Funds - AstraZeneca, BMBF (Germany), BMG (Germany), DFG (Germany), ERA PerMed, Fay Fuller Foundation, Horizon Europe (European

Union), James & Diana Ramsay Foundation (Adelaide), Johnson & Johnson, Lundbeck, La Marat de TV3, National Health and Medical Research Council (Australia), Sanofi-Synth labo, and Wellcome Trust (UK) Narc s Cardoner Grants - Spanish

Ministry of Health, Spanish Ministry of Science and Innovation (CIBERSAM), Strategic Plan for Health Research and Innovation (PERIS) 2016-2020, RecerCaixa, and La Marat de TV3. Honoraria - Adamed, Elsevier, Exeltis, Janssen, Lundbeck, Pfizer,

and Servier. Advisory Boards - Angelini, Esteve, Janssen, Lundbeck, Novartis, Pfizer, and Viatris. Lectures/Meetings - Janssen, Lundbeck, and Pfizer Kelly Doolin Employee and Shareholder - GH Research Rosa Maria Due as Herrero Principal

Investigator - Beckley Psytech and GH Research. Subinvestigator - Compass Lubo Jan Principal Investigator - GH Research John R. Kelly Principal Investigator - Compass, GH Research, and Transcend Therapeutics. Consultant - Clerkenwell

Health. Grant Funding - Health Research Board (ILP-POR-2022-030, DIFA-2023-005, KTA-2024-002) Rachael Maclsaac Employee and Shareholder - GH Research Alexander Nawka Principal Investigator - GH Research Disclosures (1 of 2) 2

Author Disclosures Tom P len ek Principal Investigator - Compass, GH

Research, MAPS, and Ketabon. Shares - Psychedelick klinika s.r.o., Spole nost pro podporu neurov dn ho v zkumu s.r.o., and AVI-X Aviation Experts s.r.o. Founder - PSYRES (Psychedelic Research Foundation). Consultant - CB21 Pharma and GH

Research V ctor P rez Sola Consultant, Honoraria, or Grants - AB-Biotics, AstraZeneca, Bristol Myers Squibb, CIBERSAM, FIS-ISCiii, Janssen Cilag, Lundbeck, Medtronic, Otsuka, and Servier Andreas Reif Honoraria for Lectures and/or Advisory

Boards - AbbVie, Boehringer Ingelheim, Cyclerion, Compass, GH Research, Janssen, LivaNova, Medice, MSD, Newron, Sage/Biogen, and Shire/Takeda. Research Grants - Medice and Janssen Claire Sweeney Employee and Shareholder - GH

Research Madhukar H. Trivedi Consultant - Acadia, Alkermes, Alto Neuroscience, Axsome, BasePoint Health Management, Biogen, Cerebral, Circular Genomics, Compass, Daiichi Sankyo, GH Research, GreenLight VitalSign6, Heading Health, Janssen,

Legion Health, Merck, Mind Medicine, Myriad Neuroscience, Naki Health, Neurocrine Biosciences, Noema Pharma, Orexo, Otsuka America, Otsuka Europe, Otsuka Pharmaceutical Development & Commercialization, Praxis Precision Medicines, PureTech

LYT, Relmada Therapeutics, Sage, Seaport Therapeutics, Signant Health, Sparian Biosciences, Titan Pharmaceuticals, Takeda, and WebMD. Grant/Research Funding - American Foundation for Suicide Prevention, NCATS, NIDA, NIMH, Patient-Centered

Outcomes Research Institute (PCORI), Blue Cross Blue Shield of Texas, SAMHSA, and the DoD. Editorial Compensation - Elsevier and Oxford University Press Velichka Valcheva Employee and Shareholder - GH Research Eduard Vieta Grants -

AB-Biotics, AbbVie, Almirall, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celon, Cephalon, Dainippon Sumitomo Pharma, Elan, Ferrer, GH Research, GlaxoSmithKline, Janssen, Lilly, Lundbeck, Orion, Otsuka, Pfizer, Sanofi Aventis,

Servier, Sunovion, and Takeda. Honoraria - Abbott, AbbVie, Angelini, AstraZeneca, Bristol Myers Squibb, Cambridge University Press, Elsevier, Farmindustria, Ferrer, Galenica, GlaxoSmithKline, Janssen, Johnson & Johnson, Lilly, Lundbeck,

Oxford University Press, Otsuka, Pfizer, Sanofi Aventis, and Viatris. Advisory Boards - AbbVie, Angelini, AstraZeneca, Biogen, Biohaven, Bristol Myers Squibb, Celon, Compass, Ferrer, GH Research, Gedeon Richter, HMNC, Idorsia, Janssen, Johnson

& Johnson, Jazz, Lilly, Lundbeck, Merck Sharp & Dohme, Novartis, Organon, Otsuka, Pfizer, Roche, Sage, Sanofi Aventis, Servier, Shire, Sunovion, Takeda, and Teva Wies aw J. Cuba a Grants - Acadia, Angelini, Beckley Psytech, GH

Research, HMNC Brain Health, Intra-Cellular Therapies, Janssen, MSD, Neumora, Novartis, Otsuka, Recognify Life Sciences. Honoraria - Angelini, GH Research, Janssen, and Novartis. Advisory Boards - Douglas Pharmaceuticals, GH Research, Janssen,

MSD, and Novartis (relationships reported within the last three years) Disclosures (2 of 2) 3

Patients with TRD, representing ~30% of patients treated for MDD,1 frequently

report anxiety symptoms and greater impairment in HRQoL versus patients with treatment-responsive MDD2-4 Current therapies for TRD are limited,4 and there is a large unmet need for treatments that are well tolerated and offer rapid therapeutic

benefit and long-term remission GH001, a synthetic form of mebufotenin (5-MeO-DMT) for pulmonary inhalation, has been well tolerated in early-stage trials5,6 and shows potential to induce rapid remission of depressive symptoms in patients with

TRD6 4 Background Abbreviations: 5-MeO-DMT = 5 methoxy N,N dimethyltryptamine; CGI-S = Clinical Global Impression - Severity; HAM-A = Hamiliton Rating Scale for Anxiety; HRQoL = Health-related quality of life; MDD = Major depressive

disorder; Q-LES-Q-SF = Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form; TRD = Treatment-resistant depression. 1. Kubitz N, et al. PLoS One. 2013;8(10):e76882. 2. Johnston KM, et al. J Affect Disord. 2019;242:195-210. 3.

Rathod S, et al. J Affect Disord. 2022;300:551-562. 4. McIntyre RS, et al. World Psychiatry. 2023;22:394-412. 5. Reckweg J, et al. Front Pharmacol. 2021;12:760671. 6. Reckweg JT, et al. Front Psychiatry. 2023;14:1133414. We examined the

effects of GH001 on depressive symptoms and secondary efficacy endpoints (CGI-S, HAM-A, and Q-LES-Q-SF) from the Phase 2b trial, for up to 6 months, in patients with TRD

For re-treatment (up to five GH001 IDRsa), the patient must have met one of the

following criteria: MADRS score >18 MADRS score >10 and 18 and MADRS score 10 not observed at Day 8 of the prior treatment or at any visit since MADRS score >10 and 18 and MADRS score >18 observed since the most recent

observation of MADRS score 10 5 Trial Schematic Open-Label Extension (OLE; Part 2) N=81 Randomization 1:1 GH001 IDRa Placebo IDRa BL 2H Day 1 Primary endpoint MADRS Day 8 During the OLE, patients attended visits at Day 15,

Month 1, 2, 3, 4, 5 & 6c Additional clinic visits could be scheduled if required for medical reasons Month 6 D2 Day 2 Double-Blind Part (Part 1)b This trial was conducted under the supervision of qualified healthcare professionals,

providing psychological support per standard of care, but without any planned psychotherapeutic intervention before, during, or after dosing aA second or third dose was administered if the previous dose was well tolerated according to the

trial physician's judgement (based on vital signs and adverse events) and if the patient did not achieve an intense psychoactive effect (peak experience; defined as a mean score of 75 on the Peak Experience Scale) following the previous dose.

bEfficacy assessments were carried out by independent blinded raters in the double-blind part. cPatients also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment. Abbreviations: BL = Baseline;

CGI-S = Clinical Global Impression - Severity; D = Day; HAM-A = Hamiliton Rating Scale for Anxiety; H = Hour; IDR = Individualized dosing regimen; MADRS = Montgomery- sberg Depression Rating Scale; Q-LES-Q-SF = Quality of Life, Enjoyment, and

Satisfaction Questionnaire-Short Form. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05800860, Accessed November 13, 2025. All patients directly transitioned from the double-blind part to the OLE Efficacy Assessments MADRS and

CGI-S MADRS, CGI-S, HAM-A, Q-LES-Q-SF

6 Eligibility Criteria aCurrent MDE confirmed by the Mini-International

Neuropsychiatric Interview. Abbreviations: DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; MDD = Major depressive disorder; MDE = Major depressive episode;

MGH-ATRQ = Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire; MGH-SAFER = Massachusetts General Hospital - Structured Assessment for Evaluation of Risk; TRD = Treatment-resistant depression.

7 Baseline Characteristics Abbreviations: BMI = Body mass index; CGI-S =

Clinical Global Impression - Severity; HAM-A = Hamilton Rating Scale for Anxiety; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; MADRS = Montgomery- sberg Depression Rating Scale; Q-LES-Q-SF = Quality of Life, Enjoyment, and Satisfaction

Questionnaire-Short Form; SD = Standard deviation. GH001 (n=40) Placebo (n=41) Overall (N=81) Baseline Demographics Age, years, mean (SD) 41.6 (11.4) 43.9 (10.9) 42.8 (11.2) Sex, female, n (%) 24 (60.0) 22 (53.7) 46 (56.8) Race,

White, n (%) 40 (100) 41 (100) 81 (100) BMI, kg/m2, mean (SD) 24.8 (4.3) 27.5 (6.3) 26.2 (5.5) Previously used any psychedelic (lifetime), n (%) 4 (10.0) 5 (12.2) 9 (11.1) Baseline Disease Characteristics HAM-D-17 total score, mean

(SD) 24.9 (2.6) 24.6 (2.3) 24.8 (2.5) MADRS total score, mean (SD) 29.0 (5.4) 28.2 (4.6) 28.6 (5.0) CGI-S score, mean (SD) 4.8 (0.7) 5.0 (0.6) 4.9 (0.7) HAM-A total score, mean (SD) 21.1 (6.5) 21.2 (6.1) 21.1 (6.2) Q-LES-Q-SF

total score, mean (SD) 27.9 (9.0) 25.3 (8.1) 26.6 (8.6)

LS mean difference vs placebo: 15.5 (P<0.0001) Effect size: Cohen's d =

2.0 LS Mean ( SE) Change from Baseline in MADRS Total Score BL 2H Day 2 Day 8 Primary Endpoint: GH001 Led to 15.5 Mean MADRS Reduction from Baseline on Day 8a Compared with Placebo in the Double-Blind Part aFDA Guidance notes that

efficacy with rapid-acting antidepressants generally should be demonstrated within 1 week, supporting a primary efficacy endpoint within this timeframe. Abbreviations: BL = Baseline; FDA = Food and Drug Administration; H = Hour; LS = Least

squares; MADRS = Montgomery- sberg Depression Rating Scale; OLE = Open-label extension; SE = Standard error. GH001 (n=40) Placebo (n=41) 8 The remission rate (MADRS total score 10) was 57.5% on Day 8 in patients who received a single dose

of GH001 in the double-blind part and 73.0% in OLE completers at Month 6 after a mean of four treatments

9 Global Illness Severity Assessment CGI-S Scale1 Abbreviations: CGI-S =

Clinical Global Impression - Severity. 1. Guy W. US Department of Health, Education, and Welfare. 1976:217-222. CGI-S is a clinician-rated assessment of illness severity Assessed by a blinded independent rater Total score range, 1 7 (higher

scores indicate more severe illness)

10 More Patients Had Improvement in Global Illness Severity from Baseline at Day

8 with GH001 vs Placebo in the Double-Blind Part Percentages are for each baseline category within treatment. Abbreviations: CGI-S = Clinical Global Impression - Severity; LS = Least squares; SE = Standard error. Percentage of Patients in

Each CGI-S Category at Baseline and Day 8 GH001 (n=40) Placebo (n=41) LS Mean (SE) Change in CGI-S Score from Baseline at Day 8 GH001 (n=40) Placebo (n=41) 2.4 (0.2) 0.1 (0.2) LS mean difference vs placebo: 2.5 (P<0.0001)

11 OLE Completers Reported Improved Global Illness Severity at Month

6 Abbreviations: CGI-S = Clinical Global Impression - Severity; OLE = Open-label extension; SD = Standard deviation. Percentage of Patients in Each CGI-S Category at Baseline and Month 6 OLE Completers (n=63) Change from Baseline in CGI-S

Score at Month 6 (n=63 OLE completers) Mean (SD) P Value 3.0 (1.4) <0.0001

12 Anxiety Assessment HAM-A Scale1,2 Abbreviations: HAM-A = Hamiliton Rating

Scale for Anxiety. 1. Hamilton M. Br J Med Psychol. 1959;32:50-55. 2. Marks RM, et al. Exp Clin Psychopharmacol. 2022;30(6):841-852. HAM-A is a clinician-rated assessment of anxiety symptoms Assessed by a blinded independent rater Total

score range, 0 56 (higher scores indicate worse anxiety) The 14 items of the HAM-A scale were analyzed within psychic and somatic domains (score ranges, 0-28): Psychic symptoms Anxious mood Insomnia Behavior at

interview Tension Intellectual (cognitive) Fears Depressed mood Somatic symptoms Somatic (muscular) Respiratory Autonomic Somatic (sensory) Gastrointestinal Cardiovascular Genitourinary

13 LS Mean (SE) Change in HAM-A Total Score from Baseline at Day 8 GH001

(n=40) Placebo (n=41) 11.1 (1.0) 1.0 (1.0) LS mean difference vs placebo: 10.0 (P<0.0001) GH001 Improved Psychic and Somatic Anxiety Symptoms vs Placebo Based on HAM-A Scores at Day 8 in the Double-Blind Part Mean (SD) Change from

Baseline in HAM-A Domain Score at Day 8 Psychic Symptomsa Somatic Symptomsb aIncludes anxious mood, tension, fears, insomnia, intellectual (cognitive), depressed mood, and behavior at interview items. bIncludes somatic (muscular), somatic

(sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, and autonomic symptoms items. Abbreviations: HAM-A = Hamiliton Rating Scale for Anxiety; LS = Least squares; SD = Standard deviation;

SE = Standard error.

14 OLE Completers Reported Improved Psychic and Somatic Anxiety Symptoms at Month

6 OLE Completers (n=63) aIncludes anxious mood, tension, fears, insomnia, intellectual (cognitive), depressed mood, and behavior at interview items. bIncludes somatic (muscular), somatic (sensory), cardiovascular symptoms, respiratory

symptoms, gastrointestinal symptoms, genitourinary symptoms, and autonomic symptoms items. Abbreviations: HAM-A = Hamiliton Rating Scale for Anxiety; OLE = Open-label extension; SD = Standard deviation. Change from Baseline in HAM-A Total

Score at Month 6 (n=63 OLE completers) Mean (SD) P Value 13.3 (7.2) <0.0001 Psychic Symptomsa Somatic Symptomsb Mean (SD) Change from Baseline in HAM-A Domain Score at Month 6

15 Quality of Life Assessment Q-LES-Q-SF Scale1,2 aThe total score reported for

the double-blind part and the open-label extension is based on the abbreviated version of the Q-LES-Q-SF (which omits two questions about medication and overall life satisfaction); however, the by-domain presentation includes all 16 items. bThe

domains were developed as part of an ad hoc analysis; the Q-LES-Q-SF does not have an official subscale scoring system. cThe percentages for each domain are normalized to reflect the relative proportionality of responses, accounting for the

differing number of items per domain. dIncludes mood, overall sense of well-being, and overall life satisfaction items. eIncludes family relationships, social relationships, and sex drive/interest/performance items. fIncludes physical health,

ability to function in daily life, ability to get around physically items. gIncludes work, ability to do work/hobbies, household activities, leisure time activities, living/housing situationship, economic status, and medication

items. Abbreviations: Q-LES-Q-SF = Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form. 1. Endicott J, et al. Psychopharmacol Bull. 1993;29:321-326. 2. Riendeau RP, et al. Qual Life Res. 2018;27:2953-2964. Q-LES-Q-SF is a

patient-reported scale that measures the degree of enjoyment and satisfaction experienced by patients in various areas of daily life The 16 items of the Q-LES-Q-SF score are rated on a 1 to 5 scale, with higher scores being indicative of

greater enjoyment or satisfactiona Total score range, 14 70a Q-LES-Q-SF scale items were analyzed within four domains (score ranges, 20 100)b,c Mood and psychological well-beingd Social and relationship lifee Physical health and

abilityf Work, housing, leisure, and daily functioningg

16 LS Mean (SE) Change in Q-LES-Q-SF Total Score from Baseline at Day 8 GH001

(n=37) Placebo (n=40) 20.6 (1.8) -0.8 (1.7) LS mean difference vs placebo: 21.4 (P<0.0001) GH001 Led to Improvements in Quality of Life Across Multiple Domains vs Placebo at Day 8 in the Double-Blind Part Mean Percentage (SD) Change

from Baseline in Q-LES-Q-SF Domain Score at Day 8a The Q-LES-Q-SF domains were developed as part of an ad hoc analysis; the Q-LES-Q-SF does not have an official subscale scoring system. aThe percentages for each domain are normalized to

reflect the relative proportionality of responses, accounting for the differing number of items per domain. bIncludes mood, overall sense of well-being, and overall life satisfaction items. cIncludes family relationships, social relationships,

and sex drive/interest/performance items. dIncludes physical health, ability to function in daily life, ability to get around physically items. eIncludes work, ability to do work/hobbies, household activities, leisure time activities,

living/housing situationship, economic status, and medication items. Abbreviations: LS = Least squares; SD = Standard deviation; SE = Standard error; Q-LES-Q-SF = Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form. Mood and

psychological well-beingb Social and relationship lifec Physical health and abilityd Work, housing, leisure, and daily functioninge

17 The Q-LES-Q-SF domains were developed as part of an ad hoc analysis; the

Q-LES-Q-SF does not have an official subscale scoring system. aThe percentages for each domain are normalized to reflect the relative proportionality of responses, accounting for the differing number of items per domain. bIncludes mood, overall