Safety and Efficacy of GH001 in Treatment-Resistant Depression: Results From a Phase 2b, Double-Blind, Randomized Controlled Trial Michael E. Thase, MD Department of Psychiatry, University of Pennsylvania, and Corporal M

Safety and Efficacy of GH001 in Treatment-Resistant Depression: Results From a

Phase 2b, Double-Blind, Randomized Controlled Trial Michael E. Thase, MD Department of Psychiatry, University of Pennsylvania, and Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA Coauthors: Bernhard T. Baune,

Narc s Cardoner, Rosa Maria Due as Herrero, Lubo Jan , John R. Kelly, Shane J. McInerney, Alexander Nawka, Tom P len ek, Andreas Reif, V ctor P rez Sola, Madhukar H. Trivedi, Velichka Valcheva, Eduard Vieta, Wies aw J. Cuba a

Author Disclosures Michael E. Thase Grants - Acadia, Alkermes, Axsome,

Intra-Cellular Therapies, Janssen, National Institute of Mental Health, Otsuka, Patient-Centered Outcomes Research Institute (PCORI), and Takeda. Advisory Boards - Autobahn Therapeutics, Axsome, Clexio Biosciences, Gerson Lehrman Group, GH

Research, Lundbeck, Janssen, Johnson & Johnson, Luye Pharma, Merck, Object Pharma, Otsuka, Pfizer, Sage, Seelos Therapeutics, Sunovion, and Takeda. Royalties - American Psychiatric Association Foundation, Guilford Publications, Herald

House, Wolters Kluwer, and W W Norton & Company 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 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) Shane J.

McInerney Principal investigator - GH Research and Transcend Therapeutics. Honoraria - Janssen and Lundbeck Alexander Nawka Principal investigator - GH Research Disclosures (1 of 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 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 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 Madhukar H. Trivedi Advisory boards - Alto

Neuroscience and Base Point Health Management. Consultant - Axsome, Biogen, Daiichi Sankyo, GH Research, Legion Health, Neurocrine Biosciences, Otsuka Pharmaceutical Europe, Otsuka Pharmaceutical Development & Commercialization, Otsuka

Pharmaceutical, PureTech, and Takeda. Advisor - Cerebral Therapeutics, Circular Genomics, and Seaport Therapeutics. Scientific advisor - GreenLight VitalSign6. Board of Directors - Charities2Love Velichka Valcheva Employee and stock option

holder of 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)

4 Background TRD affects approximately 30% of patients treated for MDD1 Current

therapies for TRD are limited and there is a large unmet need for treatments that offer rapid and sustained effects Mebufotenin (5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) is a non-selective serotonin (5-HT) agonist with high affinity for

several receptor subtypes, including the 5-HT1A receptor2 GH001 is a synthetic form of mebufotenin for pulmonary inhalation3,4 Early-stage trials in healthy volunteers and patients with TRD suggest that GH001 is well tolerated and may have

the potential to induce an ultra-rapid remission in depressive symptoms3,4 The aim of this double-blind, placebo-controlled trial was to investigate the safety and efficacy of GH001 in patients with TRD MDD = Major depressive disorder; TRD =

Treatment-resistant depression. 1. Kubitz N, et al. PLoS One. 2013;8(10):e76882. 2. Shen H, et al. Curr Drug Metab. 2010;11(8):659-66. 3. Reckweg J, et al. Front Pharmacol. 2021;12:760671. 4. Reckweg JT, et al. Front Psychiatry.

5 Eligibility Criteria aCurrent MDE confirmed by the MINI. 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; MINI = Mini-International Neuropsychiatric Interview; TRD = Treatment-resistant depression.

For re-treatment (up to five GH001 IDRs), 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 6 Trial Schematic Open-Label Extension (OLE) N=81 Randomization 1:1 GH001 IDR Placebo IDR BL 2h Day 1 Primary endpoint MADRS Day 8 During the OLE, patients attended visits at Day 15, Month 1, 2,

3, 4, 5 & 6a Additional clinic visits could be scheduled if required for medical reasons MADRS assessment Month 6 D2 Day 2 Double-Blind Part 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 aPatients also attended assessment visits on Day 2 (phone call) and Day 8 after each re-treatment.

BL = Baseline; D = Day; h = Hour; IDR = Individualized dosing regimen; MADRS = Montgomery- sberg Depression Rating Scale. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05800860, Accessed March 13, 2025. All patients directly

transitioned from the double-blind part to the OLE

7 Patient Disposition and Characteristics in the Double-Blind Part aUp to three

doses of GH001 or placebo were administered to each patient. bIncludes all patients who received respective dose of GH001 or placebo, irrespective of total dose. BMI = Body mass index; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR

= Individualized dosing regimen; MADRS = Montgomery- sberg Depression Rating Scale; MDE = Major depressive episode; PsE = Psychoactive effects; SD = Standard deviation. GH001 (n=40) Placebo (n=41) Patient Disposition Completed double-blind

part, n (%) 40 (100) 41 (100) Patient Demographics Age, years, mean (SD) 41.6 (11.4) 43.9 (10.9) Female, n (%) 24 (60.0) 22 (53.7) Race, White, n (%) 40 (100) 41 (100) BMI, kg/m2, mean (SD) 24.8 (4.3) 27.5 (6.3) Previously used

any psychedelic (lifetime), n (%) 4 (10.0) 5 (12.2) Baseline Disease Characteristics HAM-D-17 total score, mean (SD) 24.9 (2.7) 24.6 (2.3) MADRS total score, mean (SD) 29 (5.4) 28.2 (4.6) MDE History at Baseline Number of MDEs Mean

(SD) 2.1 (1.4) 2.0 (1.1) 3, n (%) 14 (35.0) 13 (31.7) Time since first depressive episode, years, mean (SD) 11.3 (9.7) 12.2 (8.4) Duration of current MDE, weeks, mean (SD) 50.8 (28.3) 63.3 (106.9) Patients Receiving IDR

Dosesa First dose (6 mg GH001 or one placebo dose), n (%) 9 (22.5) 0 (0) Second dose (6+12 mg GH001 or two placebo doses), n (%) 21 (52.5) 0 (0) Third dose (6+12+18 mg GH001 or three placebo doses), n (%) 10 (25.0) 41 (100) Duration

of PsEb 6 mg (or placebo first dose), minutes, median (range) 9.0 (2 35) 0 (0 15) 12 mg (or placebo second dose), minutes, median (range) 14.0 (4 50) 0 (0 5) 18 mg (or placebo third dose), minutes, median (range) 11.5 (8 50) 0 (0 7)

Primary Endpointa: GH001 Led to Mean MADRS Reduction From Baseline of 15.5 on Day

8 vs Placebo 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 aFDA Guidance notes that efficacy with rapid-acting antidepressants generally should be

demonstrated within 1 week, supporting a primary efficacy endpoint within this timeframe. BL = Baseline; FDA = Food and Drug Administration; LS = Least squares; MADRS = Montgomery- sberg Depression Rating Scale; SE = Standard error. GH001

(n=40) Placebo (n=41) BL 2 hours Day 2 Day 8 8

9 Secondary Endpoints: GH001 Led to 57.5% Remission Rate and 60.0% Response Rate

at Day 8 vs 0% With Placebo MADRS = Montgomery- sberg Depression Rating Scale; NNT = Number needed to treat. ****P<0.0001 Remission: MADRS total score 10 | Response: 50% reduction from baseline in MADRS total score 2 Hours Day 2 Day

8 Remission Response GH001 Placebo **** **** **** **** **** **** Remission Response Remission Response NNT=2 NNT=2 NNT=2

10 Secondary Endpoints: GH001 Led to Improvements in Anxiety and Quality of Life

vs Placebo at Day 8 HAM-A Total Score Q-LES-Q-SF Total Score HAM-A = Hamilton Anxiety Rating Scale; LS = Least squares; Q-LES-Q-SF = Quality of Life Enjoyment and Satisfaction Questionnaire - Short

Form. GH001 (n=40) Placebo (n=41) GH001 (n=37) Placebo (n=39) LS Mean Change From Baseline at Day 8 LS mean difference vs placebo: 10.0 (P<0.0001) LS mean difference vs placebo: 21.5 (P<0.0001) LS Mean Change From

11 More Patients Had Improvement in Global Illness Severity From Baseline at Day

8 With GH001 vs Placebo Percentage of Patients in Each CGI-S Category at Day 8 Percentages are for each baseline category within treatment. CGI-S = Clinical Global Impression - Severity; LS = Least squares; SE = Standard error. 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)

12 Overview of Adverse Events in the Double-Blind Part TEAEs were classified

according to the Medical Dictionary of Regulatory Activities (MedDRA version 26.0). AESI = Adverse event of special interest; TEAE = Treatment-emergent adverse event. No TEAEs of flashbacks were reported Patients, n (%) GH001

(n=40) Placebo (n=41) Overview of Adverse Events Any TEAE 29 (72.5) 3 (7.3) Maximum severity of TEAEs Mild 14 (35.0) 2 (4.9) Moderate 15 (37.5) 1 (2.4) Severe 0 (0) 0 (0) Treatment-related TEAEs 29 (72.5) 1

(2.4) Device-related TEAEs 1 (2.5) 0 (0) Serious TEAEs 0 (0) 0 (0) Treatment-related serious TEAEs 0 (0) 0 (0) TEAEs leading to study drug withdrawal 0 (0) 0 (0) TEAEs leading to early withdrawal from trial 0 (0) 0 (0) AESIs 8

(20.0) 0 (0) Death 0 (0) 0 (0) Most Common TEAEs (occurring in >5% of patients in either group) by Preferred Term Nausea 17 (42.5) 0 (0) Salivary hypersecretion 8 (20.0) 0 (0) Paresthesia 8 (20.0) 0 (0) Headache 3 (7.5) 1

(2.4) Dysgeusia 3 (7.5) 0 (0)

13 Reduction in MADRS With GH001 in Double-Blind Part Reproduced in Placebo Group

With First GH001 Treatment in OLE BL = Baseline; MADRS = Montgomery- sberg Depression Rating Scale; OLE = Open-label extension; SE = Standard error. Double-blind Patients who received GH001 (n=40) OLE First treatment of placebo group with

GH001 (n=41) Mean ( SE) MADRS Total Score BL 2 hours Day 2 Day 8 BL 2 hours Day 2 Day 8

14 73.0% Remission Rate at 6 Months in OLE Completers The OLE was completed in

Q1 2025 63 completed, 18 early terminations (n=1 due to TEAE) For patients who completed the OLE: 73.0% (n=46) of patients were in remissionc at 6 months (79.4% with clinical response)d Of the 46 patients in remission, 23 were randomized

to GH001 and 23 were randomized to placebo in the double-blind part Completers (n=63) had a mean MADRS total score of 9.4 at 6 months 63.5% (n=40) received 1 4 treatments with GH001 No drug-related serious TEAEs were reported in the OLE; one

non-drug-related serious TEAE was reported during the OLEe Note: data collection for the OLE has completed but data cleaning is ongoing. All analyses of OLE data are subject to change following database lock. Double-blind n=40 patients who

received GH001 OLE n=63 OLE completersa Day 8 Month 6b a63 patients who received active drug and completed the 6-month OLE per protocol (patients who terminated early are excluded). bApproximately 6 months post-study start (mean 168 days

from Day 1 of double-blind period). cMADRS total score 10. d 50% reduction from baseline in total MADRS score. eThe non-drug-related serious TEAE reported was preferred term status migrainosus. Onset was 73 days after the patients most recent

administration of the GH001 IDR. MADRS = Montgomery- sberg Depression Rating Scale; OLE = Open-label extension; TEAE = Treatment-emergent adverse event.

Double-Blind Part The primary endpoint was met: GH001 administered as an IDR led

to significant MADRS reductions from baseline to Day 8 ( 15.5 vs placebo) Secondary endpoints: Remission rate of 57.5% at Day 8 (placebo, 0%), and improvements in anxiety, global disease severity, and quality of life were observed Safety:

GH001 was well tolerated Open-Label Extension GH001 can maintain long-term remission in TRD, with 73.0% of patients who completed the OLE in remission at 6 months Durable effects with relatively infrequent treatment visits and ultra-rapid

MADRS reduction No drug-related serious TEAEs were reported in the OLE 15 Conclusions Data analysis has been completed for the OLE, but data cleaning is still ongoing. IDR = Individualized dosing regimen; MADRS = Montgomery- sberg

Depression Rating Scale; OLE = Open-label extension; TEAE = Treatment-emergent adverse event; TRD = Treatment-resistant depression.

16 Acknowledgments This trial was sponsored by GH Research The sponsor would

like to thank the participants in the trial The sponsor would also like to thank the investigators who conducted this trial Under the guidance of the authors, medical writing and editorial support were provided by Brian Brennan, PhD, and

Claire Sweeney, PhD, of GH Research, and Jane Phillips, PhD, of OPEN Health Primary analysis of the trial was conducted by the contract research organization Worldwide Clinical Trials. Additional analyses were conducted by Rachael MacIsaac,