Exploring the Therapeutic Potential of Mebufotenin (GH001) Across Depressive Disorders ACNP 2026 Mini Panel Chair Michael E. Thase, MD Presenters Lisa Harding, MD Kristina M. Deligiannidis, MD Roger S. McIntyre, MD, FRCP

Exploring the Therapeutic Potential of Mebufotenin (GH001) Across Depressive

Disorders ACNP 2026 Mini Panel Chair Michael E. Thase, MD Presenters Lisa Harding, MD Kristina M. Deligiannidis, MD Roger S. McIntyre, MD, FRCPC

Chair Michael E. Thase, MD Department of Psychiatry, University of Pennsylvania,

and Corporal Michael J. Crescenz Veterans Affairs Medical Center Philadelphia, PA, USA GH001 Provides Rapid and Significant Antidepressant Effects in Patients with Treatment-Resistant Depression: Efficacy and Safety Results from a Phase 2b,

Double-Blind, Randomized Controlled Trial with a 6-Month Open-Label Extension Lisa Harding, MD Mood Institute and Yale School of Medicine Milton, CT, USA Rapid Improvement in Anhedonia Following GH001 Treatment in Patients with

Treatment-Resistant Depression, Postpartum Depression, and Bipolar II Disorder and a Current Major Depressive Episode Roger S. McIntyre, MD, FRCPC Department of Psychiatry, University of Toronto Toronto, ON, Canada GH001 Is Associated with

Improved Self-Reported Maternal Functioning in Patients with Postpartum Depression and Rapid Elimination from Breastmilk Kristina M. Deligiannidis, MD Feinstein Institutes for Medical Research Northwell Health Manhasset, NY, USA

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 Lisa Harding Advisory board - AbbVie, GH Research, Johnson & Johnson, and Otsuka. Consultant - GH Research

and Johnson & Johnson Kristina M. Deligiannidis Consultant Biogen, Brii Biosciences, Gerbera Therapeutics, GH Research, Lipocine, Neurocentria, Reunion Neuroscience, and Sage. Principal investigator for contracted research DuKang

Pharmaceuticals, Sage, and Woebot Health Roger S. McIntyre Consultant/speaker AbbVie, Alkermes, Atai Life Sciences, Axsome, Bausch Health, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Intra-Cellular Therapies, Janssen, Kris,

Lundbeck, Mitsubishi Tanabe, Neumora Therapeutics, NeuraWell, Neurocrine, NewBridge Pharmaceuticals, Novo Nordisk, Otsuka, Pfizer, Purdue, Sage, Sanofi, Sunovion, Takeda, and Viatris. Research grant support Canadian Institutes of Health

Research, Global Alliance for Chronic Diseases, National Natural Science Foundation of China, and the Milken Institute Disclosures

Psychoactive Molecules as Rapid-Acting Treatment for Depression Pharmacotherapy

is the first-line treatment recommendation for people with moderate to severe MDD1,2; however, there is an unmet need for rapid and effective pharmacological treatments Less than half of patients with MDD treated in clinical trials with

traditional antidepressant medications (SSRIs, SNRIs, or TCAs) achieve remission,3,4 and the proportion of patients achieving remission in clinical practice may be even smaller5 A growing body of evidence indicates that psychoactive molecules

may provide rapid reduction in severity of symptoms in patients with psychiatric disorders including MDD, TRD, BDII depression, and PPD6-9 Psychoactive molecules including LSD, ayahuasca, psilocybin, MDMA, and mebufotenin have been assessed in

clinical trials for those indications6-9 4 Abbreviations: BDII = Bipolar II disorder; LSD = Lysergic acid diethylamide; MDD = Major depressive disorder; MDMA = 3,4-methylenedioxymethamphetamine; PPD = Postpartum depression; SNRI =

Serotonin-norepinephrine reuptake inhibitor; SSRI = Selective serotonin reuptake inhibitor; TCA = Tricyclic antidepressant; TRD = Treatment-resistant depression. 1. APA Clinical practice guideline for the treatment of depression across three

age cohorts. 2019. Available at: https://www.apa.org/depression-guideline. Accessed Oct. 23, 2025. 2. Lam RW, et al. Can J Psychiatry. 2024;69(9):641-687. 3. Thase ME, et al. J Clin Psychiatry. 2005;66(8):974-981. 4. Machado M, et al. Curr Med

Res Opin. 2006;22(9):1825-1837. 5. Moller HJ, et al. World J Biol Psychiatry. 2008;9(2):102-114. 6. Yao Y, et al. Psychiatry Res. 2024;335:115886. 7. Reckweg JT, et al. Front Psychiatry. 2023;14:1133414. 8. Aaronson ST, et al. JAMA Psychiatry.

2024;81(6):555-562. 9. Jairaj C and Rucker JJ. J Psychopharmacol. 2022;36(8):920-931.

GH001 Overview Abbreviations: 5-HT = Serotonin; 5-MeO-DMT =

5 methoxy N,N dimethyltryptamine; BDII = Bipolar II disorder; MDE = Major depressive episode; PPD = Postpartum depression; TRD = Treatment-resistant depression. 1. Reckweg J, et al. Front Pharmacol. 2021;12:760671. 2. Reckweg JT, et al. Front

Psychiatry. 2023;14:1133414. 3. Halberstadt AL, et al. Psychopharmacology (Berl). 2012;221(4):709-718. 4. Shen HW, et al. Curr Drug Metab. 2010;11(8):659-666. 5. Reckweg JT, et al. J Neurochem. 2022;162:128-146. GH001 Synthetic form of

mebufotenin (5-MeO-DMT) for pulmonary inhalation GH001 has been well tolerated in early-stage trials1,2 and shows potential to induce a rapid remission of depressive symptoms in patients with TRD2 Non-selective 5-HT agonist with high

affinity for the 5-HT1A receptor3-5 Target indications: TRD, PPD, and BDII + MDE Phase 2b trial complete in TRD; Phase 2a trials complete in PPD and BDII + MDE Median duration of psychoactive effects: 11 min 5

Psychoactive Molecules Are Not Alike: Pharmacology and Phenomenology Anxious

ego-dissolution Visionary re-structuralization Oceanic boundlessness Mebufotenin5-8 Non-selective serotonin agonist with high affinity for 5-HT1A Experience of Unity Changed Meaningof

Perception Audio-VisualSynesthesia ElementaryImagery ComplexImagery Anxiety Impaired Control Disembodiment Insightfulness BlissfulState SpiritualExperience 100 80 60 40 20 0 DMT3,4 Mixed 5-HT1A/5-HT2A agonist Experience of

Unity 0 Meaning Audio-VisualSynesthesia ElementaryImagery ComplexImagery Anxiety Impaired Cognition Disembodiment Insightfulness BlissfulState SpiritualExperience 0.7 0.6 0.5 0.4 0.3 0.2 0.1 18 mg + 1.9 mg/min 14 mg + 1.5

mg/min 10 mg + 1.1 mg/min 6 mg + 0.6 mg/min Placebo LSD1,2 Non-selective serotonin and dopamine agonist Experience of Unity 100 80 70 60 50 40 30 20 10 0 90 Changed Meaningof

Percepts Audio-VisualSynesthesia ElementaryImagery ComplexImagery Anxiety Impaired Controland Cognition Disembodiment Insightfulness BlissfulState SpiritualExperience LSD 200 g p.o LSD 100 g p.o LSD 75 g i.v Abbreviations: 5-HT

= 5-Hydroxytryptamine (serotonin); DMT = N,N-Dimethyltryptamine; i.v. = Intravenous; LSD = Lysergic acid diethylamide; p.o. = Oral administration. 1. Liechti ME, et al Neuropsychopharmacology. 2017;42:2114-2127 (Figure adapted from source). 2.

Holze F, et al. Biol Psychiatry Cogn Neurosci Neuroimaging. 2024;9(5):472-489. 3. Luan LX, et al. J Psychopharmacol. 2024;38(1):56-67 (Figure adapted from source). 4. Nichols DE. Pharmacol Rev. 2016;68(2):264-355. 5.Uthaug MV, et al.

Psychopharmacology. 2019;236:2653-2666 (Figure adapted from source). 6. Shen HW, et al. Curr Drug Metab. 2010;11(8):659-66. 7. Halberstadt AL, et al. Psychopharmacology (Berl). 2012;221(4):709-718. 8. Ermakova AO, et al. Sci Rep.

7 GH001 Provides Rapid and Significant Antidepressant Effects in Patients with

Treatment-Resistant Depression Efficacy and Safety Results from a Phase 2b, Double-Blind, Randomized Controlled Trial with a 6-Month Open-Label Extension Lisa Harding, MD Mood Institute and Yale School of Medicine Milton, CT, USA

TRD remains one of the most pressing challenges in psychiatry and affects

approximately 30% of patients treated for MDD1 Current therapies for TRD are limited,2 and there is a large unmet need for treatments that are well tolerated and offer rapid reductions in depressive symptoms and long-term remission GH001, a

synthetic form of mebufotenin for pulmonary inhalation, has been well tolerated in early-stage trials3,4 and shows potential to induce rapid remission of depressive symptoms in patients with TRD4 8 Background Abbreviations: IDR =

Individualized dosing regimen; MDD = Major depressive disorder; TRD = Treatment-resistant depression. 1. Kubitz N, et al. PLoS One. 2013;8(10):e76882. 2. McIntyre RS, et al. World Psychiatry 2023;22:394-412. 3. Reckweg J, et al. Front

Pharmacol. 2021;12:760671. 4. Reckweg JT, et al. Front Psychiatry. 2023;14:1133414. This analysis presents efficacy and safety data for GH001 from a Phase 2b double-blind, placebo-controlled trial, in which patients with TRD received up to

five re-treatments of GH001 as an IDR

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 9 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 MADRS assessment 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; D = Day; H = Hour; IDR = Individualized dosing regimen; MADRS = Montgomery- sberg Depression Rating Scale. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05800860, Accessed October 28, 2025. All

patients directly transitioned from the double-blind part to the OLE

10 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.

11 Baseline Characteristics and Patient Disposition aGH001 was administered as a

monotherapy and patients who started additional antidepressant treatment were discontinued from the trial. Abbreviations: BMI = Body mass index; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; MADRS = Montgomery- sberg Depression Rating

Scale; MDE = Major depressive episode; OLE = Open-label extension; SD = Standard deviation. N=81 Baseline Demographics Age, years, mean (SD) 42.8 (11.2) Sex, female, n (%) 46 (56.8) Race, White, n (%) 81 (100) BMI, kg/m2, mean

(SD) 26.2 (5.5) Previously used any psychedelic (lifetime), n (%) 9 (11.1) Baseline Disease Characteristics HAM-D-17 total score, mean (SD) 24.8 (2.5) MADRS total score, mean (SD) 28.6 (5.0) MDE History at Baseline Number of

MDEs Mean (SD) 2.1 (1.3) 3, n (%) 27 (33.3) Time since first depressive episode, years, mean (SD) 11.7 (9.0) Duration of current MDE, weeks, mean (SD) 57.1 (78.4) Patient Disposition, n (%) Completed double-blind part 81

(100) Received GH001 in double-blind part 40 (49.4) Received placebo in double-blind part 41 (50.6) Completed OLE 63 (77.8) Reasons for Discontinuation During the OLE, n (%) 18 (22.2) Withdrawal of consent 7 (38.9) Started

additional antidepressanta 6 (33.3) Protocol deviation 2 (11.1) Other 2 (11.1) Adverse event 1 (5.6)

LS mean differenceb 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 Period aFDA Guidance notes that

efficacy with rapid-acting antidepressants generally should be demonstrated within 1 week, supporting a primary efficacy endpoint within this timeframe. bAdjusted for baseline severity of symptoms (MADRS total score). Abbreviations: BL =

Baseline; FDA = Food and Drug Administration; H = Hour; LS = Least squares; MADRS = Montgomery- sberg Depression Rating Scale; SE = Standard error. GH001 (n=40) Placebo (n=41) 12

Response: 50% reduction from baseline in MADRS total score | Remission: MADRS

total score 10 GH001 Led to 60.0% Response Rate and 57.5% Remission Rate at Day 8 vs 0% with Placebo in the Double-Blind Period Abbreviations: MADRS = Montgomery- sberg Depression Rating Scale; NNT = Number needed to

treat. 13 ****P<0.0001 2 Hours Day 2 Day 8 Response Remission GH001 Placebo **** NNT=2 **** **** NNT=2 **** **** NNT=2 **** Response Remission Response Remission NNT=2 NNT=2 NNT=2

14 Reduction in MADRS with GH001 in Double-Blind Part Reproduced in Placebo Group

with Their First Active GH001 Treatment in the OLE Abbreviations: BL = Baseline; D = Day; H = Hour; MADRS = Montgomery- sberg Depression Rating Scale; OLE = Open-label extension; SE = Standard error. Double-Blind Patients who received GH001

(n=40) Open-Label Extension First treatment of placebo group with GH001 (n=41) Mean ( SE) MADRS Total Score BL 2H D2 D8 Mean ( SE) MADRS Total Score BL 2H D2 D8

15 There Was a 73% Remission Rate at 6 Months in OLE Completers aIncludes 63

patients who completed the 6-month OLE per protocol (18 patients terminated early are excluded). bApproximately 6 months post-study start (median 168 days from Day 1 of double-blind part). cRemission defined as MADRS total score 10.

Abbreviations: MADRS = Montgomery- sberg Depression Rating Scale; OLE = Open-label extension. Double-blind n=40 patients who received GH001 OLE n=63 OLE completersa Day 8 Month 6b Percentage of Patients in Remissionc Patients who

completed the OLE received a mean of four treatments across the 6 months (double-blind part and OLE), with 63.5% (40/63) requiring one to four treatments during the 6 months

16 Remission Rate at 6 Monthsa in OLE Completersb a 6 Months' or Month 6' (end

of trial) was at approximately 6 months post-study start (median 168 days from Day 1 of double-blind part). bIncludes 63 patients who completed the 6-month OLE per protocol (18 patients terminated early are excluded). cRemission defined as a

MADRS total score 10. Abbreviations: MADRS = Montgomery- sberg Depression Rating Scale; OLE = Open-label extension. Of patients who had remission on Day 8 after their first GH001 treatment, 90% were in remission at 6 months Initial

Remitters N=40 Initial Non-remitters N=23 Percentage of Patients in Remissionc

17 Overview of Adverse Events in the Open-Label Extension aTEAEs were classified

according to the Medical Dictionary of Regulatory Activities (MedDRA) Version 26.0. Abbreviations: AESI = Adverse event of special interest; TEAE = Treatment-emergent adverse event. Patients, n (%) Overall (N=81) Overview of Adverse

Events Any TEAEa 72 (88.9) Maximum severity of TEAEs Mild 28 (34.6) Moderate 42 (51.9) Severe 2 (2.5) Treatment-related TEAEs 65 (80.2) Serious TEAEs 1 (1.2) Treatment-related serious TEAEs 0 TEAEs leading to

discontinuation 1 (1.2) AESIs 30 (37.0) Death 0 TEAEsa Occurring in >10% of Patients Overall Treatment-related TEAE Nausea 37 (45.7) 37 (45.7) Paresthesia 31 (38.3) 31 (38.3) Salivary hypersecretion 24 (29.6) 24

(29.6) Headache 16 (19.8) 11 (13.6) Muscle tightness 13 (16.0) 13 (16.0) Feeling cold 12 (14.8) 11 (13.6) Paresthesia oral 10 (12.3) 10 (12.3) Upper respiratory tract infection 10 (12.3) 0 Anxiety 9 (11.1) 8 (9.9)

18 GH001 Administration Was Well Tolerated in Patients with TRD up to 6

Months aTwo severe treatment-related TEAEs were reported in the OLE; affect lability occurred shortly after administration of GH001 and resolved within 4 minutes and one event of migraine, considered a serious TEAE not related to treatment,

started 73 days after the patient's most recent (fourth) administration of GH001. bAssessed using the Clinical Assessment of Discharge Readiness. Abbreviations: ECG = Electrocardiogram; OLE = Open-label extension; PT = Preferred term; SOC =

System organ class; TEAE = Treatment-emergent adverse event; TRD = Treatment-resistant depression. During the OLE, TEAEs were observed in 72/81 (88.9%) patients and were mostly mild or moderatea; one non treatment-related serious TEAE

(migraine) was reported No TEAEs of suicidal intent or suicidal behavior occurred The median duration of psychoactive effects after GH001 administration was 11 minutes Patients were deemed discharge-readyb by 1 hour post-dose at 99% of

19 Conclusion Abbreviations: IDR = Individualized dosing regimen; MADRS =

Montgomery- sberg Depression Rating Scale; OLE = Open-label extension; SAE = Serious adverse event; TEAE = Treatment-emergent adverse event; TRD = Treatment-resistant depression. The primary endpoint was met: GH001 administered as an IDR led

to significant MADRS reduction from baseline to Day 8 ( 15.5 vs placebo) GH001 can maintain long-term remission in TRD, with 73.0% of patients who completed the OLE in remission at 6 months GH001 was well tolerated during the 6-month OLE and

no treatment-related SAEs or TEAEs of suicidal intent or suicidal behavior occurred

20 GH001 Is Associated with Improved Self-Reported Maternal Functioning in

Patients with Postpartum Depression and Rapid Elimination from Breastmilk Kristina M. Deligiannidis, MD Feinstein Institutes for Medical Research Northwell Health Manhasset, NY, USA

We present data from this Phase 2a trial on antidepressant effects, maternal