Slide 1: Exploring the Therapeutic Potential of Mebufotenin (GH001) Across Depressive Disorders
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
Slide 2: Panel Chair and Presenters
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 Res
Slide 3: Author Disclosures
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 Therapie
Slide 4: Psychoactive Molecules as Rapid-Acting Treatment for Depression
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 clin
Slide 5: GH001 Overview
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. Fro
Slide 6: Psychoactive Molecules Are Not Alike: Pharmacology and Phenomenology
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 Elem
Slide 7: GH001 Provides Rapid and Significant Antidepressant Effects in Patients with TRD
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,
Slide 8: Background: TRD Unmet Need
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 remi
Slide 9: Trial Schematic
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 recen
Slide 10: Eligibility Criteria
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 depressi
Slide 11: Baseline Characteristics and Patient Disposition
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–Ås
Slide 12: Primary Endpoint: −15.5 Mean MADRS Reduction on Day 8
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 no
Slide 13: 60.0% Response Rate and 57.5% Remission Rate at Day 8
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–Åsberg Depression Rating Scale; NNT = Number needed to tre
Slide 14: MADRS Reduction Reproduced in Placebo Group in the OLE
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–Åsberg Depression Rating Scale; OLE = Open-label extension; SE = Standard error. Double-Blind Patie
Slide 15: 73% Remission Rate at 6 Months in OLE Completers
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
Slide 16: Remission Rate at 6 Months in OLE Completers
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). cR
Slide 17: Overview of Adverse Events in the Open-Label Extension
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) Overvi
Slide 18: GH001 Well Tolerated in Patients with TRD up to 6 Months
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 t
Slide 19: Conclusion
19 Conclusion Abbreviations: IDR = Individualized dosing regimen; MADRS = Montgomery–Åsberg 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 administere
Slide 20: GH001 and Maternal Functioning in Postpartum Depression
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
Slide 21: Background: Postpartum Depression Phase 2a Trial
We present data from this Phase 2a trial on antidepressant effects, maternal functioning, and safety in patients with PPD receiving GH001 as well as breastmilk concentrations of mebufotenin in lactating patients PPD is defined as an MDE with onset of mood symptoms during pregnancy or within 4 weeks
Slide 22: Trial Schematic
22 Trial Schematic 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 ≥7
Slide 23: Eligibility Criteria
23 Eligibility Criteria aConfirmed by the MINI. Abbreviations: DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = Major depressive disorder; MINI = Mini-International Neuropsychiatric Interview; PPD = Postpartum depr
Slide 24: Key Assessments
24 Key Assessments Abbreviations: 5-MIAA = 5-methoxyindole-3-acetic acid; BIMF = Barkin Index of Maternal Functioning; LC-MS/MS = Liquid chromatography with tandem mass spectrometry; MADRS = Montgomery–Åsberg Depression Rating Scale; PK = Pharmacokinetics. 1. Montgomery SA, Asberg M. Br J Psychiatry
Slide 25: Demographics and Baseline Clinical Characteristics
25 Demographics and Baseline Clinical Characteristics an=8 patients. Abbreviations: BIMF = Barkin Index of Maternal Functioning; MADRS = Montgomery–Åsberg Depression Rating Scale; MDE = Major depressive episode; SD = Standard deviation. N=10 Demographics Sex, female, n (%) 10 (100) Age, years, mean
Slide 26: Primary Endpoint: Reductions in Mean MADRS Total Score in PPD
26 Primary Endpoint: GH001 Was Associated with Significant Reductions from Baseline on Day 8 in Mean MADRS Total Score in Patients with PPD aSecondary efficacy endpoint. Abbreviations: BL = Baseline; H = Hours; MADRS = Montgomery–Åsberg Depression Rating Scale; PPD = Postpartum depression; SD = Stan
Slide 27: Primary Endpoint: Individual Patient MADRS Reduction
27 Primary Endpoint: GH001 Led to Substantial Reduction from Baseline on Day 8 in MADRS Total Score in All Patients with PPD Individual patient data are plotted in the figure, with each color representing 1 patient. bSecondary efficacy endpoint. Abbreviations: BL = Baseline; H = Hours; MADRS = Montg
Slide 28: BIMF Total Score Improved by a Mean of 34.1 Points
28 BIMF Total Score Improved by a Mean of 34.1 Points from Baseline on Day 8 Abbreviations: BL = Baseline; BIMF = Barkin Index of Maternal Functioning; SD = Standard deviation. Baseline (n=8) Day 8 (n=9) Mean (±SD) BIMF Total Score Better maternal functioning 56% improvement in maternal functioning
Slide 29: Breastmilk Pharmacokinetics
GH001 6+12 mg (n=3) Pre-dose Day 1 1 h post-dosea 2.5 h post-dosea ~8 h post-dosea Day 2 Day 8 Mebufotenin, ng/mL Median (range) BLQ (BLQ−BLQ) 2.2 (0.2−3.1) 0.3 (BLQ−0.6) BLQ (BLQ−0.04) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) Bufotenin, ng/mL (psychoactive) Median (range) BLQ (BLQ−BLQ) BLQ (BLQ−BLQ) BLQ (BLQ−BL
Slide 30: Safety Summary
Safety Summary 30 Patients, n (%) Overall (N=10) Overview of Adverse Events Any TEAE 8 (80.0) Mild 7 (70.0) Moderate 1 (10.0) Severe 0 Treatment-related TEAEs 7 (70.0) Serious TEAE 0 Death 0 TEAEs by Preferred Term Headache 5 (50.0) Abdominal pain 1 (10.0) Nausea 1 (10.0) Vomiting 1 (10.0) Diarrhea
Slide 31: Conclusions
Conclusions 31 In adult patients with PPD enrolled in this open-label trial, GH001 as an IDR was associated with significant reduction in MADRS total score from baseline to Day 8 Improvements were observed across BIMF domains of self-reported maternal functioning Mebufotenin and its metabolites (buf
Slide 32: Rapid Improvement in Anhedonia Following GH001 Treatment
32 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
Slide 33: Background: Anhedonia in MDD
Anhedonia is a core symptom of MDD, characterized by a lack of enjoyment from and engagement in life’s experiences, and a deficit in the ability to feel pleasure1 In patients with MDD, anhedonia at baseline is often a predictor of TRD2 Anhedonia is also associated with suicidality,3,4 poor quality o
Slide 34: Trial Designs
aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychot
Slide 35: Trial Designs
aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychot
Slide 36: Trial Designs
aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychot
Slide 37: Trial Designs
aIn the TRD trial, during the OLE, patients attended visits at Day 15, Month 1, 2, 3, 4, 5 & 6, and also attended assessment visits on Day 2 (telephone call) and Day 8 (in-person) after each re-treatment; MADRS assessment was performed at each visit. bMDD episode (per DSM-5 criteria) without psychot
Slide 38: Anhedonia Assessment: MADRS 5-item Anhedonia Subscale
The MADRS 5-item anhedonia subscale1 includes the following MADRS items: Score range, 0−30; lower scores indicate less severe anhedonia Clinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on a published analysis of patients with MDD2 38 Anhedonia
Slide 39: Baseline Characteristics and Disposition
39 Baseline Characteristics and Disposition Abbreviations: BDII = Bipolar II disorder; BMI = Body mass index; CGI-S = Clinical Global Impression-Severity; MADRS = Montgomery–Åsberg Depression Rating Scale; MDE = Major depressive episode; OLE = Open-label extension; PPD = Postpartum depression; SD =
Slide 40: TRD: Rapid Clinically Meaningful Improvements in MADRS Anhedonia Scores
40 Patients with TRD Who Received Double-Blind Treatment with GH001 Had Rapid and Clinically Meaningfula Improvements in MADRS Anhedonia Scores aClinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1 Abbreviation
Slide 41: Anhedonia Improvement Maintained at Month 6 in OLE Completers
41 aClinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1 Abbreviations: BL = Baseline; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disor
Slide 42: PPD: Clinically Meaningful Improvement in Anhedonia
42 In Patients with PPD, Clinically Meaningfula Improvement in MADRS Anhedonia Score was Observed at Each Assessment aClinically meaningful improvement in anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1 Abbreviations: BL = Baseline; D = Day;
Slide 43: BDII + MDE: Improvement in Anhedonia at Day 8
Patients with BDII + MDE had Clinically Meaningfula Improvement in MADRS Anhedonia Score at Day 8 Post-Dose BL D1 D2 D8 MADRS Anhedonia Subscale Score MADRS Anhedonia Subscale Item Scores Mean (±SD) Change from Baseline in MADRS Anhedonia Subscale Score aClinically meaningful improvement in anhedoni
Slide 44: GH001 Well Tolerated in TRD, PPD, or BDII + MDE
44 GH001 was Well Tolerated in Patients with TRD, PPD, or BDII + MDE No treatment-related serious TEAEs were reported across the TRD, PPD and BDII + MDE trialsa In all three trials, TEAEs were mostly mild or moderate in severity The most common TEAE in patients treated with GH001 was nausea in the d
Slide 45: Conclusion
Abbreviations: BDII = Bipolar II disorder; MADRS = Montgomery–Åsberg Depression Rating Scale; MDE = Major depressive episode; OLE = Open-label extension; PPD = Postpartum depression; TRD = Treatment-resistant depression. 45 Conclusion The presented trials investigating GH001 for the treatment of TRD
Slide 46: Acknowledgments
46 Acknowledgments These trials were sponsored by GH Research Ireland Limited The sponsor would like to thank the participants in the trials The sponsor would also like to thank the investigators who conducted these trials Under the guidance of the authors, medical writing and editorial support were