Long-Term Data for GH001 in Patients with Treatment-Resistant Depression Wiesław
J. Cubała, MD, PhD Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland Co-authors: Malek Bajbouj, Bernhard T. Baune, Narcís Cardoner, Fabian Devlin, Rosa Maria Dueñas Herrero, Matilde Elices, Lauren
Friend, Luboš Janů, John R. Kelly, Shane J. McInerney, Alexander Nawka, Tomáš Páleníček, Victor Perez Sola, Johannes G. Ramaekers, Andreas Reif, Fiona Ryan, Claire Sweeney, Velichka Valcheva, Eduard Vieta, Michael E. Thase
Author Disclosures Wiesław J. Cubała Grants – Acadia, Angelini, Beckley
Psytech, Compass Pathways, GH Research, HMNC Brain Health, Intra-Cellular Therapies, Janssen, MSD, MindMed, Neumora, Novartis, Otsuka, Recognify Life Sciences. Honoraria – Angelini, GH Research, Janssen, and Novartis. Advisory boards – Douglas
Pharmaceuticals, GH Research, Janssen, MSD, Novartis, Polpharma, and Tasman Therapeutics. Malek Bajbouj Advisory boards – Bayer, Johnson & Johnson. 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, Viatris, and Wyeth. Advisory boards – Biogen, Boehringer
Ingelheim, Janssen-Cilag, LivaNova, Lundbeck, Medscape, Novartis, GH Research, 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 Marató de TV3, National Health and Medical Research Council (Australia), Sanofi-Synthélabo, and Wellcome Trust
(UK). Narcís 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 Marató 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. Fabian Devlin Former employee – GH Research.
Advisory board – GH Research. Rosa Maria Dueñas Herrero Principal investigator – Beckley Psytech and GH Research. Subinvestigator – Compass. Matilde Elices Research support – GH Research, Compass, Beckley Psytech, CaixaResearch, La Marató
de TV3, and Spanish Ministry of Health. Lauren Friend Employee and stock option holder of GH Research. Luboš Janů Principal investigator – GH Research. John R. Kelly Principal investigator – Compass, GH Research, and Transcend
Therapeutics. Consultant – Clerkenwell Health. Grant funding – Health Research Board. Disclosures (1 of 2)
Author Disclosures Shane J. McInerney Principal investigator – GH Research and
Transcend Therapeutics. Honoraria – Janssen and Lundbeck. Alexander Nawka Principal investigator – GH Research. Tomáš Páleníček Principal investigator – Compass, GH Research, MAPS, and Ketabon. Shares – Psychedelická klinika s.r.o.,
Společnost pro podporu neurovědního výzkumu s.r.o., and AVI-X Aviation Experts s.r.o. Founder – PSYRES (Psychedelic Research Foundation). Consultant – CB21 Pharma and GH Research. Victor Perez Sola Consultant, honoraria, or grants –
AB-Biotics, AstraZeneca, Bristol Myers Squibb, CIBERSAM, FIS-ISCiii, Janssen Cilag, Lundbeck, Medtronic, Otsuka, and Servier. Johannes G. Ramaekers Scientific advisor – 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. Fiona Ryan Employee and stock option holder of GH Research. Claire
Sweeney Employee and stock option holder of GH Research. 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. 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. Disclosures (2 of 2)
TRD remains one of the most pressing challenges in psychiatry affecting
approximately 30% of patients treated for MDD1 Current therapies for TRD are limited, and there is a large unmet need for treatments that are well tolerated and offer rapid therapeutic benefit and long-term remission Mebufotenin
(5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) is a non-selective serotonin (5-HT) agonist with high affinity for several receptor subtypes, primarily the 5-HT1A receptor2 GH001, a synthetic form of mebufotenin for pulmonary inhalation, has
been well tolerated in early-stage trials3 and shows potential to induce rapid remission of depressive symptoms in patients with TRD4 This analysis presents the efficacy and safety data for GH001 from the 6-month OLE of a Phase 2b
double-blind, placebo-controlled trial, in which patients with TRD received up to five re-treatments of GH001 as an IDR 4 Background Abbreviations: IDR = Individualised dosing regimen; MDD = Major depressive disorder; OLE = Open-label
extension; 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. 2023;14:1133414.
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 (Part 2; OLE) N=81 Randomisation 1:1 GH001 IDRa Placebo IDRa BL 2H Day 1 Primary endpoint ΔMADRS Day 8 During the OLE, patients attended visits at Day 15,
Month 1, 2, 3, 4, 5 & 6b Additional clinic visits could be scheduled if required for medical reasons MADRS assessment Month 6 D2 Day 2 Double-Blind Part (Part 1) 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 aThe criteria for administration of the second and third doses in the IDR
were based on the patient’s subjectively reported psychoactive effects, and the safety and tolerability at the previous dose level according to the trial physician’s judgement. bPatients 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 = Individualised dosing regimen; MADRS = Montgomery–Åsberg 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 Efficacy assessments were carried out by independent blinded raters
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 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-Åsberg Depression Rating
Scale; MDE = Major depressive episode; OLE = Open-label extension; SD = Standard deviation. N=81 Baseline Demographics, n (%) Age 42.8 (11.2) Gender, female 46 (56.8) Race, White 81 (100) BMI, mean (SD), kg/m2 26.2 (5.5) Previously
used any psychedelic (lifetime) 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 (%) N=18 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 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 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. Abbreviations: BL = Baseline; FDA = Food and Drug Administration; H = Hour; LS = Least
squares; MADRS = Montgomery-Åsberg Depression Rating Scale; SE = Standard error. GH001 (n=40) Placebo (n=41) 8
****P<0.0001 Response: ≥50% reduction from baseline in MADRS total score |
Remission: MADRS total score ≤10 GH001 Placebo **** **** Remission NNT=2 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 treat. Response 9 NNT=2
10 Reduction in MADRS With GH001 in Double-Blind Part Reproduced in Placebo Group
With First Active GH001 Treatment in the OLE Abbreviations: BL = Baseline; D = Day; H = Hour; MADRS = Montgomery-Åsberg Depression Rating Scale; 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
11 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-Åsberg 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, with 63.5% (40/63) requiring one to four treatments during the 6 months
12 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 (mean 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-Åsberg Depression Rating Scale; OLE = Open-label extension. Initial Remitters N=40 Initial Non-Remitters N=23 Percentage of Patients in Remissionc Of patients who had remission on
Day 8 after their first GH001 treatment, 90% were in remission at 6 months
13 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; TRD = Treatment-resistant depression. 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) Paraesthesia oral 10 (12.3) 10 (12.3) Upper respiratory tract infection 10 (12.3) 0
(0.0) Anxiety 9 (11.1) 8 (9.9)
14 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. bIncluded the following PT: throat irritation and upper respiratory tract irritation (three events each), cough and dyspnoea (one event each), and exacerbation of
asthma. All of these treatment-related TEAEs were mild to moderate in severity and not associated with clinically significant changes in vital signs and, with the exception of the TEAE of asthma, were short-lived, resolved without treatment,
and were not associated with any clinically significant changes in spirometry parameters. Abbreviations: IDR = Individualised dosing regimen; OLE = Open-label extension; PT = Preferred term; SOC = System organ class; TEAE = Treatment-emergent
adverse event; TRD = Treatment-resistant depression. TEAEs were observed in 72/81 (88.9%) of patients and were mostly mild or moderatea One non−treatment-related serious TEAE was reported No TEAEs of suicidal intent or suicidal behaviour
occurred and lower rates of suicidal ideation were observed in comparison to baseline at all timepoints assessed during the trial There were no clinically significant changes in blood pressure or heart rate following administration of GH001
and no treatment-related TEAEs related to vital signs or ECG results Of a total of 13 TEAEs (9.9% of patients) under the SOC respiratory, thoracic, and mediastinal disorders, nine (6.2% of patients) were considered treatment-related
TEAEsb The median duration of psychoactive effects after GH001 administration was 11 minutes Patients were deemed discharge-ready by 1-hour post-dose at 99% of visits
15 Adverse Events of Special Interest in the Open-Label Extension Abbreviations:
AESI = Adverse event of special interest; TEAE = Treatment-emergent adverse event. Patients, n (%) GH001 (n=81) Any treatment-emergent AESI 30 (37.0) Anxiety 9 (11.1) Depression 8 (9.9) Affect lability 6 (7.4) Abnormal behaviour 2
(2.5) Emotional disorder 2 (2.5) Irritability 2 (2.5) Amnesia 2 (2.5) Psychomotor hyperactivity 2 (2.5) Feeling abnormal 2 (2.5) Agitation 1 (1.2) Depressive symptom 1 (1.2) Dissociation 1 (1.2) Inappropriate affect 1
(1.2) Suicidal ideation 1 (1.2) Hypersomnia 1 (1.2) Sedation 1 (1.2) Sensory disturbance 1 (1.2) Somnolence 1 (1.2) Feeling of relaxation 1 (1.2) No TEAEs of flashback were reported
16 Conclusion Abbreviations: IDR = Individualised 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 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 Patients who completed the OLE received a mean total
of four GH001 treatments, with 63.5% (40/63) requiring one to four treatments during the 6 months GH001 was well tolerated during the 6-month OLE and no treatment-related SAEs occurred No TEAEs of suicidal intent or suicidal behaviour
occurred throughout the 6-month duration of the trial
17 Poster Presentations Monday, October 13th, 12:35 – 14:00pm (Poster
Area) Devlin F et al, Poster # PS03-2265 Tuesday, October 14th, 12:35 – 14:00pm (Poster Area) Baune BT et al, Poster # PS04-3243
18 Acknowledgments This trial was sponsored by GH Research Ireland Limited 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 was provided by Brian Brennan,
PhD, of GH Research Primary analysis of the trial was conducted by the contract research organisation Worldwide Clinical Trials. Additional analyses were conducted by Rachael MacIsaac, PhD, of GH Research