GH Research (GHRS) reports strong GH001 results in TRD and PPD

Rhea-AI Filing Summary

GH Research PLC reported new clinical data on its investigational inhaled psychedelic GH001 (synthetic mebufotenin) across several depressive disorders, presented at an ACNP 2026 mini‑panel. In a Phase 2b double‑blind trial in treatment‑resistant depression, GH001 achieved the primary endpoint with a least‑squares mean MADRS reduction on Day 8 that was 15.5 points greater than placebo, with a Cohen’s d effect size of −2.0. At Day 8, 60.0% of GH001 patients met response criteria and 57.5% achieved remission, versus 0% on placebo, and among open‑label extension completers 73% were in remission at 6 months. A Phase 2a postpartum depression trial (10 patients) showed all patients in remission by Day 8 and a mean 35.4‑point MADRS reduction, alongside a 34.1‑point improvement in maternal functioning scores and rapid elimination of mebufotenin and its metabolites from breastmilk. Across TRD, PPD and bipolar II depression with a current major depressive episode, GH001 produced rapid, clinically meaningful improvements in MADRS anhedonia subscale scores and was generally well tolerated, with mostly mild to moderate treatment‑emergent adverse events and no treatment‑related serious events or suicidal behavior reported.

Positive

• Compelling Phase 2 efficacy signals for GH001 across treatment-resistant depression, postpartum depression, and bipolar II depression, including a Day 8 LS mean MADRS advantage of 15.5 points vs placebo and over 70% remission at 6 months in TRD open-label completers.
• Rapid onset and functional benefits with all 10 postpartum depression patients in remission by Day 8, a 35.4-point mean MADRS reduction, and a 34.1-point improvement in maternal functioning scores.
• Generally favorable safety profile with mostly mild to moderate treatment-emergent adverse events, no treatment-related serious adverse events, no suicidal intent or behavior, and brief psychoactive effects with quick discharge readiness.

Negative

• None.

Insights

Biotech clinical-trials analyst

GH001 shows strong Phase 2 signals in hard-to-treat depression with manageable safety.

The disclosed data position GH001, an inhaled synthetic mebufotenin, as a potentially differentiated rapid-acting antidepressant. In treatment-resistant depression, the Phase 2b double-blind trial met its primary endpoint with a least-squares mean MADRS improvement 15.5 points greater than placebo at Day 8 and a large effect size (Cohen’s d = −2.0). Response and remission were high (60.0% and 57.5% respectively at Day 8 versus 0% on placebo), and 73% of open-label extension completers remained in remission at approximately 6 months after a mean of four treatments.

The Phase 2a postpartum depression study (10 patients) reported that all participants were in remission at Day 8 with a mean MADRS reduction of 35.4 points and a 34.1‑point increase in the Barkin Index of Maternal Functioning. Breastmilk pharmacokinetic samples showed mebufotenin and its metabolites were rapidly eliminated, which may be relevant for breastfeeding patients. An anhedonia-focused analysis across TRD, PPD and bipolar II depression with a current major depressive episode found rapid, clinically meaningful reductions on the MADRS 5‑item anhedonia subscale that were maintained to Month 6 in TRD open-label completers.

Safety across the three trials was described as generally favorable: most treatment-emergent adverse events were mild or moderate, nausea and headache were the most common events, no treatment-related serious adverse events or suicidal intent/behavior were reported, and median psychoactive effects lasted 11 minutes in the TRD study with patients deemed discharge-ready by 1 hour at 99% of visits. These are still early-stage (Phase 2) datasets with small patient numbers in PPD and bipolar II cohorts, so future larger and possibly registration-enabling trials will be important to confirm robustness and generalizability of the effects.

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 6-K

REPORT OF FOREIGN PRIVATE ISSUER PURSUANT TO RULE 13a-16 OR 15d-16 UNDER THE SECURITIES EXCHANGE ACT OF 1934

For the month of January 2026.

Commission File Number: 001-40530

GH Research PLC

(Exact name of registrant as specified in its charter)

Joshua Dawson House

Dawson Street

Dublin 2

D02 RY95

Ireland

(Address of principal executive office)

Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F:

Form 20-F ☒ Form 40-F ☐

GH Research PLC (the “Company”) announces its participation in a Mini-Panel Session at the 64^th American College of Neuropsychopharmacology (ACNP) annual meeting (the “Congress”), where results related to its GH001-TRD-201, GH001-PPD-203 and GH001-BD-202 clinical trials will be discussed. The Congress is scheduled to take place from January 12-15, 2026, in Nassau, Bahamas.

The Mini-Panel Session will be chaired by Prof Michael E. Thase, featuring presentations by Lisa Harding, MD, Kristina M. Deligiannidis, MD, and Roger S. McIntyre, MD. A copy of the presentation for the Mini-Panel session is attached hereto as Exhibit 99.1.

The fact that this presentation is being made available should not be deemed an admission as to the materiality of any information contained in the material. The information contained in the presentation is being provided as of January 15, 2026, and the Company does not undertake any obligation to update the presentation in the future or to update forward-looking statements to reflect subsequent actual results.

1

EXHIBIT INDEX

99.1 Mini-Panel Session Presentation with Title: Exploring the Therapeutic Potential of Mebufotenin (GH001) Across Depressive Disorders

2

SIGNATURE

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.

	GH Research PLC
Date: January 15, 2026
	By:	/s/ Julie Ryan
	Name:	Julie Ryan
	Title:	Vice President, Finance

3

Exhibit 99.1

 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 µg p.o  LSD 100 µg p.o  LSD 75 µg 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. 2025;15(1):38874.  6 

 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   ΔMADRS  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–Åsberg 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–Åsberg 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–Åsberg 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–Åsberg 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–Åsberg 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–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 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–Åsberg 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 visits  

 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 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 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 following delivery1  PPD is associated with adverse effects on maternal well-being and mother-infant relationships that can negatively impact infant development2  Breastfeeding is associated with positive maternal and infant physical and mental health outcomes3,4; however, women with depressive disorders may be concerned about initiating pharmacotherapy while breastfeeding5  The potential antidepressant effects and safety of GH001, a synthetic form of mebufotenin for pulmonary inhalation, were investigated in a Phase 2a, single-arm, open-label trial in patients with PPD  21  Background  Abbreviations: MDE = Major depressive episode; PPD = Postpartum depression.  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013. 2. Field T. Infant Behav Dev. 2010;33(1):1-6. 3. Palancı Ay Ö and Aktaş S. Health Care Women Int. 2024;45(2):236-250. 4. Modak A, et al. Cureus. 2023;15(10):e46730. 5. Fitelson E, et al. Int J Womens Health. 2011;3:1-14. 

 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 ≥75 on the Peak Experience Scale) following the previous dose.   Abbreviations: BIMF = Barkin Index of Maternal Functioning; BL = Baseline; D = Day; H = Hour; IDR = Individualized dosing regimen; MADRS = Montgomery–Åsberg Depression Rating Scale; PK = Pharmacokinetics; PPD = Postpartum depression.   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  Day −60 to Day −2  Day 1  MADRS  PK  BIMF  Safety  Day −1  Screening  Pre-dosing day  Day 2  MADRS  PK  Safety  Single-day IDR  Patients with PPD  N=10  Dose 1  6 mg GH001  Dose 2a  12 mg GH001  Dose 3a  18 mg GH001  1-hour interval  1-hour interval  MADRS  PK  BIMF  Safety  Day 8  MADRS assessment  BL  2H  Primary endpoint   ΔMADRS  D2 

 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 depression. 

 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. 1979;134:382-9. 2. Barkin JL, et al. J Womens Health (Larchmt). 2010 Dec;19(12):2239-46.  MADRS1  Primary endpoint: change from baseline to Day 8 in MADRS total score  Total score range, 0−60  Higher scores indicate more severe depression  BIMF2  Patient-centered self-report of maternal functioning  Total score range, 0–120  Higher scores indicate better functioning  PK inBreastmilk  Concentrations were measured using LC-MS/MS in lactating patients:  Mebufotenin  Bufotenin (psychoactive metabolite)  5-MIAA (non-psychoactive terminal metabolite)  Safety  Adverse events were assessed throughout the trial 

 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 (SD)  31.6 (5.2)  Ethnicity, n (%)  Hispanic or Latino  1 (10.0)  Not Hispanic or Latino  9 (90.0)  Race, n (%)  White  9 (90.0)  Black or African American  1 (10.0)  Parity, mean (SD)  2 (1.0)  Baseline Disease Characteristics  Duration of current MDE, weeks, mean (SD)  30.9 (12.9)  MADRS total score, mean (SD)  36.7 (4.8)  BIMF total score, mean (SD)a  68.8 (15.6) 

 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 = Standard deviation.  At Day 8  All patients were in remission (MADRS total score ≤10)  ****P<0.0001 vs BL  BL  Primary endpoint  ****  2Ha  Day 2a  Day 8  ****  ****  −  −  −  −  −  −  −  −  − 

 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 = Montgomery–Åsberg Depression Rating Scale; PPD = Postpartum depression; SD = Standard deviation.  Remission (MADRS total score ≤10)  0  5  10  15  20  25  30  35  40  45  50  MADRS Total Score in Individual Patients  BL  2Hb  Day 2b  Day 8  At Day 8  Mean (SD) reduction from baseline: −35.4 (5.5); P<0.0001  Primary endpoint 

 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 with GH001  ***P<0.001 vs BL  ***  Improvement from baseline was observed in 6 of 7 BIMF domains on Day 8 

 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−BLQ)   BLQ (BLQ−BLQ)   BLQ (BLQ−BLQ)   BLQ (BLQ−BLQ)   5-MIAA, ng/mL (non-psychoactive)   Median (range)  BLQ (BLQ−BLQ)  15.4 (13.9−28.5)  12.8 (8.1−13.2)  0.4 (BLQ−0.9)  0.04 (0.03−0.2)  BLQ (BLQ−BLQ)   GH001 6+12 mg (n=3)  GH001 6+12+18 mg (n=1)  Pre-dose Day 1  1 h   post-dosea  2.5 h post-dosea  ~8 h post-dosea  Day 2  Day 8  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)   BLQ  1.5  0.3  BLQ  BLQ  BLQ  Bufotenin, ng/mL (psychoactive)   Median (range)  BLQ (BLQ−BLQ)  BLQ (BLQ−BLQ)   BLQ (BLQ−BLQ)   BLQ (BLQ−BLQ)   BLQ (BLQ−BLQ)   BLQ (BLQ−BLQ)   BLQ  BLQ  BLQ  BLQ  BLQ  BLQ  5-MIAA, ng/mL (non-psychoactive)   Median (range)  BLQ (BLQ−BLQ)  15.4 (13.9−28.5)  12.8 (8.1−13.2)  0.4 (BLQ−0.9)  0.04 (0.03−0.2)  BLQ (BLQ−BLQ)   BLQ  25.1  13.5  0.1  BLQ  BLQ  29  Mebufotenin and its Metabolites Were Rapidly Eliminated from Breastmilk  aTime after final dose on Day 1.   Abbreviations: 5-MIAA = 5-methoxyindole-3-acetic acid; BLQ = Below the limit of quantitation; H = Hour; IDR = Individualized dosing regimen.  Of the four lactating patients, three received GH001 6+12 mg and one received GH001 6+12+18 mg as part of the IDR 

 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  1 (10.0)  Dizziness  1 (10.0)  Dysgeusia  1 (10.0)  Tachycardia  1 (10.0)  Paresthesia  1 (10.0)  All patients were deemed ready for discharge within the same day of dosing  Abbreviation: TEAE = Treatment-emergent adverse event. 

 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 (bufotenin and 5-MIAA) were rapidly eliminated from breastmilk  GH001 was generally well tolerated in patients with PPD  Abbreviations: 5-MIAA = 5-methoxyindole-3-acetic acid; BIMF = Barkin Index of Maternal Functioning; IDR = Individualized dosing regimen; MADRS = Montgomery–Åsberg Depression Rating Scale; PPD = Postpartum depression. 

 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 

 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 of life,5 and functional impairment5  Improvement in anhedonia symptoms in patients with MDD has been correlated with improvements in physical, psychological, and social functioning and quality of life6,7  Safety and efficacy of GH001 were investigated in three patient populations:   One Phase 2b trial in patients with TRD  Two Phase 2a trials: one in patients with PPD and one in patients with BDII and a current MDE (BDII + MDE)  In each of the trials, GH001 has demonstrated a rapid onset of antidepressant effects and a favorable safety profile   This analysis examined the effect of treatment with GH001 on anhedonia in patients with TRD, PPD, or   BDII + MDE in these three trials  33  Background  Abbreviations: BDII = Bipolar II disorder; MDD = Major depressive disorder; MDE = Major depressive episode; PPD = Postpartum depression; TRD = Treatment-resistant depression.   1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013. 2. McIntyre RS, et al. World Psychiatry. 2023;22(3):394-412. 3. Gillies ES, et al. Psychiatr Res. 2023;158:209-215. 4. Ballard ED, et al. J Affect Disord. 2017;218:195-200. 5. Wong S, et al. J Affect Disord. 2024;356:684-698. 6. Cao B, et al. Front Psychiatry. 2019;10:17. 7. McIntyre RS, et al. J Affect Disord. 2024;363:430-435. 

 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 psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria.   Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg 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; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale.   Trial Schematics  34 

 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 psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria.   Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg 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; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale.   Trial Schematics  35 

 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 psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria.   Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg 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; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale.   Trial Schematics  36 

 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 psychotic features, current MDE confirmed by the MINI and validated based on the MGH-SAFER criteria interview; nonresponse to antidepressant treatments assessed using the MGH-ATRQ. cPer MINI diagnostic criteria. dPer DSM-5 diagnostic criteria.   Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; H = Hour; HAM-D-17 = 17-Item Hamilton Depression Rating Scale; IDR = Individualized dosing regimen; M = Month; MADRS = Montgomery–Åsberg 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; OLE = Open-label extension; PPD = Postpartum depression; R = Randomization; TRD = Treatment-resistant depression; YMRS = Young Mania Rating Scale.   Trial Schematics  37 

 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 Assessment  MADRS 5-item anhedonia subscale  Abbreviations: MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder.  1. Cao B, et al. Front Psychiatry. 2019;10:17. 2. McIntyre RS. J Affect Disord. 2024;363:430-435.  Item 1   Apparent sadness  Item 2   Reported sadness  Item 6   Concentration difficulties  Item 7   Lassitude  Item 8   Inability   to feel 

 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 = Standard deviation; TRD = Treatment-resistant depression.  TRD Trial  N=81  PPD Trial  N=10  BDII + MDE Trial  N=6  Baseline Demographics  Age, years, mean (SD)  42.8 (11.2)  31.6 (5.2)  44.2 (9.3)  Sex, female, n (%)  46 (56.8)  10 (100)  4 (66.7)  Race, n (%)  White  81 (100)  9 (90)  6 (100)  Black or African American  0  1 (10)  0  BMI, mean (SD), kg/m2  26.2 (5.5)  27.6 (6.6)  24.8 (5.0)  Baseline Disease Characteristics  MADRS total score, mean (SD)  28.6 (5.0)  36.7 (4.8)  32.0 (5.1)  Anhedonia subscale score, mean  17.5  20.8  19.2  CGI-S score, mean (SD)  4.9 (0.7)  4.8 (0.8)  5.0 (0.89)  Number of MDEs, mean (SD)  2.1 (1.3)  1.3 (1.3)  14.0 (12.4)  Duration of current MDE, weeks, mean (SD)  57.1 (78.4)  30.9 (12.9)  20.8 (22.7)  Disposition  Completed trial, n (%)  ‒  10 (100)  6 (100)  Double-blind part  81 (100)  ‒  ‒  OLE part  63 (77.8)  ‒  ‒ 

 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   Abbreviations: BL = Baseline; D = Day; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder; SD = Standard deviation; TRD = Treatment-resistant depression.   1. McIntyre RS. J Affect Disord. 2024;363:430-435.  Mean (±SD) Change from Baseline in MADRS Anhedonia Subscale Score  BL  D1  D2  D8  MADRS Anhedonia Subscale Score  MCIC for MADRS anhedonia subscale  MADRS Anhedonia Subscale Item Scores  Apparent  sadness  Reported  sadness  Concentration  difficulty  Lassitude  Inability   to feel  Mean (SD) Change from Baseline at Day 8  ****  ****P<0.0001 vs placebo  ****  ****  ****  ****  ****  ****  **** 

 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 disorder; OLE = Open-label extension; SD = Standard deviation; TRD = Treatment-resistant depression.   1. McIntyre RS. J Affect Disord. 2024;363:430-435.  In OLE completers (n=63), mean (SD) change from baseline in MADRS anhedonia subscale score  was −12.2 (4.9) at Month 6 (P<0.0001)  MADRS Anhedonia Subscale Item Scores  Among Patients Who Completed the TRD Study OLE (n=63), Clinically Meaningfula Improvement in MADRS Anhedonia Score Was Maintained at Month 6  Mean (SD) Change from Baseline at Month 6 in OLE Completers  Apparent  sadness  Reported  sadness  Concentration  difficulty  Lassitude  Inability   to feel  ****  ****  ****  ****  ****  ****P<0.0001 vs BL 

 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; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder; PPD = Postpartum depression; SD = Standard deviation.   1. McIntyre RS. J Affect Disord. 2024;363:430-435.  MADRS Anhedonia Subscale Score  MADRS Anhedonia Subscale Item Scores  BL  D1  D2  D8  Mean (SD) Change from Baseline at Day 8  ****P<0.0001 vs BL  ****  ****  ****  ****  ****  Mean (±SD) Change from Baseline in MADRS Anhedonia Subscale Score  MCIC for MADRS anhedonia subscale  ****  Apparent  sadness  Reported  sadness  Concentration  difficulty  Lassitude  Inability   to feel 

 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 anhedonia has been reported as an MCIC of –4.6 to –5.5 points based on an analysis of patients with MDD.1   Abbreviations: BDII = Bipolar II disorder; BL = Baseline; D = Day; MADRS = Montgomery–Åsberg Depression Rating Scale; MCIC = Minimal clinically important change; MDD = Major depressive disorder; MDE = Major depressive episode; SD = Standard deviation.   1. McIntyre RS. J Affect Disord. 2024;363:430-435.  Mean (SD) Change from Baseline at Day 8  MCIC for MADRS anhedonia subscale  *P<0.05 vs BL  *  *  *  *  *  *  43  Apparent  sadness  Reported  sadness  Concentration  difficulty  Lassitude  Inability   to feel 

 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 double-blind (17/40 [42.5%]) and OLE (37/81 [45.7%]) parts of the TRD trial; headache was the most common TEAE in the PPD (5/10 [50.0%]) and BDII + MDE (3/6 [50.0%]) trials; no TEAEs of of flashbacks were observed  No TEAEs of suicidal intent or suicidal behavior occurred in any of the trials  In the TRD trial, the median duration of psychoactive effects after GH001 administration was 11 minutes and patients were deemed discharge-ready by 1-hour post-dose at 99% of visits  aTEAEs were observed in 29/40 (72.5%) patients who received GH001 in the double-blind part of the TRD trial and 72/81 (88.9%) patients in the OLE, 8/10 (80.0%) in the PPD trial, and 5/6 (83.3%) in the BDII + MDE trial.  Abbreviations: BDII = Bipolar II disorder; MDE = Major depressive episode; OLE = Open-label extension; PPD = Postpartum depression; TEAE = Treatment-emergent adverse event; TRD = Treatment-resistant depression.  

 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, PPD, and BDII + MDE demonstrated rapid reductions in MADRS anhedonia subscale scores  Improvements in anhedonia subscale scores were clinically meaningful across each of the depressive disorders at Day 8 and were maintained at Month 6 in the OLE of the TRD trial  Mean reductions were observed in scores for all five items included in the anhedonia subscale  GH001 was generally well tolerated in patients with TRD, PPD, or BDII + MDE  These findings suggest that GH001 improves patients’ ability to feel pleasure and engage in activities and may improve overall functioning 

 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 provided by Brian Brennan, PhD, of GH Research, and Kathleen M. Dorries, PhD, of OPEN Health 

FAQ

What did GH Research PLC (GHRS) disclose about GH001 in treatment-resistant depression?

GH Research reported Phase 2b results showing that GH001 produced a least-squares mean reduction in MADRS depression scores that was 15.5 points greater than placebo at Day 8, with a Cohen’s d effect size of −2.0. At Day 8, 60.0% of GH001 patients met response criteria and 57.5% achieved remission versus 0% on placebo, and among open-label extension completers 73% were in remission at about 6 months.

How did GH001 perform in the postpartum depression (PPD) Phase 2a trial for GH Research (GHRS)?

In the 10‑patient open-label PPD trial, all patients were in remission (MADRS ≤10) by Day 8. The mean MADRS reduction from baseline was 35.4 points, and maternal functioning measured by the Barkin Index improved by a mean of 34.1 points, with improvement seen in most domains.

What evidence did GH Research provide on anhedonia improvements with GH001?

An analysis using the MADRS 5‑item anhedonia subscale showed rapid, clinically meaningful improvements in anhedonia scores in patients with treatment-resistant depression, postpartum depression, and bipolar II disorder with a current major depressive episode. In TRD open-label completers, mean change in anhedonia subscale score was −12.2 (SD 4.9) at Month 6, with P<0.0001 versus baseline.

What safety profile for GH001 was reported across the GH Research (GHRS) trials?

Across the TRD, PPD and bipolar II depression studies, treatment-emergent adverse events were mostly mild or moderate. Common events included nausea in the TRD trial and headache in the PPD and bipolar II trials. No treatment-related serious adverse events, no deaths, and no suicidal intent or suicidal behavior were reported. In the TRD trial, median psychoactive effects lasted 11 minutes and patients were discharge-ready by 1 hour at 99% of visits.

What did GH Research say about GH001 exposure in breastmilk for postpartum patients?

In lactating patients receiving GH001 in the PPD trial, mebufotenin and its metabolites bufotenin and 5‑MIAA were measured in breastmilk. The data showed rapid elimination, with mebufotenin and bufotenin often below the limit of quantitation at later time points and 5‑MIAA levels declining to near or below quantitation limits by Day 2 and Day 8.

Which depressive disorders is GH001 being developed for according to GH Research PLC?

GH001 is described as a synthetic form of mebufotenin (5‑MeO‑DMT) for pulmonary inhalation with target indications in treatment-resistant depression, postpartum depression, and bipolar II disorder with a current major depressive episode. Phase 2b is completed in TRD, and Phase 2a trials are completed in PPD and bipolar II depression.