# EDGAR Filing Document

**Accession Number:** 0001855129
**File Stem:** 0001140361-25-038374
**Filing Date:** 2025-10
**Character Count:** 26612
**Document Hash:** e2f22eba8a6161a71ec67da3eacad3fd
**Contains OCR:** False
**Source Format:** 

## Filing Content

## Filing Summary
**0001140361-25-038374.hdr.sgml**: 20251017

**ACCESSION NUMBER**: 0001140361-25-038374

**CONFORMED SUBMISSION TYPE**: 6-K

**PUBLIC DOCUMENT COUNT**: 4

**CONFORMED PERIOD OF REPORT**: 20251017

**FILED AS OF DATE**: 20251017

**DATE AS OF CHANGE**: 20251017

**FILER**: 

**COMPANY DATA:**
- **COMPANY CONFORMED NAME:** GH Research PLC
- **CENTRAL INDEX KEY:** 0001855129
- **STANDARD INDUSTRIAL CLASSIFICATION:** PHARMACEUTICAL PREPARATIONS [2834]
- **ORGANIZATION NAME:** 03 Life Sciences
- **EIN:** 000000000
- **STATE OF INCORPORATION:** L2
- **FISCAL YEAR END:** 1231

**FILING VALUES:**
- **FORM TYPE:** 6-K
- **SEC ACT:** 1934 Act
- **SEC FILE NUMBER:** 001-40530
- **FILM NUMBER:** 251398893

**BUSINESS ADDRESS:**
- **STREET 1:** JOSHUA DAWSON HOUSE
- **STREET 2:** DAWSON STREET
- **CITY:** DUBLIN 2
- **STATE:** L2
- **ZIP:** D02 RY95
- **BUSINESS PHONE:** 353 1 437 8334

**MAIL ADDRESS:**
- **STREET 1:** JOSHUA DAWSON HOUSE
- **STREET 2:** DAWSON STREET
- **CITY:** DUBLIN 2
- **STATE:** L2
- **ZIP:** D02 RY95

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### 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 October 2025.

#### Commission File Number: 001-40530

#### <br>

## 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 <u> ☒ </u> <br> Form 40-F <u>☐ </u>

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GH Research PLC announces the acceptance of posters related to its GH001-TRD-201 clinical trial at the 64<sup>th</sup> American College of Neuropsychopharmacology (ACNP) annual meeting (the "**Congress**"), which is scheduled to take place from January 12-15, 2026, in Nassau, Bahamas.

A copy of the abstract for the poster to be presented by Sanjay J. Mathew during the Congress is attached hereto as Exhibit 99.1.

A copy of the abstract for the poster to be presented by Lisa Harding during the Congress is attached hereto as Exhibit 99.2.

A copy of the abstract for the poster to be presented by Andreas Reif during the Congress, is attached hereto as Exhibit 99.3.

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#### EXHIBIT INDEX

#### <br>

---

| | |
|:---|:---|
| [99.1](ef20057307_ex99-1.htm) | Abstract for poster to be presented by Sanjay J. Mathew with Title: Suicidal Ideation and Behavior in Patients With Treatment-Resistant Depression Treated With GH001 |
| [99.2](ef20057307_ex99-2.htm) | Abstract for poster to be presented by Lisa Harding with Title: Rapid Antidepressant Effects of Inhaled GH001 in Treatment-Resistant Depression: Results from a Phase 2b, Double-Blind, Randomized Controlled Trial with 6-Month Follow-Up |
| [99.3](ef20057307_ex99-3.htm) | Abstract for poster to be presented by Andreas Reif with Title: Efficacy and Safety of Inhaled Mebufotenin (GH001) in Patients with Bipolar II Disorder and a Current Major Depressive Episode: Results from a Phase 2a Clinical Trial |

---

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#### 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** | **GH Research PLC** |
| Date: October 17, 2025 |  |  |
|  | By: | /s/ Julie Ryan |
|  | Name: | Julie Ryan |
|  | Title: | Vice President, Finance |

---

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## Exhibit 99.1

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#### Exhibit 99.1<br>

#### Suicidal Ideation and Behavior in Patients With Treatment-Resistant Depression Treated With GH001
Sanjay J. Mathew<sup>1,\*</sup>, Bernhard T. Baune<sup>2,3,4</sup>, Narcís Cardoner<sup>5</sup>, Wiesław J. Cubała<sup>6</sup>, Kelly Doolin<sup>7</sup>, Rosa Maria Dueñas Herrero<sup>8</sup>, David Gregory<sup>7</sup>, Luboš Janů<sup>9</sup>, John R. Kelly<sup>10,11</sup>, Rachael MacIssac<sup>7</sup>, Shane J. McInerney<sup>12</sup>, Alexander Nawka<sup>13</sup>, Tomáš Páleníček<sup>14</sup>, Víctor Pérez Sola<sup>15,16,17,18</sup>, Andreas Reif<sup>19,20</sup>, Claire Sweeney<sup>7</sup>, Madhukar H. Trivedi<sup>21</sup>, Velichka Valcheva<sup>7</sup>, Eduard Vieta<sup>22</sup>, Michael E. Thase<sup>23,24</sup>

**\*Presenting author:** Sanjay J. Mathew, Department of Psychiatry and Behavioral Sciences, Texas A&M College of Medicine, Bryan, TX, USA

<sup>1</sup>Department of Psychiatry and Behavioral Sciences, Texas A&M University Naresh K. Vashisht College of Medicine, Bryan, TX, USA; <sup>2</sup>Department of Psychiatry, University of Münster, Münster, Germany; <sup>3</sup>Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia; <sup>4</sup>The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia; <sup>5</sup>Hospital Santa Creu i Sant Pau, Mental Health Research Group, Institut de Recerca Sant Pau, Universitat Autònoma de Barcelona, CIBERSAM, Barcelona, Spain; <sup>6</sup>Department of Psychiatry, Medical University of Gdańsk, Gdańsk, Poland; <sup>7</sup>GH Research, Dublin, Ireland; <sup>8</sup>Parc Sanitari Sant Joan de Deu Hospital de Dia de Numancia, Barcelona, Spain; <sup>9</sup>A-Shine SRO, Pilsen,Czechia; <sup>10</sup>Psychedelic Research Group: Trinity College Dublin and Tallaght University Hospital, Dublin, Ireland; <sup>11</sup>Department of Psychiatry, Tallaght University Hospital, Dublin, Ireland; <sup>12</sup>Department of Psychiatry, University Hospital Galway, Galway, Ireland; <sup>13</sup>Institut Neuropsychiatrické Péče, Praha, Czechia; <sup>14</sup>Psyon s.r.o., Prague, Czechia; <sup>15</sup>Mental Health Institute, Hospital del Mar, Barcelona, Spain; <sup>16</sup>Neurosciences Research Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain; <sup>17</sup>Department of Psychiatry and Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain; <sup>18</sup>Centre for Biomedical Research in Mental Health (CIBERSAM), Madrid, Spain; <sup>19</sup>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt – Goethe University, Frankfurt am Main, Germany; <sup>20</sup>Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; <sup>21</sup>Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA; <sup>22</sup>Hospital Clinic de Barcelona, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; <sup>23</sup>Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; <sup>24</sup>Corporal Michael J Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA

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#### Abstract
**Background:** Treatment-resistant depression (TRD) is associated with reduced quality of life, impairment in psychosocial function, and higher burden of treatment compared with treatment-responsive major depressive disorder. Patients with TRD also experience a disproportionately higher rate of suicide. Thus, there is a significant unmet need for safe and effective therapies for TRD that do not exacerbate suicidal intent. In a Phase 2b trial, GH001, a synthetic form of mebufotenin (5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) for pulmonary inhalation, was well tolerated and resulted in rapid and significant improvements in depressive symptoms. Here we describe the effects of GH001 on suicidal ideation and behavior in patients with TRD enrolled in the Phase 2b trial.

**Methods:** This trial (NCT05800860) included a 7-day, randomized, double-blind part (Part 1) and a 6-month open-label extension (OLE; Part 2). In Part 1, patients were randomized 1:1 to receive an individualized dosing regimen (IDR) of up to three escalating doses of GH001 (6, 12, and 18 mg) or placebo IDR on a single day with a 1-hour interval between doses. The criteria for administration of the second and third doses in the IDR were based on patients' subjectively reported psychoactive effects, and the safety and tolerability at the previous dose level(s), according to the trial physician's judgement. In Part 2, patients could receive up to five GH001 IDR re-treatments over 6 months as needed; criteria for re-treatment were based on Montgomery-Åsberg Depression Rating Scale (MADRS) score and safety and tolerability of the previous dose(s). Trial eligibility criteria excluded patients with suicidal ideation with intent (with items 4 or 5 on the Columbia-Suicide Severity Rating Scale [C-SSRS] endorsed) within the past year or at screening or baseline; those with suicidal behaviors or non-suicidal self-injury in the past year; and those with a clinical assessment of significant suicidal risk. C-SSRS scores were assessed at all visits during Parts 1 and 2 of the trial. The clinician-rated C-SSRS quantifies suicidal ideation and behavior through a semi-structured interview. In addition, MADRS item 10 provided further quantification of suicidal ideation at frequent timepoints throughout the trial. Results were analyzed descriptively.

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**Results:** Eighty-one patients enrolled in the trial; 40 were randomized to GH001 IDR and 41 to placebo IDR in Part 1, and all transitioned directly into Part 2. Mean (SD) patient age was 42.8 (11.2) years, and 56.8% of patients were female. The number of patients with historic and current suicidal ideation were represented evenly across the GH001 and placebo groups; at screening, 21 patients (GH001, n=10; placebo, n=11) reported a lifetime history of suicidal ideation and 19 patients (GH001, n=8; placebo, n=11) reported suicidal ideation during the 12 months before screening, and at baseline, 14 patients reported current suicidal ideation via C- SSRS assessment (GH001, n=7; placebo, n=7). During Part 1, at Day 8, suicidal ideation without intent was reported for four patients in the GH001 group (all of whom had reported it at baseline) and seven patients in the placebo group (5/7 reported suicidal ideation at baseline). In Part 2 of the trial, the numbers of patients reporting suicidal ideation at all timepoints assessed during the trial were lower than that at baseline. The median (range) MADRS item 10 score was 0.0 (0 to 4) at baseline and the same at 6 months; median change from baseline (range) was 0.0 (-3 to 2) at 6 months. Across both trial parts, there were no treatment-emergent events of self- harm or suicidal behavior or of suicidal ideation with intent during follow-up. There was one treatment-emergent adverse event (TEAE) of suicidal ideation during Part 2 that was assessed as moderate in intensity, not classified as serious, and possibly related to GH001; this event lasted for 6 hours before resolving spontaneously. This TEAE was not accompanied by any changes in C-SSRS classification beyond the duration for which the thoughts occurred, and the patient did not report any further TEAEs of suicidal ideation during the trial.

**Conclusion:** In this double-blind, placebo-controlled trial with a 6-month OLE in patients with TRD, GH001 was not associated with treatment-emergent events of suicidal ideation with intent or behavior. These findings indicate that GH001 could potentially provide significant reductions in depressive symptoms without increasing the risk of suicide in patients with TRD.

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## Exhibit 99.2

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**Exhibit 99.2**<br>

#### Rapid Antidepressant Effects of Inhaled GH001 in Treatment-Resistant Depression: Results from a Phase 2b, Double-Blind, Randomized Controlled Trial with 6-Month Follow-Up
**Authors:** Lisa Harding<sup>1,2\*</sup>, Bernhard T. Baune<sup>3.4.5</sup>, Brian Brennan<sup>6</sup>, Narcís Cardoner<sup>7</sup>, Rosa Maria Dueñas Herrero<sup>8</sup>, David Gregory<sup>6</sup>, Luboš Janů<sup>9</sup>, John R. Kelly<sup>10,11</sup>, Shane J. McInerney<sup>12</sup>, Alexander Nawka<sup>13</sup>, Tomáš Páleníček<sup>14</sup>, Víctor Pérez Sola<sup>15,16,17,18</sup>, Andreas Reif<sup>19,20</sup>, Fiona Ryan<sup>6</sup>, Claire Sweeney<sup>6</sup>, Michael E. Thase<sup>21,22</sup>, Madhukar H. Trivedi<sup>23</sup>, Velichka Valcheva<sup>6</sup>, Eduard Vieta<sup>24</sup>, Wiesław J. Cubała<sup>25</sup>

**Affiliations:** <sup>1</sup>Mood Institute, Connecticut, USA. <sup>2</sup>Yale Department of Psychiatry, Yale University, Connecticut, USA. <sup>3</sup>Department of Psychiatry, University of Münster, Germany. <sup>4</sup>Department of Psychiatry, University of Melbourne, Australia. <sup>5</sup>The Florey Institute of Neuroscience and Mental Health, Parkville, Australia. <sup>6</sup>GH Research, Dublin, Ireland. <sup>7</sup>Hospital Santa Creu i Sant Pau, Mental Health Research Group, Institut de Recerca Sant Pau, Universitat Autònoma de Barcelona, CIBERSAM Barcelona, Spain. <sup>8</sup>Parc Sanitari Sant Joan de Deu Hospital de Dia de Numancia, Barcelona, Spain. <sup>9</sup>A-Shine SRO, Pilsen, Czechia. <sup>10</sup>Psychedelic Research Group: Trinity College Dublin and Tallaght University Hospital. <sup>11</sup>Department of Psychiatry, Tallaght University Hospital, Dublin, Ireland. <sup>12</sup>Department of Psychiatry, University of Galway, Galway, Ireland. <sup>13</sup>Institut Neuropsychiatrické Péče, Praha, Czechia. <sup>14</sup>Psyon s.r.o., Prague, Czechia. <sup>15</sup>Mental Health Institute, Hospital del Mar, Barcelona, Spain. <sup>16</sup>Neurosciences Research Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain. <sup>17</sup>Department of Psychiatry and Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain. <sup>18</sup>Centre for Biomedical Research in Mental Health (CIBERSAM), Madrid, Spain. <sup>19</sup>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt – Goethe University, Frankfurt am Main, Germany. <sup>20</sup>Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany. <sup>21</sup>Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA. <sup>22</sup>Corporal Michael J Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. <sup>23</sup>Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. <sup>24</sup>Hospital Clinic de Barcelona, Institute of Neuroscience, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain. <sup>25</sup>Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk.

**\*Presenting Au**t**hor:** Lisa Harding, Mood Institute, Connecticut, USA. Yale Department of Psychiatry, Yale University, Connecticut, USA.

Email: Lisa.Harding@depressionmd.com

**Background:** Treatment-resistant depression (TRD) represents a particularly challenging form of major depressive disorder (MDD), defined by an inadequate response to at least two antidepressants given at adequate dose and duration within the current depressive episode. TRD affects nearly one- third of individuals with MDD and is consistently linked to greater psychiatric and medical comorbidity, increased rates of hospitalization, elevated suicide risk, and a significantly reduced quality of life compared to non-resistant depression. There are currently only two pharmacotherapies approved for TRD in the United States (esketamine and olanzapine-fluoxetine combination) highlighting the significant unmet need for fast-acting, effective, and safe treatments. Mebufotenin (5-methoxy-N,N- dimethyltryptamine [5-MeO-DMT]) is a highly potent naturally occurring psychoactive substance from the tryptamine class which acts as a non-selective serotonin (5-HT) agonist with the highest affinity for the 5-HT<sub>1A</sub> receptor subtype. Evidence from early-phase trials suggest that GH001, a synthetic form of mebufotenin for pulmonary inhalation, is well tolerated in healthy volunteers and patients with TRD and may induce rapid improvements in depressive symptoms.

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**Methods:** This Phase 2b multicenter trial assessed the efficacy and safety of GH001 in patients with TRD (NCT05800860). Part 1 was a 7-day, randomized, double-blind, placebo-controlled part where patients were randomized in a 1:1 ratio to receive GH001 or placebo. Part 2 was a 6-month open-label extension (OLE) where up to five GH001 re-treatments were administered, based on the patients Montgomery–Åsberg Depression Rating Scale (MADRS) scores, and the safety and tolerability of the previous dose(s). On Day 8 of Part 1, all patients directly transitioned to Part 2. In both parts, GH001 (or placebo in Part 1) was administered as an individualized dosing regimen (IDR) of up to three escalating doses of GH001 (6, 12 and 18 mg, or placebo) administered on a single dosing day with a 1- hour interval between doses. The criteria for administration of the second and third doses in the IDR were based on the patient's subjectively reported psychoactive effects (PsE), and the safety and tolerability at the previous dose level, according to the trial physician's judgement. 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. Patients attended regular scheduled visits during the OLE. The primary endpoint of this trial was the mean change in MADRS from baseline to Day 8, assessed by an independent blinded rater. Patients aged 18-64 with a Hamilton Depression Rating Scale total score ≥20 at screening and baseline, and nonresponse (≤25% improvement) to ≥2 and ≤5 oral antidepressant treatments started during the current major depressive episode, were eligible to enroll in this trial.

**Results:** A total of 81 patients with TRD were enrolled in Part 1 with 40 patients randomized to GH001 and 41 randomized to placebo. Change in MADRS total score from baseline to Day 8 was significantly greater with GH001 versus placebo (least squares mean difference [standard error], -15.5 [1.7]; *P<*0.0001) with an effect size (Cohen's *d)* of -2.0. Statistically significant reductions were also observed in the GH001 group at 2 hours post-dose and on Day 2. On Day 8, remission (MADRS total score ≤10) was achieved in 57.5% of patients in the GH001 group versus 0% in the placebo group (*P*<0.0001). Of the 63 patients who completed Part 2, 73.0% (n=46) were in remission at 6 months and this was achieved with a mean of four treatments, with 63.5% (n=40) of patients requiring 1-4 treatments in 6 months. The median duration of PsE across all doses and treatment visits was 11 minutes. Inhalation of GH001 was well tolerated, and most adverse events (AEs) were mild or moderate with no treatment- related serious AEs (SAEs). One treatment-emergent SAE (preferred term migraine) occurred during the OLE and was deemed unrelated to treatment. Over the 6-month duration of the trial, lower rates of suicidal ideation compared to baseline were observed at each timepoint assessed with no treatment- emergent events of suicidal intent or suicidal behavior. At 99.0% (285/288) of treatment visits, patients were considered to be discharge ready at 1-hour post-dose on the dosing day.

#### Conclusion:
GH001 treatment was well tolerated and demonstrated rapid and significant improvements in depressive symptoms in patients with TRD. Data from Part 2 suggest that GH001 can maintain long-term remission in TRD, with 73.0% of patients who completed the OLE in remission at 6 months with infrequent retreatments. The brevity of the PsE, along with rapid symptomatic improvement, and favorable safety profile may align with patient and provider preferences and permit scalable clinical use. These results support the evaluation of GH001 in larger populations in Phase 3 trials.

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## Exhibit 99.3

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**Exhibit 99.3**<br>

**Efficacy and Safety of Inhaled Mebufotenin (GH001) in Patients with Bipolar II Disorder and a Current Major Depressive Episode: Results from a Phase 2a Clinical Trial**

Andreas Reif<sup>1,2</sup>, Michael Bauer<sup>3</sup>, Max de Leeuw<sup>4</sup>, Fabian Devlin<sup>5</sup>, Katerina Kriger<sup>6</sup>, Padraig O'Grady<sup>6</sup>, Philipp Ritter<sup>3,7</sup>, Claus Bo Svendsen<sup>6</sup>, Michael E Thase<sup>8,9</sup>, Velichka Valcheva<sup>6</sup>, Bernhard T Baune<sup>10,11,12</sup>

**\*Presenting author:** Andreas Reif, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt – Goethe University, Frankfurt am Main, Germany and Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, Germany. Email: <u>reif@med.uni-frankfurt.de</u>

<sup>1</sup>Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt – Goethe University, Frankfurt am Main, Germany; <sup>2</sup>Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, Germany; <sup>3</sup>Department of Psychiatry and Psychotherapy, Faculty of Medicine, University Hospital Carl Gustav Carus, Dresden, Germany; <sup>4</sup>Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands; <sup>5</sup>Mental Health Research for Innovation Centre, Mersey Care NHS Foundation Trust, United Kingdom; <sup>6</sup>GH Research, Dublin, Ireland; <sup>7</sup>Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom; <sup>8</sup>Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; <sup>9</sup>Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA; <sup>10</sup>Department of Psychiatry, University of Münster, Münster, Germany; <sup>11</sup>Department of Psychiatry, University of Melbourne, Melbourne, VIC, Australia; <sup>12</sup>The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia

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#### Abstract

#### Background

#### <br>
Bipolar II disorder (BDII) is a chronic psychiatric disorder marked by recurring episodes of hypomania and major depressive episodes (MDE), that places a significant burden on affected individuals. The lifetime prevalence of BDII is estimated to range between 0.4% and 5%. Current treatments for depressive symptoms in patients with BDII remain limited, offering insufficient efficacy and tolerability, highlighting the need for new therapeutic approaches. Mebufotenin (5- methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) is a rapid acting psychoactive molecule that acts as a non-selective serotonin agonist with highest affinity for the 5-HT1A receptor subtype. GH001, a synthetic form of mebufotenin for pulmonary inhalation, has been well tolerated in early-stage trials in healthy volunteers and patients with TRD, with a rapid reduction in the severity of depressive episodes. The present trial is the first to evaluate mebufotenin in patients with BDII experiencing a current MDE, focusing on the safety and antidepressant potential of GH001 in this population.

#### Methods:
This Phase 2a, proof-of-concept, open-label trial enrolled patients aged 18-64 years (inclusive) who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for BDII and a current MDE, and who had a Montgomery–Åsberg Depression Rating Scale (MADRS) score of ≥24 at pre-dose (NCT05839509). Patients were not permitted to receive any antidepressant medications (including selective serotonin reuptake inhibitor, serotonin and norepinephrine reuptake inhibitor, and tricyclic antidepressant) within 7 days or 5 half-lives, whichever was longer, prior to dosing. Lithium use within 6 months prior to dosing was not permitted, if applicable. GH001 was administered via inhalation as an individualized dosing regimen (IDR) of at least one and up to three escalating doses (6, 12, and 18 mg) on a single day (Day 1). The criteria for administration of the second and third doses were based on the patient's subjectively reported psychoactive effects (PsE), and the safety and tolerability at the previous dose level according to the trial physician's judgement. 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. The primary endpoint was the change in MADRS from baseline to Day 8. Other efficacy endpoints assessed included response (≥50% reduction from baseline in MADRS total score), remission (MADRS total score ≤10), Clinical Global Impression-Severity (CGI-S), and Bipolar Depression Rating Scale (BDRS). The safety and tolerability of GH001 were evaluated up to Day 8 in addition to manic symptoms assessed by the Young Mania Rating Scale.

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#### Results:
A total of six patients aged 32-57 with BDII and a current MDE were enrolled in this trial. Mean (SD) MADRS total score at baseline was 32.0 (5.1). The primary endpoint was achieved, with a significant reduction from baseline to Day 8 with a mean (SD) MADRS total score of -16.8 (11.1) which corresponds to a reduction of 52.5% (*P*=0.0099). Significant reductions in the mean (SD) MADRS total score were also observed at 2-hours post-dose (–16.3 [6.0; *P*<0.0006]) and on Day 2 (–13.3 [13.5; P<0.0299]). One-third (33.3%) of patients showed response to treatment on Day 8, with a remission rate of 33.3% at Day 8. The rapid reduction in depressive symptoms as assessed by the MADRS was mirrored in the CGI-S and the BDRS, with a mean (SD) reduction of –2.5 (1.5) on the CGI-S and –14.5 (11.2) on the BDRS observed from baseline and Day 8. Inhalation of GH001 was well tolerated and no treatment-related serious adverse events were reported. The majority of treatment-emergent adverse events were mild (83.3%) or moderate (11.1%) in severity, with the most commonly reported events being headache (50.0%), nausea (33.3%), and anxiety (33.3%), and all other events were only reported once. Following dosing with GH001, YMRS scores remained low and stable, decreasing from 2.2 at baseline to 1.0 by Day 8 (-1.2 [SD=1.5]), indicating no emergence of manic symptoms.

#### Conclusion:
In this trial, GH001 induced rapid and significant improvement in the symptoms of depression in patients with BDII and a current MDE and was well tolerated.

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