# EDGAR Filing Document

**Accession Number:** 0001855129
**File Stem:** 0001140361-26-011033
**Filing Date:** 2026-3
**Character Count:** 46598
**Document Hash:** 055f32a64d136bf58cb1a70d53d047ef
**Contains OCR:** False
**Source Format:** 

## Filing Content

## Filing Summary
**0001140361-26-011033.hdr.sgml**: 20260325

**ACCESSION NUMBER**: 0001140361-26-011033

**CONFORMED SUBMISSION TYPE**: 6-K

**PUBLIC DOCUMENT COUNT**: 6

**CONFORMED PERIOD OF REPORT**: 20260325

**FILED AS OF DATE**: 20260325

**DATE AS OF CHANGE**: 20260325

**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:** 26789331

**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 March, 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 <u> ☒ </u> Form 40-F  

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#### INFORMATION CONTAINED IN THIS REPORT ON FORM 6-K

On March 25, 2026, GH Research PLC (the "Company") announced the publication of results of its Phase 2b trial of mebufotenin (GH001) in treatment-resistant depression in JAMA Psychiatry. A copy of the press release is exhibited hereto as Exhibit 99.1.

The Company also announced the acceptance of a supporting manuscript for publication in Psychopharmacology Bulletin. A copy of the pre-print of the accepted manuscript is exhibited hereto as Exhibit 99.2.

The fact that this press release and pre-print of the accepted manuscript are being made available and furnished herewith should not be deemed an admission as to the materiality of any information contained in the materials. The information contained in the press release and pre-print of the accepted manuscript are being provided as of March 25, 2026, and the Company does not undertake any obligation to update the press release or pre-print of the accepted manuscript in the future or to update forward-looking statements to reflect subsequent actual results.

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#### EXHIBIT INDEX

---

| | |
|:---|:---|
| **Exhibit No.** | **Description** |
| [99.1](ef20068623_ex99-1.htm) | Press Release dated March 25, 2026 |
| [99.2](ef20068623_ex99-2.htm) | Manuscript with title: GH001 Efficacy is Independent of Prior Antidepressant Treatment Failures in Treatment-Resistant Depression: A Post Hoc Analysis of a Phase 2b Randomized Controlled 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: March 25, 2026 |  |  |
|  | 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
![](image00004.jpg)

#### GH Research Announces Publication of Phase 2b Results for Mebufotenin (GH001) in JAMA Psychiatry and Reports New Finding of Severity-Independent Efficacy in TRD
<br> • Phase 2b results for GH001 in TRD now published and peer-reviewed in *JAMA Psychiatry*

<br> • New peer-reviewed article in forthcoming issue of *Psychopharmacology Bulletin* demonstrates that GH001 efficacy is independent of prior antidepressant treatment failures<br>

Dublin, Ireland, March 25, 2026 (GLOBE NEWSWIRE) -- GH Research PLC (Nasdaq: GHRS), a clinical-stage biopharmaceutical company dedicated to transforming the lives of patients by developing a practice-changing treatment in depression, today announced two peer-reviewed publications from its Phase 2b clinical program of GH001 in treatment-resistant depression (TRD): the primary trial results in *JAMA Psychiatry*, and a new analysis demonstrating that efficacy is independent of the number of prior lifetime treatment failures in a forthcoming issue of *Psychopharmacology Bulletin*.

#### JAMA Psychiatry Publication
The peer-reviewed article, titled "GH001 vs Placebo in Patients with Treatment-Resistant Depression" has been published today in *JAMA Psychiatry* (DOI: 10.1001/jamapsychiatry.2026.0096). The publication includes the complete results from the randomized, double-blind, placebo-controlled Phase 2b trial of mebufotenin in patients with TRD, including all primary and secondary efficacy endpoints, safety and tolerability data, and initial results from the 6-month open-label extension. These results were previously reported in topline form.

*"Publication in* JAMA Psychiatry *provides independent peer-reviewed validation of our Phase 2b findings,"* said Dr. Velichka Valcheva, Chief Executive Officer. *"This supports our ongoing efforts to advance GH001 into global pivotal trials."*

#### New Finding: GH001 Efficacy Is Independent of Prior Treatment Failures
A supporting peer-reviewed article, titled "GH001 Efficacy is Independent of Prior Antidepressant Treatment Failures in Treatment-Resistant Depression: A Post Hoc Analysis of a Phase 2b Randomized Controlled Trial," will be published in a forthcoming issue of *Psychopharmacology Bulletin*.

In TRD, a well-established finding across multiple treatment modalities is that remission rates decline significantly with each successive antidepressant treatment failure. This pattern, first quantified in the landmark STAR\*D trial (see *About STAR\*D* below), represents a fundamental challenge in treating patients with extensive treatment histories. The new analysis of Phase 2b data demonstrates that GH001 does not follow this pattern:

------

![](image00004.jpg)

• Day 8 remission rates ranged from 53.9% to 63.6% across patients with 2 to ≥5 prior lifetime antidepressant failures, with no decline at higher failure counts;

• End of trial/Month 6 remission rates ranged from 61.5% to 85.7% across the same subgroups; and

<br> • No meaningful correlation was observed between the number of prior lifetime treatment failures and Montgomery-Åsberg Depression Rating Scale (MADRS) improvement at Day 8 (r=-0.13; P=0.44) or among those who completed the 6-month OLE (r=-0.10; P=0.60).

*"One interesting, unanticipated finding from this trial is that the benefit of GH001 appeared to be independent of the number of prior lifetime antidepressant failures. Remission rates were consistently high across subgroups – in contrast to the decline seen with each successive treatment that we observed in the STAR\*D trial. This suggests patients who have not responded to three or more prior courses of antidepressant therapy might benefit from this novel therapy,"* said Michael E. Thase, MD, Professor of Psychiatry, Perelman School of Medicine at the University of Pennsylvania.

Consistent with the findings of this article, GH001 efficacy is also independent from prior treatment failures within the current depressive episode in this Phase 2b trial.<br>

#### About GH Research PLC
GH Research PLC is a clinical-stage biopharmaceutical company dedicated to transforming the lives of patients by developing a practice-changing treatment in depression. GH Research PLC's initial focus is on developing its novel and proprietary mebufotenin therapies for the treatment of patients with TRD. Based on the observed clinical activity in our Phase 2b trial, where the primary endpoint was met with a MADRS reduction from baseline of -15.5 points compared with placebo on Day 8 (*P*<0.0001), we believe that our mebufotenin product candidates have the potential to change the way TRD is treated today.

#### About GH001
Our lead product candidate, GH001, is formulated for mebufotenin administration via a proprietary inhalation approach. Based on the observed clinical activity in our Phase 2b GH001-TRD-201 trial, where the primary endpoint was met with a MADRS reduction from baseline of -15.5 points compared with placebo on Day 8 (*P*<0.0001), we believe that GH001 has the potential to change the way TRD is treated today.

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![](image00004.jpg)

#### About STAR\*D
The Sequenced Treatment Alternatives to Relieve Depression (STAR\*D) trial was the largest and most comprehensive prospective study of depression treatment outcomes ever conducted. Funded by the National Institute of Mental Health (NIMH), the trial enrolled 4041 outpatients with major depressive disorder across 41 U.S. clinical sites between 2001 and 2004. The study used a sequential design in which patients who did not achieve remission on an initial antidepressant (citalopram) were moved through up to four successive treatment steps, each involving a switch to or augmentation with a different medication.

STAR\*D's central finding was that remission rates declined progressively with each treatment step: 36.8% achieved remission after the first course, 30.6% after the second, 13.7% after the third, and just 13.0% after the fourth (Rush et al., *American Journal of Psychiatry*, 2006). Cumulatively, after all four steps, approximately one-third of patients had still not achieved remission. This pattern of diminishing returns with increasing treatment resistance has been widely replicated and is now considered a defining characteristic of TRD.

&nbsp;&nbsp;&nbsp;&nbsp;<br>

#### Forward-Looking Statements
This press release contains statements that are, or may be deemed to be, forward-looking statements. All statements other than statements of historical fact included in this press release, including statements regarding our plans and expectations with respect to our global Phase 3 pivotal program for GH001, strategies and prospects for our business, including the development and therapeutic potential of mebufotenin and GH001, are forward-looking statements. Forward-looking statements appear in a number of places in this press release and include, but are not limited to, statements regarding our intent, belief or current expectations. Forward-looking statements are based on our management's beliefs and assumptions and on information currently available to our management. Such statements are subject to risks and uncertainties, and actual results may differ materially from those expressed or implied in the forward-looking statements due to various factors, including, but not limited to, those described in our filings with the U.S. Securities and Exchange Commission from time to time. No assurance can be given that such future results will be achieved. Such forward-looking statements contained in this press release speak only as of the date hereof. We expressly disclaim any obligation or undertaking to update these forward-looking statements contained in this press release to reflect any change in our expectations or any change in events, conditions, or circumstances on which such statements are based unless required to do so by applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.

#### Investor Relations
Julie Ryan

GH Research PLC

investors@ghres.com

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## Exhibit 99.2

#### Exhibit 99.2

#### GH001 Efficacy is Independent of Prior Antidepressant Treatment Failures in Treatment-Resistant Depression: A Post Hoc Analysis of a Phase 2b Randomized Controlled Trial

Michael E. Thase, MD<sup>1,2</sup>\*; Brian Brennan, PhD<sup>3</sup>; Rachael MacIsaac, PhD<sup>3</sup>; Luca Pani, MD<sup>4,5</sup>; Velichka Valcheva, MD<sup>3</sup>; Wiesław J. Cubała, MD, PhD<sup>6</sup>

<sup>1</sup>Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA. <sup>2</sup>Corporal Michael J Crescenz Veterans Affairs Medical Center, Philadelphia, PA, USA. <sup>3</sup>GH Research, Dublin, Ireland. <sup>4</sup>Miami University, Miami, USA. <sup>5</sup>University of Modena and Reggio Emilia, Modena, Italy. <sup>6</sup>Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.

**** 

<br> **\*Corresponding Author:** Michael E. Thase, MD, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Suite 670, Philadelphia, PA 19104-3309. Email: <u>thase@pennmedicine.upenn.edu</u>

**Short Title:** GH001 Efficacy is Independent of Prior Treatment Failures

**Word Count:** Abstract: 250/250 (not including subheadings); Body: 2468

**Tables/Figures:** 3 Tables, 2 Figures

**Keywords:** Treatment-Resistant Depression, Mebufotenin, GH001, 5-MeO-DMT, Prior Treatment Failures, STAR\*D

**Trial Registration:** <u>ClinicalTrials.gov NCT05800860</u>

#### <br>

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#### ABSTRACT

#### <br>
**Background:** Approximately 30% of patients treated for major depressive disorder develop treatment-resistant depression (TRD). The STAR\*D study demonstrated remission rates decline progressively with each antidepressant failure (37%, 31%, 14%, and 13%, respectively). A single-day individualized dosing regimen of GH001 (synthetic mebufotenin for inhalation) produced rapid, large improvements in depressive symptoms versus placebo in patients with TRD in a Phase 2b trial (least-squares mean difference, -15.5; effect size, -2.0; 57.5% remission at Day 8 versus 0% placebo). The current post hoc analysis examines whether GH001 efficacy varies by number of prior lifetime antidepressant treatment failures.

**** 

<br> **Methods:** This analysis included all 40 patients who received GH001 in the double-blind part of a Phase 2b trial. Spearman rank correlations between number of prior lifetime antidepressant failures and change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) scores were calculated at Day 8 and among 6-month open-label extension completers. Remission rates (MADRS ≤10) were examined by subgroup (2, 3, 4, or ≥5 prior lifetime failures).

**Results:** No meaningful correlation was observed between prior lifetime treatment failures and MADRS improvement at Day 8 (r=-0.13; *P*=0.44) or 6-month OLE completers (r=-0.10; *P*=0.60). Remission rates at Day 8 likewise were similar across subgroups (range, 53.9%–63.6%) and were maintained at end of treatment visit/Month 6 (range, 61.5%–85.7%). Secondary endpoints were not associated with treatment history.

**** 

<br> **Conclusions:** The efficacy of GH001 in patients with TRD appears largely independent of number of prior lifetime antidepressant treatments, and further research in patients with extensive treatment histories will be conducted in subsequent development stages.

**** 

<br> **Trial Registration:** <u>ClinicalTrials.gov NCT05800860</u>

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#### INTRODUCTION

#### <br>
Major depressive disorder (MDD) is a leading cause of disability, with a lifetime prevalence of approximately 20% in the United States.<sup>1</sup> Although many effective treatment strategies exist, remission remains elusive for a substantial proportion of patients. In the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR\*D) study, remission rates declined progressively with each successive antidepressant treatment failure within the same depressive episode: approximately 37% after the first adequate trial, 31% after the second, 14% after the third, and 13% after the fourth.<sup>2-4</sup> Even with 4 sequential treatment steps, the cumulative remission rate reached only 67%, leaving approximately one-third of patients without adequate symptom resolution.<sup>3</sup>

 <sup></sup> 

Treatment-resistant depression (TRD), most commonly defined as failure to benefit from at least 2 adequate antidepressant trials,<sup>5,6</sup> affects approximately 30% of patients treated for MDD.<sup>7</sup> TRD is associated with substantial morbidity, mortality, functional impairment, and economic burden, with health resource utilization and per-patient costs estimated at 2 to 3 times those of non-resistant depression.<sup>6-9</sup> Staging models for TRD have demonstrated that the number of prior treatment failures is the strongest negative prognostic factor, outweighing episode duration, baseline severity, and other chronicity markers.<sup>6,9,10</sup> In addition to within-episode nonresponse, lifetime antidepressant treatment burden is also a validated predictor of poor outcome in TRD and can serve as a pragmatic surrogate for overall illness chronicity and cumulative pharmacologic exposure. This progressive erosion of treatment response represents one of the most persistent clinical challenges in psychiatry which has not been overcome by any approved antidepressant therapies.

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GH001 is a synthetic formulation of mebufotenin (5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) for pulmonary inhalation being developed as a rapid-acting treatment for TRD. This Phase 2b (NCT05800860) randomized controlled trial, a single-day individualized dosing regimen (IDR) of GH001 produced rapid and significant improvements in depressive symptoms versus placebo in patients with TRD (least-squares mean difference in Montgomery-Åsberg Depression Rating Scale [MADRS] change, -15.5; effect size [Cohen's *d*], -2.0), with 57.5% of GH001-treated patients achieving remission at Day 8 compared with 0% of placebo-treated patients.<sup>11</sup> Given the relationship between prior treatment failures and diminished treatment response, this post hoc analysis examined whether GH001 efficacy varied as a function of the number of prior lifetime treatment failures. It was hypothesized that GH001 efficacy would not be attenuated by increasing number of prior lifetime treatment failures.

#### MATERIALS AND METHODS

#### <br>
***Study Design***: This is a post hoc analysis of the GH001-TRD-201 trial (NCT05800860), a Phase 2b, randomized, double-blind, placebo-controlled trial with a 6-month open-label extension (OLE). The trial was conducted in sites across Europe. Complete details of the trial design and primary results have been reported.<sup>11</sup>

 <sup></sup> 

The trial included a 7-day, double-blind, placebo-controlled part and a 6-month OLE part (Figure 1). In the double-blind part, 81 patients were randomized 1:1 to receive either GH001 IDR or placebo on a single day (Day 1). Following completion of the double-blind part, all patients from the GH001 and placebo groups were automatically enrolled in the 6-month OLE, during which they were eligible for up to 5 GH001 IDR treatments, administered based on MADRS score criteria (Figure 1), with the goals of achieving and maintaining remission.

******

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***Participants***: Eligible patients were adults aged 18–64 years who met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for MDD, confirmed by the Mini-International Neuropsychiatric Interview, with moderate-to-severe depressive symptoms (17-item Hamilton Depression Rating Scale [HAM-D-17] score ≥20 at screening) and nonresponse to 2–5 oral antidepressant treatments in the current major depressive episode (MDE), assessed using the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ). The current MDE was validated using the Massachusetts General Hospital-Structured Assessment for Evaluation of Risk (MGH-SAFER) criteria interview. Patients at significant suicidal risk were excluded.

******

<br> ***Interventions***: On Day 1, patients received an IDR of up to 3 escalating doses of GH001 (6, 12, and 18 mg) or a placebo IDR via pulmonary inhalation, with a 1-hour interval between doses. A 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 (defined as a mean score of ≥75 on the Peak Experience Scale) following the previous dose<sup>12</sup>. 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. Antidepressants, antipsychotics, and medications with monoamine oxidase inhibitor activity were prohibited during the trial and within 2 weeks prior to baseline; initiation or modification of psychotherapy was also prohibited.

******

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***Post Hoc Analysis Methods***: This analysis included all 40 patients who received GH001 in the double-blind part and had documented prior adequate antidepressant treatment-history, as assessed by the MGH-ATRQ; participants had 2–7 prior adequate lifetime antidepressant treatment lines. Spearman rank correlations between the number of prior lifetime treatment failures and change from baseline in MADRS total score were calculated at Day 8 (n=40) and among 31 patients who transitioned directly to the OLE and completed the 6-month phase. MADRS remission rates (total score ≤10) were calculated by prior treatment failure subgroup (2, 3, 4, or ≥5 prior failures) for all patients who received GH001 in the double-blind part (n=40) at Day 8 and at end of treatment visit/Month 6. Secondary analyses examined Spearman correlations between prior lifetime treatment failures and change from baseline in Clinical Global Impression-Severity (CGI-S), Hamilton Anxiety Rating Scale (HAM-A), and Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) at Day 8 and for patients who completed the 6-month OLE.

******

<br> ***Ethical Considerations***: The independent ethics committee for each trial site approved the protocol before patient enrollment. The trial was conducted per International Council for Harmonisation Good Clinical Practice guidelines and ethical principles derived from the Declaration of Helsinki. All patients provided written informed consent.

#### RESULTS

#### <br>
***Baseline Characteristics:*** Baseline demographic and clinical characteristics of the 40 GH001-treated patients included in this analysis are presented in Table 1. Patients had a mean (SD) of 3.7 (1.4) prior adequate lifetime antidepressant treatment lines (range, 2–7). Patients were distributed across treatment-history subgroups with similar representation: 7 patients (17.5%) had 2 prior failures, 13 (32.5%) had 3 prior failures, 8 (20.0%) had 4 prior failures, and 11 (27.5%) had 5 or more prior failures (one patient had incomplete baseline documentation of prior lifetime antidepressant treatment lines; however, all patients were required to have failed 2–5 adequate antidepressant treatments within the current MDE, as confirmed by the MGH-ATRQ). This patient was included in correlation analyses but excluded from subgroup displays).

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***MADRS Correlation Analysis:*** There was no meaningful correlation between the number of prior lifetime treatment failures and MADRS improvement at Day 8 (n=40; Spearman r=-0.13; 95% confidence interval [CI], -0.42 to 0.20; *P*=0.44) or among patients who completed the 6-month OLE (n=31; Spearman r=-0.10; 95% CI, -0.44 to 0.27; *P*=0.60) (Table 2). The negative direction of the correlations indicated, if anything, numerically greater improvement among patients with more prior failures, although this did not reach statistical significance.

******

<br> ***Remission by Prior Treatment Failure Subgroup:*** Day 8 MADRS remission rates were consistent across subgroups: 57.1% (n=4/7) with 2 prior failures, 53.9% (n=7/13) with 3 failures, 62.5% (n=5/8) with 4 failures, and 63.6% (n=7/11) with 5 or more failures (Figure 2).

Among patients who transitioned directly to the OLE, remission rates were maintained at the end of treatment visit/Month 6: 85.7% (n=6/7), 61.5% (n=8/13), 62.5% (n=5/8), and 63.6% (n=7/11) for 2, 3, 4, and 5 or more prior failures, respectively (Figure 2). Improvement in MADRS was sustained at end of treatment visit/Month 6 with infrequent treatments. Mean (SD) MADRS change from baseline was comparable across subgroups at all assessed timepoints (Table 3).

******

<br> ***Secondary Endpoint Analyses:*** The treatment-history independence observed for depressive symptoms (MADRS) was consistent across anxiety symptoms (HAM-A), global disease severity (CGI-S), and patient-reported quality of life (Q-LES-Q-SF). At Day 8, Spearman correlations between number of prior failures and change from baseline were nonsignificant for CGI-S (r=-0.20; *P*=0.22), HAM-A (r=-0.01; *P*=0.96), and Q-LES-Q-SF (r=0.12; *P*=0.46) (Table 2). At Month 6 for patients who completed the OLE, correlations were low and did not reach nominal statistical significance for all secondary endpoints: CGI-S (r=0.12; *P*=0.55), HAM-A (r=0.23; *P*=0.25), and Q-LES-Q-SF (r=-0.23; *P*=0.28).

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***Safety:*** The safety and tolerability profile of GH001 in the double-blind part of GH001-TRD-201 has been reported in detail.<sup>11</sup> Among the 40 patients who received GH001 in the double-blind part, treatment-emergent adverse events occurred in 29 (72.5%) patients. The most common events were nausea (42.5%), salivary hypersecretion (20.0%), and paraesthesia (20.0%). All adverse events were mild or moderate in severity. There were no serious adverse events, no severe adverse events, no deaths, and no discontinuations due to adverse events.

#### DISCUSSION

#### <br>
This post hoc analysis demonstrates that the efficacy of GH001 is independent of the number of prior lifetime treatment failures. Remission rates at Day 8 ranged from 53.9% to 63.6% across subgroups with 2 to 5 or more prior lifetime failures, with no evidence of the progressive attenuation that characterizes conventional antidepressant treatment. These findings were consistent across the MADRS and all other secondary endpoints (CGI-S, HAM-A, and Q-LES-Q-SF) and were maintained at last trial visit.

Staging models for TRD have identified the number of prior adequate treatment failures as one of the strongest predictor of future non-remitters.<sup>6,7,9,10</sup> The finding that patients with 5 or more prior failures achieved comparable remission rates to those with only 2 failures at Day 8 directly addresses potential concerns that the large effect size observed in the primary analysis (Cohen's *d*=-2.0) might have reflected enrollment of a less treatment-resistant population in this trial.

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These findings contrast with the progressive decline in remission rates observed across sequential antidepressant trials in STAR\*D (37% to 31% to 14% to 13%).<sup>3</sup> STAR\*D measured sequential within-episode treatment failures prospectively, whereas the current analysis examined lifetime prior adequate antidepressant treatment lines. However, all patients in the current analysis were also required to have failed 2–5 antidepressant treatments within their current MDE per trial eligibility criteria. As noted, lifetime treatment burden is a validated predictor in TRD,<sup>6,7,9,10</sup> making this comparison clinically informative. Indeed, lifetime treatment burden may represent a more stringent measure of pharmacological resistance, as it captures the full extent of prior exposure and potential for acquired treatment resistance.

While subgroups in this analysis were small (ranging from 7 to 13), the convergence of null findings across multiple outcome measures and 2 timepoints provides stronger evidence than any single correlation coefficient in isolation. The absence of a meaningful relationship between prior lifetime treatment failures and efficacy was observed consistently across MADRS, CGI-S, HAM-A, and Q-LES-Q-SF at both Day 8 and at last trial visit, a pattern of concordance that would be unlikely if a true underlying relationship existed.

Intranasal esketamine, the only currently approved rapid-acting antidepressant for TRD, has demonstrated modest pooled effect sizes (standardized mean difference, 0.36) across clinical trials when used adjunctively with oral antidepressants.<sup>13</sup> While esketamine clinical trials have included patients with varying degrees of treatment resistance, to date, limited evidence has addressed whether esketamine efficacy is independent of the number of prior treatment failures. To our knowledge, this is the first demonstration in a controlled trial of an investigational antidepressant achieving rapid and durable remission rates that appear independent of prior antidepressant treatment burden in patients with TRD.<sup>14</sup>

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The apparent independence of GH001 efficacy from prior lifetime treatment history is consistent with its known receptor binding activity. Acquired resistance to conventional antidepressants has been hypothesized to develop through changes in monoaminergic neurotransmission, including serotonin transporter upregulation and postsynaptic receptor desensitization.<sup>15</sup> GH001 is designed to engage a pharmacological pathway that is fundamentally distinct from conventional antidepressants. Its active moiety has been reported to exhibit approximately 300- to 1,000-fold higher binding affinity for the 5-HT<sub>1A</sub> receptor over the 5-HT<sub>2A</sub> receptor,<sup>16-18</sup> engaging predominantly 5-HT<sub>1A</sub>-mediated glutamatergic signaling and rapid neuroplasticity through a pathway that may not depend on the integrity of monoaminergic machinery.<sup>15,19</sup> Critically, however, the clinical expression of this pharmacology depends not only on receptor binding profile but also on formulation-specific pharmacokinetics. GH001's pulmonary delivery produces an ultra-rapid onset of psychoactive effects (within seconds) and an ultra-short duration of the psychoactive experience (median, 9.0 to 14.0 minutes for 6-, 12-,and 18-mg GH001 doses)<sup>11</sup>, generating a transient, high-amplitude pharmacodynamic pulse. This pharmacokinetic profile is unique to GH001's inhaled formulation and cannot be assumed for alternative delivery routes (e.g., intranasal, sublingual, or intramuscular administration), which produce different absorption kinetics, bioavailability, and receptor occupancy profiles that may yield different pharmacodynamic effects. The combination of 5-HT<sub>1A</sub>-predominant receptor engagement with this formulation-specific rapid pharmacokinetic pulse is fundamentally different from the prolonged receptor occupancy characteristic of psilocybin (4–6 hours) or ayahuasca-derived DMT (2–4 hours)<sup>18</sup>, and may contribute to how GH001 could bypass compromised monoaminergic pathways to achieve treatment-history-independent efficacy.

This analysis has several strengths. The parent trial was a rigorously designed, randomized, double-blind, placebo-controlled Phase 2b trial with prospective documentation of treatment-history using validated instruments (MGH-ATRQ and MGH-SAFER). The consistency of findings across multiple endpoints and timepoints strengthens confidence in the robustness of the observation.

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Several limitations warrant consideration. First, this was a post hoc analysis, and the study was not prospectively powered to detect differences across treatment-history subgroups; accordingly, the analysis cannot definitively exclude a modest relationship between prior lifetime treatment failures and efficacy. However, the convergence of null findings across 4 independent endpoints (MADRS, CGI-S, HAM-A, and Q-LES-Q-SF) at multiple timepoints provides a degree of internal replication that substantially reduces the probability that a clinically meaningful relationship was missed. Second, sample sizes within individual subgroups were modest, limiting the precision of subgroup-specific estimates, nevertheless, patients were reasonably distributed across treatment-history subgroups (ranging from 7 to 13 per subgroup), and the consistency of point estimates across all subgroups argues against a systematic trend obscured by limited power. Third, these data were drawn from a single Phase 2b trial, and replication in larger, independently powered studies is essential. Fourth, the OLE was open-label and lacked a placebo comparator, and Month 6 analyses of MADRS correlation were limited to completers, introducing potential selection bias; however, the retention rate was high, with 31 of 40 GH001-treated patients (77.5%) completing the 6-month follow-up, and the consistency between acute (Day 8, double-blind) and durable (Month 6) findings suggests that selection bias alone does not account for the observed treatment-history independence. Fifth, the current report examines only a single predictor variable, prior lifetime antidepressant treatment failures. A more comprehensive analysis of predictors including the full population of 81 patients who received their first active treatment with GH001 in the double-blind part (n=40) or the open-label extension (n=41), will be reported in a future communication. Lastly, the study population was recruited from European sites and all of the participants were White, which limits the generalizability of these findings; future studies should prioritize enrollment of racially and ethnically diverse populations.

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#### CONCLUSION

#### <br>
This post hoc analysis of the GH001-TRD-201 trial demonstrates that GH001 efficacy is independent of the number of prior lifetime treatment failures, a finding that contrasts the progressive attenuation of remission rates observed with conventional antidepressant therapies. Patients with 5 or more prior lifetime treatment failures achieved comparable remission rates to those with only 2 prior failures, both acutely (Day 8) and at end of treatment visit/Month 6. This treatment-history independence was consistent across primary and secondary efficacy endpoints. These findings support the potential of GH001 as a novel treatment for TRD, suggesting a therapeutic effect that is not attenuated by increasing prior treatment exposure.

#### ACKNOWLEDGMENTS

#### <br>
The authors thank the participants in the trial. The authors also thank the investigators and staff who were involved in the conduct of the trial and the members of the independent data monitoring committee.

**Funding:** This trial was funded by GH Research Ireland Limited, Dublin, Ireland.

**Role of the Funder/Sponsor:** This trial and manuscript were funded by GH Research Ireland Limited. Employees of GH Research Ireland Limited were involved in the study design, the collection and analysis of data, and the review of the manuscript. The authors of the manuscript were responsible for the decision to submit for publication.

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**Data Sharing Statement:** The data supporting the findings of this study are available from the sponsor upon reasonable request, subject to appropriate data sharing agreements.

#### Author Contributions

#### <br>
Drs. Cubała and Thase had full access to the data and take full responsibility for the integrity of the data and the accuracy of the data analysis.

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<br> **Concept and design:** Cubała, Valcheva, Thase.

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<br> **Acquisition, analysis, or interpretation of data:** Cubała, MacIsaac, Valcheva, Thase.

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<br> **Drafting of the manuscript:** Cubała, Brennan, MacIsaac, Pani, Valcheva, Thase.

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<br> **Critical review of the manuscript for important intellectual content:** Cubała, Brennan, MacIsaac, Pani, Valcheva, Thase.

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<br> **Statistical analysis:** MacIsaac, Valcheva.

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<br> **Administrative, technical, or material support:** Brennan, Valcheva.

#### Conflict of Interest Disclosure

#### <br>
**Michael E. Thase:** Editor-in-Chief, Psychopharmacology Bulletin. Dr. Thase will have no involvement in the editorial handling and decision-making for this manuscript; the submission will be managed by an independent editor per journal policy. 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.

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**Brian Brennan:** Employee and stock option holder of GH Research.

**Rachael MacIsaac:** Employee and stock option holder of GH Research.

**Luca Pani:** Consultant – AbbVie, USA; BCG, Switzerland; Boehringer Ingelheim International GmbH, Germany; GH Research, Ireland; Immunogen, USA; Johnson & Johnson USA; LB Pharmaceuticals, USA; Magdalena BioSciences, USA; Sanofi-Aventis-Genzyme, France and USA; Lundbeck, Denmark and Italy; Napo-Pharma, USA and EU; NetraMark, Canada; Pfizer Global, USA; Relmada Therapeutics, USA; Takeda, USA and owns shares/options from AiDvance Germany; Adapt UK, Enzeta USA, NetraMark Canada, and Relmada, USA.

**Velichka Valcheva:** Employee and stock option holder of GH Research.

**Wiesław J. Cubała:** Relationships reported within the last 3 years: Grants: Acadia, Angelini, Beckley Psytech, Compass Pathways, GH Research, HMNC Brain Health, IntraCellular Therapies, Janssen, MindMed, MSD, Neumora, Novartis, Otsuka, Recognify Life Sciences, Seaport. Honoraria: Angelini, GH Research, Janssen, Novartis. Advisory Boards: Douglas Pharmaceuticals, GH Research, Janssen, MSD, Novartis, Polpharma, Tasman Therapeutics.

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#### TABLES
**Table 1.** Baseline Demographic and Clinical Characteristics (GH001 Group, N=40)

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| | |
|:---|:---|
| **Characteristic** | **GH001 (N=40)** |
| Age, mean ± SD, years | 41.6 ± 11.4 |
| Female sex, n (%) | 24 (60.0) |
| Race, White, n (%) | 40 (100) |
| Body mass index, mean ± SD, kg/m² | 24.8 ± 4.3 |
| HAM-D-17 total score, mean ± SD | 24.9 ± 2.6 |
| MADRS total score, mean ± SD | 29.0 ± 5.4 |
| Number of MDEs, mean ± SD | 2.1 ± 1.4 |
| Duration of current MDE, mean ± SD, weeks | 50.8 ± 28.3 |
| Prior adequate lifetime antidepressant lines, mean ± SD | 3.65 ± 1.37 |
| Previously used any psychedelic (lifetime), n (%) | 4 (10.0) |

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Abbreviations: HAM-D-17 = 17-Item Hamilton Depression Rating Scale; MADRS = Montgomery-Åsberg Depression Rating Scale; MDE = Major Depressive Episode; SD = Standard Deviation.

**Table 2.** Spearman Rank Correlations Between Number of Prior Lifetime Treatment Failures and Change From Baseline in Efficacy Outcomes

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| | | | | |
|:---|:---|:---|:---|:---|
| **Outcome measure** | **N** | **Spearman r** | **95% CI** | ***P*-Value** |
| **Day 8 (Acute Phase)** |  |  |  |  |
| MADRS | 40 | -0.13 | -0.42 to 0.20 | 0.44 |
| CGI-S | 40 | -0.20 | -0.48 to 0.12 | 0.22 |
| HAM-A | 40 | -0.01 | -0.32 to 0.30 | 0.96 |
| Q-LES-Q-SF | 38 | 0.12 | -0.21 to 0.42 | 0.46 |
| **Month 6 (OLE Completers)** |  |  |  |  |
| MADRS | 31 | -0.10 | -0.44 to 0.27 | 0.60 |
| CGI-S | 28 | 0.12 | -0.27 to 0.47 | 0.55 |
| HAM-A | 28 | 0.23 | -0.16 to 0.55 | 0.25 |
| Q-LES-Q-SF | 24 | -0.23 | -0.58 to 0.19 | 0.28 |

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Abbreviations: CI = Confidence Interval; CGI-S = Clinical Global Impression-Severity; HAM-A = Hamilton Anxiety Rating Scale; MADRS = Montgomery-Åsberg Depression Rating Scale; OLE = Open-Label Extension; Q-LES-Q-SF = Quality of Life, Enjoyment, and Satisfaction Questionnaire-Short Form.

Negative r values indicate numerically greater improvement with more prior failures; all correlations nonsignificant at α=0.05.

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**Table 3.** Mean Change From Baseline in MADRS Total Score by Number of Prior Lifetime Treatment Failures

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| | | |
|:---|:---|:---|
| **Prior Failures** | **N** | **Mean (SD)** |
| **Day 8<sup>1</sup>** |  |  |
| 2 | 7 | -14.71 (10.58) |
| 3 | 13 | -14.00 (10.22) |
| 4 | 8 | -19.38 (10.49) |
| ≥5 | 11 | -14.73 (10.65) |
| **End of Treatment Visit/Month 6** |  |  |
| 2 | 7 | -20.29 (8.32) |
| 3 | 13 | -16.92 (7.91) |
| 4 | 8 | -16.88 (10.59) |
| ≥5 | 11 | -14.91 (9.87) |

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Abbreviations: MADRS = Montgomery-Åsberg Depression Rating Scale; OLE = Open-Label Extension; SD = Standard Deviation.

<sup>1</sup> One patient with incomplete baseline documentation of prior lifetime antidepressant treatment lines is excluded from subgroup displays but included in correlation analyses.

#### FIGURE LEGENDS
**Figure 1.** Trial Schematic

<sup>a</sup>The 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. <sup>b</sup>Patients 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.

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![](image0.jpg)

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<br> **Figure 2.** MADRS Remission Rates (MADRS Total Score ≤10) by Number of Prior Lifetime Treatment Failures at Day 8 and End of Treatment Visit/Month 6

Panel A: Day 8 remission rates show no attenuation with increasing prior treatment failures (range, 53.9%–63.6%). Panel B: End of Treatment Visit/Month 6 remission rates demonstrate maintained treatment-history independence (range, 61.5%–85.7%). Sample sizes by subgroup: 2 prior failures (n=7), 3 failures (n=13), 4 failures (n=8), ≥5 failures (n=11). Panel C: STAR\*D reference demonstrating progressive attenuation of remission rates with successive antidepressant trials (37% → 31% → 14% → 13%).

![](image1.jpg)

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