Company: GHRS
Filing Date: 2025-07-29
Form Type: 20-F/A
Source: 0001140361-25-027850
Chunk: 34

Company: GH Research PLC
Filing Date: 2025-07-29
Form: 20-F/A
Chunk 34
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 a lack of efficacy or emergence of unacceptable safety issues, notwithstanding promising results in earlier studies and trials. Also, a number of companies developing drug-device combination products, especially in the area of inhaled delivery of the drug component, have historically suffered significant setbacks due to technical, performance or manufacturing issues of the device component in their combination product. Most product candidates that commence clinical trials are never approved as products and there can be no assurance that any of our future clinical trials will ultimately be successful or support further clinical development of GH001, GH002 or any other product candidates. Product candidates that appear promising in the early phases of development may fail to reach the market for several reasons, including: 16 Table of Contents

| • | nonclinical studies or clinical trials may show the product candidates to be ineffective or less effective than expected (e.g., a clinical trial could fail to meet its primary endpoint(s)) or to have unacceptable side effects or 
 toxicities;                                                                                                                                                                                                                          |

| • | failure to reflect similarly efficacious activity in subsequent clinical trials with larger patient populations; |

| • | failure to use clinical endpoints that applicable regulatory authorities would consider clinically meaningful; |

| • | manufacturing issues or formulation issues with the product candidate or device that cannot be resolved; |

| • | failure to receive the necessary regulatory approvals; |

| • | manufacturing issues, formulation issues, pricing or reimbursement issues or other factors that make a product candidate or device uneconomical; and |

| • | intellectual property and proprietary rights of others and their competing products and technologies that may prevent one of our product candidates from being commercialized. |

In particular, our nonclinical studies or clinical trials may show that our product candidates have unacceptable side effects or toxicities. In this context, our completed inhalation toxicology studies in rats showed certain respiratory tract histology findings. While these findings did not affect approval of our ongoing clinical trials in Europe, they prompted the FDA to request additional nonclinical studies to be completedbefore the FDA will consider allowing us to initiate clinical studies in the United States. To date, we have assessed the intensity of psychoactive effect using a metric we devised, peak experience, or PE. We believe PE may correlate with clinical outcomes, but PE is a subjective metric, it can be inherently difficult to evaluate, and its psychometric validation has not yet been completed. It is uncertain if regulatory agencies will accept use of this metric to guide dosing in the context of the individualized dosing regimen, or IDR, in our pivotal program. In addition, differences in