PART I [Key Information](index=10&type=section&id=ITEM%203.%20KEY%20INFORMATION) This section details the significant risks associated with the company's business, financial position, and operations, highlighting its clinical-stage status, history of losses, funding needs, and uncertainties in clinical trials and regulatory approvals, particularly the clinical hold on GH001 IND by the FDA [Risk Factors](index=10&type=section&id=D.%20Risk%20Factors) This subsection provides a detailed summary of the principal risks facing the company, including financial losses, funding needs, the FDA clinical hold on GH001 IND, drug development uncertainty, controlled substance classification, reliance on third parties, intellectual property, and potential adverse U.S. tax consequences as a PFIC - The company is a clinical-stage biopharmaceutical firm with **significant losses**, expecting them to continue. Net losses were **$39.0 million in 2024** and **$35.6 million in 2023**, with an accumulated deficit of **$106.4 million** as of December 31, 2024[41](index=41&type=chunk) - The FDA has placed a **clinical hold on the study proposed in the IND for GH001**, requiring additional toxicology studies and device information, which presents a material risk to clinical development efforts in the U.S[39](index=39&type=chunk)[64](index=64&type=chunk) - The company's product candidates, **GH001 and GH002**, contain mebufotenin, a **Schedule I controlled substance** in the U.S. This classification requires a complex and uncertain rescheduling process by the DEA for commercialization, which could cause significant delays[39](index=39&type=chunk)[146](index=146&type=chunk)[148](index=148&type=chunk) - The company relies entirely on **third parties for the development and manufacturing** of its nonclinical and clinical trial supplies, including the active pharmaceutical ingredients and medical devices. Any failure by these third parties could significantly harm operations[41](index=41&type=chunk)[312](index=312&type=chunk) - The company believes it was a **Passive Foreign Investment Company (PFIC)** for the **2024 taxable year** and anticipates being a **PFIC in 2025**, which could result in **adverse U.S. federal income tax consequences for U.S. investors**[41](index=41&type=chunk)[365](index=365&type=chunk) [Information on the Company](index=94&type=section&id=ITEM%204.%20INFORMATION%20ON%20THE%20COMPANY) This section provides a comprehensive overview of GH Research PLC, a clinical-stage biopharmaceutical company focused on developing mebufotenin-based therapies for depression, detailing its history, business strategy, product pipeline, market opportunities, intellectual property, regulatory landscape, third-party manufacturing reliance, and organizational structure [History and Development of the Company](index=94&type=section&id=A.%20History%20and%20Development%20of%20the%20Company) **GH Research PLC** was incorporated in Ireland on March 29, 2021, as a holding company for **GH Research Ireland Limited**, which was founded in 2018, with its principal business in Dublin, Ireland, and primary expenditures since 2022 focused on research and development - **GH Research PLC** was incorporated in Ireland on March 29, 2021, to act as a holding company for **GH Research Ireland Limited**, which was originally incorporated on October 16, 2018[394](index=394&type=chunk) [Business Overview](index=94&type=section&id=B.%20Business%20Overview) The company focuses on developing proprietary mebufotenin therapies, **GH001** (inhalable) and **GH002** (intravenous), for **Treatment-Resistant Depression (TRD)** and other psychiatric disorders, with key clinical progress including the completion of a Phase 2b trial for **GH001** in **TRD** and ongoing development of a proprietary aerosol delivery device, despite a significant **FDA clinical hold** on the **GH001 IND** - The company's lead product candidate is **GH001, a proprietary inhalable mebufotenin therapy for TRD**. The double-blind phase of its Phase 2b trial (GH001-TRD-201) has been completed[397](index=397&type=chunk)[404](index=404&type=chunk) - The **FDA placed the GH001 IND on clinical hold** in September 2023, requesting additional toxicology studies and device information. The company completed the requested toxicology studies and plans to submit a complete response to the FDA in mid-2025[404](index=404&type=chunk)[492](index=492&type=chunk)[493](index=493&type=chunk) GH001-TRD-201 Phase 2b Double-Blind Efficacy Results (Day 8) | Metric | GH001 (N=40) | Placebo (N=41) | P-value | | :--- | :--- | :--- | :--- | | **MADRS Change from Baseline** | **-15.2 points** | **+0.3 points** | **<0.0001** | | Remission Rate (MADRS ≤ 10) | **52.5%** | **2.4%** | **<0.0001** | | Response Rate (MADRS ≥50% reduction) | **65.0%** | **2.4%** | **<0.0001** | - The company is also developing **GH002, an intravenous mebufotenin formulation**, and has completed a **Phase 1 trial** in healthy volunteers. It is exploring **GH001 for additional indications**, including **Bipolar II Disorder** and **Postpartum Depression**, with completed **Phase 2a trials** showing positive results[405](index=405&type=chunk)[455](index=455&type=chunk)[460](index=460&type=chunk) - The company relies on **Contract Development and Manufacturing Organizations (CDMOs)** for **API synthesis and product manufacturing** and is developing a proprietary delivery device for **GH001** with a CDMO[513](index=513&type=chunk) [Organizational Structure](index=138&type=section&id=C.%20Organizational%20Structure) As of December 31, 2024, **GH Research PLC** has **one subsidiary, GH Research Ireland Limited**, which is incorporated in Ireland and handles the company's clinical operations and research and development activities - The company has **one subsidiary, GH Research Ireland Limited**, which is **100% owned** and responsible for clinical operations and R&D[626](index=626&type=chunk)[627](index=627&type=chunk) [Property, Plants and Equipment](index=138&type=section&id=D.%20Property,%20Plants%20and%20Equipment) The company leases **two office facilities in Dublin, Ireland**, totaling **497 square meters**, which management believes are adequate for current and short-term needs - The company leases **two office spaces in Dublin, Ireland**: one of **106 square meters** and another of **391 square meters**[628](index=628&type=chunk) [Operating and Financial Review and Prospects](index=138&type=section&id=ITEM%205.%20OPERATING%20AND%20FINANCIAL%20REVIEW%20AND%20PROSPECTS) This section analyzes the company's financial condition and results of operations, noting its clinical-stage status with no revenue and significant losses, expecting increased expenses with advancing clinical trials, and confirming sufficient liquidity from equity financings for at least the next 12 months [Operating Results](index=138&type=section&id=A.%20Operating%20Results) The company reported a net loss of **$39.0 million in 2024**, an increase from **$35.6 million in 2023**, driven by a **$5.2 million** increase in R&D expenses to **$35.0 million in 2024** for **GH001** clinical development, and a **$3.9 million** increase in G&A expenses to **$15.3 million in 2024** due to higher professional fees and headcount, offset by net finance income and a foreign exchange gain Consolidated Results of Operations (in USD thousands) | | Year Ended December 31, | | | :--- | :--- | :--- | | | **2024** | **2023** | | Research and development | (35,016) | (29,821) | | General and administrative | (15,296) | (11,401) | | **Loss from operations** | **(50,312)** | **(41,222)** | | Net finance income | 9,222 | 8,256 | | Foreign exchange gain/(loss) | 2,129 | (2,621) | | **Loss for the year** | **(38,961)** | **(35,587)** | - R&D expenses increased by **$5.2 million** to **$35.0 million in 2024**, primarily due to increased clinical development activities for **GH001**, which saw its expenses rise by **$7.0 million**[654](index=654&type=chunk)[656](index=656&type=chunk) - General and administrative expenses rose by **$3.9 million** to **$15.3 million in 2024**, driven by higher external costs (professional fees) and increased employee expenses from a larger headcount[660](index=660&type=chunk) [Liquidity and Capital Resources](index=145&type=section&id=B.%20Liquidity%20and%20Capital%20Resources) The company has funded its operations primarily through equity financings, holding **$182.6 million** in cash, equivalents, and marketable securities as of December 31, 2024, which management believes is sufficient for at least the next 12 months, supplemented by an additional **$139.8 million** raised from a public offering in 2025 Cash and Liquidity Position (in USD millions) | | Dec 31, 2024 | Dec 31, 2023 | | :--- | :--- | :--- | | Cash, cash equivalents, other financial assets and marketable securities | $182.6 | $222.7 | Summary of Cash Flows (in USD thousands) | | Year Ended December 31, 2024 | Year Ended December 31, 2023 | | :--- | :--- | :--- | | Net cash used in operating activities | (42,285) | (33,336) | | Net cash from/(used in) investing activities | 65,135 | (54,100) | | Net cash used in financing activities | (304) | (204) | - The company believes its existing **cash and marketable securities will be sufficient to fund operating expenses and capital requirements for at least the next 12 months**[674](index=674&type=chunk) - In **2025**, the company received net cash proceeds of **$139.8 million** from a public offering of its ordinary shares[665](index=665&type=chunk)[997](index=997&type=chunk) [Directors, Senior Management and Employees](index=148&type=section&id=ITEM%206.%20DIRECTORS,%20SENIOR%20MANAGEMENT%20AND%20EMPLOYEES) This section details the company's leadership, compensation practices, and employee base, providing biographical information for executive officers and non-executive directors, outlining aggregate compensation, the Share Option Plan, employment agreements, Board composition, committee structures, and employee numbers [Directors and Senior Management](index=148&type=section&id=A.%20Directors%20and%20Senior%20Management) The company's leadership includes **Velichka Valcheva** as **Chief Executive Officer since September 2024** and **Florian Schönharting** as **Chairman of the Board of Directors**, with an executive team comprising a Managing Director, VP of Finance, and COO, and a four-member Board of Directors - **Velichka Valcheva** has served as **Chief Executive Officer since September 2024**, having previously been Chief Medical Officer[682](index=682&type=chunk) - **Florian Schönharting**, a co-founder, serves as the **Chairman of the Board of Directors**[686](index=686&type=chunk) [Compensation](index=150&type=section&id=B.%20Compensation) For the year ended December 31, 2024, the total compensation for directors and executive officers was **$3.4 million**, with options for **1,043,120 ordinary shares** granted to this group, and the Share Option Plan amended to increase available shares to **2,202,704 ordinary shares**, alongside employment agreements with key executives - Aggregate compensation paid to directors and executive officers for the year ended December 31, 2024, was **$3.4 million**[690](index=690&type=chunk) - In 2024, options to purchase an aggregate of **1,043,120 ordinary shares** were granted to directors and executive officers under the Share Option Plan[691](index=691&type=chunk) - The Share Option Plan was amended in 2024 to increase the number of shares available for grants by **999,970**, bringing the total issuable under the plan to **2,202,704 ordinary shares**[693](index=693&type=chunk)[696](index=696&type=chunk) [Board Practices](index=152&type=section&id=C.%20Board%20Practices) The Board of Directors has **four members**, **three of whom are independent**: **Michael Forer, Dermot Hanley, and Duncan Moore**, with a one-year term for each director, and has established an **Audit Committee, a Nominating and Corporate Governance Committee, and a Remuneration Committee**, following Irish home country governance practices as a foreign private issuer - The Board of Directors has **four members**, **three of whom are independent**: **Michael Forer, Dermot Hanley, and Duncan Moore**[705](index=705&type=chunk) - The Board has established an **Audit Committee, a Nominating and Corporate Governance Committee, and a Remuneration Committee**[708](index=708&type=chunk) - The Audit Committee consists of **Dermot Hanley (Chair), Michael Forer, and Duncan Moore**, all of whom are independent and considered '**audit committee financial experts**'[709](index=709&type=chunk) [Employees](index=154&type=section&id=D.%20Employees) As of December 31, 2024, the company had **50 employees**, with **34 dedicated to research and development activities**, and the remainder providing administrative, business, and operational support, with no employees represented by labor unions and good employee relations - As of December 31, 2024, the company had **50 employees**, with **34 dedicated to research and development activities**[718](index=718&type=chunk) [Major Shareholders and Related Party Transactions](index=154&type=section&id=ITEM%207.%20MAJOR%20SHAREHOLDERS%20AND%20RELATED%20PARTY%20TRANSACTIONS) This section discloses the company's major shareholders and related party transactions, noting that as of February 15, 2025, executive officers, directors, and 5% holders beneficially owned approximately **77.3% of the company's ordinary shares**, with Chairman Florian Schönharting holding **23.9%**, and outlines the company's indemnification policy for directors and a **related person transaction policy requiring approval or ratification by the Board of Directors or a designated committee** - As of February 15, 2025, officers, directors, and 5% shareholders collectively held approximately **77.3% of the company's ordinary shares**[347](index=347&type=chunk) Principal Shareholders (as of Feb 15, 2025) | Shareholder | Percentage Ownership | | :--- | :--- | | Florian Schönharting (Chairman) | 23.9% | | BVF | 16.8% | | RA Capital | 10.8% | | Lynx1 Capital Management LP | 10.2% | | Theis Terwey | 10.0% | | RTW Investments LP | 5.4% | | All executive officers and directors as a group | 24.3% | - The company has adopted a **related person transaction policy requiring approval or ratification by the Board of Directors or a designated committee** for any such transactions[729](index=729&type=chunk) [Financial Information](index=156&type=section&id=ITEM%208.%20FINANCIAL%20INFORMATION) This section contains the company's consolidated financial statements, prepared in accordance with **IFRS Accounting Standards**, noting that the company has **never paid cash dividends and does not intend to in the foreseeable future**, retaining funds for business development, with any future dividends subject to **Irish law regarding distributable reserves** - The company's financial statements are prepared in accordance with **IFRS Accounting Standards**[731](index=731&type=chunk) - The company has **never paid cash dividends and does not intend to in the foreseeable future**, retaining funds for business development. Any dividend payments would be subject to **Irish law regarding distributable reserves**[733](index=733&type=chunk)[734](index=734&type=chunk) - As of December 31, 2024, the company was **not a party to any material litigation**[732](index=732&type=chunk) [Additional Information](index=158&type=section&id=ITEM%2010.%20ADDITIONAL%20INFORMATION) This section covers supplementary details including material contracts, exchange controls, and taxation, noting generally no restrictions on capital movement in Ireland but highlighting the new **FDI Act** effective in **2025** that may impact acquisitions by non-EEA parties, and outlining potential U.S. federal income tax consequences for U.S. Holders, including the company's likely **PFIC** status, and Irish tax implications [Exchange Controls](index=158&type=section&id=D.%20Exchange%20Controls) There are currently no general restrictions on the export or import of capital in Ireland; however, the **Screening of Third Country Transactions Act 2023 (FDI Act)**, effective in **2025**, will require **prior approval for certain transactions** involving acquiring parties from **outside the EEA and Switzerland**, which could affect the ability of such parties to acquire the company's shares or assets - Ireland's **Screening of Third Country Transactions Act 2023 (FDI Act)**, effective in **2025**, will require **prior approval for certain transactions** involving acquiring parties from **outside the EEA and Switzerland**, potentially impacting acquisitions of the company's shares or assets[389](index=389&type=chunk)[747](index=747&type=chunk) [Taxation](index=159&type=section&id=E.%20Taxation) This subsection details the material U.S. and Irish tax consequences for shareholders, with a key issue for U.S. Holders being the company's likely classification as a **Passive Foreign Investment Company (PFIC)** for **2024 taxable year** and **PFIC in 2025**, potentially leading to **adverse U.S. federal income tax consequences for U.S. Holders**, and Irish tax implications including a **1% Irish stamp duty** on share transfers outside of DTC and a **25% Irish dividend withholding tax (DWT)** - The company believes it was a **Passive Foreign Investment Company (PFIC)** for its **2024 taxable year** and anticipates being a **PFIC in 2025**, which could result in **adverse U.S. federal income tax consequences for U.S. Holders**[755](index=755&type=chunk) - The company will endeavor to provide the necessary information for U.S. Holders to make a **Qualified Electing Fund (QEF) election** for the **2024 taxable year** to mitigate adverse PFIC tax consequences[762](index=762&type=chunk) - Transfers of ordinary shares outside of the DTC system may be subject to a **1% Irish stamp duty**, payable by the transferee[780](index=780&type=chunk)[782](index=782&type=chunk) - Dividends paid by the company would be subject to a **25% Irish dividend withholding tax (DWT)**, although exemptions are available for shareholders resident in the U.S. and other treaty countries who provide the necessary documentation[782](index=782&type=chunk)[785](index=785&type=chunk) [Quantitative and Qualitative Disclosures About Market Risk](index=167&type=section&id=ITEM%2011.%20QUANTITATIVE%20AND%20QUALITATIVE%20DISCLOSURES%20ABOUT%20MARKET%20RISK) The company is exposed to several market risks, primarily **foreign exchange risk**, **credit risk**, and **interest rate risk**, with a **10% weakening/strengthening of the USD against the EUR** impacting pre-tax loss by **$2.3 million higher/lower loss before tax for 2024**, and a **50 basis point increase/decrease in interest rates** impacting comprehensive loss by **$0.3 million higher/lower total comprehensive loss for 2024** - The company is exposed to **foreign exchange risk**, primarily between the U.S. dollar and the euro. A **10% weakening/strengthening of the USD against the EUR** would have resulted in a **$2.3 million higher/lower loss before tax for 2024**[801](index=801&type=chunk)[804](index=804&type=chunk) - **Credit risk is managed by holding cash at banks with a minimum S&P rating of A-** and investing in investment-grade bonds and money market funds[805](index=805&type=chunk)[971](index=971&type=chunk) - The company is exposed to **interest rate risk on its marketable securities**. A **50 basis point increase/decrease in interest rates** would have resulted in a **$0.3 million higher/lower total comprehensive loss for 2024**[807](index=807&type=chunk)[977](index=977&type=chunk) [Controls and Procedures](index=169&type=section&id=ITEM%2015.%20CONTROLS%20AND%20PROCEDURES) This section addresses the company's internal controls, with management concluding that **disclosure controls and procedures were effective as of December 31, 2024**, and **internal control over financial reporting was effective as of December 31, 2024**, based on the **COSO framework**, noting the remediation of previously identified material weaknesses and exemption from the **auditor attestation report on internal control over financial reporting** as an **emerging growth company** - Management concluded that the company's **disclosure controls and procedures were effective as of December 31, 2024**[816](index=816&type=chunk) - Management concluded that the company's **internal control over financial reporting was effective as of December 31, 2024**, based on the **COSO framework**[818](index=818&type=chunk)[819](index=819&type=chunk) - The company has **remediated the material weaknesses in internal control over financial reporting** that were previously identified in the fiscal year ended December 31, 2023. Remediation efforts included **hiring qualified professionals and implementing improved processes and IT controls**[822](index=822&type=chunk)[823](index=823&type=chunk) - As an **emerging growth company**, this annual report does not include an **auditor attestation report on internal control over financial reporting**[820](index=820&type=chunk) [Corporate Governance and Other Matters](index=170&type=section&id=ITEM%2016.%20%5BRESERVED%5D) This section covers various governance topics, including the Board's determination that **Dermot Hanley, Michael Forer, and Duncan Moore are 'audit committee financial experts' and independent**, the adoption of a **Code of Business Conduct and Ethics**, the company's adherence to **Irish corporate governance practices instead of certain Nasdaq rules** as a **foreign private issuer**, and the establishment of an insider trading policy and a **cybersecurity risk management program overseen by management and the audit committee** - The Board has determined that **Dermot Hanley, Michael Forer, and Duncan Moore are 'audit committee financial experts' and independent**[824](index=824&type=chunk) - The company has adopted a **Code of Business Conduct and Ethics** applicable to all employees, officers, and directors[825](index=825&type=chunk) - As a **foreign private issuer**, the company follows **Irish corporate governance practices instead of certain Nasdaq rules**, including those for director nominations, compensation committee composition, and shareholder approval for certain equity issuances[833](index=833&type=chunk)[844](index=844&type=chunk) - The company has a **cybersecurity risk management program overseen by management and the audit committee**, utilizing a **third-party IT service provider** for implementation and monitoring[840](index=840&type=chunk)[841](index=841&type=chunk)[842](index=842&type=chunk)[843](index=843&type=chunk) PART III [Financial Statements](index=174&type=section&id=ITEM%2018.%20FINANCIAL%20STATEMENTS) This section presents the company's audited consolidated financial statements for the three years ended December 31, 2024, prepared in conformity with **IFRS Accounting Standards**, including the report of the independent registered public accounting firm, PricewaterhouseCoopers, and the consolidated statements of comprehensive loss, financial position, changes in equity, and cash flows, along with detailed notes Consolidated Statement of Comprehensive Loss (in USD thousands) | | 2024 | 2023 | 2022 | | :--- | :--- | :--- | :--- | | Research and development | (35,016) | (29,821) | (20,484) | | General and administrative | (15,296) | (11,401) | (10,070) | | **Loss from operations** | **(50,312)** | **(41,222)** | **(30,554)** | | **Loss for the year** | **(38,961)** | **(35,587)** | **(22,456)** | | **Total comprehensive loss for the year** | **(41,188)** | **(33,154)** | **(29,030)** | Consolidated Statement of Financial Position (in USD thousands) | | Dec 31, 2024 | Dec 31, 2023 | | :--- | :--- | :--- | | **Total assets** | **188,273** | **226,300** | | Cash and cash equivalents | 100,791 | 78,420 | | Marketable securities | 62,446 | 88,667 | | **Total liabilities** | **9,322** | **7,332** | | **Total equity** | **178,951** | **218,968** | - The company's basic and diluted loss per share was **($0.75) for 2024**, compared to **($0.68) in 2023** and **($0.43) in 2022**[996](index=996&type=chunk) - The company has **not recognized any deferred tax assets** for its unused tax losses of **$102.8 million** as of December 31, 2024, due to uncertainty about generating sufficient future taxable profits[936](index=936&type=chunk)

[GH Research Full Year 2024 Financial Results and Business Updates](index=1&type=section&id=GH%20Research%20Full%20Year%202024%20Financial%20Results%20and%20Business%20Updates) [Business Updates](index=1&type=section&id=Business%20Updates) The company reports positive clinical trial results for GH001 across multiple depression indications and is addressing an FDA clinical hold [GH001 in Patients with Treatment-Resistant Depression (TRD)](index=1&type=section&id=GH001%20in%20Patients%20with%20Treatment-Resistant%20Depression%20%28TRD%29) - The Phase 2b trial for TRD met its primary endpoint, showing a **significant placebo-adjusted reduction of -15.5 on the MADRS** on Day 8[3](index=3&type=chunk)[4](index=4&type=chunk) - A **high remission rate of 57.5%** was observed in patients treated with GH001 by Day 8, compared to 0% in the placebo group[4](index=4&type=chunk) - In the ongoing open-label extension, **77.8% of completers were in remission at the 6-month visit**, with completion expected in Q1 2025[5](index=5&type=chunk)[6](index=6&type=chunk)[7](index=7&type=chunk) - GH001 was **well tolerated** during the double-blind part of the trial, with no serious adverse events reported[4](index=4&type=chunk) [GH001 Administered with Proprietary Aerosol Delivery Device](index=2&type=section&id=GH001%20Administered%20with%20Proprietary%20Aerosol%20Delivery%20Device) - A Phase 1 trial is ongoing to evaluate a **proprietary aerosol delivery device** for GH001 administration in healthy volunteers[7](index=7&type=chunk)[8](index=8&type=chunk) - This trial aims to bridge clinical data from the previous device to support the global program for GH001[8](index=8&type=chunk) [Update on IND for GH001](index=2&type=section&id=Update%20on%20IND%20for%20GH001) - The IND for GH001 remains on **clinical hold by the FDA** pending additional toxicology and device information[9](index=9&type=chunk) - The company has completed the requested additional inhalation toxicology studies, with findings supporting the company's position[10](index=10&type=chunk)[11](index=11&type=chunk) - A **full response to the IND hold is on track for submission to the FDA in mid-2025**[7](index=7&type=chunk)[12](index=12&type=chunk) [Proof-of-Concept (POC) Trials with GH001](index=2&type=section&id=Proof-of-Concept%20%28POC%29%20Trials%20with%20GH001) - The Phase 2a POC trial in postpartum depression (PPD) met its primary endpoint, with **100% of patients achieving remission** on Day 8[13](index=13&type=chunk)[14](index=14&type=chunk) - The Phase 2a POC trial in bipolar II disorder (BDII) also met its primary endpoint, with **33.3% of patients achieving remission** on Day 8[15](index=15&type=chunk) - In both POC trials, GH001 was well tolerated with no treatment-related serious adverse events reported[14](index=14&type=chunk)[15](index=15&type=chunk) [Full Year 2024 Financial Highlights](index=3&type=section&id=Full%20Year%202024%20Financial%20Highlights) The company's cash position decreased while expenses and net loss increased, though a subsequent public offering bolstered cash reserves Financial Highlights | Financial Metric | Dec 31, 2024 | Dec 31, 2023 | Change | | :--- | :--- | :--- | :--- | | Cash, cash equivalents, other financial assets and marketable securities | $182.6 million | $222.7 million | -$40.1 million | | Research & Development Expenses | $35.0 million | $29.8 million | +$5.2 million | | General & Administrative Expenses | $15.3 million | $11.4 million | +$3.9 million | | Net Loss | $39.0 million | $35.6 million | +$3.4 million | | Loss Per Share | $0.75 | $0.68 | +$0.07 | - The increase in R&D expenses was primarily due to clinical development activities, while the rise in G&A expenses was driven by higher professional fees and increased headcount[18](index=18&type=chunk)[19](index=19&type=chunk) - The company received an **additional $139.8 million in net cash proceeds** from a public offering in February 2025[7](index=7&type=chunk) [About the Company and Products](index=3&type=section&id=About%20the%20Company%20and%20Products) GH Research is a clinical-stage biopharmaceutical company developing mebufotenin-based therapies for psychiatric and neurological disorders - GH Research is a clinical-stage biopharmaceutical company focused on novel mebufotenin therapies, initially for **Treatment-Resistant Depression (TRD)**[21](index=21&type=chunk) - The lead product, **GH001**, is a proprietary inhalable mebufotenin with positive Phase 2b results for TRD treatment[22](index=22&type=chunk) - **GH002**, a secondary candidate formulated for intravenous mebufotenin administration, has completed a Phase 1 trial[23](index=23&type=chunk) [Consolidated Financial Statements](index=5&type=section&id=Consolidated%20Financial%20Statements) The company's financial statements show a widened net loss of $39.0 million for 2024 and total assets of $188.3 million [Consolidated Statement of Comprehensive Loss](index=5&type=section&id=Consolidated%20Statement%20of%20Comprehensive%20Loss) Statement of Comprehensive Loss | (in thousands, except per share amounts) | Year ended Dec 31, 2024 | Year ended Dec 31, 2023 | | :--- | :--- | :--- | | **Operating Expenses** | | | | Research and development | (35,016) | (29,821) | | General and administration | (15,296) | (11,401) | | **Loss from operations** | **(50,312)** | **(41,222)** | | Finance income | 9,873 | 8,978 | | Foreign exchange gain/(loss) | 2,129 | (2,621) | | **Loss for the year** | **(38,961)** | **(35,587)** | | **Total comprehensive loss for the year** | **(41,188)** | **(33,154)** | | **Basic and diluted loss per share (in USD)** | **(0.75)** | **(0.68)** | [Consolidated Balance Sheet](index=6&type=section&id=Consolidated%20Balance%20Sheet) Balance Sheet | (in thousands) | At Dec 31, 2024 | At Dec 31, 2023 | | :--- | :--- | :--- | | **ASSETS** | | | | Cash and cash equivalents | 100,791 | 78,420 | | Other financial assets & Marketable securities | 81,833 | 144,282 | | **Total current assets** | **154,225** | **164,089** | | **Total assets** | **188,273** | **226,300** | | **LIABILITIES AND EQUITY** | | | | Total current liabilities | 8,953 | 6,701 | | **Total liabilities** | **9,322** | **7,332** | | **Total equity** | **178,951** | **218,968** | | **Total liabilities and equity** | **188,273** | **226,300** |

Core Insights - GH Research PLC reported financial results for the year ended December 31, 2024, and provided updates on its clinical programs and financial position [1] Business Updates - GH001, an inhalable mebufotenin product candidate, is in a Phase 2b trial for treatment-resistant depression (TRD) involving approximately 80 patients [2] - The trial met its primary endpoint with a significant placebo-adjusted reduction of -15.5 in the Montgomery-Åsberg Depression Rating Scale (MADRS) on Day 8 (p<0.0001) [3] - A 57.5% remission rate was observed in patients treated with GH001 on Day 8 compared to 0% in the placebo group (p<0.0001) [3] - Safety analysis for the ongoing open-label extension (OLE) has not been completed, but as of January 22, 2025, 77.8% of OLE completers were in remission at the 6-month visit [4] - The Phase 1 trial for the proprietary aerosol delivery device is ongoing in the UK [5] Regulatory Updates - The Investigational New Drug Application (IND) for GH001 was placed on clinical hold by the FDA, which requested additional inhalation toxicology studies and device design verification [6] - The company has completed the requested inhalation toxicology studies, showing no adverse findings in the respiratory tract of dogs [7][9] - A full response to the IND hold is on track for submission in mid-2025 [10] Clinical Trials - Two Phase 2a proof-of-concept trials for GH001 in postpartum depression (PPD) and bipolar II disorder (BDII) have been completed [11] - The PPD trial met its primary endpoint with a MADRS reduction of -35.4 points (96.3%) on Day 8, with 100% of patients in remission [12] - The BDII trial also met its primary endpoint with a MADRS reduction of -16.8 points (51.9%) on Day 8, with 33.3% of patients in remission [13] Financial Highlights - As of December 31, 2024, the company had cash, cash equivalents, and marketable securities totaling $182.6 million, down from $222.7 million in 2023 [14] - Research and development expenses increased to $35.0 million in 2024 from $29.8 million in 2023, primarily due to clinical development activities [15] - General and administrative expenses rose to $15.3 million in 2024 from $11.4 million in 2023, driven by higher professional fees and increased headcount [16] - The net loss for 2024 was $39.0 million, or $0.75 loss per share, compared to a net loss of $35.6 million, or $0.68 loss per share, in 2023 [17]

Core Viewpoint - GH Research PLC's shares have surged 54.8% following the announcement of positive results from a mid-stage study of its investigational inhalable mebufotenin product candidate, GH001, for treatment-resistant depression (TRD) [1] Group 1: Clinical Study Results - In the phase IIb TRD study, patients treated with GH001 experienced a significant 15.2-point reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score by Day 8, while the placebo group showed a slight increase of 0.3 points [2] - The remission rate for patients receiving GH001 was 57.5% on Day 8, compared to 0% in the placebo group, with a 91.7% remission rate at six months for those who achieved remission on Day 8 [3] - GH001 met all secondary endpoints in the phase IIb study with clinically and statistically significant improvements on Day 8 compared to placebo [4] Group 2: Treatment Implications - GH001 offers a rapid and substantial effect for TRD patients, who often find existing therapies ineffective, potentially revolutionizing clinical practice with infrequent, short clinic visits lasting just 1-3 hours [5] - The treatment was well tolerated, with no serious adverse events reported on Day 8, and all treatment-emergent adverse events were mild or moderate [6][8] Group 3: Ongoing Development - GH Research is also evaluating GH001 for bipolar II disorder and postpartum depression in separate mid-stage proof-of-concept studies, having met primary endpoints in both studies [9] - The company's second mebufotenin product candidate, GH002, is in early-stage development as an intravenous injection for psychiatric and neurological disorders [10]

Group 1 - GH Research PLC has announced a public offering of 10,000,000 ordinary shares at a price of $15.00 per share, aiming for total gross proceeds of approximately $150 million [1] - The offering is expected to close on February 6, 2025, subject to customary closing conditions [1] - GH Research PLC has granted underwriters a 30-day option to purchase an additional 1,500,000 ordinary shares at the public offering price [1] Group 2 - Cantor, Stifel, and RBC Capital Markets are acting as joint book-running managers for the offering, while Canaccord Genuity and Citizens JMP are co-lead managers [2] Group 3 - GH Research PLC is a clinical-stage biopharmaceutical company focused on developing treatments for depression, specifically targeting treatment-resistant depression (TRD) with its proprietary mebufotenin therapies [7]

Company Overview - GH Research PLC is a clinical-stage biopharmaceutical company focused on developing transformative treatments for depression, specifically targeting treatment-resistant depression (TRD) with its proprietary mebufotenin therapies [7]. Offering Details - GH Research PLC has announced a public offering of $150 million of ordinary shares in the United States, with an option for underwriters to purchase an additional $22.5 million of shares [1]. - The offering is subject to market conditions and other factors, with no assurance on the completion or terms of the offering [1]. Underwriters - The joint book-running managers for the offering are Cantor, Stifel, and RBC Capital Markets, with Canaccord Genuity and Citizens JMP acting as co-lead managers [2]. Regulatory Information - A registration statement for the securities was filed with the U.S. Securities and Exchange Commission (SEC) and declared effective on March 17, 2023 [3]. - The offering will be conducted through a prospectus supplement and an accompanying prospectus, which will be available free of charge on the SEC's website [3]. Investor Communication - The announcement specifies that it does not constitute an offer to sell or solicit an offer to buy securities in jurisdictions where such actions would be unlawful [4]. - In the EEA and the UK, the offering is directed only at qualified investors with professional experience in investment matters [5][6].

Summary of Conference Call on GH Research's Phase IIb Trial Results Company and Industry - **Company**: GH Research - **Industry**: Biotechnology, specifically focusing on treatments for treatment-resistant depression (TRD) Core Points and Arguments 1. **Trial Overview**: The Phase IIb trial involved a double-blind placebo-controlled design with an open-label extension to assess the safety and efficacy of GA001 in patients with treatment-resistant depression [1][3] 2. **Primary Endpoint**: The primary endpoint was the mean change in the Montgomery-Åsberg Depression Rating Scale (MADRS) between GA001 and placebo at day eight, showing a statistically significant reduction of -15.5 points for GA001 compared to placebo [13][39] 3. **Efficacy Timeline**: GA001 demonstrated ultra-rapid efficacy, with significant reductions in MADRS scores observed as early as two hours post-treatment [13][39] 4. **Remission Rates**: The remission rate for GA001 was reported at 57.5% on day eight, compared to 0% for placebo, indicating a strong clinical relevance of the treatment [15][21] 5. **Safety Profile**: GA001 was well tolerated, with no serious adverse events reported. Common mild to moderate treatment-emergent adverse events included nausea and headache [22][39] 6. **Open Label Extension Results**: In the ongoing open-label extension, 77.8% of patients were in remission at six months, with 81.5% being responders, indicating sustained efficacy over time [32][40] 7. **Dosing Regimen**: Patients received individualized dosing regimens, with the majority requiring two doses on the same day. The psychoactive effects lasted approximately 15 minutes [12][57] 8. **Comparison with Existing Treatments**: GA001 showed a significant advantage over existing treatments like Spravato, with fewer required treatment visits and higher remission rates [33][38] Additional Important Content 1. **Patient Characteristics**: The trial enrolled 40 patients in the GA001 arm and 41 in the placebo arm, with a mean baseline MADRS score of 29, indicating moderate to severe depression [10][11] 2. **Retreatment Criteria**: Patients were retreated based on severity of depression, with specific MADRS cutoffs guiding the decision [5][6] 3. **Quality of Life Measures**: GA001 led to a significant increase of 20.6 points on the Quality of Life Satisfaction and Enjoyment Questionnaire (QLSF), correlating with the reduction in MADRS scores [20][34] 4. **Regulatory Engagement**: The company is preparing to engage with the FDA to resolve a clinical hold and discuss the pivotal program for GA001 [48][51] 5. **Discharge Criteria**: Patients were assessed for sedation and dissociation before discharge, with 97.5% being ready within one hour post-treatment [23][78] 6. **Hallucination Reports**: Only one patient reported a brief visual hallucination during the psychoactive phase, indicating a low incidence of such effects [78] This summary encapsulates the key findings and discussions from the conference call regarding GH Research's Phase IIb trial results for GA001, highlighting its potential as a treatment for treatment-resistant depression.

Primary endpoint met, GH001 led to an ultra-rapid anti-depressant effect with a significant placebo-adjusted MADRS reduction from baseline of -15.5 on Day 8 (p<0.0001)The majority of the patients treated with GH001 achieved remission with a 57.5% remission rate on Day 8 compared with 0% in the placebo group (p<0.0001)All other secondary endpoints were met with clinically and statistically significant improvements on Day 8, compared with placeboDuring the double-blind part, GH001 was well tolerated and no se ...

Core Insights - GH Research PLC is a clinical-stage biopharmaceutical company focused on transforming the treatment of psychiatric and neurological disorders [3] - The company will host a conference call on February 3, 2025, to provide updates on the Phase 2b trial of GH001 for treatment-resistant depression (TRD) [1][2] Company Overview - GH Research PLC is dedicated to developing novel therapies for psychiatric and neurological disorders, with a primary focus on mebufotenin for TRD [3] - The lead product candidate, GH001, utilizes a proprietary inhalation method for administration [4] Clinical Trial Insights - In the completed Phase 1/2 trial (GH001-TRD-102), 87.5% of patients with TRD achieved ultra-rapid remission with the individualized single-day dosing regimen [4]

Primary endpoint met in phase 2a POC trial in postpartum depression with a MADRS reduction from baseline of –35.4 points (p<0.0001, n=10) and 100% of patients in remission at Day 8Primary endpoint met in phase 2a POC trial in bipolar II disorder with a current major depressive episode with a MADRS reduction from baseline of –16.8 points (p=0.0099, n=6) and 33% of patients in remission at Day 8In both trials, GH001 was well tolerated and no treatment-related serious adverse events were reportedInhalation tox ...