Announcement PDF Appendix 4D Half Year Financial Report Name of entity: ACTINOGEN MEDICAL LIMITED ABN or equivalent company reference: 14 086 778 476 Current Period: 1 July 2024 to 31 December 2024 (Previous corresponding period: 1 July 2023 to 31 December 2023) RESULTS FOR ANNOUNCEMENT TO THE MARKET BRIEF EXPLANATION OF THE ABOVE FIGURES Revenues from ordinary activities relates to interest revenue from cash held in interest-bearing accounts and short-term deposits. The total net loss after tax decreased by 29%. The primary expenditure item was Research & Development. Refer to the attached Directors’ Report and financial statements for further information. Details of entities over which control has been gained or lost during the period Not applicable. There has been no entity over which control has been gained or lost during the period. Dividend / Distribution Payments or Reinvestment Plans Not applicable. No dividends have been paid or declared during the half year ended 31 December 2024, in the previous financial year ended 30 June 2024 or in the previous corresponding period. The Company does not propose to pay dividends in the immediate future. Associates / Joint Ventures Not applicable. The Company has not engaged in the acquisition of associates, nor has it engaged in any joint ventures in the half year ended 31 December 2024. Foreign Entities Not applicable. Review Conclusion This Report is based on the Interim Financial Report for the half year ended 31 December 2024. The financial report has been subject to a review by an independent auditor and the review is not subject to qualification. Authorised for release by the Board. Dr Steven Gourlay Managing Director 24 February 2025 Sydney, New South Wales 2025 Interim report Contents Operating & financial review 3 Directors’ report 11 Auditor’s independence declaration 12 Statement of comprehensive income 13 Statement of financial position 14 Statement of changes in equity 15 Statement of cash flows 16 Notes to the financial statements 17 Directors’ declaration 24 Independent auditor’s report 25 Corporate directory 27 Disclaimer This Interim Report may contain certain "forward-looking statements" that are not historical facts; are based on subjective estimates, assumptions and qualifications; and relate to circumstances and events that have not taken place and may not take place. Such forward looking statements should be considered “at-risk statements” - not to be relied upon as they are subject to known and unknown risks, uncertainties and other factors (such as significant business, economic and competitive uncertainties / contingencies and regulatory and clinical development risks, future outcomes and uncertainties) that may lead to actual results being materially different from any forward looking statement or the performance expressed or implied by such forward looking statements. You are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof. Actinogen Medical does not undertake any obligation to revise such statements to reflect events or any change in circumstances arising after the date hereof, or to reflect the occurrence of or non-occurrence of any future events. Past performance is not a reliable indicator of future performance. Actinogen Medical does not make any guarantee, representation or warranty as to the likelihood of achievement or reasonableness of any forward-looking statements and there can be no assurance or guarantee that any forward-looking statements will be realised. Operating & financial review 1. PRINCIPAL ACTIVITIES The principal activity of the company during the year focused on the ongoing clinical development of Xanamem ® (emestedastat), a unique inhibitor of the 11β- HSD1 enzyme that achieves target engagement in the brain. It is an oral medication for neurological diseases amenable to its mechanism of controlling cortisol in brain cells. Brain cortisol is associated with a number of neurological diseases, including neurodegenerative diseases such as Alzheimer’s disease (AD) and neuropsychiatric diseases like major depressive disorder (MDD). 2. OPERATIONS REVIEW Highlights – Advancing to late-stage clinical development Progressed two major phase 2 clinical trial programs in Alzheimer’s disease and depression World Health Organization (WHO) granted new and unique International Nonproprietary Name (INN) ‘emestedastat’ to Xanamem Published an academic manuscript in peer-reviewed journal, Clinical Pharmacology in Drug Development Commenced production of scale-up batch of drug substance from contract manufacturer to create tablet supply for current and future trials, and confirm readiness for future commercial quantity production Preparing for commercialization in all other major aspects of the business Received a $9.0 million Research & Development (R&D) tax incentive rebate in November 2024. Funding secured to midlate CY 2026 CEO and CMO presented at numerous significant international conferences and conducted meetings at industry gatherings to continue evaluating potential value-add regional and global business development opportunities. The first half of the company’s 2025 financial year was marked by robust clinical pipeline progress and several major milestones and events including the initiation of preparations for the approaching commercialization of Xanamem. XanaMIA phase 2b/3 AD trial stepping up The XanaMIA phase 2b/3 clinical trial in patients with biomarker-positive mild to moderate Alzheimer’s disease is picking up pace as clinical sites step up activity with 25 sites now actively pre-screening potential trial participants. The trial is enrolling a total of 220 participants with mild to moderate AD and elevated levels of the blood biomarker pTau181, designed to identify participants with biomarker-positive AD whose disease is likely to progress during the 36-week treatment period. This design augments the ability to detect a Xanamem 10 mg daily treatment benefit versus placebo over the observation period, as suggested by the analysis of pTau-positive patients in a previous phase 2a trial over 12 weeks (Taylor et. al. 2024). The primary endpoint of the trial is the Clinical Dementia Rating – Sum of Boxes (CDR-SB) scale, universally included in contemporary AD trials. Other measures include the effects of Xanamem on clinical endpoints of cognition and functional ability. More than 300 people have been pre-screened with a blood pTau test and approximately 40 have entered the 36-week treatment phase of the trial with another 20 in the latter stages of screening. Final results are expected in the second half of 2026 with interim results anticipated in Q4 this year. Patients or families and carers of those interested in participating in the XanaMIA phase 2b/3 AD trial in the USA or Australia can seek further information and check for eligibility to join the trial by visiting the company’s website. ® Xanamem is a registered trademark of Actinogen Medical Limited 3 XanaCIDD phase 2a MDD trial completed - seeking partner(s) to conduct phase 2b trial The XanaCIDD trial was a six-week phase 2a, proof-of-concept, placebo-controlled, parallel group trial in 165 patients with cognitive impairment in major depressive disorder (MDD). Xanamem (10 mg) or placebo was added to the existing antidepressant therapy (n=134) or, in patients with a previous history of anti-depressant treatment not currently on an antidepressant, as a stand-alone treatment (n=31). Results were reported in August 2024. There was a clinically meaningful and persistent improvement in depression measured by the key secondary endpoint of MADRS 1 and in the Patient Global Impression of Severity (PGI-S) measure at multiple timepoints. Improvement in depressive symptoms was statistically significant in the overall population four weeks after the end of 6 weeks of treatment (Week 10), and at both Week 6 and Week 10 in participants taking a background selective serotonin reuptake inhibitor anti-depressant simultaneously. Cognition improved to a similar extent in both Xanamem and placebo groups (p not significant). This outcome provides further evidence to support Xanamem as a cortisol control mechanism and indicates that the 10 mg daily dose is clinically effective at reducing symptoms of depression, supporting the selection of 10mg as a clinically active dose for the XanaMIA AD trial. The company has completed its data analysis and is exploring the path forward for larger trials in MDD with regulators, global thought leaders and potential strategic partners. New and unique name ‘emestedastat’ granted to Xanamem by WHO In January 2025, the WHO granted the nonproprietary name ‘emestedastat’ to Actinogen for Xanamem. An INN is a unique, globally recognized name for a pharmaceutical drug or active ingredient. Each active substance that is to be marketed as a pharmaceutical must be granted a unique name of worldwide acceptability to ensure the clear identification, safe prescription and dispensing of medicines to patients. Nonproprietary names are intended for wide use ranging from labelling and product information to drug regulation and scientific literature. By granting the INN, the WHO recognized Xanamem (emestedastat) as the first drug to be named for the class of enzyme inhibitors of 11β-HSD1 by assigning it the unique suffix of ‘-stedastat’ pertaining to its mechanism of action on 11β-HSD1. Emestedastat is a unique orally administered molecule in its own class as a ‘brain tissue cortisol synthesis inhibitor’ Published clinical pharmacology academic manuscript in peer-reviewed journal, Clinical Pharmacology in Drug Development Two academic manuscripts were published in 2024 in the peer-reviewed Journal of Alzheimer’s Disease. On 6 February 2025 the company announced the publication of its latest peer-reviewed journal article entitled Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease in the journal associated with the American College of Clinical Pharmacology, Clinical Pharmacology in Drug Development. The review confirms the utility of the 10 mg daily dose of Xanamem being used in current clinical trials. The journal article can be accessed here. Manufacturing During the period, the company commenced production of a scale-up batch of drug substance from its contract manufacturer which will progressively be manufactured into Xanamem tablets for use in current and future trials. This step will also confirm readiness for eventual commercial quantity production to potential pharma partners and regulators. Preparing for commercialization The company has provided clinical ‘proof of concept’ in two separate clinical indications to date – AD and MDD. These phase 2 trial data add to the validation of the Xanamem program from prior clinical trials in healthy volunteers and the high levels of target engagement in the brain seen with PET imaging. At this stage the company believes Xanamem’s action to control tissue production of cortisol in the brain, also known as ‘The Cortisol Hypothesis’, is now well-established as a new therapeutic mechanism. With the Xanamem program in late-stage clinical development, the company is actively engaging in an important range of initiatives in addition to those outlined above to prepare for the approaching commercialization phase. These include: • Appointment of inaugural Chief Commercial Officer (CCO) - In October 2024, the company appointed Mr Andy Udell as CCO. Mr Udell is a commercial leader with demonstrated success taking biotech companies from the clinic through market planning, commercial readiness and full commercial integration and is already proving to be a valuable commercially savvy resource The company also continues to fill other strategic operational roles to ensure the success of its clinical development program, including those required for the XanaMIA phase 2b/3 Alzheimer’s disease trial in Australia and the USA • 1 Regulatory meetings – the company continues to plan its path forward in both AD and MDD, with the focus for 2025 being the implementation of the XanaMIA phase 2b/3 trial and meetings with regulators for both AD and MDD to understand registrational requirements for marketing approvals MADRS: The Montgomery-Asberg Depression Rating Scale is a structured psychiatric interview evaluating MDD symptoms 4 • Partnering – dialogue continues with multiple parties spanning potential regional and/or global partnership arrangements, with an emphasis on those organizations that are interested in both AD and MDD. The company is also investigating Australian and international grant opportunities that could be used to support expansion of the AD and MDD clinical trial programs • Intellectual property protection from future generic competition – as a new chemical entity and unique class of drug, Xanamem has additional commercial protection from data exclusivity laws independent of protection provided by approved patents. Data exclusivity laws provide protection against generic manufacturers using Actinogen’s clinical or nonclinical data for a substantial period from the date of marketing approval and therefore effectively block generic competition from the market during that time. Data exclusivity periods vary by country, for example, five years in Australia and the US and ten years in the EU In addition, patents typically have a period of 20 years from the date of grant. Actinogen has key patents granted for the Xanamem molecule’s chemistry and continues to prosecute newer patents in multiple countries covering the treatment of cognitively normal people, manufacturing process and the treatment of patients with depression supporting an overall robust framework of intellectual property protection • Ancillary nonclinical and clinical studies – clinical pharmacokinetic (measuring blood levels in the body) and nonclinical studies are being conducted in parallel with the XanaMIA trial appropriate to Xanamem’s late-stage clinical development to support the Xanamem development program. $9.0 million R&D tax incentive rebate received and strong cash runway In November 2024, the company announced that it had received a $9.0 million R&D tax incentive rebate from the Australian Tax Office for the 2024 financial year. The R&D tax incentive is an Australian federal government program under which companies receive cash refunds for eligible research and development expenditure. Combined with the proceeds of an $11.1 million capital raising during the half, the company had a closing cash balance of $22.9 million at 31 December 2024. Based on the current enrolment profile for the Alzheimer’s clinical trial and other committed expenditure, the company is funded to mid-late CY2026. Presented at numerous international and Australian AD conferences and conducted investment and partnering meetings associated with events and conferences, including as set out below. CMO Dr Dana Hilt presented an academic poster at the Alzheimer’s Association International Conference (AAIC) in Philadelphia, USA on 29 July 2024 summarizing the comprehensive clinical pharmacology approach used by the company integrating data from multiple clinical trials to determine the target dose range for Xanamem. The AAIC is a leading global forum to advance dementia science. CEO Dr Steven Gourlay presented to the Pitt Street Research Conference in Sydney on 18 September 2024, discussing Xanamem’s attractive therapeutic profile for the treatment of neurologic conditions by controlling brain cortisol, and the positive outlook for the company as it enters late-phase clinical trials. Dr Gourlay presented at the Dementia Trials Australia Annual Scientific Meeting in Sydney on 11 October 2024. His presentation included an analysis of the important validation of Xanamem’s mechanism of action to control brain cortisol provided by the anti-depressant activity identified in the XanaCIDD phase 2a depression trial. Dr Hilt and Senior Clinical Scientist Dr Jack Taylor presented an academic poster at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain on 31 October 2024. The poster presented data to show that elevated plasma pTau181 is useful in predicting clinical decline in patients with mild, clinically diagnosed AD. Dr Hilt and Dr Gourlay presented at the Sachs Associates 8th Annual Neuroscience Innovation Forum in San Francisco on 12 January 2025. Their presentation was titled Oral emestedastat (Xanamem®/UE2343): Controlling brain cortisol to slow progression in Alzheimer’s disease. While in San Francisco, members of the ACW leadership team participated in a significant number of partnering, analyst and investor meetings associated with the 43rd Annual J.P. Morgan Healthcare Conference from January 13 to 16, 2025. For further information on all the above milestones and events, please refer to the ASX announcements section under the Investor Centre tab on the Actinogen website www.actinogen.com.au. 5 3. FINANCIAL REVIEW (a) Financial Performance The financial performance of the company during the half year ended 31 December 2024 is as follows: Half year ended Half year ended 31/12/2024 $ 31/12/2023 $ 244,406 1,015,804 (8,168,979) (11,556,659) (0.28) (0.56) - - As at As at 31/12/2024 30/06/2024 $ $ Cash and cash equivalents 22,865,981 9,450,735 Net assets / Total equity 23,968,845 19,696,499 Contributed equity 113,814,110 100,023,653 Accumulated losses (89,904,814) (81,735,835) Revenue and other income ($) Net loss after tax ($) Loss per share (cents) Dividend ($) (b) Financial Position The financial position of the company as at 31 December 2024 is as follows: 6 4. MATERIAL RISKS In addition to risks associated with any business there are specific, material risks that, either individually or in combination, may materially and adversely affect the future operating and financial performance and prospects of Actinogen and the value of its shares. Some of these risks may be mitigated by Actinogen’s internal controls and processes but some are outside the control of Actinogen, its directors and management. The material risks identified by management are described below: Risk Implication Mitigation Research and Development Activities Actinogen’s future success is dependent on the performance of Actinogen’s lead molecule, Xanamem, in clinical trials and whether it proves to be a safe and effective treatment. Xanamem is an experimental product in late-stage clinical development. Product commercialization resulting in potential product sales revenues are likely to be some years away without any guarantee that it will be successful. It requires additional research and development, including ongoing clinical evaluation of safety and efficacy in clinical trials and regulatory approval prior to marketing authorization. Until Actinogen is able to provide further clinical evidence of the ability of Xanamem to improve outcomes in patients, the future success of its technology remains speculative. Research and development risks include uncertainty of the outcome of results, difficulties or delays in development and generally the uncertainty that surrounds the scientific development of pharmaceutical products. Mitigation measures include ‘following the science’ of the data generated for Xanamem to date, hiring expert clinical development professionals to design, oversee and analyse the trial program, engagement of leading contract research organisations to manage components of the trials and drive recruitment as well as engagement of well-qualified clinical sites experienced in clinical trial execution and in the relevant therapeutic areas. Regulatory Approvals Actinogen operates within a highly regulated industry, relating to the manufacture, distribution and supply of pharmaceutical products. There is no guarantee that Actinogen will obtain the required approvals, licenses and registrations from relevant regulatory authorities in jurisdictions in which it operates. The commencement of clinical trials may be delayed and Actinogen may incur further costs if the Food and Drug Administration (FDA) and other regulatory agencies are tardy or observe deficiencies that require resolution or request additional studies be conducted in addition to those that are currently planned. A change in regulation may also adversely affect Actinogen’s ability to commercialize and manufacture its treatments. Mitigation measures include operating under a US FDA Investigational New Drug (IND) process, engagement of suitably qualified and experienced persons with expertise in the regulation of small molecule therapies, establishing relationships with regulators to facilitate feedback and guidance from them, regular review of evolving regulatory requirements and analysis of the company’s activities and plans against regulatory expectations in key jurisdictions, and ensuring that the expectations and uncertainties related to regulatory approvals, and the timing of such approvals, are included in business plans. Intellectual Property Securing rights in technology and patents is an integral part of securing potential product value in the outcomes of biotechnology research and development. Competition in retaining and sustaining protection of technology and the complex nature of technologies can lead to patent disputes. Actinogen’s success depends, in part, on its ability to obtain patents, maintain trade secret protection and operate without infringing the proprietary rights of third parties. Because the patent position of biotechnology companies can be highly uncertain and frequently involves complex legal and factual questions, neither the breadth of claims allowed in biotechnology patents, nor their enforceability can be predicted. There can be no assurance that any patents which Actinogen may own, access or control will afford Actinogen commercially significant protection of its technology or its products or have commercial application or that access to these patents will mean that Actinogen will be free to commercialize its technology. Competitors may file patents which could limit the company's freedom to operate for its technologies. The granting of a patent does not guarantee that the rights of others are not infringed or that competitors will not develop technology or products to avoid Actinogen's patented technology. Actinogen’s current patenting strategies do not cover all countries which may lead to generic competition arising in those markets. Mitigation measures include use of expert patent attorneys, regular review of the relevant patent landscape, filing of additional patents and maintenance of patents in a broad geography covering major pharmaceutical markets. The company also has significant protection by virtue of data exclusivity regimes, which in most countries afford extensive multiyear protection from the date a marketing approval is obtained in relation to data generated in the clinical and non-clinical trial processes undertaken in the process of obtaining such an approval. 7 Risk Implication Mitigation Partnership Model While undertaking its phase 2/3 clinical program the company is actively pursuing value-add partnership(s) to expand the trial program further and secure commercialization pathways in one or more territories. This model, which typically involves entering into commercial arrangements with other companies in which Actinogen would license its Xanamem technology to the partner in one or more indications and/or geographies and the partner assumes some or all responsibility for progressing, and paying for, the clinical trials and eventual commercialization. This strategy involves the risk that the company will lose some or all control of the development timetable of its products to its commercial partner(s), which may give rise to an unanticipated delay in any commercial returns. Further, the company may be unable to enter into arrangements with suitable commercial partners in respect of relevant indications. If either of these outcomes occurred, the company’s business and operations may be adversely affected. Mitigation measures employed by the company include using expert business development professionals to build relationships with potential partners, performing rigorous due diligence, ensuring that the commercial terms negotiated are fair and utilising expert legal advice to ensure that appropriate warranties and commitments are included in contracts, and that the contracts reflect the agreed commercial position. The company also seeks to form partnerships with relevant regulatory agencies including the FDA, EMA, and MHRA. Manufacturing The company’s products are manufactured using a specialised manufacturing process at an expert third party facility, as is the norm in the industry. An inability of these third-party contract manufacturing organisations to continue to manufacture the company’s products in a timely, economical and/or consistent manner, including any scale up of manufacturing processes, or to maintain legally compliant manufacturing to maintain product supply, could adversely impact on the progress of the company’s development programs and potentially on the financial performance of the company. Mitigation measures include performing rigorous due diligence on contract manufacturers, engaging contract manufacturers with strong track records and sufficient capability to meet the company’s foreseeable needs, employing senior managers responsible for managing and monitoring the performance of contract manufacturers, gradually scaling up batch production runs to ensure scalability and maintenance of quality systems and related documentation. Fundraising risk Actinogen is reliant upon fundraising to fund its operations. Funds may be available in the future from grants, development and commercial partnerships, tax incentives and capital markets but are not guaranteed. Capital market volatility may impact Actinogen’s ability to raise future funds. Currency market fluctuations could impact the amount of funding required where expenditure is denominated in currencies other than the Australian dollar. Mitigation measures include prudent cash flow forecasting, filing of multiple grant applications, key management focus on partnership relationships, use of specialist advisors in tax, business development and investor relations, maintaining high quality analyst coverage, frequent communications to retail and institutional investors and having a presence at many scientific and business conferences. 8 5. BUSINESS STRATEGY & OUTLOOK Actinogen’s strategic priorities are focused on four key elements: Accelerate clinical development in Alzheimer’s disease Evaluate the optimal phase 2b development pathway in depression Forward planning and preparing for commercialization Proactively engage with regulators, prospective development and commercial partners • • • • Accelerate clinical development in Alzheimer’s disease The phase 2a clinical biomarker trial highlighted the considerable potential benefits of Xanamem in biomarker-positive patients with AD. These results strongly supported the feasibility of using both the CDR-SB and cognitive function endpoints to evaluate the efficacy of Xanamem to slow or halt disease progression in our XanaMIA phase 2b/3 AD trial. These data were used to simulate and design the current phase 2b/3 trial to increase its chances of achieving successful outcomes Key features of the phase 2b/3 trial are: Enrolment of the same patient population where the large Xanamem effect was seen in patients with mild AD and elevated pTau181 protein in the blood (an indication of progressive AD) in Australia and the USA Rapidly pre-screen patients for elevated pTau and key clinical criteria to reduce later screening failures which are more costly High quality rating training and standardization to minimize ‘noise’ in subjective endpoints like the CDR-SB ‘Hands on’ clinical operations and management based in Australia supplemented by select use of USA-based contractors to speed timelines and reduce cost. • • • • Evaluate the optimal development pathway in depression The positive phase 2a XanaCIDD trial in patients with MDD and cognitive dysfunction provided a rich dataset with which to explore potential responder characteristics and design the next phase 2b trial. Xanamem treatment in the phase 2a trial showed clinically meaningful and persistent improvement in depression measured by the key MADRS endpoint and in the Patient Global Impression of Severity (PGI-S) measure at multiple endpoints. Maximal benefits on depression for all endpoints were evident at Week 10, four weeks after the end of treatment, indicating a durable therapeutic effect resulting from controlling brain cortisol. Full analysis of the phase 2a clinical trial data has been completed to identify ideal population and endpoints for future trials. Key upcoming actions of the phase 2b design phase are: Finalize discussions and proposed protocol design with key stakeholders, including: • o o o • • Local and global thought leaders in MDD Potential strategic development partners The FDA and possibly the EMA Submit protocol to the FDA IND dossier in Q1 2025 and wait 30 days for clearance Continue exploring a range of funding options such as grants or potential licensing or partnership arrangements Forward planning and preparing for commercializaton In addition to conducting high quality clinical trials there are numerous other important activities for successful drug development which form part of the company’s forward planning including preparing for the commercialization of Xanamem. Key actions under this strategic priority are: • • • • • • •