Announcement PDF 2024 Annual report Contents Who we are 1 Highlights 2 The Xanamem pipeline 3 XanaCIDD depression trial results 4 Xanamem progressing to advanced clinical trial phase 6 Clinical trials program overview 7 Chair’s letter 8 Chief Executive Officer’s letter 10 Vision and strategy 12 Operating & financial review 14 Board of directors 22 Executive leadership team 24 Directors’ report 26 Remuneration report (Audited) 29 Auditor’s independence declaration 42 Financial report 43 Notes to the financial statements 48 Directors’ declaration 68 Independent auditor’s report 69 Shareholder information 73 Corporate directory 75 Disclaimer This annual 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. Actinogen is a neurotherapeutics developer realizing a revolutionary therapy so neurology patients and their families can live their best lives. Annual Financial Report 1 Highlights Positive depression results in the phase 2a XanaCIDD trial confirm clinical activity and validate Xanamem’s brain cortisol control mechanism Announced positive depression results in the XanaCIDD phase 2a trial, confirming the clinical activity of 10 mg Xanamem® dose and validating its brain cortisol control mechanism Received approval from the UK MHRA1 for an Innovation Passport under Innovative Licensing and Access Pathway (ILAP) for Xanamem treatment of AD Commenced screening & enrolment in Australia for XanaMIA phase 2b AD trial with additional five sites opening in the USA in Q3 CY2024 Recruited and treated 167 patients in phase 2a depression trial in circa 16 months reinforcing excellence of hybrid model of clinical trial operations Strengthened IP portfolio with development of an improved synthetic manufacturing process of Xanamem drug substance Completed and published two academic manuscripts in peer-reviewed journal, The Journal of Alzheimer’s disease including groundbreaking phase 2a biomarker trial Initiated strategic changes and additions to the executive and operational teams including new full‑time CFO and strategic reorganization of clinical operations team Secured $19 million2 in two successful capital raisings, providing essential funds to support ongoing clinical trial program to late CY2025 Facilitated potential partner engagement and relationship building as a phase 2 clinical stage company through attendance at significant international conferences Conducted two highly informative “plain English” neuroscience webinars Presented Actinogen and met with most key neuroscience companies at the Sachs neuroscience meeting in San Francisco Improved drug substance manufacturing process with 1 kg demonstration batch at our new manufacturer Asymchem ® Xanamem is a registered trademark of Actinogen Medical Limited 1 UK Medicines and Healthcare products Regulatory Agency. ILAP is the UK version of the FDA’s “breakthrough” designation 2 Unless stated otherwise, all financial data is in Australian dollars 2 Actinogen Medical Limited The Xanamem pipeline Indication Preclinical Phase 1 Alzheimer’s disease Ongoing phase 2b Major depressive disorder Topline results phase 2a Fragile X syndrome Phase 2a paused Phase 2 Phase 3 Open INDs phase 2 trials Schizophrenia - CIAS Frontotemporal dementia Potential next indications Lewy-body dementia CI and dementia PD CIAS: Cognitive impairment associated with schizophrenia; CI: Cognitive impairment; PD: Parkinson’s disease Annual Financial Report 3 XanaCIDD depression trial results • There was a clinically meaningful and persistent improvement in depression measured by the key secondary endpoint of MADRS and in the Patient Global Impression of Severity (PGI-S) measure • This outcome indicates potential modification of the underlying biology of depression as a result of inhibition of tissue cortisol synthesis – a completely novel mechanism for the treatment of depression. Xanamem benefit at Week 6 & 10 All randomized participants (n = 165) Xanamem Baseline Placebo Week 2 Week 4 Week 6 Week 10 post treatment 0 MADRS LS mean change from baseline (± SE) Actinogen has achieved clinically and statistically significant superiority of Xanamem over placebo in depression in XanaCIDD phase 2a trial: BETTER -2 PT 2.7-point difference Cohen’s d = 0.43 p = 0.02 -4 -6 -8 EOT 1.5-point difference Cohen’s d=0.24 p=0.11 -10 -12 FOLLOW UP ON TREATMENT Xanamem PGI-S separation from Week 2 All randomized participants (n = 165) Dr Dana C Hilt Actinogen’s Chief Medical Officer Xanamem Baseline Placebo Week 2 Week 4 Week 6 Week 10 post treatment 0 PGI-S LS mean change from baseline (± SE) This encouraging result on depression is very positive to the whole Xanamem program and confirms 10 mg daily is an active clinical dose with the ability to potentially modify underlying biological processes in the brain. -0.2 BETTER -0.4 PT 0.28-point difference Cohen’s d = 0.29 p = 0.13 -0.6 -0.8 -1 EOT 0.22-point difference Cohen’s d = 0.23 p = 0.19 -1.2 -1.4 ON TREATMENT FOLLOW UP Abbreviations: MADRS = Montgomery-Åsberg Depression Rating Scale; EOT: End of Treatment; PT: Post Treatment 4 Actinogen Medical Limited The excellent safety profile of Xanamem was again demonstrated in this trial and the significant treatment benefits seen in depression are encouraging for both the depression and Alzheimer’s disease programs. We believe the trial confirms the ability of Xanamem 10 mg daily to safely provide benefit to patients by controlling levels of cortisol in the brain. Dr Steven Gourlay Actinogen’s CEO Annual Financial Report 5 Xanamem progressing to advanced clinical trial phase Major Xanamem development risks mitigated Highly attractive phase 2/3 profile in dementia and major depression Now and in future Phase 2b/3 trials in AD and depression Recently Positive phase 2a depression data Previously In the beginning Positive human PET study confirms 5-10 mg daily target dose Positive 11B-HSD1 AD mouse model Positive phase 1b trials on cognition Low in vitro drugdrug interaction potential 6 Actinogen Medical Limited Positive phase 2a AD data To-be-marketed tablet formulation Excellent safety profile (n>380) 1500-person safety database Marketing approvals Clinical trials program overview Phase 2 and 3 trials to achieve marketing approvals Current phase 1 & 2 datasets Safety, cognition activity (n>380) Phase 2b Phase 2a Alzheimer’s disease Cognitive impairment and depression 1x Phase 3 2x Phase 2b/3 Alzheimer’s disease Depression Annual Financial Report 7 Chair’s letter Dr Geoff Brooke, Chair Dear Shareholder, I am pleased to present to you the Actinogen Medical Annual Report for the financial year ended 30 June 2024. The Company continues to make compelling progress in the execution of its strategy, focusing on “following the science” in the successful development of our novel, small molecule drug Xanamem, to treat illnesses such as Alzheimer’s disease and depression. We continue to believe that Xanamem’s mechanism of “tissue cortisol synthesis inhibition” to reduce excess cortisol inside brain cells has the potential to have a major impact on the lives of patients and their families suffering from many neurological and neuropsychiatric conditions. It was great to witness gradually improving conditions in the biotech market from the start of 2024, especially as key licensing and M&A activity signalled a change in sentiment from the very challenging market headwinds of 2023, particularly in the small-cap biotech sector. A year of achievement The Company enjoyed a productive financial year with the achievement of several major milestones including the execution of two phase 2 trials running concurrently during the second half. It takes significant effort to get a trial to the starting line, let alone manage the complexities of running two sizeable trials across different jurisdictions simultaneously. The XanaCIDD phase 2a depression trial completed its final patient treatment on 1 July 2024, having recruited 167 patients in 16 months – a tremendous effort from Actinogen staff, our collaborators and the participants. An unexpectedly high placebo effect impacted our ability to see a potential Xanamem effect in the cognition primary endpoint. In the targeted secondary endpoint, we were very pleased to see positive benefits on depression, confirming the clinical activity of our 10 mg dose and validating the drug’s mechanism to control brain cortisol. The XanaMIA phase 2b Alzheimer’s disease trial commenced in April 2024 and, typical of early phases in a trial, screening and enrolment is gradually ramping up in Australia and will be aided by the addition of new sites opening in the USA. 8 Actinogen Medical Limited In another highlight, the Company received approval from the UK Medicines and Healthcare products Regulatory Agency of its application for a UK Innovation Passport as part of the Innovative Licensing and Access Pathway (ILAP) for Xanamem in the treatment of Alzheimer’s disease. This UK version of the FDA’s “breakthrough” designation represents a significant independent endorsement by an international regulator of the potential medical importance of the Xanamem program. The team has also continued to work diligently to complete two academic manuscripts that were published in the peerreviewed journal, The Journal of Alzheimer’s Disease in the second half of the financial year, with further academic papers planned. Executive leadership CEO Dr Steven Gourlay has continued to lead the executive team with distinction. He has the relevant experience needed of a biotech CEO for a Company in the mid-late stage of vital clinical development with a view to commercialisation. Steven navigates the big-picture strategy with a clear view and plans for later-stage requirements yet is proactive and attentive to the many details and intricacies of the here and now of drug clinical development. I firmly believe he has the experience and agility to steer through complex situations while balancing our budget in a high-cost industry. Dr Gourlay leads a small but innovative, high calibre executive leadership team with complementary skills that produces results. We added to the team’s skillset this year with the appointment of the Company’s first full-time Chief Financial Officer, Mr Will Souter, who is a first-class CFO with a wealth of biotech, financial and corporate communications experience. Will has taken responsibility for finance, communications, information technology and human resources, and is skilfully leading capital management activities with the CEO. I also commend the hard work and achievements of Ms Cheryl Townsend and her clinical operations team during the past year. I cited earlier the complexities of running two sizeable trials simultaneously across different jurisdictions, including significant pre-trial preparations, and the successful delivery of those responsibilities is due in no small part to Cheryl’s leadership. And I take this opportunity to thank the wider executive leadership team and the Actinogen workforce, as well as key contractors, who all work so diligently to manage a very effective and efficient clinical development program and corporate functions required of a listed biotech. Board, corporate governance and advisory boards The board seeks continuous improvement in its governance and management oversight capability. During the past year we again conducted a review of all activities and responsibilities, including assessing the Board skills matrix to identify gaps and opportunities for improvement. Our significant corporate The Actinogen team has again proven its ability to effectively and efficiently deliver high quality clinical trial programs, with the depression trial successfully concluded and the pivotal Alzheimer’s phase 2b trial well under way as we head into the new financial year. policies and other corporate governance materials are posted on our website, and we maintain a robust corporate governance framework to support the management and execution of our long-term strategy and annual strategic priorities. I thank my fellow board members for their contributions during a productive year which has necessarily required a significant planning agenda for the next stages in the Company’s development. I would especially like to acknowledge the contribution of Dr Nicki Vasquez who joined the board in March 2023 and with her astute insights, has proven to be a valuable contributor to board deliberations. We will continue to assess our corporate board skillsets and, where appropriate, make changes or additions as we did with Dr Vasquez’s appointment. Actinogen continues to utilise world-leading advisors on our advisory boards to help drive our strategic initiatives and ensure the success of our clinical development program. This year we welcomed Dr Steve Targum, a world-renowned psychiatrist as an external advisor and chair of the XanaCIDD trial safety committee. Shareholders may have seen Dr Targum as an external expert commentator on the XanaCIDD results webinar providing valuable input to the understanding of the topline trial results. I thank all our esteemed independent external advisory board and committee members for their important contributions to the success of the Company in FY2024. Further details on the Actinogen corporate board, advisory boards and senior executive personnel can be found on the Company’s website: https://actinogen.com.au/our-team/ Capital management The Company successfully completed two capital raisings totalling $18.9 million during the year and I thank shareholders for your strong support in the 2023 entitlement offer and the recent May 2024 raising, where the entitlement offer was oversubscribed approximately 1.8 times. Additional funding has been received from the conversion of options associated with those two capital raisings. If you have any questions relating to your shareholding in Actinogen, please contact Automic at hello@automicgroup.com.au or on 1300 288 664 (within Australia) or +61 2 9698 5414 (outside Australia). A further $9.0 million related to the 2024 R&D tax incentive rebate is expected to be received in Q4 CY2024. With a cash balance of $9.5 million at 30 June 2024 and the additional funding sources described above, the company and its current programs are funded to late CY2025. Annual General Meeting This year’s Annual General Meeting will be held in Sydney on Thursday 14 November 2024, and we invite shareholders to attend in person. Details of the meeting time and Sydney location will be announced in due course. Outlook Actinogen has again proven its ability to deliver high quality clinical trials in an efficient and effective manner. A key focus in FY2025 will be on planning for follow on activities in our depression trial program following the release of positive topline results for the XanaCIDD phase 2a trial announced earlier this month. This includes deeper analysis of the full results dataset and announcing and publishing additional information where relevant. Plus, we will be undertaking discussions with regulators such as the FDA, EMA and the TGA to identify the optimal trial design as we enter the next phase. We look forward to making further progress in our XanaMIA phase 2b Alzheimer’s disease clinical trial in FY2025 as we activate sites in the USA and ramp up patient screening and enrolments at all locations, ahead of an interim analysis in mid CY2025. The design and enrolment criteria for this phase 2b trial are based on the strong scientific rationale derived from the findings of the biomarker trial, published recently in the peer reviewed Journal of Alzheimer’s Disease, which showed that Xanamem potentially slows disease progression in AD patients with elevated levels of plasma pTau. The board looks forward with confidence to a very exciting 2025 financial year for Actinogen. As always, we remain vigilant in our governance and proactive in our management as we deliver on our strategic priorities. On behalf of the Board, I would like to thank you, our shareholders, for your ongoing support, and we look forward to updating you on our progress during the coming year. Dr Geoff Brooke Chair 30 August 2024 Visit the Automic website https://investor. automic.com.au/#/home to register as an ACW shareholder or log in to your existing account. Annual Financial Report 9 Chief Executive Officer’s letter Dr Steven Gourlay, CEO & Managing Director Dear Shareholder, The “rights” for Xanamem: The Xanamem program is now in advanced late-stage clinical development. • Hitting the right target – 11β-HSD1 in the brain Actinogen has now reached a transformational stage in its clinical development of Xanamem, with positive results on depression in our XanaCIDD phase 2a trial. The improvements seen in depression symptoms clearly show that Xanamem’s mechanism of action in the brain to inhibit tissue production of cortisol has major clinical impact. The associated lack of superiority over placebo in short-term cognitive enhancement was surprising but instructive for the depression program. The FDA has long argued that cognitive dysfunction improves as depression improves, although the scientific literature has established that the correlation is by no means universal. Based on our XanaCIDD results, we will be pursuing depression itself, not short-term cognitive enhancement, in future clinical trials – a much more straightforward path with regulators like the FDA, EMA and TGA. In contrast, trials of Xanamem in patients with Alzheimer’s disease will continue to include both functional and cognitive measures in order to adequately describe the potential slowing of disease progression in this confirmatory, late-stage trial. Xanamem is a unique orally administered molecule in its own class as a “brain tissue cortisol synthesis inhibitor”. In fact, the International Non-proprietary Names for Pharmaceutical Substances (INN) of the World Health Organization recognized this by giving its future “generic” or non-proprietary name a unique suffix (name to be announced in early 2025 pending final vetting). No other brain-penetrant modifiers of tissue cortisol synthesis are in development to our knowledge and no other 11β-HSD1 inhibitors have ever received an INN name. So how did we get here and where do we go to from here? As we have explained before, the science of clinical development is all about getting many details right and I’m pleased to say it has the potential to pay off handsomely for the many possible future patients who may benefit from Xanamem. • Having a drug with the right properties – brain-penetrant, low dose, low drug interaction potential • Using the right biomarkers and assessments – hormone, PET and blood biomarkers like pTau • Targeting the right dose – multiple trials show clinical activity of doses of ≤ 10 mg daily • Selecting the right trial participants – for example, patients with AD and elevated pTau • Using the right trial design – world-class trials and statistics approved by the FDA • Ensuring the right safety profile – excellent safety profile in >380 people treated. The “stages” for Xanamem: Completed • Preclinical: animal studies, laboratory benchtop studies etcetera • Phase 1: measuring levels of the drug and its effects on systems in the body, typically healthy volunteers, in order to select a dose range for future testing and establish early human safety • Phase 2: trials in patients to show clinical activity and select future sensitive endpoints and the ideal patients for phase 3 Coming up or in progress • Phase 3 or 2b/3: “pivotal”, confirmatory trials designed to inform marketing approvals with the FDA and other regulators • Phase 4: post-marketing studies to primarily monitor the safety of the drug in the “real world” Moving ahead in major depressive disorder (MDD) Our latest phase 2a trial, XanaCIDD, has provided positive data on depression and an extensive, high-quality dataset from which future trials can be designed in conjunction with input from experts and regulators. Initial, topline results indicate that Xanamem had benefit on MDD symptoms in multiple subgroups of patients. These findings are being explored by additional analyses intended to confirm the characteristics of the potential responder population compared to the overall population. This analysis will guide the selection criteria for patients with MDD in future trials. Moving ahead with the phase 2b trial in Alzheimer’s disease (AD) Publication of our groundbreaking phase 2a biomarker trial data in the Journal of Alzheimer’s Disease1 in June was 1 Plasma pTau181 Predicts Clinical Progression in a phase 2 Randomized Controlled Trial of the 11β-HSD1 Inhibitor Xanamem® for Mild Alzheimer’s Disease Jack Taylor, Mark Jaros, Christopher Chen, John Harrison and Dana Hilt. Article published to the Journal of Alzheimer’s Disease 26 June 2024. 10 Actinogen Medical Limited Our strategy is to extend phase 2a clinical validation of Xanamem’s brain cortisol mechanism in Alzheimer’s disease and major depressive disorder into phase 2b/3 trials. validation of the methods used to analyze the effects of Xanamem in patients with a biomarker-positive signature. Elevated levels of pTau in the blood are being increasingly recognized as a highly accurate way to diagnose progressive Alzheimer’s disease and have been incorporated into new, draft US guidelines for the disease2. Elevated pTau is a key entry criterion for the on-going XanaMIA phase 2b trial. The key findings reported in the Journal of Alzheimer’s disease were: • Patients with elevated pTau181 had much more rapid progression than patients with lower pTau181 levels in four key clinical endpoints: ADCOMS (p<0.001), CDR-SB (p<0.001), MMSE (p=0.12) and ADAS-Cog14 (p=0.19)3 • In the 34 patients with lower pTau181 there was no progression in any of those endpoints, indicating that approximately half of the original trial population had nonprogressive disease and perhaps in many cases, did not have Alzheimer’s disease • In the 34 patients with elevated pTau181 a potentially large and clinically meaningful Xanamem treatment effect compared to placebo was seen in the CDR-SB (mean difference 0.6 units, p=0.09) and positive trends were observed in a Neuropsychological Test Battery of cognition (LS mean difference 1.8 units, p=NS). Using the biomarker trial data as a simulation of the phase 2b trial, a design was chosen that enables assessment of Xanamem’s potential benefit to slow disease progression by accurately evaluating performance on both clinical function, measured with endpoints like the CDR-SB and activities of daily living scores, and a broad testing system for cognition. Thirty-six weeks duration has been chosen for the XanaMIA phase 2b trial to enable sufficient time for Xanamem treatment effects to become evident in AD patients, especially those effects of improving clinical function (slowing progression). The trial is further enhanced by using our new, to-be-marketed tablet formulation. Interim results are anticipated by mid-2025, with final results in 2026. In my view, this trial has a high probability of success given the benefits seen in the biomarker-positive patients with Alzheimer’s disease and our new findings on depression that validate clinical activity of the 10 mg daily dose level. Moving ahead with Good Manufacturing Practice (GMP) manufacturing Because Xanamem is a low dose drug we are in the fortunate position of needing only a modest volume of drug supply and few manufacturing runs to complete the clinical trial program. We intend to make scale up batches in the coming year to further validate the commercially-ready manufacturing process. Our tablets are produced in the USA by Catalent, Inc. using drug substance produced by Corden in Switzerland or Asymchem in China. Business development & partnering Business development and partnering activities have been strengthened with the new XanaCIDD trial data and the two peer-reviewed publications published earlier this year. We continue to see a high level of interest in our programs especially as biopharma market conditions have gradually improved since their 2023 nadir with notably stronger merger, licensing and funding activity in the neuroscience sector in late 2023 and 2024. We again attended many important international conferences during the year to enhance Actinogen’s credentials as a phase 2 clinical-stage company and facilitate potential partner engagement and relationship building. At the recent Alzheimer’s Association International Conference (AAIC 2024) in late July our CMO Dr Dana Hilt presented an academic poster that summarized the comprehensive clinical pharmacology approach used by Actinogen integrating data from multiple clinical trials to determine the target dose range for Xanamem. Other meetings included a CMO presentation at the Sachs Neuroscience Innovation Forum and meetings at Biopartnering @JPM associated with the 42nd annual JP Morgan HealthCare Conference in San Francisco in January. Xanamem clinical data keeps getting stronger Xanamem’s promising story as a breakthrough oral therapy for Alzheimer’s disease and many other illnesses continues to mature, with our latest XanaCIDD trial showing activity on depression in patients with pre-treated MDD. We are delighted with our success in the past year, and I would like to extend my thanks to the team for all their hard work. Based on the results of our trials conducted in >380 patients so far, we firmly believe that Xanamem has the potential to be a first-in-class drug for the treatment of AD and potential as a first-in-class antidepressant with a novel mechanism unlike any competitors. Thank you for your ongoing support for Actinogen and we look forward to updating you on our progress in the near future with each successive trial and corporate milestone. Yours sincerely, Dr Steven Gourlay, CEO & Managing Director 30 August 2024 2 https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13859 3 ADCOMS: Alzheimer’s Disease Composite Score; CDR-SB: Clinical Disease Rating Scale – Sum of Boxes; MMSE: Mini Mental State Examination; ADAS-Cog14: Alzheimer’s Disease Assessment Scale – Cognition version 14 Annual Financial Report 11 Vision and strategy Our fundamentals Quality In conjunction with the US FDA and other regulatory authorities, we strive for excellence in science and clinical data within our programs. As a result, we’ve conducted multiple high-quality clinical trials to bring our molecule, Xanamem, to this phase 2 stage of development. Valued We are valued and respected by patients, physicians, and industry peers to bring Xanamem’s development forward. Science, data and transparency guide us to bring hope and potentially change the world of cognitive impairment forever. Bold Building on the solid scientific rationale for Xanamem’s action, we are rapidly developing programs in multiple disease areas, with a priority on Alzheimer’s disease and depression. Next-Gen Xanamem is a cutting-edge therapy and world-class product that reduces cortisol (the “stress hormone”) levels in the brain. As a result, it is a catalyst for new approaches in managing neurodegenerative and other illnesses. 12 Actinogen Medical Limited Our Vision To realize a revolutionary therapy so that neurology patients and their families can live their best lives. FY2024 Strategic priorities Accelerate clinical development in Alzheimer’s disease • Enrol same patient population where the large Xanamem effect was seen in patients with AD elevated blood pTau181 protein • Rapidly pre-screen patients for elevated pTau and key clinical criteria to minimize later costly screening failures • Ensure high quality rating training and standardization to minimize noise in subjective endpoints like the CDR-SB • Leverage ‘hands on’ Australian-based clinical operations and management supplemented by select use of US contractors to speed timelines and reduce cost. Evaluate the optimal phase 2b trial design in depression Forward planning • Complete full analysis of phase 2a clinical trial data to identify ideal population and endpoints for future trials • Use to-be-marketed tablet formulation in all trials • Discuss results and proposed protocol design with major stakeholders, including local and global thought leaders in MDD, potential strategic development partners and key regulators • Submit protocol to the