Announcement PDF Actinogen Medical Limited ACN 086 778 476 Suite 901, Level 9, 109 Pitt Street, Sydney NSW 2000 +61 2 8964 7401 | actinogen.com.au 1 ASX ANNOUNCEMENT Xanamem oral presentation at the 6th International Conference on Cognitive and Behavioral Neurosciences by Actinogen’s Chief Medical Officer Dr Dana Hilt Sydney, 9 September 2026. Actinogen Medical ASX: ACW (“ACW” or “the Company”) is pleased to announce the international presentation by the Company’s CMO, Dr Dana Hilt, entitled Controlling cortisol in CNS1 disease – Xanamem;® a selective 11β-HSD1 inhibitor as a potential new therapeutic for neuropsychiatric diseases. This academic, oral presentation was given overnight to the 6th International Conference on Cognitive and Behavioral Neurosciences in Paris, France, and is included in this announcement. Presentation highlights: • “Stress” and/or genetic factors may drive multiple Alzheimer’s disease (AD) mechanisms via cortisol • Optimal brain function requires “normal” levels of brain cell cortisol which are largely driven by local 11β-HSD1 enzyme activity • Elevated brain cortisol levels are associated with AD and its major genetic risk factor, Apoprotein E4 • Inhibition of 11β-HSD1 in the brain may reduce cortisol’s toxic effects on brain cells, inflammation and AD-related proteins • Xanamem is an oral, brain-penetrant inhibitor of 11β-HSD1 with a high level of target enzyme engagement in the brain • Xanamem has shown encouraging clinical activity in two phase 2a trials: a. Ability to slow the progression of AD in biomarker-selected patients over 12 weeks of treatment (n=34) b. Improvement in depression symptoms in a difficult-to-treat population (n=165). • The first pivotal trial of Xanamem, comparing 36 weeks of treatment to placebo in patients with mild to moderate AD, will report topline, final results in November this year (n=247) • Xanamem has been safe and well-tolerated in more than 500 people treated. View this announcement on our InvestorHub: https://investors.actinogen.com.au/link/rDvJny ENDS Investors Media Dr Steven Gourlay Michael Roberts George Hazim CEO & Managing Director Communications Media & Public Affairs Australia P: +61 2 8964 7401 M: +61 423 866 231 M: +61 417 516 262 E. steven.gourlay@actinogen.com.au E. michael.roberts@actinogen.com.au E: georgehazim@mediaaffairs.com.au 1 CNS: Central Nervous System ® Xanamem is a registered trademark of Actinogen Medical Limited Actinogen Medical Limited ACN 086 778 476 Suite 901, Level 9, 109 Pitt Street, Sydney NSW 2000 +61 2 8964 7401 | actinogen.com.au 2 Announcement authorised by the Disclosure Committee of Actinogen Medical Limited About Actinogen Medical Actinogen Medical (ACW) is an ASX-listed, biotechnology company developing a novel therapy for neurological and neuropsychiatric diseases associated with dysregulated brain cortisol. There is a strong association between cortisol and detrimental changes in the brain, affecting cognitive function, harm to brain cells and long-term cognitive health. Cognitive function means how a person understands, remembers and thinks clearly. Cognitive functions include memory, attention, reasoning, awareness and decision-making. Actinogen is currently developing its lead compound, Xanamem, as a promising new therapy for Alzheimer’s Disease. It has also conducted a phase 2 trial in patients with cognitive impairment and depression and may study Fragile X Syndrome and other neurological and psychiatric diseases in the future. Reducing cortisol inside brain cells could have a positive impact in these and many other diseases. The cognitive dysfunction, behavioural abnormalities, and neuropsychological burden associated with these conditions is debilitating for patients, and there is a substantial unmet medical need for new and improved treatments. Clinical Trials The XanaMIA Phase 2b/3 Alzheimer’s disease trial is a double-blind, 36-week treatment, placebo-controlled, parallel group design trial in 247 patients with mild to moderate AD and progressive disease, determined by clinical criteria and confirmed by an elevated level of the pTau181 protein biomarker in blood. Patients receive Xanamem 10 mg or placebo, once daily, and its ability to slow progression of Alzheimer’s disease is assessed with a variety of endpoints. The primary endpoint of the trial is the internationally-recognized CDR-SB (Clinical Dementia Rating scale – Sum of Boxes). The trial is being conducted in Australia and the US and is now closed to participant recruitment. It has passed an independent Data Monitoring Committee safety and efficacy futility review and final topline results are expected in November 2026. The XanaMIA-OLE Alzheimer’s disease open-label extension is an open-label phase of up to 25 months treatment where all participants will receive active Xanamem 10 mg once daily. The trial evaluates safety and a limited number of efficacy endpoints such as the CDR-SB. The trial commenced in March 2026 and is open to all former and current participants in the XanaMIA Phase 2b/3 trial. The XanaCIDD Phase 2a depression trial was a double-blind, six-week proof-of-concept, placebo-controlled, parallel group design trial in 167 patients with moderate, treatment-resistant depression and a degree of baseline cognitive impairment. Participants were evenly randomized to receive Xanamem 10 mg once daily or placebo, in most cases in addition to their existing antidepressant therapy, and effects on cognition and depression were assessed. Trial results were reported in August 2024 and showed clinically and statistically significant benefits on depression symptoms with positive effects on the MADRS scale (a validated scale of depression symptom measurement) and the PGI-S (a valid patient reported assessment of depression severity). Cognition improved markedly and to a similar extent in both Xanamem and placebo groups. The peer-reviewed publication relating to this trial can be accessed for free via this link: https://tinyurl.com/ckm63z63. About Xanamem (emestedastat) Xanamem’s novel mechanism is to control elevated levels of cortisol (aka the “stress hormone”) in the brain through the inhibition of the cortisol synthesis enzyme, 11β-HSD1, without affecting production of cortisol by the adrenal glands which is essential for the body’s normal functioning. Xanamem is a first-in-class, once-a-day pill designed to deliver high levels of cortisol control in key areas of the brain related to Alzheimer’s and other diseases such as the hippocampus and frontal cortex. To view Xanamem’s two-minute Mechanism of Action animation, click here. Chronically elevated cortisol is associated with progression in Alzheimer’s Disease and excess cortisol is known to be toxic to brain cells. Cortisol itself is also associated with depressive symptoms and when targeted via other mechanisms has shown some promise in prior clinical trials. The recent XanaCIDD trial demonstrated clinically and sometimes statistically significant benefits on depressive symptoms, further validating the cortisol control mechanism for the Xanamem 10 mg oral daily dose. The Company has studied 11β-HSD1 inhibition by Xanamem in more than 500 volunteers and patients in eight clinical trials. Xanamem has a promising safety profile and has demonstrated clinical activity in patients with depression, patients Actinogen Medical Limited ACN 086 778 476 Suite 901, Level 9, 109 Pitt Street, Sydney NSW 2000 +61 2 8964 7401 | actinogen.com.au 3 with biomarker-positive Alzheimer’s disease and cognitively normal volunteers. High levels of target engagement in the brain with doses as low as 5 mg daily have been demonstrated in a human PET imaging study. Xanamem is an investigational product and is not approved for use outside of a clinical trial by the FDA or by any global regulatory authority. Xanamem® is a trademark of Actinogen Medical. Disclaimer This announcement and attachments 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. 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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 MEDICAL ENCOURAGES ALL CURRENT INVESTORS TO GO PAPERLESS BY REGISTERING THEIR DETAILS WITH THE DESIGNATED REGISTRY SERVICE PROVIDER, AUTOMIC GROUP. Controlling cortisol in CNS1 disease – Xanamem;® a selective 11β-HSD1 inhibitor as a potential new therapeutic for neuropsychiatric diseases. Dana C Hilt MD CMO, Actinogen Medical Limited 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 1 CNS: Central Nervous System ® Xanamem is a registered trademark of Actinogen Medical Limited 2 This presentation is dated June 2026 and has been prepared by Actinogen Medical Limited. (“Actinogen” or the “Company”) based on information available to it as at the date of this presentation. 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Disclaimer 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 The potential role of brain cortisol in Alzheimer’s disease (AD) 3 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Cortisol and the Alzheimer’s brain “Stress” and/or genetic factors may drive multiple AD mechanisms via cortisol 4 Seckl J 2024 (left panel); Milligan Armstrong et al. 2021 https://doi.org/10.1111/brv.12750 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Widely expressed in neurons and microglia Impact of cortisol on cognition Abnormal brain cortisol levels alter cognition Brain Cortisol Levels Optimal Low High Cognition/ Memory Performance Addison’s Disease Stress Aging Depression Alzheimer’s Cushing’s syndrome Optimal cognition requires ‘normal’ brain cell cortisol levels - largely driven by local 11β-HSD1 activity Seckl, J Jour Int Med 295, 2023. Di Vencenzo, M etal Intl Jour Mol Sci 26, 2025 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 5 Elevated human brain cortisol levels linked to AD Brain fluid cortisol measurements best reflect the tissue cortisol environment 6 Popp et al, 2015 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Cognitive Normal MCI Other MCI AD AD dementia CSF cortisol (μg/dl) p<0.001 Popp et al., 2015, Neurobiol. Aging 36:601–607 CSF: Cerebrospinal fluid German Dementia Competency Network study 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Major AD genetic risk factor of ApoE4 associated with elevated brain cortisol levels ~67% of patients in AD trials have one or two copies of the ApoE4 gene 7 Gil-Bea et al. 2010 a) CSF cortisol level by disease classification (SCI: subjective cognitive impairment; SMCI stable mild cognitive impairment: progressive mild cognitive impairment; AD Alzheimer’s disease b) As above by known ApoE4 genetic status (0 vs. 1-2 copies) 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Cortisol excess is toxic to the brain Literature from clinical use as a therapeutic and excess cortisol in Cushing’s syndrome Symptom or sign of brain toxicity Trends to worsening Alzheimer’s disease Shrinkage to hippocampus General brain shrinkage Memory impairment Executive function impairment Difficulty learning Poor concentration Anxiety Depression 8 Data reported for Cushing’s syndrome of endogenous excess cortisol and/or therapeutic corticosteroids Dekkers et al. 2022; Liu et al. 2022; De Alcubierre et al. 2023; Katragadda et al. 2025 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Therapeutic cortisol worsened AD over 12 months Historical trial of 10mg prednisone in patients with mild to moderate disease (n=138) 9 Aisen et al. Neurology 54:Feb 2000; dropouts were more common in the prednisolone group 0 1 2 3 4 5 6 7 8 9 Cognition Dementia Depression Placebo Prednisone Worsening Point Change In Score ADAS-cog P=0.16 CDR-SB P=0.07 Ham-D P=0.25 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Summary: Cortisol: guilty by association • Multiple studies support the association between cortisol and AD development and progression1-5 • Cognitive impairment in patients with neuroendocrine dysfunction6-9 • Compelling evidence provided by the Australian Imaging, Biomarker & Lifestyle Study of Ageing (AIBL) study (2017)5 o Higher plasma cortisol leads to a much greater risk of developing AD o Cortisol accelerates toxic effects of Αβ+ on decline in global cognition, episodic memory, and attention • Individuals with the APOE-ε4 allele have higher CSF cortisol8 • Higher CSF cortisol levels in AD patients are associated with more rapid clinical worsening and cognitive impairment10,11 • High cortisol and low folate predict probable Alzheimer’s disease after age 7512 10 [1] Geerlings et al., 2015, Neurology 85: 1-8; [2] Lehallier et al., 2016, JAMA Neurology 73(2), 203-212; [3] Popp et al., 2015, Neurobiol. Aging 36:601–607; [4] Ennis et al., 2017, Neurology 88(4):371-378; [5] Pietrzak et al., 2017, Biol Psychiatry: Cognitive Neuroscience and Neuroimagery, 2:45-52; [6] Lupien et al., 2009, Nat Rev Neurosci 10:434–445; [7] Starkman et al., 1999, Biol Psychiatry 46: 1595–1602; [8] Lupien et al., 1998, Nat Neurosci 1:69–73; [9] MacLullich et al., 2005, Psychoneuroendocrinology 30:505–515; ; [10] Cernansky et al., 2006, Am J Psychiatry 163:2164-2169; [11] Kornhuber & Jensen, 2015, Neurobiol Aging 36:601-607; [12] Hinterberger et al., J Am Ger Soc 2013 61(4):648-651; Popp et al, 2015 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Cognitive Normal MCI Other MCI AD AD dementia CSF cortisol (μg/dl) p<0.001 MEAN CSF CORTISOL LEVELS Potential benefits of 11β-HSD1 inhibition affect multiple disease pathways Aging, genetics ↑11β-HSD1 expression Chronic Stress ↑HPA axis ↑systemic cortisol Intracellular cortisol↑↑ 11β-HSD1: cortisone →cortisol ↑Aβ production ↑BACE1, ↑APP 11β-HSD1 Inhibitors ↓ cortisol ↑Tau pathology ↑kinase activation hyperphosphorylation Neuroinflammation GR desensitization ↑IL-1β, IL-6, TNF-α Hippocampal atrophy ↓neurogenesis dendritic retraction Alzheimer’s Progression neurodegeneration & cognitive decline Failed HPA feedback X 11β-HSD1 inhibitors limit tissue synthesis of cortisol Xanamem may counteract the deleterious effects of elevated brain cortisol Brain cortisol has multiple negative effects in AD pathophysiology 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Once-daily oral treatment with a unique mechanism Good safety profile in ~400 treated Brain-penetrant at low doses (5-10mg) Potentially disease-modifying in AD Anti-depressant activity in phase 2 Low drug interaction potential ideal for combination therapy Xanamem is a selective cortisol synthesis inhibitor (11β-HSD1 enzyme) Mouse experimental studies, brain cortisol levels & human clinical trials validate cortisol as a target for the treatment of AD 12 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Xanamem achieves high brain target occupancy Distribution of cortisol synthesis enzyme 11β-HSD1 shown in left panel SUVRcarotid 5 mg Xanamem Baseline After 7 days of daily dosing 10 mg Xanamem 20 mg Xanamem Journal of Alzheimer’s Disease 97 (2024) 1463–1475 Brain 11-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem Assessed by PET in Alzheimer’s Disease and Cognitively Normal Individuals Victor L. Villemagne, Vincent Dor, Lee Chong, Michael Kassiou, Rachel Mulligan, Azadeh Feizpour, Jack Taylor, Miriam Roesner, Tamara Miller and Christopher C. Rowe Reduction in tracer signal (loss of color) indicates high 11β-HSD1 occupancy Strong target occupancy observed across evaluated clinical doses 13 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 14 0.36 0.98 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Baseline Week 12 Xanamem Placebo Xanamem vs. Placebo • Mean 0.6 units • Median 0.8 units • p = 0.09 • Cohen’s d = 0.4 CDR-SB units Change from Baseline (SE) Worse performance 14 Large Xanamem benefit1 in high pTau1812 patients (1) Phase 2a biomarker study: major slowing of CDR-SB decline over 12 weeks (n=34) Journal of Alzheimer’s Disease 100 (2024) 139–150 Plasma pTau181 Predicts Clinical Progression in a Phase 2 Randomized Controlled Trial of the 11-HSD1 Inhibitor Xanamem® for Mild Alzheimer’s Disease Jack Taylor, Mark Jaros, Christopher Chen, John Harrison and Dana Hilt 1. Using a linear extrapolation to 18 months 5-6x better than anti-amyloid antibody therapy 2. Pre-specified in SAP as above the median 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 15 15 Xanamem 10 mg protected the majority of AD patients from progression Large Xanamem benefit in high pTau181 patients (2) Twice as many patients in the Xanamem group had stable or improved disease compared with placebo1 … meaning 56% of patients treated with Xanamem were stable or improved vs. 28% in placebo Large effect size vs. placebo of 0.6 – 0.8 units over 12 weeks 1. Where CDR-SB decreased or was unchanged - Xanamem 9 of 16 (56%) vs. Placebo 5 of 18 (28%) 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Final study results November 2026 16 NIA-AA=National Institute of Aging - Alzheimer’s Association; CDR-SB Clinical Dementia Rating Scale – Sum of Boxes 40 Weeks -4 0 36 Weeks 10mg Xanamem Placebo Screening from Dec 23 Double-blind, randomised treatment period (N=247) Follow-up & open label Key Inclusion Criteria Primary Endpoint Key Secondary Endpoints Implementation • Blood pTau biomarker positive • (pTau181 >1.6 pg/ml) • Mild-moderate Alzheimer’s by NIA-AA clinical criteria • CDR-SB (functional and cognitive measure) @36 weeks • Cognitive Test Battery (7 cognitive measures well- validated in the Alzheimer’s field) • Amsterdam Activity of Daily Living (functional measure) • Enrolment at 15 Australian & 20 US sites • *2 yr open-label extensions phase open and enrolling XanaMIA phase 2b/3 trial in Alzheimer’s disease 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Xanamem for the treatment of Major Depressive Disorder (MDD) Phase 2 study of difficult-to-treat MDD patients with: 1. Significant residual depression (HamD > 17) 2. Measurable cognitive deficit (≥0.5 SD deficit on a coding test vs. normal) 17 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 18 XanaCIDD trial design and methods – completed CY2024 Phase 2, double-blind, proof-of-concept controlled trial to assess safety and efficacy Enrolled MDD patients that have both depression and measurable cognitive deficit 10 Weeks post-treatment -4 0 6 Weeks 10mg Xanamem +/- Existing Antidepressant Placebo +/- Existing Antidepressant Screening Double-blind, randomized treatment period (N=167) Double-blind Follow-up Primary Endpoint Key Secondary Endpoints • Cogstate Cognitive Test Battery Attention Composite (attention and working memory) • Montgomery-Åsberg Depression Rating Scale (MADRS) • Patient Global Impression-Severity (PGI-S) • Other MDD and cognitive measures 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Durable antidepressant activity in phase 2 MDD trial Separation from placebo overall and on background SSRI therapy* EOT 2.6-point difference Cohen’s d = 0.38 p = 0.15 PT 4.2-point difference Cohen’s d = 0.64 p = 0.03 Abbreviations: SSRI, selective serotonin reuptake inhibitor. *Data from planned phase 3 population with background SSRI therapy shown; Taylor et. al. Brit J Psychiatry 1–8. doi: 10.1192/bjp.2026.10689 MADRS LS mean change from baseline (± SE) Xanamem (n=37) Placebo (n=39) ON TREATMENT AND BACKGROUND SSRI THERAPY (n=76)* FOLLOW UP -12 -10 -8 -6 -4 -2 0 Baseline Week 2 Week 4 Week 6 Week 10 19 Better Performance 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 20 Self-reported benefit in patients taking SSRI (n=75)* 20 -1.6 -1.4 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 Baseline Week 2 Week 4 Week 6 Week 10 PT PGI-S LS mean change from baseline (± SE) Xanamem (n=36) Placebo (n=39) EOT 0.41-point difference Cohen’s d = 0.43 p = 0.08 PT 0.59-point difference Cohen’s d = 0.62 p = 0.03 6th International Conference on Cognitive and Behavioral Neurosciences September 8, 2026 Better Performance Measured by Patient Global Impression – Severity score (PGI-S) *Data from planned phase 3 population with background SSRI therapy shown; Taylor et. al. Brit J Psychiatry 1–8. doi: 10.1192/bjp.2026.10689 21 Phase 2a MDD summary 21 Clinical benefit observed on both MADRS and PGI-S:  Clinically significant benefits commencin