Announcement PDF ASX ANNOUNCEMENT Actinogen CEO presents at Dementia Trials Australia Annual Scientific Meeting in Sydney Sydney, 11 October 2024. Actinogen Medical ASX: ACW (“ACW” or “the Company”) is pleased to announce that its CEO, Dr Steven Gourlay, will present at the Dementia Trials Australia Annual Scientific Meeting in Sydney today, which is focused on the theme The new era in AD therapies. Dr Gourlay’s presentation is titled “Oral Xanamem: ® How Xanamem’s benefit on depressive symptoms translates to possible efficacy in Alzheimer’s disease”. The presentation outlines the encouraging data showing clinically and statistically significant anti-depressant activity in ACW’s latest phase 2a trial. He discusses the important validation this provides for Xanamem’s mechanism of action to control cortisol in the brain, and for the 10 mg daily dose also being used in the Alzheimer’s program. Dr Gourlay’s presentation slides are attached to this announcement. ENDS Dr. Steven Gourlay CEO & Managing Director P: +61 2 8964 7401 E. steven.gourlay@actinogen.com.au Investors Media Michael Roberts Investor Relations M: +61 2 8964 7401 George Hazim Media & Public Affairs Australia M: +61 417 516 262 E. michael.roberts@actinogen.com.au E: georgehazim@mediaaffairs.com.au Announcement authorised by the Board of Directors of Actinogen Medical 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. ® 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 1 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 and Depression and hopes to 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. Current Clinical Trials 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 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. Positive topline results on depression were announced 12 August CY2024 and updated 26 August CY2024. The XanaMIA Phase 2b Alzheimer’s disease trial is a double-blind, 36-week treatment, placebo-controlled, parallel group design trial in 220 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). Initial results from an interim analysis of the first 100 participants are anticipated in mid 2025 and final results mid 2026. About Xanamem Xanamem’s novel mechanism of action is to control the level of cortisol in the brain through the inhibition of the cortisol synthesis enzyme, 11β-HSD1, without affecting production of cortisol by the adrenal glands. Xanamem is designed to get into the brain after it is absorbed in the intestines upon swallowing. 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. The Company has studied 11β-HSD1 inhibition by Xanamem in more than 380 volunteers and patients in eight clinical trials. Xanamem has a promising safety profile and has demonstrated clinical activity in patients with depression, patients 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. 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. 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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 Oral Xanamem® Controlling brain cortisol to treat depression and slow progression in Alzheimer’s disease - a novel therapeutic mechanism in late phase trials How Xanamem’s benefit in depression translates to possible efficacy in Alzheimer’s Dementia Trials Australia Annual Scientific Meeting 2024 11 October 2024 ® Xanamem is a registered trademark of Actinogen Medical Limited Disclaimer • This presentation 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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Actinogen DTAus 2024 2 Once-daily oral treatment with a unique mechanism Xanamem controls tissue cortisol via inhibition of the 11β-HSD1 enzyme Knockout mice protected against age-related cognitive decline Memory improvements shown in mice with 27-60% enzyme inhibition Murine AD model with 30% enzyme inhibition showed complete cognitive protection over 13 months independent of amyloid Reduced hippocampal inflammation Mouse studies, human brain cortisol levels and now Xanamem clinical trials validate brain cortisol control for the treatment of AD and MDD Actinogen DTAus 2024 3 Cortisol: guilty by association in humans in many ways • 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 MEAN CSF CORTISOL LEVELS o Higher plasma cortisol leads to a much greater risk of developing AD • 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 0.7 0.6 CSF cortisol (μg/dl) o Accelerated effect of Αβ+ on decline in global cognition, episodic memory, and attention p<0.001 0.5 0.4 0.3 0.2 0.1 0 Cognitive Normal MCI Other MCI AD AD dementia Popp et al, 2015 [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; Actinogen DTAus 2024 4 Xanamem controls cortisol by inhibition of 11β-HSD11 Controlling brain cortisol2 has potential durable benefits “STRESS” in the brain becomes “CHILL” RAPID changes in kinases, cell function, neurotransmitters over hours to days lead to short-term “low stress” settings “Lower stress” shorter term e.g. • Reducing inflammation • Improving neurotransmitter balance • Decreasing cell death SLOW changes in gene expression and protein synthesis over days to weeks lead to durable “low stress” settings “Lower stress” longer term e.g. • Improving neural circuitry • Generating new brain cells • Ideal receptor configurations 1. For a comprehensive review of 11β-HSD1 see Seckl J. 2024 2. Ramamoorthy & Cidlowski 2016 Actinogen DTAus 2024 5 Human PET study shows full target engagement Other 11β-HSD1 enzyme inhibitors have not achieved adequate brain levels Baseline After 7 days of daily dosing 5 mg Xanamem 10 mg Xanamem 20 mg Xanamem SUVRcarotid Xanamem extensively binds to the 11β-HSD1 enzyme throughout the brain, with high post-treatment effects (absence of colour) after 7 days at all doses, slightly less at a 5 mg dose. This is consistent with full hormonal pharmacodynamic activity seen in clinical trials with doses as low as 5 mg. Validates 10mg daily dose in efficacy trials Actinogen DTAus 2024 6 Positive phase 2a depression data Actinogen DTAus 2024 7 Background to development in depression Xanamem’s unique mechanism and safety differentiate it from other anti-depressants Scientific rationale Promising Xanamem clinical data • More than 50 years of research associated cortisol with depression • Good tolerability 5mg to 70mg daily • Elevated CSF and plasma cortisol levels associated with diagnosis, treatment outcomes and relapse1-3 • Human PET study confirms dose range of 5-10mg • Positive effects of cortisol receptor antagonism reported with mifepristone4 • Once-a-day, half-life ~12 hours • Positive effects at 5, 10 and 20mg daily on attention and working memory in older volunteers • Large potential benefits in patients with AD A safe, effective and combinable small molecule is an attractive product profile for depression 1. Quantitative summary of four decades of research, Stetler & Miller 2011 2. Depression literature review, Malhi & Mann 2018; HPA axis in major depression, 3. Keller et al. 2016 4. A meta-analysis Ding et al. 2021 Actinogen DTAus 2024 8 XanaCIDD trial design Standard phase 2a design with 6 weeks treatment 10mg Xanamem +/- Existing Antidepressant Follow-up Screening Placebo +/- Existing Antidepressant -4 0 10 Weeks post-treatment 6 Weeks Double-blind, randomised treatment period (N=167) Primary Endpoint • Cogstate Cognitive Test Battery Attention Composite (attention and working memory as used in prior trials) Key Secondary Endpoints • Montgomery-Åsberg Depression Rating Scale (MADRS) • Patient Global Impression-Severity (PGI-S) • Executive Function Cognitive Composite (EFC) • Memory Function Cognitive Composite (MC) Actinogen DTAus 2024 9 Xanamem MADRS separation from Week 6 All randomized participants (n = 165) Xanamem 0 Baseline Week 2 Week 4 Placebo Week 6 Week 10 PT BETTER MADRS LS mean change from baseline (± SE) -2 PT 2.7-point difference Cohen’s d = 0.43 p < 0.05 -4 -6 -8 EOT 1.5-point difference Cohen’s d = 0.24 p = 0.23 -10 -12 Abbreviations: MADRS = Montgomery-Åsberg Depression Rating Scale ON TREATMENT FOLLOW UP Actinogen DTAus 2024 10 Xanamem PGI-S separation from Week 2 All randomized participants (n = 165) Xanamem 0 Baseline Week 2 Week 4 Placebo Week 6 Week 10 PT BETTER PGI-S LS mean change from baseline (± SE) -0.2 -0.4 PT 0.28-point difference Cohen’s d = 0.29 p = 0.12 -0.6 -0.8 -1 EOT 0.22-point difference Cohen’s d = 0.23 p = 0.19 -1.2 -1.4 Abbreviations: PGI-S = Patient Global Impression of Severity ON TREATMENT FOLLOW UP Actinogen DTAus 2024 11 Xanamem major improvement in depression response Increased rates of remission (MADRS < 10) and large (50%) improvements % with < 10 points on MADRS % with ≥ 50% reduction in MADRS 40 >50% more 35 30 >50% more 25 30 20 25 20 15 15 10 10 5 5 0 Week 2 Week 4 Xanamem % Week 6 Placebo % Week 10 0 Week 2 Week 4 Xanamem % Week 6 Week 10 Placebo % Actinogen DTAus 2024 12 Excellent safety profile consistent with prior trials Summary of Treatment-Emergent Adverse Effects (TEAE) Xanamem N = 82 Placebo N = 83 Overall N = 165 Any TEAE 69 (84.1%) 67 (80.7%) 136 (82.4%) TEAE related to trial drug 27 (32.9%) 24 (28.9%) 51 (30.9%) Serious adverse event 0 1 (1.2%) 1 (0.6%) 3 (3.7%) 1 (1.2%) 4 (2.4%) Headache 11 (13.4%) 16 (19.3%) 27 (16.4%) Fatigue 6 (7.3%) 5 (6.0%) 11 (6.7%) Nasopharyngitis 4 (4.9%) 6 (7.2%) 10 (6.1%) Upper respiratory tract infection 5 (6.1%) 5 (6.0%) 10 (6.1%) Related TEAE discontinuation or interruption of drug TEAEs with incidence ≥ 5% overall Actinogen DTAus 2024 13 Clinically and statistically significant benefits Depression phase 2a summary • Heavily pre/co-treated population with moderately severe MDD • Treatment benefits on depressive symptoms for MADRS and patient-reported outcome of severity • Consistent depression efficacy across subgroups • Cognition improved markedly in both Xanamem and placebo groups without evidence of greater Xanamem benefit vs. placebo (data not shown) • Xanamem was safe and well tolerated (n=165 treated) with no suggestion of suicide risk or withdrawal syndrome • The trial was well-conducted, with excellent data quality, no major differences between Australia and the UK or at high enrolling clinical sites Anti-depressant clinical activity validates Xanamem’s cortisol control mechanism and supports the likelihood of success in AD trial at 10 mg dose Actinogen DTAus 2024 14 Alzheimer’s disease phase 2b/3 Actinogen DTAus 2024 15 Donanemab only modestly slows AD progression Ideally patients with AD would not worsen on treatment at all 0.5 Worsening of CDR-SB over 18 months Ideal trajectory with disease stabilization 0 -0.5 Unmet need despite amyloid therapy -1 -1.5 Benefit of donanemab over 18 months -2 -2.5 Worse performance -3 donanemab all placebo all halt progression New or combination treatment needed to stabilize AD without progression Actinogen DTAus 2024 16 Xanamem slows AD progression markedly over 12 weeks Phase 2a data in biomarker (pTau181)-positive patients used to design next AD trial (n=34)1 Xanamem Placebo 0 0.2 0.36 0.4 CDR-SB units Change from Baseline (SE) Xanamem vs. Placebo • • • • 0.6 0.8 Mean 0.6 units Median 0.8 units p = 0.09 Cohen’s d = 0.4 0.98 1 1.2 Worse performance 1.4 Baseline Week 12 pTau-positive patients enrolling in new XanaMIA trial without PET scanning 1. Taylor et al. 2024, biomarker is pTau181 measured in blood Actinogen DTAus 2024 17 XanaMIA phase 2b/3 trial in Alzheimer’s disease Interim results mid 2025, final results mid 2026 Follow-up & open label 10mg Xanamem Screening from Dec 23 Placebo -4 0 Key Inclusion Criteria • Blood pTau biomarker positive • Mild-moderate Alzheimer’s by NIAAA criteria Double-blind, randomised treatment period (N=220) Interim analysis N=100 @ 24 weeks Primary Endpoint • CDR-SB (functional and cognitive measure) Key Secondary Endpoints 36 Weeks 40 Weeks Implementation • Amsterdam Activity of Daily Living (functional measure) • To-be-marketed tablet formulation • Cognitive Test Battery (7 cognitive measures wellvalidated in the Alzheimer’s field) • Enrolment at 15 Australian sites • Currently expanding to 10 sites in US • Interim analysis when 100 people complete 24 weeks NIA-AA=National Institute of Aging - Alzheimer’s Association; CDR-SB Clinical Dementia Rating Scale – Sum of Boxes Actinogen DTAus 2024 18 Conclusions Actinogen DTAus 2024 19 Validation of cortisol mechanism supports AD program XanaMIA Alzheimer’s disease trial implemented as a pivotal, phase 2b/3 design • XanaMIA AD trial is now being conducted as one of two potential “pivotal” trials by: • CDR-SB amended as the primary endpoint • 220 participants gives full statistical power on CDR-SB and cognition • Fully Independent Data Monitoring Committee • “Phase 3-standard” statistical methods • Full statistical power for primary endpoint (p ≤ 0.05) • Sequential examination of secondary endpoints after primary (p ≤ 0.05) • High standard of quality oversight and auditing of trial sites, vendors and procedures • Interim results mid 2025, final results mid 2026 Actinogen DTAus 2024 20 Appendix Actinogen DTAus 2024 21 Xanamem pipeline Indication Preclinical Phase 1 Phase 2 Alzheimer’s disease On-going phase 2b/3 MDD Phase 2a complete, Phase 2b/3 in planning Fragile X syndrome Phase 2a on hold Phase 3 Next Milestone Results 25-26 Open INDs FDA meeting On hold Bipolar disorder PTSD Lewy-body dementia Potential next indications Frontotemporal dementia MDD: Major depressive disorder; CIAS: Cognitive impairment associated with schizophrenia; CI: Cognitive impairment; PD: Parkinson’s disease Actinogen DTAus 2024 22 Experienced board and management team Board of Directors Dr. Geoff Brooke Chairman MBBS; MBA Dr. Steven Gourlay CEO & MD MBBS; FRACP; PhD; MBA Mr. Malcolm McComas Non-Executive Director BEc, LLB; FAICD; SF Fin Dr. George Morstyn Non-Executive Director MBBS; PhD; FRACP CD Dr. Nicki Vasquez Non-Executive Director PhD Management Team Dr. Steven Gourlay CEO & MD Dr. Dana Hilt Chief Medical Officer MD Will Souter Chief Financial Officer BComm, LLB Andrew Udell Chief Commercial Officer MBA Cheryl Townsend VP Clinical Operations RN, M Health Law Fujun Li Head of Manufacturing PhD Michael Roberts Head of IR & Comms B.Ec (Hons), CPA, FFIN Brief Corporate Presentation October 2024 23 Key references Other references see also https://actinogen.com.au/xanamem 11β-HSD1 inhibition • Seckl J. 11β-Hydroxysteroid dehydrogenase and the brain: Not (yet) lost in translation. J Intern Med. 2024 Jan;295(1):20-37. doi: 10.1111/joim.13741. Epub 2023 Nov 8. PMID:37941106. https://onlinelibrary.wiley.com/doi/10.1111/joim.13741 • Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s Disease: Sooy, K., Noble, J., McBride, A., Binnie, M., Yau, J. L. W., Seckl, J. R., Walker, B. R., & Webster, S. P. 2015. Endocrinology, 1-12. • Partial deficiency or short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice Sooy, K., Webster, S. P., Noble, J., Binnie, M., Walker, B. R., Seckl, J. R., & Yau, J. L. W. 2010. Journal of Neuroscience, 30(41), 13867-13872. Xanamem clinical trials • Plasma pTau181 Predicts Clinical Progression in a Phase 2 Randomized Controlled Trial of the 11β-HSD1 Inhibitor Xanamem® for Mild Alzheimer’s Disease Taylor J, Jaros M, Chen C, Harrison J, Hilt D J Alz Dis 2024; 100: 139-150 • Brain 11-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem Assessed by PET in Alzheimer’s Disease and Cognitively Normal Individuals Villemagne VL, Dore V, Chong L, Kassiouf M, Mulligan, R, Feizpoura A, Taylor J, Roesner M, Miller T, Rowe CC J Alz Dis 2024: 97: 1463–1475 • Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem ) Webster, S. P., Ward, P., Binnie, M., Craigie, E., McConnell, K. M., Sooy, K., Vinter, A., Seckl, J.R. & Walker, B. R. 2007. Bioorganic & medicinal chemistry letters, 17(10), 2838-2843. • Various podium and poster presentations on website Technical references • CDR-SB Clinical Dementia Rating Scale – Sum of Boxes is an 18-point, 6-domain measure of patient cognition and function and is a common endpoint used by regulators. Patients in the Xanamem biomarker phase 2a analysis had a baseline of approximately 4 points, similar to that in the donanemab phase 3. • Cohen, J. (1992). A power primer. Psychological Bulletin, 112(1), 155– 159. https://doi.org/10.1037/0033-2909.112.1.155 • Hengartner MP, Jakobsen JC, Sørensen A, Plöderl M (2020) Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials. PLOS ONE 15(2): e0229381. https://doi.org/10.1371/journal.pone.0229381 Alzheimer’s disease and cortisol • Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study Pietrzak RH, Laws SM, Lim YY et. al. for the Australian Imaging, Biomarkers and Lifestyle Research Group 2017. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging 2017; 2(1):45-52 • Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease Starkman, M. N., Giordani, B., Gebarski, S. S., Berent, S., Schork, M. A., & Schteingart, D. E. 1999. Biol psych, 46(12), 1595-1602. Depression and cortisol • Ding et. al. Front. Pharmacol 2021 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461240/ • Effect of glucocorticoid and 11β-hydroxysteroid-dehydrogenase type 1 (11β-HSD1) in neurological and psychiatric disorders Dodd S, Skvarc D R, Dean OM, Anderson A, Kotowicz M, Berk M Int J Neuropsychopharmacol 2022; 25(5):387-398 • Depression and Hypothalamic-Pituitary-Adrenal Activation: A Quantitative Summary of Four Decades of Research Stetler C, Miller GE Psychosom Med 2011; 73(2):114-26 Market & cost of treatment estimates • Matthews, K. A., Xu, W., Gaglioti, A. H., Holt, J. B., Croft, J. B., Mack, D., & McGuire, L. C. (2018). Racial and ethnic estimates of Alzheimer’s disease and related dementias in the United States (2015–2060) in adults aged≥ 65 years. Alzheimer’s & Dementia. https://doi.org/10.1016/j.jalz.2018.06.3063 • Hurd MD, Martorell P, Delavande A, Mullen KJ, Langa KM. Monetary costs of dementia in the United States. NEJM. 2013;368(14):1326-34. • https://www.cdc.gov/aging/aginginfo/al