Announcement PDF ASX ANNOUNCEMENT Actinogen CEO & CMO present at Sachs Neuroscience Innovation Forum & JPM Week meetings Sydney, 8 January 2024. Actinogen Medical ASX: ACW (“ACW” or “the Company”) is pleased to announce that Chief Medical Officer Dr Dana Hilt will present today at the Sachs Associates 7th Annual Neuroscience Innovation Forum in San Francisco (7 January USA PST). Dr Hilt is joined in San Francisco by ACW CEO Dr Steven Gourlay. The Sachs Forum brings together large and small pharmaceutical companies and investors who are focused on neuroscience as a key component of their pipelines and portfolios. The audience includes buy and sell side analysts from investment banks and funds, along with partnering executives from pharma, biotech, medtech, neurotech and diagnostics companies. After more than two years of subdued conditions and performance in the biotech sector, the neuroscience industry received a major boost in 2023 with approval of the anti-amyloid antibody drug Leqembi™ for Alzheimer’s disease and announcement of the Phase 3 success for donanemab. Recently, dealmaking has accelerated with the US$8.7 billion Abbvie acquisition of Cerevel Therapeutics for their psychiatric and neurological treatments including those for schizophrenia, Parkinson's disease and mood disorders announced on 6 December, and the US$14 billion acquisition of Karuna Therapeutics by Bristol Myers Squibb for their psychiatry and neurology assets, announced on 22 December. While in San Francisco, Dr Gourlay and Dr Hilt will also participate in a significant number of partnering, analyst and investor meetings associated with the 42nd Annual J.P. Morgan Healthcare Conference from 8 to 12 January (JPM Week). The information used for all Sachs Innovation Forum and JPM Week presentations and meetings is attached to this announcement or has been previously announced. The attached presentation recaps the success of Xanamem, ® ACW’s novel pro-cognitive and potentially disease-modifying small molecule drug and examines the two near-term major Phase 2 readouts in Depression and Alzheimer's disease in 2024 and 2025 respectively. Dr Steven Gourlay, Actinogen’s CEO and Managing Director, said: “In San Francisco we are focused on briefing potential pharmaceutical partners on our progress and planned data readout for the XanaCIDD Phase 2a depression trial in less than 6 months. Novel mechanisms to successfully treat depression are very important and valuable clinical opportunities. "We will also be briefing potential partners on the XanaMIA Phase 2b Alzheimer’s disease trial, which is expected to release interim results on the first 100 patients in the first half of 2025. We have a high level of ® 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 confidence in the utility of Xanamem for treating Alzheimer’s disease based on the positive results seen in three prior independent, placebo-controlled trials.” ENDS Investors Dr. Steven Gourlay CEO & Managing Director P: +61 2 8964 7401 E. steven.gourlay@actinogen.com.au Michael Roberts Investor Relations M: +61 423 866 231 E. michael.roberts@actinogen.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. 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 and Upcoming Clinical Trials The XanaCIDD Phase 2a depression trial is a double-blind, six-week proof-of-concept, placebo-controlled, parallel group design trial in 160 patients. Patients are evenly randomized to receive Xanamem 10 mg once daily or placebo, in some cases in addition to their existing antidepressant therapy, and effects on cognition and depression are assessed. 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 a pTau protein biomarker in blood. Patients receive Xanamem 10 mg or placebo, once daily, and effects on cognition, function and progression of Alzheimer’s disease are assessed. Thus, Xanamem is being assessed in this trial for its potential effects as both a cognitive enhancer and a disease course modifier. About Xanamem Xanamem’s novel mechanism of action is to block the production of cortisol inside cells through the inhibition of the 11βHSD1 enzyme in the brain. Xanamem is designed to get into the brain after it is absorbed in the intestines upon swallowing. Chronically elevated cortisol is associated with cognitive decline in Alzheimer’s Disease and excess cortisol is known to be toxic to brain cells. Cognitive impairment is also a feature in Depression and many other diseases. Cortisol itself is also ® 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 associated with depressive symptoms and when targeted via other mechanisms has shown some promise in prior clinical trials. The Company has studied 11β-HSD1 inhibition by Xanamem in approximately 350 volunteers and patients, so far finding a statistically significant improvement in working memory and attention, compared with placebo, in healthy, older volunteers in two consecutive trials and clinically significant improvements in functional and cognitive ability in patients with biomarkerpositive mild AD. Previously, 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. A series of Phase 2 studies in multiple diseases is being conducted to further confirm and characterize Xanamem’s therapeutic potential. 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. 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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 Xanamem: A novel pro-cognitive and potentially disease modifying drug Two near-term major Phase 2 readouts in Depression and Alzheimer's disease in 2024 & 2025 Presented at the 7th Sachs Neuroscience Innovation Forum and JPM week meetings San Francisco, 7 - 12 January 2024 Non-confidential ® 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. The information in this presentation is provided in summary form and does not contain all information necessary to make an investment decision. 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Sachs Neuroscience Innovation Forum January 2024 2 Xanamem: Oral, once-a-day treatment with a unique, non-amyloid/non-tau mechanism Mouse experimental studies & clinical trials validate cortisol as a target for the treatment of AD1-4 Inflammation and glucose/lipid dysregulation emerging as key mechanisms in AD5 Xanamem is a brain penetrant 11β-HSD1 small molecule enzyme inhibitor which reduces brain cortisol3,4 Potential to be: ▪ ▪ ▪ ▪ ▪ Rapidly cognitive enhancing Disease-modifying (slowing progression)1,3 Anti-depressant effects Anti-inflammatory effects Insulin sensitizing 1. Sooy et al. 2015 showing effects on amyloid plaque reduction in an aged mouse model after 28 days associated with increases in insulin degrading enzyme – at 13 month cognitive protection was independent of continued amyloid deposition; 3 2. Popoli et al. 2011 microglial cell modulation in rats, effects on glutamate, cannabinoid and other signalling pathways; 3. Hilt, D. Oral symposium AD/PD International Conference 2023; Actinogen website: Actinogen – News; 4. based on human PET scan evidence (data on file), Webster et al. 2017 Selection and early clinical evaluation of the brain‐penetrant 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) inhibitor UE2343 (Xanamem™); 5. CTAD conference Oct 2023 January 2024 PET data shows full target engagement in the brain at low doses Previous enzyme inhibitors1 have not achieved adequate brain concentrations Baseline After 7 days of daily dosing 5 mg Xanamem 10 mg Xanamem 20 mg Xanamem SUVRcarotid PET data2 demonstrates that 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. 1. ABT-384 was claimed to have brain penetrant ability based on likely hepatic effects on deuterated cortisol (Katz et al. 2013), negative 12-week AD trial (Marek et al. 2014) 2. Study population consisted of ~50% healthy older subjects who were cognitively normal and ~50% with Alzheimer's disease. Subjects dosed for seven days. Baseline: Mean of baseline scans of patients in that dose group; After dose: Mean of post-dosing (7 days) scans in that dose group. Sachs Neuroscience Innovation Forum January 2024 4 Two large clinical opportunities: Depression and AD Rapidly acting oral therapy with dual action on cognitive impairment / depression Depression market size ~$17 billion in 2032 Cognitively enhancing and disease modifying oral therapy for all stages of Alzheimer’s disease not just MCI Alzheimer’s market ~$14 billion in 2030 Depression market size ~$17 billion in 2032 1. 2. https://www.futuremarketinsights.com/reports/depression-treatment-market 3 Nov 2023 Global Data report 7 June 2023 Sachs Neuroscience Innovation Forum January 2024 5 Actinogen Xanamem Phase 2 trials underway De-risked by extensive existing clinical data from four previous trials of Xanamem 10mg Phase 2a proof-of-concept trial in Depression/Cognitive Impairment (n=160) Phase 2b confirmatory trial in mild-moderate Alzheimer’s disease (n=220) Results Q2 2024 Interim results H1 2025 n~100 Sachs Neuroscience Innovation Forum January 2024 6 Targeting brain cortisol with Xanamem is a promising strategy in depression ✓ 80-90% of MDD patients report neurocognitive symptoms1 ✓ Cognitive symptoms often persist during remission1 ✓ Elevated cortisol associated with severe, melancholic depression2 ✓ Cortisol levels associated with treatment outcomes, relapse, & cognition3 ✓ Positive effects with GR receptor antagonism with mifepristone4 ✓ Meta-analysis of clinical cortisol approaches5 ✓ Xanamem has improved human cognition in 2 trials with same cognitive endpoint to be used6 1. 2. 3. 4. 5. 6. 3-year prospective study and review, Conradi et al. 2011 Quantitative summary of four decades of research, Stetler & Miller 2011 Depression literature review, Malhi & Mann 2018; HPA axis in major depression, Keller et al. 2016 GR, glucocorticoid receptor; Combined analysis of mifepristone for psychotic depression, Block et al. 2018; mifepristone effects on depression in biopolar disorder, Young et al. 2004; Evidence from clinical studies with CRH1 receptor antagonists, Holsboer & Ising 2008 Meta-analysis of prior trials aimed at reducing cortisol, Ding et. al 2021 Two Xanamem placebo-controlled trials showing improved working memory & attention (Actinogen data on file) Sachs Neuroscience Innovation Forum January 2024 7 7 XanaCIDD proof-of-concept Phase 2a trial in Depression and Cognitive Impairment 10mg Xanamem +/- existing antidepressant Follow-up Screening Placebo +/- existing antidepressant -4 0 6 10 Weeks Double-blind, randomised treatment period (N=160) Key inclusion/exclusion criteria • Primary diagnosis of MDD • Persistent depressive symptoms/deficit despite existing therapy or no therapy • Cognitive impairment relative to demographic norms (~0.5 SD) Primary Endpoints • Cogstate Cognitive Test Battery Attentional Composite (attention and working memory)* Key Secondary Endpoints • Montgomery-Åsberg Depression Rating Scale (MADRS) • Executive Function Cognitive Composite • Memory Function Cognitive Composite * Same attention and working memory tests shown to demonstrate Xanamem effect in the XanaHES and XanaMIA Part A trials (see Slide 7) Key Implementation Features • Australia & UK trial sites • Actinogen “hands-on” operational model • ~100 enrolled • Final Results Q2 CY24 Sachs Neuroscience Innovation Forum January 2024 8 The answers to Alzheimer’s Disease are starting to emerge in the clinic… Alzheimer’s proteins amyloid and tau are the pathology – not the cause… Clearing amyloid produces a very modest benefit Other causal processes are involved like inflammation, lipids and glucose handling… Sachs Neuroscience Innovation Forum January 2024 9 Newer anti-amyloid “immunotherapy” antibodies shown to slow but not halt progression of AD1 Ideally patients would not worsen on treatment 0 Worsening of CDR-SB2 over 18 months -0.5 Large area of unmet need requires nonamyloid therapies -1 -1.5 Benefit of donanemab -2 -2.5 donanemab all placebo all halt progression -3 Drugs targeting other mechanisms like Xanamem are needed 1. 2. Donamemab is an anti-amyloid antibody given as an intravenous infusion every 4 weeks until amyloid clearance (Sims JR at al. JAMA. Published online July 17, 2023. Sachs Neuroscience Innovation Forum January 2024 10 doi:10.1001/jama.2023.13239 Data shown are for whole population studied with absolute difference to placebo of 0.7 points, intermediate tau population difference also 0.7 points CDR-SB is an 18-point scale measuring functional status on an 18 point scale, patients in the donanemab trial had an average baseline score of 4 ± 2 points Dr Howard Fillit, Founder Alzheimer’s Drug Discovery Foundation1 “Seventy-eight percent …. of all drugs in clinical development are nonamyloid, non-tau drugs. Multiple targets are being addressed now, which is great for the field because I think the way we're going to have to go is combination therapy, addressing all the multiple pathways that are involved in Alzheimer’s.” 1. https://www.neurologylive.com/view/looking-ahead-development-alzheimer-disease-howard-fillit; updated at recent October 2023 CTAD conference as 78% of programs Sachs Neuroscience Innovation Forum January 2024 11 Cortisol in AD: Guilt by association • Multiple studies support the association between elevated 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 MEAN CSF CORTISOL LEVELS 0.7 • 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 0.6 CSF cortisol (μg/dl) • Individuals with the APOE-ε4 allele have higher CSF cortisol8 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; Sachs Neuroscience Innovation Forum January 2024 12 11β-HSD1 inhibition and attenuated cognitive decline Xanamem has pleiotropic mechanisms of action to reduce or halt cognitive decline Increased synaptic plasticity cortisone (inert) z X Lowers brain cortisol Greater dendritic complexity reduced GR/MR activation Less negative feedback • • Increases pituitary ACTH within normal range No reduction of plasma cortisol at doses ≤10 mg Better working & episodic memory Larger hippocampal volume + Reduced amyloid synthesis Increased IDE amyloid clearance Reduced tau phosphorylation Reduced neurodegeneration Less excitotoxicity - glutamate 11β-HSD1 inhibition cortisone (inert) zX Altered neuroinflammation Lowers liver & fat cortisol improved Insulin sensitivity + Improved glucose handling Reduced vascular pathology Potential metabolic benefits Sachs Neuroscience Innovation Forum January 2024 13 Methods for double-blind, prospective assessment of biomarker-positive mild AD patients in Phase 2a1 Re-examining the 12-week XanADu Phase 2a trial with biomarkers - a simulation of the 36-week XanaMIA Phase 2b trial Measure disease biomarkers Week 0 & 12 72 patients with stored blood samples Phase 2a trial (XanADu2) • Blinded laboratory and company staff • N=34 with elevated pTau • pTau181 • Amyloid 42/40 ratio • GFAP • Assess change over time Assess efficacy trends on clinical endpoints • Effects in biomarker-positive patients • Endpoints including CDR-SB, executive function, ADAS-Cog • Cohen’s d to measure clinical effect size • 185 people with mild AD treated for 12 weeks with 10 mg or placebo 1. Used a pre-specified protocol and statistical analysis plan, blinded laboratory and company personnel 2. Prior phase 2a trial completed in 2019 included participants with a clinical diagnosis but no PET or biomarker confirmation https://clinicaltrials.gov/ct2/show/results/NCT02727699?term=actinogen&draw=2&rank=3 Sachs Neuroscience Innovation Forum January 2024 14 Xanamem significantly slows the rate of functional decline (CDR-SB) in patients with mild AD* Patients with elevated plasma pTau181 indicating progressive, amyloid-positive disease (n=34) Xanamem 0 Placebo 0 0.2 CDR-SB units Change from Baseline (SE) 0.36 0.4 * Difference vs. placebo 0.6 0.8 0.98 1 Worse * • • • • Mean 0.6 units Median 0.8 units p = 0.09 Cohen’s d = 0.4 1.2 1.4 Baseline Week 12 Xanamem benefits extrapolated to 18 months would produce a large effect size * CDR-SB Clinical Demetia Rating Scale – Sum of Boxes is a measure of patient function and is an endpoint used by the FDA; Patients with a pre-treatment plasma pTau181 level greater than the prespecified median of 6.74 pg/mL to indicate AD pathology and likelihood of progressive disease; similar effect size for pTau >10.2 pg/mL cutoff; extrapolated effect size 8-10 times greater than 0.4-0.45 reported for lecanemab (USPI Leqembi 2023 & van Dyck et al. 2022; DOI: 10.1056/NEJMoa2212948) if extrapolated to 18 months; no treatment effect detected in ADASCog-14 or ADCOMS January 2024 15 Cognitive improvements suggest potential clinical benefits across dementia patient sub-types* Positive trends in both high and low plasma pTau biomarker groups Higher pTau biomarker (n=34) Lower pTau biomarker (n=34) 0.3 Composite Units (SE) Composite Units (SE*) 0.3 0.2 0.1 0 -0.1 -0.2 -0.3 Worse 0.2 0.1 0 -0.1 -0.2 -0.3 Xanamem Placebo Preserved cognition Xanamem Placebo Cognitive enhancement Consistent with Xanamem activity as a cognitive enhancer & disease-modifier * Post hoc analysis of composite of word recall & recognition, CFT & COWAT tests (p=NS), error bars show Standard Error of the Mean; low pTau patients less likely to have amyloid-positive disease, results consistent with volunteer data shown in Slide 7 Sachs Neuroscience Innovation Forum January 2024 16 XanaMIA Phase 2b trial in Alzheimer’s Disease Matching patients and endpoints in Phase 2b as in the positive Ph 2a analysis 10mg Xanamem Follow-up & open label Screening from Dec 23 Placebo -4 0 40 Weeks 36 Double-blind, randomised treatment period (N=220) Interim analysis N=100 @ 24 weeks Key inclusion/exclusion criteria • Clinical diagnosis of mild to moderate dementia due to AD (NIA-AA, MMSE 18-26) • Elevated blood p-tau181 to confirm progressive AD diagnosis • Cognitive impairment test deficit Primary Endpoints • Cognitive Test Battery (7 cognitive measures) NIA-AA=National Institute of Aging - Alzheimer’s Association; CDR-SB Clinical Dementia Rating Scale – Sum of Boxes Key Secondary Endpoints Key Implementation Features • CDR-SB (functional measure) • Amsterdam Activity of Daily Living scale • Executive Function & Episodic Memory Function Composites • Care Giver questionnaire / Patient Global Improvement • Initial 100 patients in Australia with Administrative IA in H1CY25 • Expand to global trial sites including US, Asia, EU and other post IA • Actinogen “hands-on” operational model assures high quality Sachs Neuroscience Innovation Forum January 2024 17 Xanamem AD & Depression programs Building on multiple Phase 1 and 2 studies showing safety and procognitive activity Prior Phase 1 & 2a studies Safety (n~350), cognition, clinical activity demonstrated in 3 prior trials Phase 2a (n=160) Phase 2b (n=220) Cognitive Impairment in Depressive Disorder (CIDD) Final results Q224 Alzheimer’s Disease (AD) Initial results H125 Phase 3 Phase 3 Cognitive Impairment in Depression Alzheimer’s Disease with focus on cognitive enhancement Sachs Neuroscience I