Announcement PDF ASX ANNOUNCEMENT Actinogen XanaMIA Phase 2b Alzheimer’s disease (AD) trial amendment and Clinical Trials Science Forum 2023 presentation slides Sydney, 24 May 2023. Actinogen Medical ASX: ACW (“ACW” or “the Company”) announces specific amendments to the upcoming XanaMIA Phase 2b clinical trial in patients with AD and release of the presentation slides for this morning’s Clinical Trials Science Forum webinar commencing at 11am AEST. XanaMIA Phase 2b AD trial amendment Having completed a number of key steps to develop a global syndicate of investigators and trial sites for the upcoming trial, Actinogen is making several improvements to the trial design while submitting updated regulatory documentation to the FDA and other regulators. FDA approval of the tablet formulation and protocol changes outlined below is expected early in H2 CY23 and the first patient is expected to be treated in the subsequent months. Results are expected in H2 CY25. Principal components of the XanaMIA Phase 2b trial amendment are: • • • • • The newly manufactured tablet formulation will be used in the Phase 2b trial Patients will be enrolled for a 36-week double-blind treatment period (24 weeks previously) to improve initial assessment of disease-modification effects An interim analysis will be included around the middle of trial enrolment Patients with “moderate AD” are now included to match the Phase 2a population more closely with elevated pTau levels in the blood analysed and previously reported to have a large Xanamem  effect Following extensive data analysis of prior trial data, the primary endpoint will be a cognitive composite of several tests, reflecting the strong cognitive effects of Xanamem in prior trials. The CDR-SB functional score remains a key secondary endpoint along with the assessment of activities of daily living. Clinical Trials Science Forum webinar Event registration: https://us02web.zoom.us/webinar/register/WN_5gdyj5DpRJ-XORhbhafIPQ ‘Following the Science’ is fundamental to all Actinogen’s activities and a primary foundation for today’s presentation titled Alzheimer’s disease: amyloid therapies are only part of the answer. The presentation is designed to explain the science behind targeting amyloid in Alzheimer’s disease and the opportunity for nonamyloid treatments such as Xanamem. The quest to find drug therapies to cure AD has only just begun. The approval of two recent anti-amyloid antibody drugs in the USA and another with positive late-stage clinical results is a great beginning for AD  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 therapy but this approach does not halt disease progression, requires intravenous infusion, and is associated with serious but rare side effects. Actinogen is a leader in clinical AD research having the only oral therapy to have demonstrated benefits on cognition in multiple placebo-controlled trials. 1 We consider the ‘weight of evidence’ from academic work and our own trials has validated Xanamem’s cortisol mechanism and are excited to now conduct our two larger Phase 2 controlled trials in AD and cognitive impairment in depression. Today’s plain English webinar has been designed for a broad audience, including those from non-technical backgrounds. The presentations will explore the following topics: • • • An overview of the current ‘state of play’ on clinical AD research (CEO, Dr Steven Gourlay) An introduction to the Xanamem drug product and in particular its tablet formulation by Dr Fujun Li, Head of Manufacturing, that has been developed for the upcoming XanaMIA Phase 2b AD trial and all subsequent trials An insightful high-level analysis from ACW CMO and neurologist, Dr Dana Hilt on the role of treating AD with anti-amyloid antibody therapy and the significant opportunity remaining for alternative and complementary approaches A copy of the full presentation is attached to this announcement. As soon as practicable after the conclusion of the webinar a full recording will be made available on the company’s website: www.actinogen.com.au. Dr Steven Gourlay, Actinogen CEO and MD, commented: “Actinogen is at a remarkably important juncture in the world of drug development with its promising oral therapy Xanamem. While recent data on new amyloid antibody infusions give Alzheimer’s patients hope, they do not halt disease progression, highlighting the continued and urgent need to find effective and safe nonamyloid therapies. “Today’s Clinical Trials Science Forum will cover three important topics: Xanamem manufacturing, understanding how to put amyloid and non-amyloid therapies into context, and the XanaMIA Phase 2b trial design update. “We remain committed to our high-quality and timely Phase 2 trials in both Alzheimer’s and cognitive impairment in depression and believe they will demonstrate and confirm the potent clinical benefit of Xanamem therapy.” 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 1 Companies claiming efficacy based on uncontrolled data, biomarkers or imaging not included in this comparison 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 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. 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 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 more than 300 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 ENCOURAGES ALL CURRENT INVESTORS TO GO PAPERLESS BY REGISTERING THEIR DETAILS WITH THE DESIGNATED REGISTRY SERVICE PROVIDER, AUTOMIC GROUP. ® 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 3 FOLLOWING THE SCIENCE Clinical Trials Science Forum Alzheimer’s disease: amyloid therapies are only part of the answer Xanamem® targets brain cortisol and is one of a few programs that has demonstrated clinical benefit Wednesday 24 May 2023 | 11.00am AEST ® 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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Clinical Trials Science Forum 2 Introduction and welcome Michael Roberts BEc Hons, CPA, Ffin Dr Steven Gourlay MBBS FRACP PhD MBA Investor Relations Chief Executive Officer • 25+ years' business experience • Industry physician with more than 25 years experience • Senior IR & comms professional in top-50 listed companies • Strategic corporate comms advisor • Venture capital 8 years • Recent successful startup exit with sale of Principia Biopharma to Sanofi for US$3.7 billion Clinical Trials Science Forum 2023 3 Clinical Trials Science Forum 4 Agenda Welcome Michael Roberts Investor Relations Dr Steven Gourlay Introduction Chief Executive Officer Introduction of Xanamem drug product Dr Fujun Li The treatment of Alzheimer’s disease: Amyloid is not the entire problem … so, it is only part of the solution Dr Dana Hilt Summary Moderator Dr Steven Gourlay Questions and wrap-up Moderator Dr Steven Gourlay Head of Manufacturing Chief Medical Officer Clinical Trials Science Forum 5 Introduction Dr Steven Gourlay Chief Executive Officer Clinical Trials Science Forum 6 Actinogen is a leader in clinical Alzheimer’s research Only amyloid antibody infusions and oral Xanamem have multiple, positive cognitive trial data1 Actinogen Oral Xanamem • Safely targets brain tissue cortisol • 2 trials: improved attention & working memory • 1 trial: trends to reduce AD progression, improve cognition Eisai-Biogen i.v. infusion of lecanemab • Approved on ability to reduce brain amyloid • Causes brain swelling and bleeding • 2 trials reduced progression modestly • Will need to be combined with other therapies Lilly i.v. infusion of donanemab • Full approval expected ~8 months, reduces brain amyloid • Causes brain swelling and bleeding • 2 trials reduced progression modestly • Will need to be combined with other therapies 1 Companies claiming efficacy based on uncontrolled data, biomarkers or imaging not included in this comparison Clinical Trials Science Forum 7 Introduction of Xanamem drug product Dr Fujun Li, Ph.D. Head of Manufacturing Clinical Trials Science Forum 8 Xanamem is promising small molecule pharmaceutic • Small molecule, once-a-day pill or capsule for oral administration • High solubility and high membrane permeability - well absorbed through gastrointestinal tract (intestines) • Crystalline material and stable at room temperature C19H19N5O2S Molecular Wt: 381.45 Drug in tablet Dissolution in stomach Drug in solution Absorption in intestines Drug in blood and brain Xanamem has favourable characteristics for an oral drug Clinical Trials Science Forum 9 Xanamem capsules and now (commercial) tablets Xanamem was initially formulated in gelatin capsules that were used in early Phase 1 and Phase 2 clinical studies As Actinogen prepares for and implements late phase clinical studies, a tablet formulation has been developed that provides advantages over capsules • Capsules contained simple blend of drug substance and inactive ingredients • Typically, has longer shelf-life Capsule formulation offered flexibility to accommodate changes of dose in early clinical trials • Manufacturing is easy to scale-up and more cost effective Capsule formulation Tablet formulation • • Variety of shapes, sizes, colors and identifiers Clinical Trials Science Forum 10 Advantages of Xanamem tablets over injectables like anti-amyloid antibodies • Xanamem tablets are manufactured using a conventional tablet manufacturing process according to Good Manufacturing Practice (GMP) standards • Small pill and easy to swallow for elderly patients • Once a day oral dosing at home unlike intravenous injections or infusions needing clinic visits • No infusion-related adverse effects • No requirement for frequent brain scans to monitor for brain swelling • Storage at room temperature - no need for refrigeration Xanamem oral tablet is convenient to take, cost effective to manufacture and designed to minimize patient burden Clinical Trials Science Forum 11 The treatment of Alzheimer’s disease (AD) Amyloid is not the entire problem … so, it is only part of the solution Dr Dana C Hilt MD Chief Medical Officer Clinical Trials Science Forum 12 Alois Alzheimer and amyloid The historical background of amyloid in AD In November 1901, Dr. Alois Alzheimer, a German neurologist, made his first examination of a 51-year-old woman named Auguste Deter who was experiencing problems with memory and language as well as various psychological problems such as disorientation and hallucinations. These symptoms matched the definition of what was then called ‘dementia’, but she was very young to be displaying them, so he diagnosed her as having “presenile dementia”. This came to be known as Alzheimer’s disease. The pathological hallmarks of AD include: • amyloid plaques - deposits of extracellular amyloid; and • neurofibrillary tangles - intracellular deposits of tau protein The plaques and tangles of AD Tau tangles Amyloid plaques Clinical Trials Science Forum 13 Amyloid as the cause of AD: A closer look Reducing amyloid to treat AD Amyloid can not be the entire solution • • Mutations in amyloid and enzymes processing amyloid account for a very small fraction <2% of all AD patients1 • • All genetic cases of AD are associated with some defect in amyloid protein processing: mutation in the amyloid gene or mutation in the enzymes processing amyloid All cases of AD have the signature of amyloid and tau protein deposition in the brain Overexpression of amyloid in animal models of AD can lead to nervous system pathology and behavioral abnormalities • Amyloid (or Tau) mutations are not the cause of the vast majority of AD cases • AD greatest genetic risk - ApoE4 gene - encodes a protein linked to lipid/fat metabolism not amyloid metabolism • The association with amyloid and tau deposition in the brain and AD clinical stage is low2 • ~33% of older cognitively normal people have amyloid in their brains at the same level as in AD3 1. 2. 3. Haas etal Plos Biol 2022 Tideman etal Neurology 2022 Jansen etal JAMA Neurol 2022 Clinical Trials Science Forum 14 Amyloid as the cause of AD: A closer look Reducing amyloid to treat AD Amyloid can not be the entire solution • The amyloid gene is contained on chromosome 21 • Trisomy (3 copies) of chromosome 21 causes Down Syndrome which is characterized by early cognitive impairment (early AD) and AD pathology • >15 anti-amyloid therapies have been taken into large clinical trials • A mutation in the amyloid gene decreasing production of amyloid has been detected and individuals with decreased amyloid production are partially protected against AD • Some of these drugs have demonstrated significant clearing of amyloid from the brain - but no benefit • Stated at the recent AD Congress: ‘To date we have ‘Only 1½ drugs which have an effect’ 1: lecanemab and aducanumab’ • Other drugs that have cleared amyloid to approximately the same degree… have had no effect… some have made the condition worse • The treatment effects of the most successful anti-amyloid antibodies (lecanemab and donanemab) are modest For every complex question, there is a simple answer… and it is wrong2 1. 2. AD/PD Congress, April 2023 Variously attributed the either HL Mencken or Mark Twain Clinical Trials Science Forum 15 The effects of clearing amyloid in AD Correlations between amyloid clearance and clinical benefit in anti-amyloid antibody studies are modest • A number antibodies have shown clearance of amyloid but few have shown benefit1 • In some antibody studies (e.g. aducanumab and donanemab) brain volume actually shrinks on treatment • Weak correlation between amyloid removal and clinical benefit (CDR-SB)2. Recently, more robust clearance does seem to correlate with clinical benefit for lecanemab and donanemab • Lecanemab showed an ~0.45 point CDR-SB change in the Phase 3 study over 18 months – well below the Minimal Clinically Important Difference (MCID) for the CDR-SB in AD of ~1.5 points3 The clinical benefits of anti-amyloid antibody infusions are modest 1. 2. 3. Haas etal Plos Biology 2022 Clinical Dementia Rating Scale- Sum of Boxes Andrews etal Alzheimer’s Dementia 2022 Clinical Trials Science Forum 16 Anti-amyloid approach leaves significant unmet medical need Lecanemab1 slows progression modestly during the first 12 months CDR-SB units Blue area = treatment effect 1. Lecanemab is an anti-amyloid antibody given as an intravenous infusion every 2 weeks and largely clears brain of amyloid largely by 12 months, accelerated approval given by the US FDA based the ability of the drug to clear amyloid, full approval pending. Used a functional AD scale called the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) with an effect size reported of 0.4-0.45 points at 18 months; Leqembi USPI & van Dyck et al. 2022; DOI: 10.1056/NEJMoa2212948 Clinical Trials Science Forum 17 Anti-amyloid approach leaves significant unmet medical need CDR-SB* units Area of unmet need for newer and novel non-amyloid therapies like Xanamem ~1.2 points Area of treatment effect ~0.4 points Drugs targeting other mechanisms like Xanamem will be required to fill this gap * Lecanemab is an anti-amyloid antibody given as an intravenous infusion every 2 weeks and largely clears brain of amyloid by 12 months, accelerated approval given by the US FDA based the ability of the drug to clear amyloid, full approval pending. Used (CDR-SB) with an effect size reported of 0.4-0.45 points at 18 months; Leqembi USPI & van Dyck et al. 2022; DOI: 10.1056/NEJMoa2212948 n=1795) Clinical Trials Science Forum 18 The road forward to better treatment • Reducing amyloid to treat AD can provide modest clinical benefit (lecanemab and donanemab antibodies) • The benefit seen for lecanemab and donanemab is likely to be the maximal effect of anti-amyloid therapy as they clear amyloid rapidly and to a great extent • The effects may wane after ~12 months • Intravenous infusions required, side effects like brain swelling and bleeding may be fatal, require monitoring including multiple MRI brain scans The challenge The goal Identification of additional therapies to add to the presently approved treatments Enhance function and clinical benefit for patients Virtually all chronic illnesses require multiple therapies to make a significant impact on the disease AD is no exception: Better or combination therapies will be the key to effective treatment Clinical Trials Science Forum 19 Xanamem: Oral, low dose, once-a-day treatment with a unique non-amyloid/tau mechanism Only known brain penetrant 11β-HSD1 small molecule enzyme inhibitor Reduces cortisol in brain - modulating signalling pathways and potentially underlying disease processes1,2 11β-HSD1 is preferentially expressed in brain and liver but minimally expressed in endocrine tissues Xanamem has potential to: • • Enhance cognition • Be anti-depressant/procognitive in depression 1. 2. Slow progression or produce durable delay in symptoms in AD Xanamem® is a CNS (Central Nervous System) penetrant small molecule based on human PET scan evidence and cerebrospinal fluid (CSF) measurements 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; Popoli et al. 2011 microglial cell modulation in rats, effects on glutamate, cannabinoid and other signalling pathways Clinical Trials Science Forum 20 Elevated cortisol leads to human brain dysfunction • 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 MEAN CSF CORTISOL LEVELS o Higher plasma cortisol leads to a much greater risk of developing AD o Accelerated effect of Αβ+ on decline in global cognition, episodic memory, and attention 0.7 • • 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 is one of the predictors of probable AD after age 7512 CSF cortisol (μg/dl) • 0.6 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; Clinical Trials Science Forum 21 Xanamem clinical trial data Two separate normal volunteer studies have shown positive procognitive effects of Xanamem: attention, working memory, and executive function1 Oral Xanamem 5 and 10 mg/d have excellent CNS penetration and target occupancy by PET scanning while being safe and well tolerated New analyses of the Phase 2 XanADu