Slides
Page 1
Oral Xanamem® (emestedastat) Controlling brain cortisol to slow progression in Alzheimer’s disease and treat depression Corporate Presentation October 2025 ® Xanamem is a registered trademark of Actinogen Medical Limited
Page 2
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. • This presentation does not constitute an offer, invitation, solicitation or recommendation with respect to the purchase or sale of any security in Actinogen, nor does it constitute financial product advice or take into account any individual’s investment objectives, taxation situation, financial situation or needs. An investor must not act on the basis of any matter contained in this presentation but must make its own assessment of Actinogen and conduct its own investigations. Before making an investment decision, investors should consider the appropriateness of the information having regard to their own objectives, financial situation and needs, and seek legal, taxation and financial advice appropriate to their jurisdiction and circumstances. Actinogen is not licensed to provide financial product advice in respect of its securities or any other financial products. Cooling off rights do not apply to the acquisition of Actinogen securities. • Although reasonable care has been taken to ensure that the facts stated in this presentation are accurate and that the opinions expressed are fair and reasonable, no representation or warranty, express or implied, is made as to the fairness, accuracy, completeness or correctness of the information, opinions and conclusions contained in this presentation. To the maximum extent permitted by law, none of Actinogen its officers, directors, employees and agents, nor any other person, accepts any responsibility and liability for the content of this presentation including, without limitation, any liability arising from fault or negligence, for any loss arising from the use of or reliance on any of the information contained in this presentation or otherwise arising in connection with it. • The information presented in this presentation is subject to change without notice and Actinogen does not have any responsibility or obligation to inform you of any matter arising or coming to their notice, after the date of this presentation, which may affect any matter referred to in this presentation. • This presentation is not for general distribution or third party reliance or use. • This presentation contains certain budget information, forecasts and forward looking statements that are based on the Company’s management’s beliefs, assumptions and expectations and on information currently available to management in respect of which there is NO guarantee of future performance. Such budget information, forecasts and forward looking statements involve known and unknown risks, uncertainties, and other factors which may cause the actual results or performance of Actinogen to be materially different from the results or performance expressed or implied by such forward looking statements. These risks and uncertainties include, but are not limited to the performance of Actinogen in its clinical trials including whether it's technology proves to be a safe and effective treatment, market penetration, competition from any other similar products, intellectual property risks (including securing rights in technology and patents) and global economic conditions. Furthermore, Actinogen's research, product development, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. There is no guarantee that Actinogen will obtain the required approvals, licences and registrations from the relevant authorities in jurisdictions in which it operates. Actinogen or others could identify product and efficacy issues relating to the safety of our technology. Accordingly, all forward looking statements are based on numerous assumptions regarding the Company’s present and future business strategies and the political and economic environment in which Actinogen will operate in the future, which are subject to change without notice. Past performance is not necessarily a guide to future performance and no representation or warranty is made as to the likelihood of achievement or reasonableness of any forward looking statements or other forecast. There is no guarantee that Actinogen will achieve its stated objectives/milestones, that any of its forecasts will be met or that forward looking statements will be realised. You are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof, and we do not undertake any obligation to revise and disseminate forward-looking statements to reflect events or circumstances after the date hereof, or to reflect the occurrence of or non-occurrence of any events. • Neither Actinogen nor any other entity or person in or associated with Actinogen guarantee any return (whether capital or income) or generally the performance of Actinogen or the price at which its securities may trade. Any investment in Actinogen is subject to investment risks including the possibility of loss of capital invested and no return of income or payment of any dividends. • To the maximum extent permitted at law, Actinogen and all of its representatives, directors, officers, partners, employees or professional advisers (Parties) exclude all direct and indirect liability arising out of or in connection with any use or reliance of the information contained or described within this presentation. Other than to the extent required by law (and only to that extent), the Parties do not make any representation or give any assurance, guarantee or warranty (express or implied) as to, nor assume any responsibility or liability for, the authenticity, origin, validity, accuracy, suitability or completeness of, or any errors in or omissions from, any information, statement or opinion contained in this presentation or any accompanying, previous or subsequent material or presentation. Corporate Presentation October 2025 2
Page 3
Corporate Presentation October 2025 3 Overview
Page 4
Xanamem: Clear pathway to Alzheimer’s approval 4 • FDA confirms development pathway to US marketing approval using one additional pivotal trial of 10 mg vs. placebo and open-label safety studies • Clear guidance on minimal ancillary nonclinical and clinical pharmacology work • Agreement on key manufacturing items • Ongoing XanaMIA clinical trial: • Brisk enrolment at 35 clinical centers in US and Australia • Excellent safety profile maintained • Interim analysis of safety and efficacy futility in Jan 2026 • On-track for final results in late 2026 • Phase 3 planning commencing in parallel with discussions re potential partnerships Corporate Presentation October 2025 Phase 2b/3 trial on track, FDA agreement streamlines development
Page 5
First-in-class therapy with strong IP and large market potential Novel 11β-HSD1 cortisol control mechanism, oral, attractive safety profile • Brain cortisol has been proposed as pathogenic mechanism in Alzheimer’s & major depressive disorder • Unique brain-penetrant tissue cortisol synthesis inhibitor that leaves adrenal cortisol synthesis unaffected Patent/data protection and advanced manufacturing • Composition of matter protection to 2036 in all major markets, newer patents to 2044 • Data exclusivity protects Xanamem data from use by others for 5 to 10 years from approval • Manufacturing process scaled up and patented, tablets manufactured in US by Catalent Large clinical and commercial opportunities • No other brain-penetrant cortisol control drugs in development • Multiple clinical trials showing treatment benefits • First to be awarded INN and USAN names1 • 2025 estimated 7.2 million Alzheimer’s patients in the US alone with the cost to treat $384 billion2 5Corporate Presentation October 2025 1. Xanamem’s International Nonproprietary Name (INN) , emestedastat, was awarded by a naming committee of the World Health Organization: “-stedastat” chosen for the first time for all 11β-HSD1 inhibitors; USAN (United States Adopted Name) 2. U.S. burden of Alzheimer’s disease, related dementias to double by 2060 | CDC Online Newsroom | CDC and The Cost of Dementia in 2025 - April 23, 2025 - USC Schaeffer
Page 6
6 Management Team 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 Dr. Dana Hilt Chief Medical Officer MD Dr. Steven Gourlay CEO & 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 Corporate Presentation October 2025
Page 7
Corporate snapshot ASX-listed company founded in 2014 • Market Cap ~$100 million • Cash runway to at least mid 2026 • Seasoned Board and Management team with a track-record of success Key shareholders • CEO Steve Gourlay ~5% (including via ~$2 million invested personally) • Top 20 ex-Gourlay ~23% Phase 2b/3-stage clinical programs are in the “sweet spot” for partnering • Alzheimer’s disease phase 2b/3 ongoing – interim January 2026, final results Q4 2026 • Positive depression trial phase 2a completed, peer-review publication pending • FDA confirms development pathway to US marketing approval (Type C meeting, Sept 2025) Fundraising history • Merger of U Edinburgh spinout Corticrine with Actinogen ASX-listed shell (2014) • Equity raises on ASX and Australian R&D tax incentive cash rebates (e.g. $9 million received in 2024) • Option exercise funds (2024-25) 7Corporate Presentation October 2025
Page 8
Xanamem – Pipeline focused on Alzheimer’s as lead 8 Indication Preclinical Phase 1 Phase 2 Phase 3 Next Milestone Alzheimer’s disease MDD Fragile X syndrome Results 2025-26 Non-dilutive funding Non-dilutive funding Bipolar disorder PTSD Lewy-body dementia Frontotemporal dementia Ongoing phase 2b/3 Phase 2b/3-ready Phase 2a-ready Open INDs Potential next indications MDD: Major depressive disorder Corporate Presentation October 2025 Depression phase 2a results support further development
Page 9
9 Xanamem Corporate Presentation October 2025
Page 10
Clinically validated and differentiated Alzheimer's program ✓ Mouse experimental studies, brain cortisol levels & human clinical trials validate cortisol as a target for the treatment of AD ✓ Excellent safety profile, 400+ patients treated, no related serious adverse events ✓ Fully brain-penetrant oral therapy clearly demonstrated on brain PET scan imaging ✓ Positive clinical data demonstrated in phase 2 trials in patients with biomarker-elevated Alzheimer’s and moderately severe depression ✓ Differentiated from antibody drugs: oral pill, suitable for general practice use, no invasive monitoring ✓ Open INDs and collaborative FDA engagement 10Corporate Presentation October 2025
Page 11
Xanamem’s unique mechanism of action animation 11Corporate Presentation October 2025 Click here for animation video
Page 12
Controlling brain cortisol2 has potential durable benefits Xanamem controls cortisol by inhibition of 11β-HSD11 12 SLOW changes in gene expression and protein synthesis over days to weeks lead to durable “low stress” settings RAPID changes in kinases, cell function, neurotransmitters over hours to days lead to short-term “low stress” settings “Lower stress” longer term e.g. • Improving neural circuitry • Generating new brain cells • Ideal receptor configurations “Lower stress” shorter term e.g. • Reducing inflammation • Improving neurotransmitter balance • Decreasing cell death 1. For a comprehensive review of 11β-HSD1 see Seckl J. 2024 2. Ramamoorthy & Cidlowski 2016 Reduction of “stress response” in brain Corporate Presentation October 2025
Page 13
Other 11β-HSD1 enzyme inhibitors have not achieved adequate brain levels Xanamem extensively binds to the 11β-HSD1 enzyme throughout the brain, with high post-treatment effects (absence of color) 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. SUVRcarotid 5 mg Xanamem Baseline After 7 days of daily dosing 10 mg Xanamem 20 mg Xanamem Human PET study shows full target engagement 13 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 Corporate Presentation October 2025
Page 14
Alzheimer’s disease program 14Corporate Presentation October 2025
Page 15
Alzheimer’s disease market is large and growing Strong cortisol control scientific rationale to address huge unmet medical need • Cortisol levels elevated in brain fluid in early AD • Chronic corticosteroid treatment leads to hippocampal atrophy and cognitive impairment • Elevated cortisol levels are associated with clinical progression • Alzheimer’s disease mouse model: 30–60% inhibition of 11β-HSD1 provides full neuroprotection • AD phase 2a trial shows slowed disease progression in biomarker-positive patients • Safe & effective oral therapy is “holy grail” Growing Alzheimer’s Disease market – U.S. Large, unsatisfied and growing market Rationale 15Corporate Presentation October 2025
Page 16
-3 -2.5 -2 -1.5 -1 -0.5 0 0.5 donanemab all placebo all halt progression Worsening of CDR-SB over 18 months Benefit of donanemab over 18 months 16 Worse performance Ideal trajectory with disease stabilization Drugs targeting other mechanisms like Xanamem are needed Unmet need despite amyloid therapy Anti-amyloid therapy modestly slows AD progression Ideally patients with AD would not worsen on treatment at all Corporate Presentation October 2025
Page 17
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 17 Large Xanamem benefit in high pTau181 patients 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 Corporate Presentation October 2025
Page 18
Initial, interim results January 2026, final results Q4 2026 18NIA-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 = 220) Interim analysis ~ n = 110 Follow-up & open label Key Inclusion Criteria Primary Endpoint Key Secondary Endpoints Implementation • Blood pTau biomarker positive • Mild-moderate Alzheimer’s by NIA-AA 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 • Interim analysis planned when ~100 people complete 24 weeks (efficacy, futility and safety) XanaMIA phase 2b/3 trial in Alzheimer’s disease Corporate Presentation October 2025
Page 19
Commercial readiness 19Corporate Presentation October 2025
Page 20
Direct insights from the front line of Alzheimer’s care Physician perspectives on current practice, unmet needs, and future therapies* • Market research with over 100 general neurologists and dementia/geriatric specialists • Representative of the AD-treating physician population as it relates to geography and practice type, and: • 18 mean years in practice • 94% of time in clinical practice setting • Mean of 222 Alzheimer’s patients (median: 175) under personal care (per physician) Current Market Perceptions: 20Corporate Presentation October 2025 * Spherix Global Insights: Market Dynamics and Custom Research 2025 “I think eventually what will happen is that we're not going to be just treating patients with an amyloid remover, but also anti-neuroinflammation, mitochondrial enhancers, synaptic enhancers and so on and so on, in order to actually stop or substantially slow down the progression of the disease.”
Page 21
Strong physician response to Xanamem’s target profile Over half of their current AD patients fall within Xanamem’s addressable market 21Corporate Presentation October 2025
Page 22
Driving awareness of Xanamem and cortisol biology Expanding education, engagement and visibility • Educational need identified: Qualitative research and advisory boards revealed limited physician understanding of the role of cortisol in the brain and its link to Alzheimer’s pathology • Action taken: Developed a concise two-minute animation explaining Xanamem’s unique “cortisol control” mechanism of action • Scientific presence: Active participation at major Alzheimer’s conferences, including a booth at AAIC and presence at CTAD and other key global meetings • KOL engagement: Ongoing collaboration with leading neurologists and psychiatrists through advisory boards, 1:1 discussions, and planning for future review papers and publications • Broader awareness: Continuing to elevate Xanamem’s visibility and differentiation through consistent medical, scientific, and educational initiative 22Corporate Presentation October 2025
Page 23
Depression program 23Corporate Presentation October 2025
Page 24
There remains significant unmet need in depression Xanamem’s unique mechanism and safety differentiate it from older drugs • More than 50 years of research associates cortisol with depression • Elevated CSF and plasma cortisol levels associated with diagnosis, treatment outcomes and relapse • Positive effects of cortisol receptor antagonism reported with mifepristone3 • Now positive phase 2a data on depressive symptoms for Xanamem (MADRS, PGI-S) Scientific rationale U.S. Depression market large unmet need • 21M patients have had ≥ 1 MDD episode • Two-thirds with an episode with severe impairment in the past year • 61% of all adults with MDD episodes receive treatment • ≥365 M prescriptions per year 24 A safe, durably effective and combinable small molecule is a very attractive product profile for depression AND Alzheimer’s 3. Ding et al 2021 Corporate Presentation October 2025
Page 25
Phase 2a depression symptom benefits (2024) - major scientific and drug development achievement 25 • Clinically and statistically significant treatment benefits on depressive symptoms • Predominantly co-treated population with moderate MDD • Consistent depression efficacy across subgroups • Xanamem was safe and well tolerated (n=165 treated) with no observed suicide risk or withdrawal syndrome • The trial was well-conducted with no major differences between Australia and the UK or at high enrolling clinical sites • Benefits on depression are a desirable feature for an Alzheimer’s drug • Funding for the next depression trial being investigated with potential partners and/or granting bodies Corporate Presentation October 2025 Further XanaCIDD phase 2a depression trial results shown in the Appendix Data support further MDD development and are a positive for Alzheimer’s too
Page 26
Conclusion 26Corporate Presentation October 2025
Page 27
On track to deliver transformative Alzheimer’s data 27 • On-track with XanaMIA trial in patients with mild-moderate Alzheimer’s disease ✓ FDA confirms development pathway to US marketing approval ✓ Full enrolment of 220 participants in Q4 2025 ✓ Formal interim analysis of safety and efficacy futility January 2026, final results Q4 2026 • Positive phase 2a depression data validates Xanamem clinical activity in the brain ✓ Clinical benefit of unique “cortisol control” mechanism of action and 10 mg dose ✓ Reinforces the likelihood of seeing a disease-modifying effect in Alzheimer’s disease ✓ Peer-reviewed journal publication pending • Company funded to at least mid 2026 • Commercial & partnership planning underway • Other trial, regulatory, publication and presentation milestones Corporate Presentation October 2025 Multiple catalysts ahead as Xanamem advances towards pivotal results
Page 28
Multiple near-term milestones in coming year Milestone Likely Timing Screening activities close, XanaMIA AD trial Q4 25 Full enrolment, 220 patients with AD, XanaMIA AD trial Q4 25 XanaCIDD MDD peer-reviewed journal publication Q4 25 / Q1 26 CTAD conference AD presentation in San Diego Q4 25 Meetings at JP Morgan Healthcare conference week, San Francisco Mid Jan 26 Interim analysis XanaMIA AD trial Late Jan 26 ADPD conference AD presentation in Copenhagen Q1 26 EMA Scientific Advice meeting for AD Q2 26 Clinical Trials Science Forum – focus on commercial planning Q2 26 BIO conference in San Diego Q2 26 AAIC AD conference in London Q3 26 Final results, XanaMIA AD trial Q4 26 28Corporate Presentation October 2025
Page 29
Appendix 29Corporate Presentation October 2025
Page 30
Early commercial planning drives strategy and impact Discovery Preclinical Development Phase 1: Clinical Trials Phase 2 (2a/2b): Clinical Trials Phase 3: Clinical Trials Registration Launch / Post Registration 30Corporate Presentation October 2025 Xanamem (emestedastat) current stage Biotechs typically initiate commercial planning “Typical” partnering process
Page 31
Current Alzheimer’s treatments Significant unmet need persists despite two approved anti-amyloid mAbs 31Corporate Presentation October 2025 Top Barriers to Prescribing Anti-Amyloid DMTs % of respondents 56% 36% 35% 32% 27% Patients/caregivers unwilling after hearing about risks & benefits Patients do not have necessary support for treatment logistics Patient/family unable to cover OOP costs Difficulty getting insurance coverage for required testing Burden of MRI monitoring ▪ Neurologists are conscious of the advances current DMTs offer in a field that has seen sparse innovation for decades and they acknowledge the potential benefits these DMTs offer. ▪ However, both neurologists and patients/caregivers remain cautious about the current generation of DMTs, leaving ample opportunity for new entrants to capture both prescribers and brand share. Though acknowledging advance of current DMTs, neurologists remain cautious.
Page 32
AD Pipeline: Opportunity for differentiated therapies Combination approaches likely needed for meaningful impact • Amyloid-targeting therapies: Demonstrated limited efficacy; market differentiation remains modest • Anti-Tau programs: Many early candidates have not achieved clinical success, highlighting development challenges • GLP-1 therapies: Upcoming Q4 2025 trial results are highly anticipated; physician feedback has been mixed, though success could broaden interest in novel MoAs aligned with Xanamem • Pipeline outlook: No single “silver bullet” anticipated; as with other chronic diseases, effective treatment may require complementary therapies 32Corporate Presentation October 2025
Page 33
XanaCIDD trial design and methods – completed CY2024 Phase 2, double-blind, proof-of-concept controlled trial to assess safety and efficacy 33 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 Corporate Presentation October 2025
Page 34
-12 -10 -8 -6 -4 -2 0 Baseline Week 2 Week 4 Week 6 Week 10 PT Xanamem MADRS improvement from Week 6 (n=165) All randomized participants 34Abbreviations: MADRS = Montgomery-Åsberg Depression Rating Scale – a structured interview to assess depression severity BETTER MADRS LS mean change from baseline (± SE) ON TREATMENT FOLLOW UP EOT 1.5-point difference Cohen’s d = 0.24 p = 0.23 PT 2.7-point difference Cohen’s d = 0.43 p < 0.05 Corporate Presentation October 2025 Xanamem (n=82) Placebo (n=83)
Page 35
-12 -10 -8 -6 -4 -2 0 Baseline Week 2 Week 4 Week 6 Week 10 MADRS benefit in patients also taking SSRI (n=76) 35 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 Corporate Presentation October 2025 MADRS LS mean change from baseline (± SE) Xanamem (n=37) Placebo (n=39) ON TREATMENT FOLLOW UP BETTER Largest co-treatment subgroup
Page 36
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 36 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. 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. 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 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 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/alzheimers.htm#treated • https://www.nimh.nih.gov/health/statistics/major-depression • Symphony Health and ICON plc Company, Metys® database full year 2023 Currencies • Currencies are in Australian dollars unless otherwise stated Key references Other references see also https://actinogen.com.au/xanamem Corporate Presentation October 2025
Page 37
• 11β-HSD1 – 11 beta HydroxySteroid Dehydrogenase-1 enzyme. Selectively expressed in brain, liver, adipose. • Aβ – Amyloid beta – a type of amyloid protein associated with Alzheimer’s Disease, 42 and 40 are different forms • ACTH – Adrenocorticotropic hormone that regulates blood levels of cortisol • AD – Alzheimer’s disease • ADAS-Cog – Alzheimer’s Disease Assessment Score - Cognition • ApoE4 – Apoprotein genotype associated with genetic risk of Alzheimer’s Disease • ATN – Amyloid, Tau, Neurodegeneration • Clinical Scales – Measure how a patient feels, performs and functions • CDR-SB – Clinical Dementia Rating “Sum of Boxes” scale measuring cognition and function on an 18-point scale (high worse) • CNS – Central nervous system • CSF – Cerebrospinal fluid • CTAD – Clinical Trials on Alzheimer’s Disease (conference) • CTB – Cognitive Test Battery of computerized tests • Double-blind – Investigators, participants and company do not know who has active vs placebo treatment during a trial • EMA – European Medicines Agency • FDA – US Food & Drug Administration • Filamen A – A protein believed to relate to amyloid toxicity • GFAP – Glial Fibrilliary Acidic Protein – a marker of microglial cell activation in the brain • IDSST – International Digit Symbol Substitution Test of cognition Selected Glossary 1 37Corporate Presentation October 2025
Page 38
• IQCODE – Informant Questionnaire on Cognitive Decline in the Elderly • MCI – Mild Cognitive Impairment – memory, executive function deterioration with retained functional abilities • MDD – Major Depressive Disorder • MMSE – Mini Mental State Examination – a 30-point scale of simple questions to assess mental abilities • NfL – Neurofilament Light – a nerve protein in the brain and rest of the body too • NIA-AA – National Institutes of Aging and Alzheimer’s Association • NMDA – A type of receptor for glutamate in the brain • NPI – Neuropsychiatric Inventory to assess psychiatric symptoms • NTB – A Neurologic Test Battery, in this presentation one designed to measure executive function aspects of cognition • PET – Positron Emission Tomography – a type of body scan • Placebo controlled – Non-active treatment for double-blind design • p-Tau181 or 217 AD – Biomarker of phosphorylated Tau protein • QPCT – Glutaminyl-peptide cyclotransferase is an enzyme proposed to create toxic amyloid species • RAVLT – Rey Auditory Visual Learning Test • RBANS – Repeatable Battery for the Assessment of Neuropsychological Status (a test of mental abilities) • ROC AUC – Receiver Operating Curve Area Under the Curve (1.0 ideal) – a type of statistical test to compared two methods of measurement • SSRI – selective serotonin reuptake inhibitor • Tau – A brain protein • Ttau – Total tau levels including both phosphorylated and non-phosphorylated tau Selected Glossary 2 38Corporate Presentation October 2025
Page 39
Contacts Michael Roberts Investor Relations P: +61 2 8964 7401 M: +61 423 866 231 E. michael.roberts@actinogen.com.au Steven Gourlay CEO & Managing Director P: +61 2 8964 7401 E. steven.gourlay@actinogen.com.au 39Corporate Presentation October 2025 Join the Actinogen Investor Hub: https://investors.actinogen.com.au/