11β-HSD1

多囊卵巢综合征（PCOS）是生育年龄妇女常见的一种复杂的内分泌及代谢异常所致的疾病，以慢性无排卵（排卵功能紊乱或丧失）和高雄激素血症（妇女体内男性激素产生过剩）为特征，主要临床表现为月经周期不规律、不孕、多毛和/或痤疮，关键的病理变化包括神经内分泌失调、雄激素过度产生、胰岛素抵抗和脂肪组织生物学的变化，是最常见的女性内分泌疾病。除了众所周知的高雄激素血症和排卵功能障碍的临床表现外，多囊卵巢综合症患者还会增加不良心理健康后果、妊娠并发症和心脏代谢疾病的风险。现有治疗方式如避孕药，抗雄性激素药物，胰岛素增敏剂的效果仍然有限，一些药物也存在各类的副作用。核心原因在于对潜在病理和生理过程的不完全了解阻碍了药物开发，而随着近年来，遗传学、代谢组学和脂肪细胞生物学的等多方面的进展，对于PCOS靶点的开发也提上了日程。近日，著名医学期刊BMJ发表了了一篇关于PCOS的综述性文献，本文将对其列举靶点进行汇总和补充。（点击文末“阅读原文”可获得PCOS靶点临床药物汇总）KisspeptinKisspeptin是调节女性生殖功能重要的神经肽，由下丘脑神经元群表达，通过与KISS1R（G蛋白偶联受体）结合，刺激促性腺激素释放激素释放，进而调节下丘脑-垂体-性腺轴，在这一轴中具有重要作用，除下丘脑之外，卵巢、子宫内膜、滋养层等组织与细胞中也发现kisspeptin及其受体KISS1R的表达，局部表达的kisspeptin/KISS1R参与多种生理活动，对卵细胞成熟、胚胎着床等过程意义重大。虽然开始的研究着重于使用天然的Kisspeptin，KP54来诱导排卵。然而，使用KP54作为排卵诱导剂可能会受到快速免疫的限制。因为KP54比卵泡刺激素更优先刺激黄体生成素的分泌，也有人担心长期服用kisspeptin可能会加重多囊卵巢综合征患者卵泡刺激素的缺乏。在这种情况下PCOS中，Kisspeptin的作用似乎是矛盾的，这使得Kisspeptin激动剂和kisspeptin受体拮抗剂目前都被开发用于治疗多囊卵巢综合症。因为抑制剂又具有使黄体生成素的高分泌正常化、恢复卵泡生成和排卵以及改善卵巢雄激素过多的潜力。目前激动剂已经进入临床，疗效体现了上文所述的矛盾性，黄体生成素的分泌情况和KP54类似，而拮抗剂尚处于临床前研究阶段。神经激肽3受体同样位于下丘脑神经元群的还有神经激肽3受体（NK3R），同样也是PCOS的治疗靶点之一，通过拮抗NK3R，抑制剂可以阻断神经激肽B（NKB）与kisspeptin/神经激肽B/强啡肽（KNDy）神经元的结合，从而调节内分泌系统，有望恢复PCOS患者体内代谢和激素水平的平衡。目前，神经激肽3受体拮抗剂展现出了满足多囊卵巢综合征理想治疗的许多特性。MLE4901(也称为AZD4901)虽然因为肝毒性而停药，但是其他指标相当优秀，而肝毒性是MLE4901所独有的，其他NK3R拮抗剂中并没有观察到这一现象。另外一款神NK3R拮抗剂fezolinetant的疗效显著，不仅降低了睾酮水平，还降低了黄体生成素水平。临床前研究也强调了神经激肽3受体拮抗剂的潜在代谢益处。在双氢睾酮诱导的多囊卵巢综合征小鼠模型中，用神经激肽3受体拮抗剂治疗降低了体重和肥胖。强啡肽强啡肽是一种吗啡样活性肽，具有多种生理功能，包括镇痛、镇静、催眠和抗焦虑。当强啡肽与阿片受体结合时，kisspeptin向促性腺激素释放激素神经元的释放受到抑制，因此具有中枢作用的选择性阿片受体激动剂可能降低促性腺激素释放激素的脉动性。但是阿片受体激动剂本身具有成瘾性，相关药物的开发应当相当谨慎。而在美国，因为产业和政策相关原因，已有选择性κ受体激动剂上市，用于治疗瘙痒，而关于多囊卵巢综合症的适应症正在探索中。在多囊卵巢综合征的产前雄激素化小鼠模型中，difelikefalin降低了血清中促黄体生成激素和睾酮的水平，恢复了发情周期和排卵，并减少了下丘脑视前区KISS1 mRNA的过度表达。γ-氨基丁酸（GABA）GABA（γ-氨基丁酸）是一种抑制性神经递质，广泛存在于中枢神经系统中。GABA通过与其相应的受体结合而发挥作用。GABA对胰岛β细胞发挥保护和再生作用，并逆转糖尿病。在大脑之外，在胰岛、胃肠道、卵巢和肾上腺髓质中也有GAD和GABA受体的报道。在人体中，GABA受体分为多种类型，包括GABA A、GABA B和GABA C等。其中，GABA A受体是最主要的类型之一，也是最具有药理作用的一种。中枢作用的GABA A受体抑制剂可以抑制促性腺激素的分泌，从而减少雌激素的合成和释放。这种抑制作用有助于减轻多囊卵巢综合症患者的高雄激素血症和胰岛素抵抗等症状。（如果雌激素的水平降低，雄激素的水平也会相对降低，从而有助于改善高雄激素血症的症状）早先的研究表明，癫痫等神经疾病常见治疗方法之一的丙戊酸钠（一种GABAA激动剂）会增加中枢神经系统中的GABAA水平，这些患者会出现多囊卵巢综合症发病率提升的情况（尽管体重增加也可以部分解释其原因）。而外周GABA和中枢GABA的开发完全相反，并非采用中枢一样的拮抗作用，而是因为多囊卵巢综合征患者外周GABA水平降低，在临床前研究中，肠内给药GABAA降低了来曲唑诱导的多囊卵巢综合征大鼠模型中的体重指数和睾酮水平。抗缪勒管激素抗缪勒管激素（AMH）是一种由卵巢内窦前卵泡和小窦卵泡分泌的糖蛋白，能够反映卵巢内储备的卵泡数量，是近年来被认为能评估卵巢功能最有效和敏感的指标。抗缪勒管激素水平与卵巢储备功能的变化密切相关，可以预测女性的卵巢功能是否衰退。抗缪勒管激素途径的拮抗作用也可能是治疗上有用的；最近对抗缪勒管激素与抗缪勒管激素受体2型结合的结构基础的深入研究有助于合理设计抗缪勒管激素拮抗剂。靶向类固醇生成中的关键酶AKR1C3是醛酮还原酶家族的一员，能够催化多种类固醇激素和药物的还原反应。同时，它还在雄性激素的合成过程中起到了关键作用，可以转化雄烯二酮为睾酮，以及转化11-酮雄烯二酮为11-酮睾酮。这种转化过程对于经典的和11-氧化的雄激素合成来说非常重要。目前已经开发了各种AKR1C3抑制剂，其抗肿瘤作用和抑制去势抵抗性前列腺癌、急性髓细胞性白血病和雌激素受体阳性乳腺癌中前列腺素F合酶活性的能力结果不一。虽然基于类固醇的AKR1C3抑制剂正在开发中，但在多囊卵巢综合征的临床前模型中的治疗潜力尚未得到检验。在多囊卵巢综合征的啮齿动物模型中用BVT.2733选择性抑制11β-HSD1可改善胰岛素抵抗、生殖激素功能障碍和多囊卵巢形态学。这些初步疗效相当可观，但在AKR1C3和11β-HSD1抑制剂的潜在治疗益处可以在患者中测试之前，还需要进一步的临床前工作。GLP-1：司美格鲁肽又要跨界胰高血糖素样肽1 (GLP-1)受体激动剂通过体重减轻(通过刺激饱腹感)和抑制脂肪组织中的炎症，增加葡萄糖依赖性胰岛素分泌，抑制胰高血糖素分泌，并增加外周胰岛素敏感性。一些研究表明，GLP-1受体激动剂改善了月经的规律性或频率，并且月经频率的改善与体重的减轻相关。GLP-1受体激动剂也显示出降低雄激素水平和改善心血管风险的标志物。八项随机对照试验的荟萃分析得出结论，GLP-1激动剂在改善稳态模型评估方面比二甲双胍更有效——胰岛素抵抗(标准平均差0.40，95%可信区间0.74至0.06)、腹围(0.45，0.89至0.00)和体重指数(1.02，1.85至0.19)，但在改善月经频率(0.15，-0.24至0.54)或血清方面无效。而新型长效GLP-1类似物，如司美格鲁肽或度拉糖肽，或双重GLP-1-葡萄糖依赖性促胰岛素多肽激动剂，如替泽帕肽，则可以提供更多的治疗机会，具有更好的减肥效果、更长的作用持续时间和改善的依从性的潜在益处。司美格鲁肽是目前口服制剂中唯一可用的GLP-1激动剂，目前正在对患有多囊卵巢综合症和肥胖症的青春期女孩进行临床试验研究(用司美格鲁肽治疗PCOS与积极生活方式干预(TEAL)、NCT03919929)。钠-葡萄糖协同转运蛋白抑制剂（SGLT-2）钠-葡萄糖协同转运蛋白2（SGLT-2）主要分布在肾脏近曲小管，是一种低亲和力、高转运能力的转运体，其主要生理功能是在肾脏近曲小管重吸收肾小球滤过液中80%-90%的葡萄糖。SGLT-2抑制剂则减少了肾脏近曲小管对葡萄糖的重吸收，促进了尿葡萄糖的排泄，还减少了其他人群的体重和心血管事件。目前关于多囊卵巢综合征患者的数据仅限于四项小型随机对照试验。与二甲双胍相比，卡格列净对多囊卵巢综合征女性的体重指数(P=0.006)、基础代谢率(P=0.02)和脂肪量(P=0.02)有更大的改善，但在激素或代谢参数方面没有改善在超重和肥胖多囊卵巢综合征患者中，卡格列净-二甲双胍联合治疗3个月的总睾酮、葡萄糖曲线下面积、胰岛素和葡萄糖曲线下面积之比的降低幅度大于单用二甲双胍治疗，但在月经频率、体重指数、或体内平衡模型评估-治疗组之间的胰岛素抵抗却没有改善。利格列净是钠-葡萄糖共转运蛋白1 (SGLT1)和2 (SGLT2)的双重抑制剂。同时抑制SGLT1和SGLT2可提供更有效的减肥效果，因为单独抑制SGLT1可刺激肠道分泌GLP-1。在一项包含29例患者的2期随机对照试验中，利格列净可使多囊卵巢综合征女性的雄烯二酮水平降低19%，硫酸脱氢表雄酮水平降低24%，高胰岛素血症水平降低70%。最近完成的一项dapagliflozin对多囊卵巢综合征患者胰岛素抵抗和血清雄激素水平的随机对照试验(dapagliflozin Efficacy and Action in PCOS (DEAP)， NCT04213677)的结果正在等待中。总结总体来看，因为多囊卵巢综合征经常伴随各类因素，所以可能后续的研究会致力于排除肥胖，糖尿病等因素，或者是设定特殊人群而进行细分，未来的临床规划可能朝着这一方向迈进。参考来源：孙轶群,赵军招.Kisspeptin在辅助生殖过程中的研究进展[J].温州医科大学学报,2023,53(09):761-767.https://bmjmedicine.bmj.com/content/2/1/e000548

Xanamem® is an oral, brain-penetrant tissue cortisol synthesis inhibitor that has shown promising safety and clinical activity in three placebo-controlled trials and has the potential to treat a variety of neurodegenerative and neuropsychiatric diseases SYDNEY, Oct. 13, 2023 /PRNewswire/ -- Actinogen Medical Limited (ASX: ACW) CEO Dr Steven Gourlay will conduct a series of meetings at the BIO Investor Forum, San Francisco on October 17-18, 2023. The following week, Dr Gourlay and CMO Dr Dana Hilt will participate in the 16th annual CTAD conference in Boston where they will present a scientific poster on October 25 and conduct a number of stakeholders meetings. Dr Gourlay and Dr Hilt will be discussing progress made with the Company's two ongoing Phase 2 trials: XanaCIDD Phase 2a trial in patients with cognitive impairment and major depressive disorder Enrolment continues in the XanaCIDD Phase 2a proof-of-concept trial in 160 patients with cognitive impairment associated with persistent Major Depressive Disorder (MDD). Cognitive impairment is common in MDD and currently there are no anti-depressant drugs approved for its treatment, although some companies have reported trials to assess effects of their anti-depressants on cognition. Consequently, there is a high unmet need for novel and safe treatments for this indication. The trial is being conducted in Australia, the UK and the USA. It is treating patients with 10 mg of Xanamem or placebo once daily for six weeks as monotherapy or added to stable background anti-depressant therapy. The primary endpoint is an attention composite of three computerized cognitive tests measuring attention and working memory. Depression is assessed as a key secondary endpoint using the MADRS scale. The trial is expected to report results in the first half of 2024. XanaMIA Phase 2b trial in patients with mild-moderate Alzheimer's Disease (AD) On 26 September Actinogen announced that it had redesigned operational features of the XanaMIA Phase 2b clinical trial of Xanamem in patients with mild to moderate AD to reduce the cost and time to initial results. Key features of the revised XanaMIA Phase 2b trial: The trial will enrol patients with an elevated blood pTau biomarker (the same group shown to have a large Xanamem clinical effect in the previous Phase 2a biomarker trial) and keeps the same endpoints and 36‑week treatment length. The removal of the 5mg dose arm reduces patient numbers by one-third to 220 patients, who will receive either 10mg or placebo daily Enrolment of the first 100 patients will take place at Australian sites and initial efficacy and safety results from an administrative interim analysis will occur when approximately 100 patients reach 24 weeks of treatment, expected in the first half of 2025 Collectively, these changes reduce trial costs significantly and increase forecast receipts from Australian R&D tax incentive cash refunds by focusing on Australian R&D activities in the near term. Net forecast savings between now and June 2025 will be in the order of A$30 million compared to the original plan The XanaMIA Phase 2b trial will finalize Australian clinical site start up activities as soon as possible, with site activation expected before the end of the year Final results are anticipated in the second half of 2025. Dr Steven Gourlay, Actinogen CEO and MD, commented: "Actinogen is at an important juncture in the world of drug development with its promising oral therapy Xanamem. While recent positive 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 non-amyloid therapies to arrest cognitive decline. "Our high quality randomized XanaMIA Phase 2b trial will be conducted in 220 patients with mild-moderate AD who are biomarker-positive and thus likely to have progressive disease. We will finalize Australian clinical site start up activities as soon as possible, with site activation expected before the end of the calendar year. "Our XanaCIDD Phase 2a trial assessing the effects of Xanamem on cognition and depression represents a novel and important approach towards treating patients with MDD with the hope that the therapy will be rapidly acting on cognition, as we have seen in two prior trials in cognitively normal people, and also have effects on depression itself." 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 the pTau181 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 a 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 11β-HSD1 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 biomarker-positive 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. 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. You are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof. Actinogen Medical does not undertake any obligation to revise such statements to reflect events or any change in circumstances arising after the date hereof, or to reflect the occurrence of or non-occurrence of any future events. Past performance is not a reliable indicator of future performance. Actinogen Medical does not make any guarantee, representation or warranty as to the likelihood of achievement or reasonableness of any forward-looking statements and there can be no assurance or guarantee that any forward-looking statements will be realised. ® Xanamem is a registered trademark of Actinogen Medical Limited SOURCE Actinogen Medical Limited

Highlights Changes to the XanaMIA protocol reduce cost by AUD 30 million over the next two years and speed time to initial results while preserving the 36-week design and trial endpoints. UK sites added to the XanaCIDD trial of cognitive impairment associated with depression, due to report results mid-2024. SYDNEY, Sept. 26, 2023 /PRNewswire/ -- XanaMIA Phase 2b trial optimization Actinogen Medical Limited (ASX: ACW) is pleased to announce optimization of the XanaMIA Phase 2b trial in patients with mild-to-moderate Alzheimer's disease to reduce the cost and time to initial results. The current, FDA-approved three-arm trial was designed to confirm the safety, pro-cognitive and clinical benefits of Xanamem® and explore two dose levels. The new design keeps the same endpoints, 36-week treatment length and other features except for the 5 mg dose group. Actinogen Chief Medical Officer, Dr Dana Hilt, commented: "Removal of the 5 mg dose group, while deferring the dose-ranging aspect of the Xanamem program to the next, likely Phase 3 trial, does not detract from the strong confirmatory value of the trial design. The trial retains its ability to robustly demonstrate the clinical benefit of Xanamem in patients with Alzheimer's disease." Operationally, the trial has been streamlined with the following modifications: New: 10 mg or placebo daily vs. 10 mg, 5 mg or placebo previously New: 220 patients vs. 330 patients previously but still studying patients with the elevated blood pTau biomarker (the same group shown to have a large Xanamem clinical effect in the previous Phase 2a biomarker trial) New: Australian sites to enroll the first 100 patients vs. simultaneous global site activation previously New: Initial efficacy and safety results from an administrative interim analysis when approximately 100 patients reach 24 weeks of treatment vs. unspecified previously. Collectively these changes reduce trial costs significantly and increase forecast receipts from Australian R&D tax incentive cash refunds by focusing on Australian R&D activities in the near term. Net forecast savings between now and June 2025 will be in the order of $30 million compared to the original plan. The new implementation plan assumes that expansion of the XanaMIA trial will occur when potentially new, positive clinical data is received from the XanaCIDD trial by mid-2024 and/or the redesigned XanaMIA interim analysis, planned for H1 2025. Xanamem's promising safety pro been demonstrated in more than 300 people to date. The XanaMIA Phase 2b trial will finalize Australian clinical site start up activities as soon as possible with patient recruitment expected before the end of the year. General Business Update 1. XanaCIDD Phase 2a trial The Company is also pleased to advise that it has expanded the XanaCIDD Phase 2a randomized clinical trial in patients with cognitive impairment associated with depressive disorder (CIDD) from Australia to include UK sites, which have commenced screening. The XanaCIDD Phase 2a depression trial is a double-blind, six-week proof-of-concept, placebo-controlled, parallel group design trial in 160 patients with both depression and cognitive impairment. 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. Results of the XanaCIDD trial are anticipated by mid-2024. Leading neuroscience authority and cognition expert, Professor Paul Maruff,[1] said: "Xanamem is one of the few drugs being developed for neurodegenerative diseases such as Alzheimer's disease or neuropsychiatric diseases such as major depressive disorder, that throughout development has shown consistent and substantial benefits to cognition. These have been observed in healthy healthy older adults, and in adults with mild dementia. This evidence provides an excellent foundation for the full development of Xanamem." 2. Neuroscience webinar The Company conducted a highly informative 'Fireside Chat' webinar on 31 August 2023 with Professor Paul Maruff and CMO, Dr Dana Hilt, who discussed and reviewed progress in the evaluation of cognition, Alzheimer's disease and Xanamem's clinical data. Click on the following link to access the neuroscience webinar recording: 3. Rights issue capital raising ACW successfully closed an AUD 10 million rights issue capital raising from existing shareholders and selected new shareholders on September 4, 2023. 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 the pTau181 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 a 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 11β-HSD1 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 biomarker-positive 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. 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. You are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof. Actinogen Medical does not undertake any obligation to revise such statements to reflect events or any change in circumstances arising after the date hereof, or to reflect the occurrence of or non-occurrence of any future events. Past performance is not a reliable indicator of future performance. Actinogen Medical does not make any guarantee, representation or warranty as to the likelihood of achievement or reasonableness of any forward-looking statements and there can be no assurance or guarantee that any forward-looking statements will be realised. ACTINOGEN MEDICAL ENCOURAGES ALL CURRENT INVESTORS TO GO PAPERLESS BY REGISTERING THEIR DETAILS WITH THE DESIGNATED REGISTRY SERVICE PROVIDER, AUTOMIC GROUP. [1] Professor Paul Maruff is a Professor in Neuroscience at the Florey Institute of Neuroscience and in Psychology at Monash University, Melbourne Australia. He is also co-founder of Australian public company Cogstate Limited, which plays a major role in the assessment of Alzheimer's disease globally. Professor Maruff has more than 30 years of experience in the assessment of cognition (how you think, remember and solve problems) and other tests used to assess AD and other diseases associated with cognitive impairment. ® Xanamem is a registered trademark of Actinogen Medical Limited Company Codes: Australia:ACW