Announcement • Jul 20
Actinogen Medical Announces Results from Xanamem Phase 2 Depression Proof-Of-Concept Trial Actinogen Medical announced that results from its proof-of-concept trial, entitled “A phase 2 randomised, double-blind, placebo-controlled trial of emestedastat in patients with major depressive disorder (MDD) and cognitive impairment (CI)” have just been published as a peer-reviewed article in the British Journal of Psychiatry. Key conclusions from the article: Xanamem (emestedastat) may be a novel antidepressant and worthy of further investigation (further Xanamem trials in MDD will depend on future funding and partnership arrangements). In contrast to the previously held belief that cognition improves along with depressive symptoms, there was no correlation of improvement in cognition with improvement in depression. Unique trial design studied participants with both measurable cognitive impairment and depression to assess potential Xanamem benefit on both - in other aspects the trial was a standard phase 2a design for MDD using a six-week treatment period with a further four weeks of blinded follow up. Enrolled 165 participants characterized as having “difficult-to-treat” MDD, with clinically significant residual MDD and measurable CI, most of whom were on another anti-depressant in addition to the trial treatment. Anti-depressant benefit vs. placebo was maximal at Week 10 (2.7 MADRS points, p < 0.05) during the blinded follow up phase. A similar benefit was seen in key subgroups including the 46% of patients who were on background SSRI medication (4.2 MADRS points, p < 0.05). The observed “lag” in Xanamem benefit to improve depression scores is consistent with the known timeframe of onset and reversal of chronic cortisol-related side effects, e.g. when starting or stopping chronic prednisolone treatment. A larger placebo group improvement in CI symptoms than previously reported was observed, with no evidence of Xanamem treatment benefit. Xanamem was safe and well-tolerated. The XanaMIA Phase 2b/3 Alzheimer’s disease trial is a double-blind, 36-week treatment, placebo-controlled, parallel group design trial in 247 patients with mild to moderate AD and progressive disease, determined by clinical criteria and confirmed by an elevated level of the pTau181 protein biomarker in blood. Patients receive Xanamem 10 mg or placebo, once daily, and its ability to slow progression of Alzheimer’s disease is assessed with a variety of endpoints. The primary endpoint of the trial is the internationally-recognized CDR-SB (Clinical Dementia Rating scale – Sum of Boxes). The trial is being conducted in Australia and the US and is now closed to participant recruitment. It has passed an independent Data Monitoring Committee safety and efficacy futility review and final topline results are expected in November 2026. The XanaMIA-OLE Alzheimer’s disease open-label extension is an open-label phase of up to 25 months treatment where all participants will receive active Xanamem 10 mg once daily. The trial evaluates safety and a limited number of efficacy endpoints such as the CDR-SB. The trial commenced in March 2026 and is open to all former and current participants in the XanaMIA Phase 2b/3 trial. The XanaCIDD Phase 2a depression trial was a double-blind, six-week proof-of-concept, placebo-controlled, parallel group design trial in 167 patients with moderate, treatment-resistant depression and a degree of baseline cognitive impairment. Participants were evenly randomized to receive Xanamem 10 mg once daily or placebo, in most cases in addition to their existing antidepressant therapy, and effects on cognition and depression were assessed. Trial results were reported in August 2024 and showed clinically and statistically significant benefits on depression symptoms with positive effects on the MADRS scale (a validated scale of depression symptom measurement) and the PGI-S (a valid patient reported assessment of depression severity). Cognition improved markedly and to a similar extent in both Xanamem and placebo groups. Xanamem’s novel mechanism is to control elevated levels of cortisol (aka the “stress hormone”) in the brain through the inhibition of the cortisol synthesis enzyme, 11ß-HSD1, without affecting production of cortisol by the adrenal glands which is essential for the body’s normal functioning. Xanamem is a first-in-class, once-a-day pill designed to deliver high levels of cortisol control in key areas of the brain related to Alzheimer’s and other diseases such as the hippocampus and frontal cortex. Chronically elevated cortisol is associated with progression in Alzheimer’s Disease and excess cortisol is known to be toxic to brain cells. Cortisol itself is also associated with depressive symptoms and when targeted via other mechanisms has shown some promise in prior clinical trials. The recent XanaCIDD trial demonstrated clinically and sometimes statistically significant benefits on depressive symptoms, further validating the cortisol control mechanism for the Xanamem 10 mg oral daily dose. The Company has studied 11ß-HSD1 inhibition by Xanamem in more than 500 volunteers and patients in eight clinical trials. Xanamem has a promising safety profile and has demonstrated clinical activity in patients with depression, patients with biomarker-positive Alzheimer’s disease and cognitively normal volunteers. High levels of target engagement in the brain with doses as low as 5 mg daily have been demonstrated in a human PET imaging study. Xanamem is an investigational product and is not approved for use outside of a clinical trial by the FDA or by any global regulatory authority. New Risk • Jun 17
New minor risk - Shareholder dilution The company's shareholders have been diluted in the past year. Increase in shares outstanding: 15% This is considered a minor risk. Shareholder dilution occurs when there is an increase in the number of shares on issue that is not proportionally distributed between all shareholders. Often due to the company raising equity capital or some options being converted into stock. All else being equal, if there are more shares outstanding then each existing share will be entitled to a lower proportion of the company's total earnings, thus reducing earnings per share (EPS). While dilution might not always result in lower EPS (like if the company is using the capital to fund an EPS accretive acquisition) in a lot cases it does, along with lower dividends per share and less voting power at shareholder meetings. Currently, the following risks have been identified for the company: Major Risk Earnings are forecast to decline by an average of 37% per year for the foreseeable future. Minor Risks Currently unprofitable and not forecast to become profitable over next 2 years (AU$34m net loss in 2 years). Shareholders have been diluted in the past year (15% increase in shares outstanding). Market cap is less than US$100m (AU$128.0m market cap, or US$90.4m). Announcement • May 28
Actinogen Medical Limited Announces Positive EMA Scientific Advice and Provides Update on Xanamem Alzheimer’s Disease Program Actinogen Medical Limited announced the successful outcome of its scheduled scientific advice meeting (written response) on Alzheimer’s disease (AD) with the European Medicines Agency (EMA). Actinogen and the EMA reached a common understanding of the pathway to marketing approval for AD in the European Union (EU). This includes agreements related to regulatory starting materials used in drug substance synthesis, design considerations for one additional pivotal clinical trial and the limited number of ancillary clinical pharmacology trials and nonclinical studies required. Key understandings include: Agreement on the suitability of the ‘Regulatory starting materials’ for the commercial manufacturing of Xanamem (emestedastat) drug substance; Design of one additional, well-controlled, pivotal (phase 3) trial to follow a positive XanaMIA pivotal trial – both use a 10 mg dose vs. placebo; Standard total number of people to be treated with Xanamem to be described in the Marketing Authorization Application – that is, the proposed makeup of the planned safety database consistent with EMA and FDA guidelines; Small number of ancillary clinical pharmacology trials to be conducted parallel with the next pivotal trial; Small number of nonclinical studies required to further characterize safety, metabolism and excretion pathways to be conducted parallel with the next pivotal trial. The outcome reached at this meeting aligns closely with the guidance received at an earlier meeting with the FDA’s Neurology-I Division in September 2025. With the new EMA advice, Actinogen now has a clear pathway and guidance towards marketing approvals in two key pharmaceutical markets. Approvals in the US and EU also contribute to approvals in many other countries and regions. The advice from both the FDA and EMA provides regulatory clarity for ongoing discussions with potential development and marketing partners. Topline results from the randomized phase of the XanaMIA pivotal Alzheimer’s disease trial of Xanamem 10 mg vs. placebo are expected in November this year. The trial enrolled 247 participants in the US and Australia with mild to moderate Alzheimer’s disease and elevated levels of plasma pTau181. Earlier this year the Independent Data Monitoring Committee (DMC) recommended the trial continue unchanged after a confidential assessment of unblinded safety and efficacy futility data. All XanaMIA participants are now potentially eligible to extend their treatment by participation in the Open Label Extension (OLE) phase. The OLE will provide valuable data on longer-term safety and efficacy trajectories. The XanaMIA trial is intended to serve as one of two pivotal trials supporting the earliest possible marketing approvals for Xanamem in multiple regions. If the trial results are strongly positive in November, the Company will also explore expedited approval pathways with relevant regulators while commencing the new pivotal phase 3 trial. The FDA recently announced a new policy supporting approval based on a single pivotal trial with adequate supporting evidence. Xanamem’s novel mechanism of action is to control the level of cortisol in the important areas of the brain through the inhibition of the cortisol synthesis enzyme, 11ß-HSD1, without blocking normal production of cortisol by the adrenal glands. Xanamem is a first-in-class, once-a-day pill designed to deliver high levels of brain cortisol control in regions where 11ß-HSD1 is highly expressed such as the hippocampus. Chronically elevated cortisol is associated with progression in Alzheimer’s Disease and excess cortisol is known to be toxic to brain cells. Elevated cortisol is also associated with depressive symptoms. Xanamem has demonstrated excellent brain target engagement and in human trials has shown potential to slow progression of Alzheimer’s disease and improve depressive symptoms in patients with moderately severe depression. 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. 
