Xanamem (emestedastat) / Actinogen Medical - LARVOL DELTA

Targeting Brain Cortisol: Xanamem Shows Promise in Depression and Alzheimer Disease (Psychiatric Times) - "Actinogen investigated Xanamem in patients with residual depression who after at least 6 weeks of treatment with an antidepressant medication...Participants, who had Hamilton Depression Rating Scale (HAM-D) scores of 17 or higher as well as demonstrated cognitive impairment, were randomized to placebo or 10 mg of Xanamem daily for 6 weeks, followed by a 4-week blinded observation period. 'At the end of 10 weeks, there was a statistically significant separation with the treated patients doing better as compared to the placebo'"

Clinical data • Alzheimer's Disease • Depression

Actinogen provides pivotal Alzheimer’s trial enrolment update and other business news (GlobeNewswire) - "Actinogen Medical Limited...announces that its Alzheimer’s disease phase 2b/3 trial has now enrolled 60 participants and expects to reach 100 by the end of this quarter. That milestone will trigger an interim analysis of available trial data by an independent Data Monitoring Committee approximately 6 months later. Final results for the full 220 participants are expected in Q4 2026....A similar Type C meeting for Alzheimer’s disease (AD) will be held with the FDA’s Neurology Division later in 2025 to define the optimal path to a marketing approval."

Enrollment status • FDA event • P2/3 data • Alzheimer's Disease

PLASMA PTAU181 PREDICTS CLINICAL PROGRESSION IN MILD ALZHEIMER'S DISEASE IN A RANDOMIZED CONTROLLED TRIAL. (ADPD 2025) - "Together, these data suggest elevated plasma pTau181 may have utility for patient enrichment in future AD trials of patients with mild AD. Enrichment in this way may reduce sample size, cost, and duration of clinical trials. Xanamem showed evidence of potentially clinically meaningful benefits in these patients that will be further explored."

Clinical • Alzheimer's Disease • CNS Disorders • p-tau181

Role of 11β-Hydroxysteroid Dehydrogenase and Mineralocorticoid Receptor on Alzheimer's Disease Onset: A Systematic Review. (PubMed, Int J Mol Sci) - "However, clinical trials, including those involving ABT-384 and Xanamem, have produced mixed results, with no substantial cognitive improvements despite effective enzyme inhibition...Ongoing research is focusing on optimizing 11β-HSD1 inhibitors, identifying biomarkers for patient selection, and investigating combination therapies to enhance treatment efficacy. Ultimately, 11β-HSD1's role in AD presents a promising therapeutic target, but further studies are required to fully understand its potential in managing the disease."

Journal • Review • Alzheimer's Disease • CNS Disorders • Inflammation

Actinogen announces peer-reviewed clinical pharmacology manuscript for Xanamem (emestedastat) published in Clinical Pharmacology in Drug Development journal (PRNewswire) - "Actinogen Medical Limited...announces that the publication of its most recent peer-reviewed journal article entitled Clinical Pharmacology and Approach to Dose Selection of Emestedastat...The review confirms the utility of the 10 mg daily dose of Xanamem being used in current clinical trials. From a drug development perspective, it demonstrates the value of using central pharmacodynamics (PD), including positron emission tomography (PET) and computerized cognitive testing, to supplement pharmacokinetic (PK) and endocrine-based PD for determining the target dose range for clinical efficacy testing...The XanaMIA Phase 2b/3 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...Initial results from an interim analysis of the first 100 participants are anticipated in Q4 2025 and final results H2 2026."

Clinical • P2/3 data • Alzheimer's Disease

Actinogen announces new and unique nonproprietary name of 'emestedastat' for Xanamem (PRNewswire) - "Actinogen Medical Limited...announces that the World Health Organization (WHO) has granted the nonproprietary name of 'emestedastat' to Actinogen for its Xanamem/UE2343 once-a-day small molecule in accordance with the WHO's Procedure for the Selection of Recommended International Nonproprietary Names (INN) for Pharmaceutical Substances...XanaMIA Alzheimer's disease phase 2b/3 trial sites enrolling in the USA and Australia...Final results are expected in the second half of 2026 with interim results anticipated in Q4 this year."

Commercial • P2/3 data • Alzheimer's Disease

Drug Development. (PubMed, Alzheimers Dement) - "This series of trials demonstrates that the optimal dose of Xanamem can be selected based on CNS PET occupancy data coupled with pharmacodynamic endocrinology and quantitative cognition testing. Pro-cognitive and potentially disease modifying effects were observed at doses consistent with high CNS target occupancy. Xanamem is now in larger Phase 2 clinical outcome trials in MDD and mild/mod AD."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Endocrine Disorders • Inflammation • Mental Retardation • Psychiatry • p-tau181

Actinogen randomizes first US participant in XanaMIA phase 2b/3 Alzheimer's disease trial (PRNewswire) - "Actinogen Medical Limited...announces that the first participant was randomized and treated Friday in the United States in the XanaMIA phase 2b/3 clinical trial in patients with biomarker-positive mild to moderate Alzheimer's disease (AD). The trial is designed to select 220 participants with a progressive clinical profile, determined by elevated levels of the blood biomarker pTau181. It measures the effects of a Xanamem 10 mg daily dose versus placebo over a 36-week treatment period on multiple clinical endpoints of function and cognition....An interim analysis is planned for Q3 2025 when approximately 100 patients reach 24 weeks of treatment, with final results anticipated in H2 2026."

P2/3 data • Trial status • Alzheimer's Disease

Xanamem® in Adults With Major Depressive Disorder and Impaired Cognition (XanaCIDD) (clinicaltrials.gov) - P2 | N=167 | Completed | Sponsor: Actinogen Medical | Active, not recruiting ➔ Completed

Trial completion • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Positive Xanamem biomarker trial published in the Journal of Alzheimer's Disease demonstrating potential Xanamem efficacy in patients with elevated blood pTau (PRNewswire) - P2b | N=220 | XanaMIA (NCT06125951) | Sponsor: Actinogen Medical | "Highlights of the publication include...Patients with elevated pTau181 had much more rapid progression than patients with lower levels in four key clinical endpoints: ADCOMS (p<0.001), CDR-SB (p<0.001), MMSE (p=0.12) and ADAS-Cog14 (p=0.19); In the 34 patients with elevated pTau181 a potentially large and clinically meaningful Xanamem treatment effect compared to placebo was seen in the CDR-SB (LS[2] mean difference 0.6 units, p=0.09) and positive trends were observed in a Neuropsychological Test Battery of cognition (LS mean difference 1.8 units, p=NS)...The XanaMIA trial is anticipated to report interim results mid-2025 and final results in 2026."

P2b data • Alzheimer's Disease • CNS Disorders

Development of Xanamem, an isoform 1 specific inhibitor of 11-βHSD, as a procognitive and disease modifying treatment for mild/moderate Alzheimer’s disease. A pharmacodynamic and biomarker driven approach. (AAIC 2024) - "This series of trials demonstrates that the optimal dose of Xanamem can be selected based on CNS PET occupancy data coupled with pharmacodynamic endocrinology and quantitative cognition testing. Pro-cognitive and potentially disease modifying effects were observed at doses consistent with high CNS target occupancy. Xanamem is now in larger Phase 2 clinical outcome trials in MDD and mild/mod AD."

Biomarker • PK/PD data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • Mental Retardation • Psychiatry • p-tau181

Plasma pTau181 Predicts Clinical Progression in a Phase 2 Randomized Controlled Trial of the 11β-HSD1 Inhibitor Xanamem® for Mild Alzheimer's Disease. (PubMed, J Alzheimers Dis) - "This trial demonstrates that elevated plasma pTau181 identifies participants more likely to have progressive AD and is a suitable method for enrichment in AD clinical trials. Xanamem treatment showed evidence of potential clinically meaningful benefits."

Journal • P2 data • Alzheimer's Disease • CNS Disorders • p-tau181

Xanamem® in Adults With Major Depressive Disorder and Impaired Cognition (XanaCIDD) (clinicaltrials.gov) - P2 | N=160 | Active, not recruiting | Sponsor: Actinogen Medical | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

First patient treated in Actinogen's XanaMIA phase 2b Alzheimer's disease trial (PRNewswire) - "Actinogen Medical Limited...announces that the first patient has been randomized and treated in the XanaMIA phase 2b clinical trial in patients with biomarker-positive mild to moderate Alzheimer's disease (AD). This represents the culmination of the site and screening setup phase of the trial when patient pre-screening for elevated levels of the pTau blood biomarker commenced at multiple clinical sites. The XanaMIA trial is a double-blind placebo-controlled randomized trial design which will enrol 220 participants with mild to moderate AD and elevated levels of plasma pTau. The trial measures the effects of a Xanamem 10 mg daily dose versus placebo on safety and its ability to preserve cognition and function over a 36-week treatment period....An interim analysis is planned for mid-2025 when approximately 100 patients reach 24 weeks of treatment, with final results anticipated in H1 2026."

P2b data • Trial status • Alzheimer's Disease

The Importance of PET Imaging to Understanding Whole-Body Cortisol Metabolism in Alzheimer's Disease. (PubMed, J Alzheimers Dis) - "In this current issue, high regional brain occupancy of Xanamemtrademark, determined by [11C]TARACT PET imaging of 11β-HSD1, in cognitively normal individuals and mild cognitive impartment/Alzheimer's disease (AD) patients is presented. In the future, comprehensive kinetic modeling using arterial sampling for occupancy studies, and whole-body PET imaging of 11β-HSD1 enzyme levels, in combination with stable isotope studies of cortisol metabolism, can provide broad insight into enzyme levels and activity in AD and other relevant diseases."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Xanamem® in Adults With Major Depressive Disorder and Impaired Cognition (XanaCIDD) (clinicaltrials.gov) - P2 | N=160 | Recruiting | Sponsor: Actinogen Medical | Trial primary completion date: Mar 2024 ➔ Jul 2024

Trial primary completion date • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

XanaMIA: Effect of 10 mg Xanamem on Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P2 | N=220 | Recruiting | Sponsor: Actinogen Medical | Not yet recruiting ➔ Recruiting

Enrollment open • Alzheimer's Disease • CNS Disorders • Dementia • p-tau181

DESIGN OF A STATE-OF-THE-ART PHASE 2B TRIAL TO EVALUATE THE EFFICACY OF A SPECIFIC INHIBITOR OF 11Β-HSD1, XANAMEM®, IN MILD AND MODERATE ALZHEIMER'S DISEASE (ADPD 2024) - "The XanaMIA Phase 2B trial is a robustly designed trial using a contemporary rationale to select validated and treatment-sensitive endpoints, and patient enrichment strategies to demonstrate the procognitive and disease-course modifying benefits of Xanamem."

Clinical • P2b data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • p-tau181

Positive Xanamem human PET study published in the Journal of Alzheimer's Disease demonstrating robust CNS[1] target enzyme occupancy (PRNewswire) - P=NA | N=NA | "Actinogen Medical Limited...announces that its human Positron Emission Tomography (PET) study, confirming high levels of Xanamem target occupancy in the brain at safe, well tolerated, and biologically active doses, has been published in the Journal of Alzheimer's Disease....The primary conclusion from the study was that Xanamem achieved high target occupancy of 66-85%, which exceeded the 30-60% inhibition required for effectiveness in animal models. The authors further concluded that a dose level of 10 mg daily achieved near saturation of the enzyme target, meaning that higher doses achieved little additional occupancy. The study results support exploring doses of ≤10 mg in clinical trials, consistent with the on-going XanaCIDD (Phase 2a, depression) and XanaMIA (Phase 2b, Alzheimer's disease) trials."

Clinical data • Alzheimer's Disease • CNS Disorders

Brain 11β-Hydroxysteroid Dehydrogenase Type 1 Occupancy by Xanamem™ Assessed by PET in Alzheimer's Disease and Cognitively Normal Individuals. (PubMed, J Alzheimers Dis) - "TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

XanaMIA: Effect of 10 mg Xanamem on Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P2 | N=220 | Not yet recruiting | Sponsor: Actinogen Medical

Trial completion date • Trial initiation date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Dementia • p-tau181

XanaMIA: Effect of 10 mg Xanamem on Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P2 | N=220 | Not yet recruiting | Sponsor: Actinogen Medical | Phase classification: P2b ➔ P2

Phase classification • Alzheimer's Disease • CNS Disorders • Dementia • p-tau181

XanaMIA: Effect of 10 mg Xanamem on Dementia Due to Alzheimer's Disease (clinicaltrials.gov) - P2b | N=220 | Not yet recruiting | Sponsor: Actinogen Medical

New P2b trial • Alzheimer's Disease • CNS Disorders • Dementia • GFAP • p-tau181

Rationale and design of a Phase 2b trial to evaluate the efficacy of a specific inhibitor of 11β-HSD1, Xanamem®, in mild and moderate AD (CTAD 2023) - "Xanamem displays activity in multiple domains of cognition including attention, working memory, and executive function with clinically meaningful effects in normal subjects and in patients with p-tau181-elevated mild AD. The XanaMIA Phase 2B trial is a robustly designed study using contemporary, treatment-sensitive endpoints, and patient enrichment strategies to demonstrate the procognitive and diseasecourse modifying benefits of Xanamem."

Clinical • P2b data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • p-tau181

Actinogen to present progress on Phase 2 trials at the BIO Investor Forum, San Francisco and Clinical Trials on Alzheimer’s Disease (CTAD) Conference, Boston (PRNewswire) - "Actinogen Medical Limited...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...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)....Final results are anticipated in the second half of 2025."

P2a data • P2b data • Alzheimer's Disease • CNS Disorders • Depression • Major Depressive Disorder