There was a clinically meaningful and persistent improvement depression measured by the key secondary endpoint of MADRS.^[1] The primary endpoint of superiority to placebo in a cognitive "attention composite" of three Cogstate computerized tests was not met with large improvements seen in both Xanamem and placebo groups. Xanamem was safe and well tolerated.

SYDNEY, Aug. 12, 2024 /PRNewswire/ -- Actinogen Medical ASX: ACW ("ACW" or "the Company") announces that Xanamem treatment had clinically and statistically significant (p < 0.05) benefits on depression in its phase 2a XanaCIDD trial of Xanamem in patients with cognitive dysfunction and major depressive disorder (MDD). This outcome indicates potential modification of the underlying biology of depression as a result of inhibition of tissue cortisol synthesis – a completely novel mechanism for the treatment of depression. The trial did not meet the primary endpoint of improving the "Attention Composite" in the context of an unexpectedly large improvement in the placebo group.

Key XanaCIDD trial findings and their implications are:

• Xanamem was safe and well-tolerated with a promising safety profile consistent with prior trials
• MADRS depression score improvement in all 165 patients favoured Xanamem over placebo. These clinically significant benefits (Cohen's d (Cd) > 0.2) in change from baseline was observed at the end of 6 weeks of treatment (1.5 points, Cd = 0.24, p = 0.11) and were statistically significant four weeks after the end of treatment (2.7 points, Cd = 0.43, p = 0.02). The placebo group improvement from baseline of 26% was within the expected range for trials of this type.
• Greater Xanamem benefit on MADRS scores was evident in the pre-specified group of 81 patients with less severe depression: at the end of treatment (3.6 points, Cd = 0.88, p = 0.02) and four weeks later (3.6 points, Cd = 0.87, p = 0.03). The large clinically and statistically significant benefits in this responder population are particularly notable and the characteristics of the group will be fully explored to inform future trials
• Greater Xananem benefit on MADRS scores was also evident in a smaller pre-specified group of 31 patients taking the drug as monotherapy, that is, without other anti-depressant medication: clinically significant at the end of treatment (4.3 points, Cd = 0.64, p = 0.06) but not four weeks after treatment
• The trial did not meet the primary endpoint of an "attention composite" of three Cogstate computerized tests measuring attention and working memory with similar and large improvements in performance observed. Mean improvements in the Xanamem and placebo groups were 0.3 and 0.4 z-score points, respectively (p not significant). The unexpectedly large placebo mean improvement may have impaired the ability of the trial to observe any short-term pro-cognitive effects of Xanamem
• The Cogstate Attention Composite is not used in the on-going XanaMIA Alzheimer's disease trial due to report results in 2025 and 2026. In XanaMIA key endpoints focus on a broader range of tests validated in the Alzheimer's field including a 7-point cognitive composite, the Clinical Dementia Rating Scale – Sum of Boxes functional scale and the Amsterdam Activities of Daily Living scale.

Dr Dana C Hilt, Actinogen's Chief Medical Officer, said:

"This encouraging result on depression is very positive to the whole Xanamem program and confirms 10 mg daily is an active clinical dose with the ability to potentially modify underlying biological processes in the brain. We will continue to examine these topline data in detail and the larger dataset to better understand the complete results and determine next steps for the depression program. The unexpected cognition placebo effect appears to have impaired the ability of Xanamem to show the pro-cognitive effects that we have observed in three previous studies.

"Our on-going XanaMIA phase 2b trial in biomarker-positive patients with mild to moderate Alzheimer's disease continues to enrol and remains on-track to deliver initial results in the middle of next year. I believe the results on acute symptomatic cognitive enhancement in XanaCIDD do not alter the chances of success for Xanamem in Alzheimer's disease where cortisol is implicated in the underlying biology of long-term disease progression reflected as functional and cognitive decline."

Dr Steven Gourlay, Actinogen's CEO said:

"The excellent safety profile of Xanamem was again demonstrated in this trial and the significant treatment benefits seen in depression are encouraging for both the depression and Alzheimer's disease programs. We believe the trial confirms the ability of Xanamem 10 mg daily to safely provide benefit to patients by inhibiting the synthesis of the "stress hormone" cortisol in the brain.

"The Actinogen team has done an outstanding job to deliver this trial aimed at acute symptom improvement in depressed patients suffering from cognitive dysfunction. Our primary objective remains the current XanaMIA Phase 2b trial designed to measure Xanamem's ability to slow or halt Alzheimer's disease progression over 36 weeks."

Details of the design of the XanaCIDD phase 2a trial in patients with CI and MDD:

• Randomized, double-blind, exploratory, proof-of-concept, placebo-controlled, parallel group, six-week trial in 167 patients with persistent MDD and measurable cognitive impairment at baseline (165 patients had at least one efficacy assessment)
• Xanamem 10mg or placebo was added to the existing stable anti-depressant therapy (n = 134), or used as monotherapy in patients with a previous history of anti-depressant treatment (n = 31)
• The primary endpoint was the computerized Cogstate "Attention Composite" test battery, measuring attention and working memory. This measure was shown to be a sensitive measure of short-term Xanamem cognition benefit in the prior XanaMIA Part A and XanaHES trials^[2] conducted in cognitively normal, older volunteers. In the XanaMIA Part A trial, a placebo improvement of approximately 0.15 points was observed
• The key secondary endpoint was the MADRS which is a structured psychiatric interview evaluating MDD symptoms. The MADRS is the commonly used endpoint for major MDD trials and regulatory approvals of anti-depressant medications. Improvements in placebo groups of 20-40% are commonplace. Approved anti-depressants typically report average MADRS improvements of ~2 to 3 points over placebo groups^[3]
• The three subgroups pre-specified for efficacy analyses were patients with or without background anti-depressant therapy, patients with higher vs. lower levels of baseline depression, and patients with higher vs. lower levels of baseline cognitive dysfunction
• Other secondary endpoints remain the subject of on-going analysis include an executive function cognitive composite, a memory function cognitive composite, proportions of responders and global clinical assessment scores. 

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 Clinical Trials

The XanaCIDD Phase 2a cognition & depression trial is a double-blind, six-week proof-of-concept, placebo-controlled, parallel group design trial in 167 patients. Participants 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. Positive topline results on depression were announced 12 August CY2024.

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. Initial results from an interim analysis of the first 100 participants are anticipated in mid 2025.

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.