Xanamem’s 10 mg Dose Confirmed Effective by New Pharmacology Research

• Peer-reviewed publication confirms 10 mg daily Xanamem dose
• Clinical pharmacology approach integrates PET and cognitive testing
• Positive phase 2a depression trial results support dose selection
• XanaMIA phase 2b/3 Alzheimer's trial underway with 10 mg dose
• Xanamem targets brain cortisol synthesis enzyme 11ß-HSD1

Actinogen’s Dose Confirmation Advances Xanamem Development

Actinogen Medical (ASX: ACW) has taken a significant step forward in its clinical development program with the publication of a peer-reviewed article in the journal Clinical Pharmacology in Drug Development. The article rigorously validates the 10 mg daily dose of Xanamem (emestedastat), a novel inhibitor of brain cortisol synthesis, as the optimal therapeutic dose for central nervous system diseases including Alzheimer's and depression.

The study highlights the company’s sophisticated clinical pharmacology approach, combining pharmacokinetics (PK), endocrine pharmacodynamics (PD), positron emission tomography (PET) imaging, and computerized cognitive testing. This multi-modal strategy has allowed Actinogen to refine dose selection beyond traditional methods, ensuring that the 10 mg dose achieves sufficient brain enzyme inhibition without unnecessary escalation.

Clinical Trial Context and Implications

Earlier pharmacokinetic modeling had suggested a 20 mg dose might be required to maintain cerebrospinal fluid concentrations above the half maximal inhibitory concentration for the 11ß-HSD1 enzyme. However, PET imaging data demonstrated that doses as low as 5 to 10 mg daily effectively inhibit the target enzyme in the brain. This finding aligns with cognitive testing results showing consistent pro-cognitive benefits at these doses, particularly improvements in attention and working memory.

These insights underpin the dosing regimen used in Actinogen’s ongoing XanaMIA phase 2b/3 trial in mild to moderate Alzheimer's disease patients. The trial, enrolling 220 participants across Australia and the US, is testing the ability of 10 mg daily Xanamem to slow disease progression, with interim results expected in late 2025. The dose confirmation also builds on positive outcomes from the XanaCIDD phase 2a trial in treatment-resistant depression, where the 10 mg dose produced statistically significant improvements in depressive symptoms and cognitive function.

Strategic Significance and Future Outlook

Actinogen’s Chief Medical Officer, Dr Dana Hilt, emphasized the value of the stepwise clinical pharmacology process, stating it provides confidence in the dose selection for ongoing trials. CEO Dr Steven Gourlay echoed this sentiment, highlighting the importance of direct brain effect measurements in guiding development decisions.

With approximately 400 volunteers and patients studied across eight clinical trials, Xanamem has demonstrated a promising safety profile and consistent target engagement. The drug’s novel mechanism, selectively inhibiting brain cortisol synthesis without affecting adrenal cortisol production, addresses a critical unmet need in neurodegenerative and neuropsychiatric disorders linked to cortisol dysregulation.

While Xanamem remains investigational and unapproved outside clinical trials, this peer-reviewed validation strengthens Actinogen’s position as it advances toward pivotal efficacy data. The integration of biomarker-driven patient selection and advanced imaging techniques may set a new standard for dose optimization in CNS drug development.

Bottom Line?

Actinogen’s dose validation for Xanamem sets the stage for pivotal trial readouts and potential regulatory milestones ahead.

Questions in the middle?

• Will the XanaMIA trial’s interim data confirm Xanamem’s efficacy in slowing Alzheimer’s progression?
• How might regulatory agencies view the novel clinical pharmacology approach used for dose selection?
• Could Xanamem’s mechanism extend to other neuropsychiatric conditions beyond Alzheimer’s and depression?