Alzheimer’s disease is a chronic neurodegenerative condition leading to rapid cognitive decline. ‘Cognition’ relates to how a person understands and acts in the world around them.
Fragile X syndrome is a rare, serious, life-long genetic disorder caused by alterations in the Fragile X gene (FMR1).
Actinogen has conducted a substantial number of pre-clinical studies with Xanamem, covering all mandated pre-clinical investigations across aspects of absorption, distribution, metabolism, and excretion (ADME), as well as acute toxicology, genotoxicity, immunotoxicity, photo safety testing, and drug-drug interaction studies. Planned pre-clinical studies include carcinogenicity, developmental and reproductive toxicology (DART), and additional drug-drug interaction studies.
Actinogen is conducting a range of toxicology studies as required by the regulatory authorities in the development of any drug, and particularly with drugs that are likely to be used long-term, like Xanamem. These studies will help define and guide the safe long-term use of Xanamem in humans, as will be necessary in the potential treatment of Alzheimer’s disease, and other neurological diseases associated with raised cortisol.
A Phase I, single ascending dose (SAD), randomised, double-blind, placebo-controlled study was successfully completed in 2013 with 48 healthy human volunteers. Xanamem was well tolerated with no serious adverse events, and demonstrated potent effects on pharmacodynamic biomarkers, consistent with substantial inhibition of 11β-HSD1 for at least 24 hours after a single dose.
A second Phase I study, a multiple ascending dose (MAD), randomised, double-blind, placebo-controlled study in 40 healthy volunteers was successfully completed in 2015. The primary endpoint of the study demonstrated the safety, tolerability, and pharmacokinetics of Xanamem. Additionally, the trial confirmed Xanamem efficiently crosses the blood-brain barrier in concentrations that are expected to adequately inhibit the excess production of cortisol in the brain.
In 2016, Actinogen Medical initiated XanADu, a Phase II, double-blind, 12-week, randomised, placebo-controlled study to assess the safety, tolerability and efficacy of 10mg daily Xanamem in patients with mild Alzheimer’s disease. Patient recruitment and treatment commenced in mid-2017 and was completed in 2018 with 186 patients randomised across 25 sites in Australia, the UK and USA.
The initial results from the XanADu trial were announced in May 2019. The trial established that a 10mg daily dose of Xanamem is safe and inhibits cortisol production, as demonstrated by the expected increase in related hormones, including adrenocorticotropic hormone (ACTH), androstenedione, and DHEAS. However, Xanamem at 10mg daily did not demonstrate adequate efficacy in improving cognition in mild, clinically diagnosed Alzheimer’s disease over a 12 week period. The primary and secondary endpoint measures did not show statistical differences between Xanamem 10mg and placebo.
While it is clear that Xanamem is a pharmacologically active drug, further analysis of the XanADu dataset coupled with the output and analyses of the other ongoing Xanamem studies (summarised below), have informed the future strategic clinical development program for the drug.
Further information and updates on XanADu, can be found at Clinicaltrials.gov.
XanaHES was a Phase I, single-blinded, central reader blinded, placebo-controlled study of Xanamem® to assess safety and tolerability in healthy elderly subjects, and explore cognitive activity with the Cogstate Cognitive Test Battery.
This safety study was conducted by Linear Clinical Research, QEII Medical Centre, Western Australia.
The safety and tolerability of Xanamem 20 mg or placebo, given once daily (QD), was studied over 12 weeks from Baseline to End of Treatment (EOT). As well as safety assessments, the trial also included an exploratory assessment of cognition, using the industry standard Cogstate Cognitive Test Battery to evaluate six domains of cognition.
Positive and clinically meaningful effects were seen in multiple domains of the Cogstate test, and these were statistically significant at EOT for attention and working memory.
This is a positron emission tomography (PET) trial assessing receptor occupancy of multiple doses of Xanamem using the 11β-HSD1-specific radiolabelled imaging tracer [11C]TARACT002.
Use of [11C]TARACT002 provides the opportunity for Actinogen to demonstrate that Xanamem binds to the 11β-HSD1 enzyme in the brain through a competitive binding PET study. Quantification of the binding and uptake curves of Xanamem will reveal the optimal dose where maximum binding at the enzyme receptor sites is achieved. This information is being used in parallel with the XanADu and XanaHES study data to inform the further clinical development of Xanamem.
Interim data suggest good target occupancy of doses of 5mg daily and above.
Actinogen Medical is open to receiving expressions of interest from academic and commercial parties looking to develop research partnerships in Actinogen’s focus areas.
Modulation of cortisol levels via treatment with Xanamem is potentially clinically useful for a broad range of neurological and metabolic disorders associated with elevated cortisol.
Actinogen is seeking commercial partners to co-invest in the clinical development of Xanamem, to study its use in a variety of strategic indications in addition to those being actively pursued by the company.
Actinogen is open to receiving both private or public capital investment to support its R&D strategy.