Oral Anavex 2-73 Eases Dementia, Disease Symptoms in Phase 2 Trial

Anavex Life Sciences’ investigational oral therapy Anavex 2-73 (blarcamesine) leads to clinically meaningful cognitive improvements while reducing motor and non-motor symptoms in people with Parkinson’s disease dementia (PDD), according to data from a Phase 2 trial.

These benefits also significantly associated with increases in the levels of sigma-1 receptor (SIGMAR1), Anavex 2-73’s target, confirming the therapy’s biological effects and SIGMAR1 as a reliable response biomarker.

The findings, indicating that the trial met its main and secondary efficacy goals, continue to support Anavex 2-73’s development as a treatment of PDD. The therapy is also being tested in people with Alzheimer’s disease, for which it was initially developed, and in those with Rett syndrome — diseases where cognitive impairment is also prevalent.

“This is now the second independent placebo-controlled clinical Anavex 2-73 Phase 2 study to confirm the predictive biomarker of response established with SIGMAR1,” Christopher U. Missling, PhD, Anavex’s president and CEO, said in a press release.

“We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS [central nervous system; brain and spinal cord] indication with unmet medical need,” Missling added.

“This data further strengthens the foundation of ANAVEX 2-73 as a cross-platform CNS” therapy.

Anavex plans to present these data at an upcoming science meeting and to submit them to the U.S. Food and Drug Administration to seek regulatory guidance for future Phase 3 trials.

Anavex 2-73 is an orally available small molecule that works by activating SIGMAR1. This protein receptor is involved in several cell functions, including response to cellular stress; the correction of protein misfolding; neuroinflammation; and nerve cell survival, growth, and plasticity. Nerve cell plasticity is the ability to adapt in order to compensate for injury.

By activating SIGMAR1, Anavex 2-73 is expected to lower the toxic accumulation of misfolded proteins in nerve cells, dysfunction in mitochondria (the cells’ energy sources), as well as oxidative stress and neuroinflammation — all involved in Parkinson’s, Alzheimer’s, and Rett syndrome. Of note, oxidative stress is an imbalance between the production and clearance of toxic reactive species that are harmful to cells.

The proof-of-concept Phase 2 ANAVEX 2-73-PDD-001 study (NCT03774459), completed in September, evaluated the safety, tolerability, and early effectiveness of Anavex 2-73 in 132 adults, ages 50–85, with PDD. The trial was supported by the Michael J. Fox Foundation for Parkinson’s Research and León Research.

Participants, recruited at multiple sites in Spain and Australia, were randomly assigned to one of two doses of Anavex 2-73 (30 or 50 mg oral capsules) or to a placebo, once daily for 14 weeks (about 3.5 months).

The trial’s main goals were to assess the therapy’s safety and changes in patients’ cognitive function, measured using the cognitive drug research computerized assessment system — a test that looks at multiple cognitive skills, such as choice reaction time (choosing between similar objects), vigilance, and episodic memory (remembering new personal experiences or shared information).

Secondary goals included changes in patients’ motor abilities — assessed with the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III — and sleep quality.

Previously reported results showed that Anavex 2-73 was generally safe, significantly improved several cognitive skills, and lessened REM sleep behavior disorder, in which patients physically act out while dreaming. This sleep disorder is associated with greater cognitive impairment and a higher risk of dementia.

Newly shared data confirmed these cognitive and sleep benefits, and showed that the therapy’s high dose (50 mg) led to statistically significant and clinically meaningful reductions in motor and non-motor Parkinson’s symptoms, as assessed with the MDS-UPDRS total score.

After 14 weeks, the MDS-UPDRS total score dropped by 10.98 points (indicating an easing in disease severity) in the high-dose group and rose by 3.53 points in the placebo group. This represented an adjusted mean improvement of 14.51 points — surpassing the established, clinically meaningful 7.1 point-cut-off — and a relative improvement of 18.9% over 14 weeks.

These findings highlight Anavex 2-73’s ability to not only slow, but also reverse, symptoms that progress in Parkinson’s disease, potentially fulfilling an urgent unmet medical need, Anavex stated in its release.

Anavex 2-73’s use by patients also resulted in a significant increase in SIGMAR1 levels, a rise that was significantly associated with improvements in attention measures, and reductions in both MDS-UPDRS total and MDS-UPDRS Part III (motor scores).

Overall, these data confirmed the therapy’s mechanism of action and supported SIGMAR1 as a biomarker of clinical response to Anavex 2-73.

After completing the PDD-001 trial, patients had the option of being treated with Anavex 2-73 for nearly one year in its extension study, called ANAVEX 2-73-PDD-EP-001 (NCT04575259).

Expected to conclude in October, the extension study is assessing the therapy’s longer-term safety and effectiveness in PDD patients, as well as possible treatment effects on their gut bacteria.

Of note, up to 80% of Parkinson’s patients are thought to eventually develop disease-related dementia.