Blarcamesine Deemed Safe, Effective in Phase 2 Extension Study of Parkinson Disease Dementia

Anavex Life Sciences has announced findings from the 48-week, open-label extension of its phase 2 study, ANAVEX2-73-PDD-EP-001 (NCT04575259), demonstrating that its investigational agent ANAVEX2-73, or blarcamesine, met its primary and secondary objectives in a cohort of individuals with Parkinson disease dementia (PDD).¹

Because of the COVID-19 pandemic, the start of the extension phase was delayed, on average, by approximately 41 weeks at the end of the double-blind period, resulting in reduced enrollment rate and a “drug holiday.” At the end of the double-blind period and OLE, all efficacy end points, which included Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts II and III and Clinical Global Impression-Improvement (CGI-I) were consistently improved when patients resumed treatment.

"It is encouraging that the patients’ clinical symptoms consistently improved longitudinally over time during the extension phase under active ANAVEX2-73 treatment,” Christopher U. Missling, PhD, president and chief executive officer, Anavex, said in a statement.¹ "This data suggests ANAVEX2-73’s potential capability to slow and potentially reverse the life altering symptoms of Parkinson’s disease, an urgent unmet global need."

From OLE baseline to week 48, investigators recorded a change of –2.25 (SE, 6.656) in MDS-UPDRS total score and change of –0.7 (SE, 0.309) in CGI-I. Additionally, at this time point, there were mean changes of –1.2 (SE, 0.537) in Montreal Cognitive Assessment and mean changes of –0.524 (SE, 0.620) in REM Sleep Behavior Disorder Screening Questionnaire. On specific MDS-UPDRS scores, patients on blarcamesine recorded mean changes of –3.95 (SE, 4.067) in Part III scores and mean changes of –2.20 (SE, 5.314) in part II and III scores combined.

Previously reported, at the end of the double-blind period, patients on high-dose blarcamesine saw improvements of –10.98 points on MDS-UPDRS total score in comparison with the placebo group, which worsened by 3.53 points (adjusted mean difference, –14.51 points; P = .034). This corresponded to a relative improvement of 18.9% over 14 weeks. Additionally, the data was consistent with expression levels of pathological dysregulated neurodegenerative genes, including PD genes, which were significantly restored by the therapeutic effect of blarcamesine (P <.005).

Due to the nature of the study and the small sample sizes, the investigators noted these results should be interpreted with caution. At the request of the participants who completed the 48-week OLE, continued treatment with blarcamesine was allowed through a compassionate use Special Access Scheme. Additionally, the 2 major end points, MDS-UPDRS II + III and CGI-I, are expected to be the primary end key secondary end points in Anavex’s forthcoming 6-month PD study.

Full results from the original phase 2 proof-of-concept study highlighted blarcamesine’s impact on increasing sigma-1 receptor (SIGMAR1) mRNA expression, which correlated with the primary and secondary end points observed. Specifically, this corresponded with clinical efficacy as measured by the Cognitive Drug Research (CDR) system Continuity of Attention (P = .029) and CDR system Power of Attention (P = .015), the primary end point. The correlation also remained true on secondary end points of MDS-UPDRS Part III (P = .024) and MDS-UPDRS total (P = .038) scores.²

The phase 2 study included 132 patients with PDD randomized 1:1:1 to blarcamesine 30 mg, 50 mg, or placebo for up to 14 weeks. Study participants were allowed to be on a stable regimen of anti-PD medications, including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone (Comtan; Novartis). The clinically meaningful improvements observed in patients with PDD suggest that the agent has the capability of slowing and reversing symptoms that progress in PD, an urgent unmet need for this patient population. Notably, blarcamesine did not impair sleep and had a positive effect on rapid eye movement (REM) sleep behavior disorder.

REFERENCES
1. ANAVE2-73 (Blarcamesine) shows clinical benefit in long-term 48-week phase 2 extension study in patients with Parkinson’s disease dementia. News release. Anavex Life Sciences. March 30, 2023. Accessed March 30, 2023. https://www.globenewswire.com/news-release/2023/03/30/2637477/0/en/ANAVEX-2-73-Blarcamesine-Shows-Clinical-Benefit-in-Long-Term-48-Week-Phase-2-Extension-Study-in-Patients-with-Parkinson-s-Disease-Dementia.html
2. Anavex Life Sciences announces ANAVEX 2-73 (blarcamesine) improved both primary cognitive and secondary MDS-UPDRS efficacy end points with significant biomarker correlation in placebo-controlled phase 2 clinical trial. News release. June 28, 2021. Accessed March 30 2023. https://www.biospace.com/article/anavex-life-sciences-announces-anavex-2-73-blarcamesine-improved-both-primary-cognitive-and-secondary-mds-updrs-efficacy-endpoints-with-significant-biomarker-correlation-in-placebo-controlled-phase-2-clinical-trial/