Patients who received high-dose blarcamesine experienced a 14.51-point MDS-UPDRS total score improvement compared to placebo in a phase 2 study of the Anavex Life Sciences agent.
Full results from the proof-of-concept phase 2 study (NCT03774459) of blarcamesine (Anavex Life Sciences) suggest that the drug’s impact on increasing sigma-1 receptor (SIGMAR1) mRNA expression corresponded significantly with responses on primary and secondary end points in patients with Parkinson disease dementia (PDD). Anavex noted it plans on submitting these data to the FDA to seek regulatory guidance.1
Treatment with blarcamesine, formerly known as ANAVEX 2-73, resulted in significant (P = .035) mRNA expression increase of SIGMAR1, which correlated with clinical efficacy as measured by the Cognitive Drug Research (CDR) system Continuity of Attention (CoA; P = .029) and CDR system Power of Attention (PoA; P = .015), the primary end point. The correlation also remained true on secondary end points such as Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III (P = .024) and MDS-UPDRS total (P = .038) scores.
"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 mRNA expression,” Christopher U. Missling, PhD, president and chief executive officer, Anavex, said in a statement.1 "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 indication with unmet medical need. This data further strengthens the foundation of ANAVEX 2-73 as a cross-platform [central nervous system] drug.”
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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).
Those included in the high-dose group demonstrated statistically significant improvements compared to placebo for MDS-UPDRS total score (P = .034). By the end of the study period, the MDS-UPDRS total score improved by 10.98 points in the 50-mg dose group and worsened by 3.53 points in the placebo group, corresponding to a relative improvement of 18.9%. This far exceeds an empirically established cutoff of a 7.1-reduction for detecting meaningful clinical change.
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.
Previously reported data presented at the Clinical Trials on Alzheimer’s Disease (CTAD) 2020 Annual Meeting showed a dose-dependent (P = .003), statistically significant improvement of CDR system Episodic Memory of 42.22 points between 50-mg blarcamesine and placebo. CDR system Episodic Memory has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).
Patients in the high-dose group also experienced an ADAS-Cog mean change from baseline of –1.9, an 8% mean improvement from baseline to 14 weeks. Investigators documented a 4-point improvement difference of calculated corresponding ADAS-Cog score between the blarcamesine treatment group and the placebo group from baseline to the end of the study period. Anavex is also evaluating blarcamesine in a phase 2b/3 study that features patients with Alzheimer disease (AD). The company recently announced that they have exceeded their target enrollment goal of 450 patients, and topline results from the ongoing study are expected to be announced by mid-2022.2