Blarcamesine Exceeds Enrollment, Higher Plasma Nusinersen Leads to Meaningful Improvements, Neurodevelopmental Outcomes Unchanged by Maternal ASMs


Neurology News Network for the week ending June 19, 2021.

This week Neurology News Network covered the phase 2b/3 study evaluating blarcamesine in patients with Alzheimer disease, the effect of higher nusinersen levels on outcomes in patients with spinal muscular atrophy, and data from the MONEAD study which evaluated the neurodevelopment of children of women with epilepsy taking antiseizure medications.

Welcome to this special edition of Neurology News Network. I’m Marco Meglio. Please excuse our appearance this week as a majority of the US workforce, including the NeurologyLive team, moves to working remote as we come together to help reduce the spread of the novel coronavirus.

Anavex Life Sciences recently announced that it has exceeded its enrollment target of 450 patients for its ongoing phase 2b/3 study evaluating its investigational agent blarcamesine, formerly known as ANAVEX 2-73, in patients with Alzheimer disease (AD). Topline results from the study are expected to be announced by mid-2022. The double-blind, placebo-controlled 48-week clinical study is using the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) subscales as primary end points to assess the cognitive and functional efficacy of blarcamesine. Patients included in the study will be randomized 1:1:1 to 2 different blarcamesine doses or placebo. Blarcamesine, an orally available investigational agent, will also be evaluated on SIGMAR1 gene expression, a prespecified precision medicine biomarker. This gene expression correlated with direct measures of clinical benefit, cognition, and activities of daily living and function in the previously completed phase 2a study, the first genome-wide search for biomarkers associated with therapeutic response in AD.

Analysis presented at the 2021 Cure SMA Research & Clinical Care Meeting, showed that higher nusinersen (Spinraza; Biogen) levels are associated with greater decrease of plasma pNF-H levels in patients with spinal muscular atrophy (SMA) and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose. The pharmacokinetic/pharmacodynamic (PK/PD) model indicated that patients exposed to higher nusinersen cerebrospinal fluid (CSF) were correlated with greater efficacy, as measured by change from baseline in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores. Furthermore, exposure levels also predicted clinically meaningful increases of at least 5 points on CHOP INTEND. Nusinersen, an antisense oligonucleotide administered intrathecally, received FDA approval for the treatment of children and adults with SMA in December 2016. Since its approval, the drug has had a multitude of studies conducted to further confirm its efficacy and safety in this patient population.

Data from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study showed that children of women with epilepsy (WWE) taking antiseizure medications (ASMs) did not differ in neurodevelopmental outcomes compared to those of healthy women. Overall, investigators found no significant differences between children of WWE vs healthy women for the primary language domain outcome. In the full model, significant factors such as higher maternal IQ, birth weight, and female child sex were associated with higher language domain scores. The study authors wrote, “This encouraging finding may be due to the use of newer ASMs with lower risk of affecting the immature brain. However, these findings must be interpreted within the context that neuropsychological assessments conducted at 2 years of age are not as strongly associated with adolescent/adult functioning as assessments performed in older children, which will be conducted subsequently in the MONEAD study.”

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