Communication Critical for Dravet Syndrome, DNL343 to Enter HEALEY ALS Trial, Combination of Seizures and Dementia Leads to Worse Outcomes

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Welcome to this special edition of Neurology News Network. I’m Marco Meglio.

In a recent qualitative study, findings suggested that a strong foundation of trust between clinicians and the caregivers of patients with Dravet syndrome (DS) is a critical component for successful treatment decision in this patient population. This analysis provided evidence that most effective way to combat the complexity of treatment for the disease is communication. In the study, investigators observed high levels of anxiety in all caregivers of patients with DS that was linked to the treatment decisions for these patients. They concluded that having trust in a healthcare provider is important for the caregivers, allowing them to feel more confident to discuss their concerns, thus potentially may improving engagement with care priorities. Although, building a foundation of trust with a clinician for caregivers may be a challenge especially after poor past experiences.

Newly announced interim results from a phase 1b study of Denali Therapeutics’ eIF2B agonist DNL343 showed that the agent was well tolerated and demonstrated robust blood-brain barrier penetration in patients with amyotrophic lateral sclerosis (ALS). Denali also announced the design of a phase 2/3 study for entry into the HEALEY ALS Platform trial, the first such study assessing multiple agents for ALS.In the double-blind, multicenter, placebo-controlled trial, the mean ratio of DNL343 in cerebrospinal fluid compared with unbound drug in plasma ranged from 1.02-1.23, suggesting that the agent effectively crossed the BBB and was extensively distributed in the central nervous system. Additionally, following treatment with DNL343, biomarkers associated with integrated stress response (ISR)—ATF4 and CHAC1—were attenuated. The interim analysis included 20 of the expected 29 patients with ALS in the trial who were on either DNL343 or placebo. Like many early-stage trials, the study’s main goal was safety, with incidence of treatment-emergent adverse events as the primary outcome.

In a recent multivariate logistic regression analysis, findings revealed that patients with dementia and active seizures at a younger age have worse cognition, poorer function, and higher mortality rates in comparison with patients without seizures who have dementia.1 This study bridges the gap of knowledge in the impact that seizures have on clinical and mortality outcomes in patients with dementia. Additionally, the data showed that patients with dementia are at a higher risk of having active seizures if they have dementia onset at an early age, a history of a dominant Alzheimer disease mutation, stroke, transient ischemic attacks, traumatic brain injury, Parkinson disease, active depression (OR, 1.61; P <.001), and lower education. The findings suggest that the risk factors of patients with dementia might be considered for EEG in early identification and treatment of seizures to improve outcomes.

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