VY-HTT01 IND Accepted, SUDEP Associated With Abnormal Cardiac Response, Humoral Response in MS DMTs Identified


Neurology News Network for the week ending May 8, 2021.

This week Neurology News Network covered the FDA clearance of the investigational new drug application for Huntington disease treatment VY-HTT01, a study linking abnormal cardiac autonomic response to patients with sudden death in epilepsy, and a study evaluating the humoral response to the COVID-19 vaccine in multiple sclerosis disease modifying therapy users.

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.

Voyager Therapeutics has received FDA clearance for its investigational new drug (IND) application for VY-HTT01, a gene therapy candidate for the treatment of Huntington disease (HD), and may proceed with its planned phase 1/2 clinical trial, according to a recent announcement. Voyager submitted the IND for the drug in September of 2020 and was notified a month later that it had been placed on clinical hold pending the resolution of certain chemistry, manufacturing, and controls (CMC) matters.2 Upon full comprehensive review of those CMC matters, the FDA felt as though the company could proceed. The trial, named VYTAL, is a dose-escalation study to evaluate the safety and tolerability of VY-HTT01 in patients with early manifest HD and is set to be initiated this year. The gene therapy is comprised of an adeno-associated virus capsid (AAV1) designed to reduce the expression of huntingtin (HTT), thereby altering disease progression.

Data from a recent study published in Neurology suggest that most patients with subsequent sudden unexpected death in epilepsy (SUDEP) had an abnormal cardiac autonomic response to sympathetic stimulation by hyperventilation.Investigators found that in patients who died from SUDEP, heart rate and root mean square of successive differences between normal heartbeats (RMSSD) did not change significantly during or after hyperventilation. A difference in heart rate between the end of the hyperventilation and 4 minutes after its end discriminated between SUDEP patients and control patients with an area under the curve of (AUC) of 0.870, a sensitivity of 85%, and a specificity of 75%. The study authors wrote, “There is a currently unmet need for predictive biomarkers that identify patients with the highest risk of SUDEP. Given that functional alterations of the autonomic nervous system appear to have a critical role in the pathophysiology of SUDEP, heart rate variability (HRV) has been extensively studied, especially in interictal state.”

Research published in Therapeutic Advances in Neurological Disorders characterized humoral immunity in patients with multiple sclerosis (MS) who have received mRNA-COVID-19 vaccines and were treated with high-efficacy disease-modifying therapies (DMT) and found that cladribine was the only DMT observed to not impair humoral response. Lead author Anat Achiron, and colleagues evaluated the Pfizer-BioNTech vaccine in 125 adults with multiple sclerosis to provide evidence-based guidelines to the MS community regarding the magnitude of protective humoral immunity in patients treated with high-efficacy DMTs. Protective humoral immunity was demonstrated in 46 of 47 (97.9%) of healthy subjects (n = 47) and untreated patients with MS (n = 32). All patients (100%) treated with cladribine (n = 23) developed a high level of antibodies post-COVID-19 vaccination (<.0001). Notably, cladribine was the only DMT with a 100% protective humoral immunity rate.

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