Ocrelizumab Reduces Thalamic Volume Loss, Cenobamate Shines in C017 Study, Trial of LRRK2 Inhibitor BIIB122 Commences

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

Using the phase 3 OPERA I and II and ORATORIO studies, investigators found significantly reduced thalamic volume loss in patients with relapsing (RMS) and primary progressive multiple sclerosis (PPMS) treated with ocrelizumab (Ocrevus; Genentech) compared with those on interferon beta-1a or placebo.Led by Douglas Arnold, MD, neurologist, Montreal Neurological Institute and Hospital, and Department of Neurology and Neurosurgery, McGill University, the study showed that ocrelizumab had the greatest effect on thalamic volume compared with whole brain, and white or cortical gray matter. “This could be explained from the perspective that thalamic injury may reflect much of the MS-related damage that occurs throughout the whole CNS and may not be specific to the thalamus only,” Arnold et al wrote. Thalamic loss, typically occurring early in patients with MS, has been associated with loss in disability progression, measured by changes in Expanded Disability Status Scale (EDSS) and cognitive impairment.

Newly published data from the long-term, open-label extension (OLE) of the randomized, placebo-controlled C017 study of cenobamate (Xcopri; SK Life Sciences) showed that the antiseizure medication sustained efficacy after 48 months, with more than 15% of patients achieving 100% seizure freedom.Approved in 2019 to treat partial-onset seizures, cenobamate was evaluated in a cohort of 355 patients, aged 18 to 70 years, with uncontrolled focal seizures who completed the 18-week double-blind study. At months 12, 24, 36, and 48, a total of 83%, 71%, 65%, and 62% of patients were retained on cenobamate treatment. Despite failing 1 to 3 previous antiseizure medications, 16.4% (36 of 220) and 39.1% (86 of 220) achieved 100% or at least 90% seizure reduction, respectively, during months 36 through 48. As of July 2019, 58.9% (209 of 355) of patients were continuing in the OLE, with 16.6% discontinuing because of lack of efficacy, 8.7% because of withdrawal by patient, and 7.6% because of adverse events (AEs). During the first 6 months of the OLE, investigators observed a median percent reduction of 65.4% (interquartile range [IQR], 52%) for all individuals on cenobamate, regardless of previous treatment with placebo. With each 6-month OLE interval, the median percent reduction continued to increase, up to 76.1% at months 43 to 48.

Dosing for the global phase 2b LUMA study (NCT05348785), which will evaluate the efficacy and safety of BIIB122 (also known as DNL151), an investigational LRRK inhibitor for patients with Parkinson disease (PD), has officially commenced, according to an announcement from Biogen and Denali Therapeutics.The double-blind, placebo-controlled study includes 640 participants between the ages of 30 and 80 years with early-stage PD who will be randomly assigned to 225 mg of oral BIIB122 or placebo once daily for a minimum of 48 weeks and a maximum of 144 weeks. To understand whether BIIB122 slows the worsening of symptoms, researchers will evaluate patients on Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) parts II and III. Discovered and developed by Denali, BIIB122 is a selective, central nervous system-penetrant small molecule inhibitor of LRRK2 that is hypothesized to improve dysfunction. To date, the investigational drug has not had its efficacy and safety established. As part of the clinical program, another trial, a phase 3 study called LIGHTHOUSE, will evaluate BIIB122’s effectiveness in nearly 400 patients with LRRK2-mutated PD.

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