Alzheimer Agent Simufilam Fails Phase 3, Lamotrigine Trial in DLB, Hearing Loss Independent Risk Factor for Parkinson

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

New topline data from the phase 3 ReThink-ALZ study (NCT04994483) showed that treatment with investigational simufilam (Cassava Sciences), a small molecule agent targeting an altered form of filamen A (FLNA), did not meet each of its pre-specified co-primary, secondary, and exploratory biomarker end points in patients with mild-to-moderate Alzheimer disease (AD). As a result of these findings, the company has decided to discontinue its second phase 3 study of simufilam, ReFocus-ALZ (NCT05026177). ReThink-ALZ was a double-blinded study that randomly assigned 804 patients with confirmed mild or moderate AD to either simufilam 100 mg (n = 403) or a matched placebo (n = 401), dosed orally twice daily (BID) for 52 weeks. After 52 weeks of treatment, simufilam failed to distinguish itself from placebo on the primary end points of Alzheimer’s Disease Assessment Scale-Cognitive Subscale 12 and Alzheimer’s Disease Cooperative Study-Activities of Daily Living.

At the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held September 27-October 1, in Philadelphia, Pennsylvania, investigators presented an outline of a new phase 2a study evaluating the therapeutic potential of lamotrigine (Lamictal), an FDA-approved antiseizure medication, in patients with dementia with Lewy bodies (DLB). The study, which will enroll 60 patients aged 60 years and older from a hospital in Seoul, Korea, is estimated to be completed in early 2025.In the study, eligible participants will be randomly assigned 1:1 to either standard of care (rivastigmine) plus either oral lamotrigine or matching placebo for a 20-week treatment period. The trial will use change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) as the primary end point, with additional secondary end points that included Mini Mental State Examination, CDR, Caregiver Administered-Neuropsychiatric Inventory, Mayo Fluctuation Scale, and Timed up and Go test, among others.

Recently published data using electronic health records for more than 3 million US veterans revealed that hearing loss was an independent risk factor for later development of Parkinson disease (PD), even after adjusting for competing risk of death, age, head trauma, frailty, and established prodromal disorders. Investigators concluded that hearing screening and hearing intervention are low-cost, low-risk measures that may influence the later development of synucleinopathy and could be the most important modifiable risk factor for both dementia in midlife and PD.Published in JAMA Neurology, the analysis included electronic health record data from the US Department of Veterans Affairs for veterans who had an audiogram (n = 3,596,365) from January 1999 to December 2022. Of those included, 20.8% (n = 750,010) had normal hearing (<20 dB) at the time of audiometry examination.

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