SavaDx, a novel plasma biomarker to detect Alzheimer’s disease, confirms mechanism of action of simufilam

Le résumé fourni par la source

Abstract Background The diagnosis and management of Alzheimer’s disease (AD) would be greatly aided by sensitive, accurate and scalable biomarkers. SavaDx is proposed as a novel plasma diagnostic/biomarker candidate for Alzheimer’s disease. SavaDx detects altered filamin A, a previously described proteopathy in AD. SavaDx was evaluated as an exploratory endpoint in a clinical trial of simufilam, a drug candidate for AD that targets and reverses altered filamin A, the proteopathy detected by SavaDx. Method SavaDx was evaluated in a multi‐center, randomized, controlled trial of simufilam completed in 2020. This Phase 2b study enrolled 64 patients with mild‐to‐moderate AD, MMSE 16 to 26 and CSF total tau/Aβ42 ratio ≥ 0.28. Patients were randomized (1:1:1) to placebo, 50 mg, or 100 mg b.i.d. oral simufilam for 28 days. CSF and blood samples were collected at baseline and Day 28. Plasma p‐tau181 was measured in duplicate by SIMOA®. Data with Coefficients of Variation >11% were repeated and excluded if >15% on repeat. Biomarker analyses were conducted blind to treatment. Day 1 and Day 28 samples for each patient were analyzed together. SavaDx, a non‐published investigational assay, was used to estimate altered filamin A levels in brain. Result This Phase 2b study met all co‐primary CSF biomarker endpoints, as previously reported. Simufilam 50 mg and 100 mg twice daily significantly improved eleven CSF biomarkers of AD pathology, neurodegeneration and neuroinflammation, baseline to Day 28 versus placebo. SavaDx values decreased 44% and 48% in the 50 and 100 mg arms, respectively, (p=0.02 and p=0.005 versus placebo) versus a 3% decrease in the placebo arm. Plasma p‐tau181 values decreased 15% and 17% in the 50 and 100 mg arms, respectively (both p<0.05), versus a 20% increase in placebo. Conclusion SavaDx detected treatment effects in a randomized, controlled trial of simufilam, a drug candidate that targets and reverses a critical proteopathy in AD. These data offer quantitative evidence of drug‐target engagement in patients, confirming simufilam’s mechanism of action. These data also suggest the use of the SavaDx assay to detect and monitor AD in plasma. This work was funded by NIA grants AG057329 and AG060878.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.