Alzheimer's Disease Therapeutics: Donanemab Dosing, Anti-Tau Antibody E2814, and Combination Intranasal Insulin/Empagliflozin Show Promise
核心洞察
Enhanced titration dosing of donanemab in the TRAILBLAZER-ALZ-6 trial significantly reduced the frequency and severity of ARIA-E in early symptomatic Alzheimer's disease (搜索) patients.
Phase 1b/2 study data of E2814, an anti-tau (搜索) therapeutic antibody, demonstrated a significant impact on early and late tau biomarkers in patients with dominantly inherited Alzheimer's disease (搜索).
A phase 2 trial showed that combination treatment with intranasal insulin and empagliflozin improved cognition and modulated immune/inflammatory biomarkers in mild cognitive impairment (搜索) or early Alzheimer's disease (搜索).
New research presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference in Madrid, Spain, highlights advancements in Alzheimer’s disease therapeutics, focusing on optimized donanemab dosing, the anti-tau (搜索) antibody E2814, and a novel combination therapy using intranasal insulin and empagliflozin.
Enhanced Donanemab Dosing Reduces ARIA Risk
Findings from the phase 3b TRAILBLAZER-ALZ-6 trial (NCT05738486) investigated an enhanced titration dosing regimen of donanemab (Kisulna; Eli Lilly) to mitigate the risk of amyloid (搜索)-related imaging abnormalities-edema (ARIA-E). The study involved 843 adults with early symptomatic Alzheimer's disease (搜索), stratified by apolipoprotein E (APOE) genotype and baseline amyloid levels. Participants were randomized in a 1:1:1:1 ratio to either a standard dosing arm or one of three alternative dosing arms. By week 24, the frequency of ARIA-E was 23.7% in the standard dosing arm, compared to 18.6%, 13.7%, and 18.3% in the alternative dosing arms. These results suggest that the enhanced titration dosing regimen can reduce ARIA-E while maintaining effective amyloid reduction.
Anti-Tau Antibody E2814 Shows Impact on Tau Biomarkers
Data from the E2814-G000-103, an open-label, phase 1b/2 study (NCT04971733), evaluated the investigational anti-tau (搜索) therapeutic antibody E2814 (Eisai) in patients with dominantly inherited Alzheimer's disease (搜索) (DIAD). The study included 8 participants with confirmed mutations in the presenilin 1 (PSEN1), amyloid (搜索) precursor protein (APP), or presenilin 2 (PSEN2) genes. Patients received E2814 intravenously every 4 weeks, with escalating doses from 750 mg to 4500 mg. The results indicated that E2814 significantly affected both early and late tau biomarkers in treated patients. Notably, E2814 did not affect phosphorylated tau (p-tau)217 or MTBR-tau243 levels in healthy volunteers, suggesting its effects are specific to those with tau pathology. This specificity supports the continued clinical development of E2814.
Combination Intranasal Insulin and Empagliflozin for Cognitive Improvement
New data from a placebo-controlled phase 2 trial (NCT05081219), known as the SNIFF study, demonstrated the therapeutic potential of combining intranasal insulin (INI) and empagliflozin (empa) in patients with mild cognitive impairment (搜索) (MCI) or early Alzheimer's disease (搜索) (AD). The study assigned patients to one of four arms: placebo, INI (40 IU QID regular insulin), empa (10 mg QD), or insulin plus empa (INI+empa). Over a 4-week treatment period, researchers compared insulin-treated (INI and INI+empa) vs non-insulin-treated (placebo and empa only) patients on cerebrospinal fluid (CSF) and plasma biomarkers, diffusion tensor imaging (DTI) global white matter fractional anisotropy, and cognitive function. The results indicated positive effects on cognition and several immune/inflammatory biomarkers, supporting further investigation of this combination method for AD, potentially in conjunction with approved anti-amyloid (搜索) therapies.