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E2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR-tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer's Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive...

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Veröffentlicht in:Alzheimer's & dementia 2023-12, Vol.19 Suppl 24, p.e082771
Hauptverfasser: Zhou, Jin, Rawal, Sumit, Yagi, Takuya, Wildsmith, Kristin R, Takahashi, Eri, Horie, Kanta, Barthélemy, Nicolas R, Aluri, Jagadeesh, Lalovic, Bojan, Boyd, Peter, Bateman, Randall J, Reyderman, Larisa
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Sprache:eng
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Zusammenfassung:E2814 is a human IgG1 antibody that binds to microtubule binding region of tau (MTBR-tau), a critical domain for the seeding and spreading of tau pathology in Alzheimer's Disease (AD). It is being developed for the treatment of AD by stopping tau propagation and slowing the associated cognitive decline. E2814 has been evaluated in healthy and Dominantly Inherited Alzheimer's Disease (DIAD) participants for safety, pharmacokinetics (PK), and cerebrospinal fluid (CSF) target engagement. Seventy-two healthy participants were enrolled in single and multiple ascending dose cohorts of Study 001 (NCT04231513) and received randomized, double-blind, placebo-controlled treatment of E2814. Intravenous infusion of single and multiple doses (once every 4 weeks for three times) were administered. In Study 103 (NCT04971733), 7 DIAD participants with confirmed mutations and mild to moderate cognitive impairment were enrolled and received open-label treatment of E2814. Four sequential doses were evaluated as intravenous infusion every 4 weeks. Serum and CSF PK, and CSF target engagement (by analyzing both bound and unbound MTBR-tau299 and MTBR-tau354 [containing the epitopes of E2814]) were measured in both healthy and DIAD participants, as well as safety assessments. CSF MTBR-tau243 recapitulating AD tau pathology was also measured in DIAD participants using methods previously described (Horie et al., J Prev Alz Dis 2022). E2814 was safe and well-tolerated over a wide dose range. No infusion-related reactions or other clinically significant safety signals were observed with single or repeated dose administration for up to 15 months. E2814 showed a dose-related increase in serum and CSF exposure with CSF-to-serum ratio of ∼0.2%, comparable between healthy and DIAD participants. CSF target engagement was demonstrated by concentration-related and sustained MTBR-tau299 and MTBR-tau354 binding in healthy and DIAD participants. More importantly, E2814 elicited a rapid and robust reduction on MTBR-tau243, a neurofibrillary tangle-specific biomarker, in DIAD participants. E2814 demonstrated promising safety, PK and CSF target engagement profile in DIAD participants, and showed evidence of downstream effects on tangle-specific biomarker MTBR-tau243. Data supports further evaluation in the ongoing Ph2/3 DIAN-TU Tau NexGen Platform Study in DIAD (NCT05269394) and future exploration in sporadic AD.
ISSN:1552-5279
1552-5279
DOI:10.1002/alz.082771