Effects of ALZ-801, an Oral Amyloid Oligomer Inhibitor, on Biomarkers of Alzheimer’s Disease (AD): 12-Month Results of Phase 2 Biomarker Study in Early AD (S26.007)

Abstract

<h3>Objective:</h3> To evaluate effects of ALZ-801 on plasma and imaging biomarkers of AD pathology. <h3>Background:</h3> ALZ-801 (valiltramiprosate) is an oral small molecule inhibitor of amyloid oligomer formation. Fully enrolled Phase 2 study in APOE4 carriers is evaluating effects on plasma biomarkers, including hyperphosphorylated tau (p-tau₁₈₁) and beta amyloid (Aβ42 and Aβ40). Plasma p-tau₁₈₁ is elevated in AD and reduced by efficacious doses of lecanemab and aducanumab. APOLLOE4 Phase 3 trial is ongoing in Early AD patients with APOE4/4 genotype. <h3>Design/Methods:</h3> Phase 2 study enrolled subjects with MMSE ≥ 22 and CDR-G 0.5/1, and amyloid positive by CSF or PET scans who received ALZ-801 265 mg BID over 2 years (7 European sites). Biomarker analyses were conducted with Lumipulse (CSF) and Simoa (plasma) assays at Dr. Kaj Blennow’s laboratory. Hippocampal volume (HV) atrophy was assessed by Clario. Changes from baseline were analyzed in mITT population on observed data with paired t-tests and 2-sided p-values. <h3>Results:</h3> mITT population included 84 subjects with 75 completing 52 weeks. Mean age was 69 years, 51% female, MMSE 26.0, 70/30% MCI/Mild AD. Significant plasma p-tau₁₈₁ reduction started at 13 weeks and reached −41% at 52 weeks (p=0.016), with significant reduction in plasma Aβ42 and Aβ40 at 52 weeks (−5%, p=0.002 &amp; p=0.005). Hippocampal atrophy was reduced by 25% compared to matched ADNI controls. Composite cognitive Z-score improved significantly at 13 and 26 weeks and remained above baseline at 52 weeks. Common adverse events were mild nausea and COVID infection, with no drug-related serious events or ARIA-E. <h3>Conclusions:</h3> ALZ-801 produced a significant reduction of plasma p-tau₁₈₁, a marker of amyloid-induced neuronal injury in AD, as well as slowing of hippocampal atrophy at 1 year and cognitive stabilization, suggesting a disease modifying effect in AD patients. These biomarker and clinical effects are being confirmed in the Phase 3 trial. <b>Disclosure:</b> Dr. Hey has received personal compensation for serving as an employee of Alzheon. Dr. Hey has stock in Alzheon. Dr. Hey has stock in Alzheon. Dr. Hey has received intellectual property interests from a discovery or technology relating to health care. Dr. Abushakra has received personal compensation for serving as an employee of Alzheon Inc. Dr. Abushakra has stock in Alzheon Inc. The institution of Dr. Abushakra has received research support from NIA. Dr. Abushakra has received intellectual property interests from a discovery or technology relating to health care. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen, Axon, JOMDD, Roche, Siemens. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis, Julius Clinical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for MagQu. Dr. Scheltens has nothing to disclose. Dr. Hort has received personal compensation in the range of $0-$499 for serving as a Consultant for Alzheimerchain. Dr. Hort has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Hort has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Schwabe. Dr. Hort has stock in Alzheon. Dr. Sheardova has stock in Alzheon. Niels Prins has nothing to disclose. Mrs. Rutgers has received personal compensation for serving as an employee of Brain Research Center Amsterdam B.V.. Dr. Dautzenberg has nothing to disclose. Dr. Pazdera has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Pazdera has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Teva. Patrick Kesslak has nothing to disclose. Rosalind Mandelbaum has nothing to disclose. Dr. Power has received personal compensation for serving as an employee of Alzheon. Dr. Power has stock in Pfizer. Dr. Power has stock in Alzheon. Dr. Tolar has received personal compensation for serving as an employee of Alzheon. Dr. Tolar has received intellectual property interests from a discovery or technology relating to health care.