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Introduction: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E ( APOE ) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD., Methods: This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265 mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes., Results: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024., Discussion: APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population., Highlights: The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E ( APOE ) ε4/ε4 genotype.The enrolled early AD population ( N  = 325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects., Competing Interests: Drs. Susan Abushakra, Aidan Power, Earvin Liang, J. Patrick Kesslak, John A. Hey, Susan Flint, Rosalind McLaine, and Martin Tolar are employees and own stocks or stock options in Alzheon Inc.; Drs. Anton P. Porsteinsson, Marwan Sabbagh, and Merce Boada are advisors to several companies developing AD drugs. Drs. David Watson, Emer MacSweeney, and Merce Boada are investigators in the Phase 3 study and are active investigators in multiple AD clinical trials with various mechanisms of action. Author disclosures are available in the supporting information., (© 2024 Alzheon, Inc. and The Author(s). Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abstract: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results., (Copyright © 2021 International Association for the Study of Pain.)