LeonaBio (LONA) Status Update summary

LIFT-AD study design and objectives

• LIFT-AD is a Phase II/III trial evaluating fosgonimeton in mild to moderate Alzheimer's disease, focusing on cognition and function as primary measures using the Global Statistical Test (GST), a composite of ADAS-Cog11 and ADL-23.

• The study design was adapted to exclude patients on cholinesterase inhibitors (AChEI) due to observed pharmacodynamic interactions, and the 70 mg dose was dropped for tolerability reasons.

• 554 patients were enrolled, with 315 in the primary analysis group (40 mg fosgonimeton or placebo, no cholinesterase inhibitors); enrollment is complete.

• The trial includes a 26-week double-blind period and an optional 48-month open-label extension.

• An interim analysis by an independent DMC confirmed the study could proceed, with futility not met and sample size reassessed for statistical power.

Rationale for GST and clinical context

• GST combines cognition and function, providing a robust, less variable measure suitable for disease-modifying therapies in Alzheimer's disease.

• Composite endpoints like GST offer greater stability and predictive value in phase II studies, as seen in prior Alzheimer's trials (lecanemab, donanemab).

• GST effect sizes can be interpreted as percent slowing of disease progression or time saved, making results more meaningful for patients and clinicians.

• A statistically significant GST requires directionally positive results in both cognition and function, reducing the risk of false positives from single endpoints.

• Disease-modifying effects are permanent, slowing progression and preserving function, while symptomatic effects are temporary; GST is designed to capture both.

Current treatment landscape and unmet need

• Mild to moderate Alzheimer's disease is a stage of rapid clinical decline with few effective treatment options and no approved disease-modifying therapies.

• Existing symptomatic treatments (cholinesterase inhibitors, memantine) offer modest benefits and are often poorly tolerated or discontinued.

• Monoclonal antibodies target earlier disease stages and require complex administration and monitoring, limiting global accessibility.

• There is a high unmet need for accessible, disease-modifying treatments that can be used in broader populations, especially in less-resourced regions.

• Delaying disease progression by two years could reduce the global burden by 22.5% by 2050 and have a major societal and economic impact.