Core Insights - Alector, Inc. announced results from the Phase 3 INFRONT-3 trial for latozinemab (AL001) targeting frontotemporal dementia caused by a progranulin gene mutation, which did not meet its primary clinical endpoint [1][2] Trial Results - The 96-week study did not achieve the co-primary endpoint of slowing FTD-GRN progression as measured by the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Sum of Boxes [2] - Although there was a statistically significant effect on the biomarker co-primary endpoint of plasma progranulin concentrations, secondary and exploratory endpoints showed no treatment-related effects on FTD-GRN [3] - Preliminary safety data did not indicate major safety concerns, but further analysis is ongoing [3] Future Plans - The open-label extension of the INFRONT-3 trial and the continuation study for latozinemab will be discontinued based on the trial results [4] - Alector is collaborating with GSK on nivisnebart (AL101/GSK4527226) in a 76-week Phase 2 trial for early Alzheimer's disease, with trial completion expected in 2026 [5] Financial Outlook - As of September 30, 2025, Alector has approximately $291.1 million in cash and equivalents, expected to provide financial runway through 2027 [6] Analyst Commentary - William Blair downgraded Alector from Outperform to Market Perform, with analyst Myles Minter removing latozinemab from the FTD-GRN opportunity [7] - Despite observing plasma and CNS PGRN elevations to normal levels, the link between PGRN insufficiency and FTD-GRN remains uncertain [7] Stock Performance - Following the announcement, Alector shares fell by 51.09% to $1.57, nearing a 52-week low of $0.87 [8]

Financial Data and Key Metrics Changes - The company closed the quarter with $307.3 million in cash, which is expected to provide runway into 2027 [38] - Updated financial guidance for 2025 includes collaboration revenue anticipated between $13 million and $18 million, total research and development guidance between $130 million and $140 million, and total general and administrative guidance between $55 million and $65 million [38] Business Line Data and Key Metrics Changes - The pivotal Phase III INFROM3 trial of Latozinimab is expected to provide top-line data by mid Q4 2025, focusing on frontotemporal dementia due to the GRN gene mutation [5][6] - The Phase II trial of AL-101, targeting early Alzheimer's disease, completed enrollment in April 2025, with trial completion expected in 2026 [7][30] Market Data and Key Metrics Changes - FTD GRN accounts for approximately 5% to 10% of all FTD cases, representing about 8,000 to 17,000 cases in the US and EU [22] - The incidence of FTD in the US is estimated to be 15 to 22 cases per 100,000 person-years, resulting in a prevalence of about 50,000 to 60,000 concurrent cases [15] Company Strategy and Development Direction - The company aims to deliver therapies that eradicate neurodegeneration and improve patient outcomes, focusing on building a durable biotechnology company [9] - The proprietary Electric Brain Carrier technology platform is designed to enable effective delivery of therapies across the blood-brain barrier [8][33] Management's Comments on Operating Environment and Future Outlook - Management emphasized the urgent unmet need in treating frontotemporal dementia and the importance of their clinical programs [10][22] - The company is preparing for potential BLA and MAA submissions in 2026 based on the strength of their trial design and clinical data [29] Other Important Information - The INFROM3 trial is a 96-week randomized, double-blind, placebo-controlled global trial evaluating Latozinimab in symptomatic and at-risk individuals with confirmed GRN mutations [25] - The company has received breakthrough therapy and fast track designations from the FDA for Latozinimab [28] Q&A Session Summary Question: Clarification on the statistical analysis plan changes - The change to include progranulin as a co-primary endpoint was made at the request of the FDA, recognizing its mechanistic role [42] Question: Concerns about plasma progranulin levels - The FDA did not specify a threshold for progranulin levels but emphasized its importance as a biologically meaningful marker [51] Question: Thoughts on the potential for a 25% slowing of cognitive decline - A 25% reduction would be meaningful in a disease with no other therapeutic options, and the safety profile appears favorable compared to anti-amyloid therapies [56][58] Question: Discussion on the open-label extension of the INFROM study - The company is satisfied with the number of subjects opting into the open-label extension, which will provide meaningful data on treatment persistence [108]