Alector's Dementia Drug Failure Leads to Major Restructuring, Casting Doubt on Progranulin-Targeting Therapies

Alector Therapeutics, a California-based biotech company, has announced the discontinuation of its lead dementia drug candidate latozinemab following disappointing results from a Phase III clinical trial. The failure of this GSK-partnered antibody has prompted a significant restructuring of the company, including substantial layoffs and a shift in research focus.

Trial Failure and Company Restructuring

Latozinemab, also known as AL001, failed to meet its primary endpoint in the INFRONT-3 Phase III trial for frontotemporal dementia (FTD) caused by progranulin gene mutations. While the drug successfully increased plasma progranulin levels, it did not demonstrate a significant effect on slowing disease progression compared to placebo. The 96-week study also missed key secondary endpoints, showing no treatment effect on volumetric magnetic resonance imaging outcomes or other fluid biomarker concentrations.

In response to this setback, Alector has announced a strategic review of its business, resulting in the following actions:

• Layoffs affecting approximately 49% of its workforce, potentially impacting around 116 employees
• Discontinuation of the open-label extension and continuation studies for latozinemab
• The resignation of Sara Kenkare-Mitra, Alector's president and head of R&D, effective December 22, 2025

The company's stock price plummeted by 51% to $1.57 per share in after-hours trading following the announcement.

Implications for Progranulin-Targeting Therapies

The failure of latozinemab raises questions about the clinical translatability of targeting plasma progranulin concentrations in neurodegenerative diseases. This setback represents Alector's second failed neurodegenerative asset in a year, following the discontinuation of an AbbVie-partnered Alzheimer's drug in late 2024.

Despite these challenges, Alector remains committed to its ongoing collaboration with GSK. The partnership, established in July 2021 with a $700 million upfront payment and up to $1.5 billion in potential milestones, continues to focus on AL101 (nivisnebart), another progranulin-modulating antibody currently in Phase II trials for early Alzheimer's disease.

Future Directions and Pipeline Focus

Alector is now shifting its focus to other assets in its pipeline:

• The PROGRESS-AD Phase II trial of nivisnebart in early Alzheimer's disease, with an independent interim analysis scheduled for the first half of 2026
• Preclinical development of AL137, an anti-amyloid beta antibody for Alzheimer's disease
• AL050, an enzyme replacement therapy for Parkinson's disease, also in preclinical testing

The company reports having $291.1 million in cash, cash equivalents, and short-term investments as of September 30, 2025, which it expects will fund operations through 2027.

As the pharmaceutical industry grapples with the implications of this latest setback in neurodegenerative disease research, attention now turns to the remaining clinical trials and emerging therapies in the field. The outcome of Alector's ongoing studies and its ability to pivot its research focus will be closely watched by investors and industry observers alike.