GSK4527226 (AL101) is a monoclonal antibody therapeutic candidate developed by GlaxoSmithKline (GSK) in collaboration with Alector Inc. that targets progranulin (PGRN) for the treatment of early Alzheimer's disease. The drug is designed to elevate progranulin levels in the brain, addressing a novel mechanistic pathway involved in neurodegeneration.
Trial Identifier: NCT06079190 (PROGRESS-AD)
Status: Active, not recruiting (as of November 2025)
Start Date: October 20, 2023
Estimated Completion: November 23, 2026
Phase: Phase 2
Enrollment: 367 participants (actual)
Progranulin (PGRN) is a multifunctional growth factor protein expressed widely in the brain, particularly in neurons and microglia. It plays critical roles in:
- Lysosomal function: PGRN is essential for proper lysosomal activity and autophagy
- Microglial activation: Regulates neuroinflammatory responses
- Neuronal survival: Supports neuronal viability and function
- Synaptic plasticity: Involved in synaptic maintenance and function
The development of AL101 is based on compelling genetic evidence:
- Genetic risk factor: Heterozygous mutations in the GRN gene (which reduce progranulin levels by ~50%) are associated with increased risk of both Alzheimer's disease and Parkinson's disease
- Protective effects: Increased PGRN levels have demonstrated protective effects in animal models of neurodegeneration
- Therapeutic window: Moderately elevating PGRN may provide beneficial effects without causing toxicity
¶ Antibody Mechanism
AL101 is a monoclonal antibody that binds to an as-yet-specified target to increase progranulin levels in the brain. The antibody approach allows for:
- Central nervous system penetration
- Targeted delivery to increase PGRN specifically
- Potential disease-modifying effects through modulation of lysosomal and microglial function
- Allocation: Randomized
- Intervention Model: Parallel Group
- Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
- Purpose: Treatment
| Arm |
Type |
Description |
| GSK4527226 Dose 1 |
Experimental |
Low dose intravenous infusion |
| GSK4527226 Dose 2 |
Experimental |
High dose intravenous infusion |
| Placebo |
Placebo Comparator |
Matching intravenous infusion |
Primary Outcome Measure: Change from Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score for Dose 1 vs Placebo
- Time Frame: Baseline, Week 52, 64, and 76
Cognitive Measures:
- Integrated Alzheimer's Disease Rating Scale (iADRS)
- ADAS-Cog14 Score (Alzheimer's Disease Assessment Scale - Cognitive Subscale 14)
- ADCS-ADL-MCI Score (Alzheimer's Disease's Disease Cooperative Study - Activities of Daily Living)
- ADCS-iADL component Score
- Alzheimer's Disease Composite Score (ADCOMS)
- Start Date: October 20, 2023
- Primary Completion: September 30, 2026 (estimated)
- Study Completion: November 23, 2026 (estimated)
- Age 50–85 years at screening
- Early AD (MCI due to AD or mild AD dementia per NIA-AA framework)
- Evidence of amyloid positivity (PET scan or CSF biomarkers)
- MMSE score: 21–29
- CDR-global score: 0.5–1.0
- Memory Box score ≥ 0.5
- Objective episodic memory impairment (≥1 SD below age-adjusted mean on WMS-IV LMII)
- Neurological conditions other than AD
- Recent stroke or transient ischemic attack (TIA)
- Active psychiatric diagnosis
- Suicidal ideation or behavior
- MRI findings of significant cerebrovascular disease
- Use of AD disease-modifying therapies within 6 months
- Other significant medical conditions
The trial is being conducted at multiple international sites across:
- United States (multiple sites)
- Argentina
- Australia
- Canada
- Finland
- France
- Germany
- Italy
- Netherlands
- Norway
- South Korea
- Spain
- Sweden
- Taiwan
- Turkey
- United Kingdom
¶ Significance and Future Directions
AL101 represents a fundamentally different approach to Alzheimer's disease treatment:
- Not amyloid-targeting: Unlike lecanemab, donanemab, or aducanumab, AL101 targets progranulin
- Disease-modifying potential: By addressing lysosomal dysfunction and microglial activation, the therapy may modify disease progression
- Genetic validation: The therapeutic approach is supported by human genetics showing that reduced PGRN increases AD risk
¶ Competitive Landscape
AL101 joins a small number of progranulin-targeting therapies in development:
- AL101 (GSK4527226): Phase 2 for AD and PD
- AL002 (Evinamab): Another progranulin-modulating antibody from Alector in development
If Phase 2 results are positive, the development path may include:
- Phase 3 confirmatory trials
- Potential combination with existing amyloid-targeting therapies
- Expansion to Parkinson's disease trials