GSK4527226 (AL101) for Early Alzheimer's Disease (NCT06079190)

Overview

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["@clinicaltrialsgov"][@alector]. The drug is designed to elevate progranulin levels in the brain, addressing a novel mechanistic pathway involved in neurodegeneration["@alector"].

Overview

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["@clinicaltrialsgov"][@alector]. The drug is designed to elevate progranulin levels in the brain, addressing a novel mechanistic pathway involved in neurodegeneration["@alector"].

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)

Mechanism of Action: Progranulin Elevation

What is Progranulin?

Progranulin (PGRN) is a multifunctional growth factor protein expressed widely in the brain, particularly in [neurons](/entities/neurons) and [microglia](/cell-types/microglia-neuroinflammation)[@ahmed2007]. It plays critical roles in:

• Lysosomal function: PGRN is essential for proper lysosomal activity and [autophagy](/entities/autophagy)
• Microglial activation: Regulates neuroinflammatory responses
• Neuronal survival: Supports neuronal viability and function
• Synaptic plasticity: Involved in synaptic maintenance and function

Therapeutic Rationale

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[@alector][@rademakers2012]
• Protective effects: Increased PGRN levels have demonstrated protective effects in animal models of neurodegeneration[@alector]
• 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

Trial Design (PROGRESS-AD)

Study Type

• Allocation: Randomized
• Intervention Model: Parallel Group
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Purpose: Treatment

Treatment Arms

| 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 Endpoint

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[@clinicaltrialsgov]

Secondary Outcomes

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)[@clinicaltrialsgov]

Study Timeline

• Start Date: October 20, 2023
• Primary Completion: September 30, 2026 (estimated)
• Study Completion: November 23, 2026 (estimated)[@clinicaltrialsgov]

Eligibility Criteria

Inclusion Criteria

• 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)[@clinicaltrialsgov]

Exclusion Criteria

• 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[@clinicaltrialsgov]

Trial Sites

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[@clinicaltrialsgov]

Significance and Future Directions

Novel Mechanism

AL101 represents a fundamentally different approach to Alzheimer's disease treatment:

• Not amyloid-targeting: Unlike [lecanemab](/entities/lecanemab), [donanemab](/entities/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

Future 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

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References