Abstract Details

Title A First-in-Human Study of the Anti-Sortilin Antibody AL101

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P5 - Poster Session 5 (11:45 AM-12:45 PM)

Poster/Presentation
Number 3-003

Objective The first-in-human Phase 1 study was designed to investigate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101, administered intravenously (IV) and subcutaneously (SC).

Background Progranulin gene (GRN) mutations are implicated in a number of neurodegenerative disorders, including Frontotemporal dementia, Alzheimer’s disease and Parkinson’s disease. The Sortilin receptor is a key regulator of progranulin (PGRN) levels. AL101 is a human monoclonal IgG1 antibody, downregulates Sortilin and increases PGRN in pre-clinical models of neurodegenerative disorders. Increasing PGRN levels may be an effective therapeutic approach, potentially reducing neuronal loss and clinical decline in neurodegenerative diseases.

Design/Methods Healthy volunteers received a single dose of AL101 in ascending IV dose cohorts of 6, 15, 30 and 60 mg/kg (randomized 8:3 AL101:placebo) and a single 600 mg SC dose of AL101 in an open-label cohort (n=9) to assess bioavailability. Standard clinical safety measures, pharmacokinetic (PK) and pharmacodynamic (PD) markers in plasma and CSF were assessed. CSF profiles of AL101 and PGRN were measured up to 85 days after AL101 administration. Safety follow-up was conducted for up to 16 weeks in the 60 mg/kg IV cohort and 12 weeks in all other cohorts.

Results AEs were generally mild to moderate and self-limiting, most frequent treatment emergent AEs were headache (19%), anemia (9%), and procedural pain (9%). AL101 exhibited dose-proportional serum PK, with some increase in clearance at the lowest doses. AL101 increased levels of PGRN in the CNS of healthy volunteers to approximately twice baseline levels, with prolonged CSF elevation with increasing dose.

Conclusions

AL101 was generally safe and well tolerated with single-dose IV or SC administration in healthy volunteers. AL101 is a potent modulator of PGRN levels in the CSF, with a PK/PD profile that supports development of SC AL101 in chronic conditions.

Authors/Disclosures
Michael Ward PRESENTER	Michael Ward has received personal compensation for serving as an employee of Alector. Michael Ward has stock in Alector. Michael Ward has received intellectual property interests from a discovery or technology relating to health care. Michael Ward has a non-compensated relationship as a Reviewer with ADDF that is relevant to AAN interests or activities.
Robert Paul, MD, PhD	Dr. Paul has received personal compensation for serving as an employee of Alector. Dr. Paul has received stock or an ownership interest from Alector.
	No disclosure on file
	No disclosure on file
Michael Kurnellas (Stanford University)	Michael Kurnellas has received personal compensation for serving as an employee of Alector. Michael Kurnellas has received stock or an ownership interest from Alector. Michael Kurnellas has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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