Abstract Details

Title Repeat IV and SC Dosing of the Anti-Sortilin Antibody AL101

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P7 - Poster Session 7 (8:00 AM-9:00 AM)

Poster/Presentation
Number 7-007

Objective To investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 following repeated intravenous (IV) or subcutaneous (SC) administration.

Background Variants in GRN, the coding gene for progranulin (PGRN), have been implicated in a number of neurodegenerative disorders, including frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease. Sortilin, expressed on neurons and microglia, is a key regulator of PGRN levels through sortilin-mediated degradation. Increasing PGRN levels may reduce rates of neuronal loss and clinical decline in neurodegeneration. AL101 is a human IgG1 monoclonal antibody that decreases sortilin and increases PGRN levels in preclinical models and in single-dosed healthy volunteers, and is being developed for neurodegenerative disorders.

Design/Methods

Healthy volunteers received repeat doses of AL101 in two cohorts: 300 mg SC q2w for a total of 7 doses and 30 mg/kg IV q4w for a total of 4 doses. Safety measures and PK/PD markers in plasma and cerebrospinal fluid (CSF) were assessed at up to 16 and 20 weeks for SC and IV cohorts, respectively.

Results Adverse events were generally mild to moderate in severity and self-limiting, consistent with preliminary single-dose AL101 data. There were no severe or serious adverse events related to repeat-dose administration. Subjects in the SC repeat-dose cohort reported a higher number of overall injection site reactions that were mild in severity. Repeat-dose AL101 increased CSF PGRN levels of healthy volunteers up to approximately 80% above baseline. PK/PD modeling based on data from these repeat-dose cohorts supports dosing intervals of up to q8w.

Conclusions Repeat IV or SC administration of AL101 is generally safe and well tolerated. AL101 is a potent modulator of PGRN levels in the CSF, with a PK/PD profile that supports its further development in neurodegenerative diseases.

Authors/Disclosures
Balasubrahmanyam Budda, PhD (Alector, Inc) PRESENTER	Dr. Budda has received personal compensation for serving as an employee of Alector. Dr. Budda has received personal compensation for serving as an employee of Acceleron Pharma. Dr. Budda has stock in Alector. Dr. Budda has stock in Acceleron Pharma.
	No disclosure on file
	No disclosure on file
Michael Ward	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.
	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

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