Lovingly Park1, Daniel Maslyar1, Michael Ward1, Felix Yeh1, Hua Long1, Michael Kurnellas1, Mayura Vadhavkar1, Balasubrahmanyam Budda1
1Alector, Inc.
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.