Distribution and target engagement of peripherally administered fremanezumab in the cerebrospinal fluid of healthy volunteers.

OBJECTIVES/BACKGROUND: Our objective was to describe the distribution of fremanezumab to the cerebrospinal fluid (CSF) in healthy volunteers, and investigate its engagement and stabilization of its target, calcitonin gene-related peptide (CGRP). Fremanezumab is a CGRP-targeting monoclonal antibody approved for migraine prevention. Although the efficacy of peripherally administered monoclonal antibodies targeting CGRP, such as fremanezumab, has been established for the modulation of migraine, the extent of their distribution and target engagement within the central nervous system remains largely uncharacterized. METHODS: This open-label, nonrandomized, parallel-group, no-treatment control, pharmacokinetics clinical trial was conducted between February 16, 2023, and April 1, 2023, in the United States. Healthy volunteers were assigned to one of five groups: Group 1 had no drug intervention, and Groups 2-5 received 900 mg fremanezumab intravenously. Blood and CSF samples were collected in Group 1 (n=6; baseline for blood and CSF control) and at 1 day (Group 2; n=5), 3 days (Group 3; n=5), 15 days (Group 4; n=5), and 30 days (Group 5; n=5) postinfusion. Additional blood sampling occurred in select groups at 15 min postinfusion and at predetermined time points up to 31 days postinfusion. Plasma and CSF samples were analyzed for fremanezumab and total CGRP using in-house immunoassays and high-performance liquid chromatography tandem-mass spectrometry. RESULTS: Mean (SD) plasma fremanezumab concentration peaked at the end of the 1-h intravenous infusion (333599.2 ng/mL [54658.6]) and decreased over the subsequent 31 days postinfusion (60482.3 ng/mL [10473.9]). CSF fremanezumab was detected at the earliest measured time point of 1 day postinfusion (mean [SD]=134.2 ng/mL [38.8]), increased at 15 days (243.6 ng/mL [189.4]), and remained sustained 30 days postinfusion (219.3 ng/mL [77.3]). Mean (SD) CSF-to-plasma concentration ratios increased over time, from 0.06% (0.02%) at 1 day to 0.36% (0.14%) at 30 days postinfusion. In plasma, sustained target engagement was demonstrated through the rapid rise of total CGRP, peaking at 15 days (mean [SD]=359.1 pg/mL [90.0]), and was sustained to 31 days postinfusion (260.5 pg/mL [43.0]). In the CSF, total CGRP was below detection limits for the control (Group 1) but was quantifiable at 1 day and sustained to 30 days postinfusion, with mean (SD) values ranging from 1.8-3.3 pg/mL (0.4-2.2). No severe or treatment-related adverse events were reported, and no participant withdrew due to an adverse event. CONCLUSION: The present findings suggest the rapid distribution of fremanezumab into the central nervous system after peripheral administration, and the persistent retention of fremanezumab and target engagement of CGRP in the CSF. Further studies are required to determine whether entry into the CSF and target engagement play a role in the clinical efficacy of fremanezumab observed in people with migraine. TRIAL REGISTRATION: TV48125-PK-10183; EUPAS103511.