To estimate the potential distribution and target engagement of a monoclonal antibody (mAb) to calcitonin-gene related peptide (CGRP) in the cerebrospinal fluid (CSF) and brain interstitial fluid (ISF).

Anti-CGRP mAbs are effective in the prevention of migraine.  Although they are administered peripherally, the question of a potential site of action within the central nervous system (CNS) remains unresolved.

We recently reported that a single intravenous dose of fremanezumab (900 mg) could result in the rapid and persistent rise of fremanezumab within the CSF of singly-sampled healthy subjects at a range of post-infusion times: 24 hr (n=5), 72 hr (n=5), 15 days (n=5) and 30 days (n=4), compared to an untreated cohort as comparator (n=5). Fremanezumab and total CGRP were detected in plasma at multiple time points and at a specified single time from CSF of each subject.  The lower limit of quantification of fremanezumab = 250 ng/mL in plasma and 30 ng/mL in CSF; for total CGRP 2.0 pg/mL in plasma and 0.25 pg/mL in CSF.

The exposure profile of fremanezumab in plasma was consistent with previous studies. In CSF, fremanezumab was detectable within a day of infusion, peaked at 15 days, and plateaued through day 30; concentrations ranged from 134 to 244 ng/mL, with CSF–to-plasma ratios of 0.06% to 0.36%. Accordingly, total CGRP rose quickly and stably, in plasma with a range from 57.6 to 359 pg/mL, and in CSF from 1.79 to 3.35 pg/mL.  We will present ongoing work using standard pharmacometric approaches to estimate corresponding exposures and engagement in CSF and brain ISF at clinical doses of fremanezumab.

The presented data affirms the potential for fremanezumab to access the CNS and engage its target.