Effect of Fremanezumab Monthly and Quarterly Doses on Efficacy Responses

Abstract

Objective.-Exposure-response (E-R) models were developed to provide a description of the time-course of treatment effect for monthly and quarterly dosing regimens of fremanezumab. Background.-Fremanezumab is a monoclonal antibody for preventive treatment of episodic migraine (EM) and chronic migraine (CM). In phase 2b and 3 clinical studies of fremanezumab, significant reductions in migraine and headache days and other clinical endpoints were observed for patients with EM and patients with CM. Development of E-R models relating individual-specific measures of drug exposure to clinical endpoints provides a more granular understanding of the expected effects of different doses on therapeutic outcomes by accounting for variability in pharmacokinetic (PK) properties. Methods.-Data from 2 phase 2b and 2 phase 3 studies of adults with EM or CM were used. Individual exposures were calculated from a population PK model and related to monthly migraine days in EM and moderate-severe (M/S) headache days in CM. Model-based stochastic simulations were performed to compare predicted responses for the various treatment regimens. Results.-The effect of average fremanezumab concentration compared to placebo on the reduction in migraine days and M/S headache days was predicted by the models to be similar for 225 mg monthly and 675 mg once quarterly over time for both EM and CM patients. Both regimens were associated with better response than placebo. A similar percent of EM and CM responders was predicted across the range of observed body weights. Conclusions.-Exposure-response evaluations showed that both monthly (225 mg) and quarterly (675 mg) fremanezumab dosing regimens were appropriate in achieving clinical benefit in adult patients with EM or CM.

Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine

“…Fremanezumab has a long half-life (30 days) as well as prolonged absorption, which support the use of quarterly or monthly dosing [23]. Furthermore, a recent exposure-response analysis showed similar responses over time with both quarterly and monthly fremanezumab dosing [24]. In this article, we review the phase 3 clinical development of fremanezumab, highlighting key efficacy outcomes across different populations with migraine, including those with CM and EM, as well as different types of difficult-to-treat migraine.…”

“…All studies were performed in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. Study protocols were reviewed and approved by local independent ethics committees or institutional review boards [22][23][24][25]. Two pivotal phase 3 studies of fremanezumab enrolled participants with CM (HALO CM; ClinicalTrials.gov Identifier: NCT02621931) [25] or participants with EM (HALO EM; NCT02629861) [26].…”

Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies

“…Maximum plasma concentration of fremanezumab after a single administration is reached after 5-7 days (from 3 to 20 days) [16,84,[91][92][93][94][95][96][97], and the absolute bioavailability is 55% and 66% for 225 mg and 900 mg, respectively. A steady-state is achieved within approximately 168 days [91][92][93][94][95][96][97]. There is no need to modify the dosage in the elderly or in patients with mild to moderate renal or hepatic impairment [92,93].…”

“…There is no need to modify the dosage in the elderly or in patients with mild to moderate renal or hepatic impairment [92,93]. Using population pharmacokinetic modeling and simulation of fremanezumab in healthy subjects and patients with migraine, it was shown, however, that higher body weight was associated with a lower exposure of fremanezumab (an increased central clearance and distribution volume) [96].…”

Dose selection for fremanezumab (AJOVY) phase 3 pediatric migraine studies using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach

“…In pharmacokinetic (PK) analyses of adult patients and healthy volunteers, fremanezumab has a median time to maximum concentrations (t max ) of 5–7 days, a median half-life of 30 days and an absolute bioavailability of 55% to 66%. Steady-state systemic exposure is expected by approximately 6 months in adult patients following the 225 mg monthly and 675 mg quarterly dosing regimens (3).…”