Anti-drug Antibody Validation Testing and Reporting Harmonization.

Evolving immunogenicity assay performance expectations and a lack of harmonized anti-drug antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. Following debate at the American Association of Pharmaceutical Sciences National Biotechnology Conference, a group was formed to address these gaps. Over the last 3 years, 44 members from 29 organizations (including 5 members from Europe and 10 members from FDA) discussed gaps in understanding immunogenicity assay requirements and have developed harmonization tools for use by industry scientists to facilitate filings to health authorities. Herein, this team provides testing and reporting strategies and tools for the following assessments: (1) pre-study validation cut point; (2) in-study cut points, including procedures for applying cut points to mixed populations; (3) system suitability control criteria for in-study plate acceptance; (4) assay sensitivity, including the selection of an appropriate low positive control; (5) specificity, including drug and target tolerance; (6) sample stability that reflects sample storage and handling conditions; (7) assay selectivity to matrix components, including hemolytic, lipemic, and disease state matrices; (8) domain specificity for multi-domain therapeutics; (9) and minimum required dilution and extraction-based sample processing for titer reporting.

Immunogenicity of biologic therapies for migraine: a review of current evidence.

BACKGROUND: Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have been shown to be effective in migraine prevention. Eptinezumab, erenumab, fremanezumab, and galcanezumb have shown efficacy in clinical trials along with favorable safety and tolerability profiles. Although erenumab is a human mAb and the others have been humanized to varying degrees, they all have the capacity to provoke immune reactions. The present review article aims to discuss the current relationship between mAbs targeting the CGRP pathway (CGRP mAbs) and immunogenicity and their potential clinical implications. FINDINGS: The incidence of patients developing anti-drug antibodies (ADAs), their titer, and clinical significance are highly variable and depend on a variety of different drug and patient factors. Neutralizing ADAs (NAbs) bind to and inhibit or reduce the pharmacologic activity of the biologic drug molecule, whereas non-neutralizing antibodies (Non-NAbs) bind to the biologic drug molecule without affecting pharmacologic activity in an in vitro test, although pharmacokinetics and drug clearance may be affected. A direct comparison of immunogenicity data across clinical trials with different biologics is not possible due to a lack of standardized assays. Several phase 2, phase 3, and long-term studies evaluating CGRP mAbs for migraine prevention have reported immunogenicity data (5 studies each for eptinezumab, erenumab, fremanezumab, and galcanezumab). Across these studies, prevalence of ADAs varied, ranging from < 1% to ~ 18%. Neutralizing ADAs were slightly less common, with a prevalence ranging from 0 to 12%. Adverse events related to ADA formation were rare. CONCLUSIONS: As more CGRP mAb studies are conducted and more long-term follow-up data become available, evidence is increasing that immunogenicity rates of biologic therapies for migraine are low, and adverse events related to ADAs are rare. Taken together, these results add to the growing body of evidence for the safety and tolerability of this class of migraine medications.

A Pharmacokinetic Bioequivalence Study of Fremanezumab Administered Subcutaneously Using an Autoinjector and a Prefilled Syringe.

Fremanezumab (AJOVY; Teva Pharmaceutical Industries Ltd, Netanya, Israel), approved for the preventive treatment of migraine, is available as a subcutaneous injection either once a month or once every 3 months using an autoinjector or a prefilled syringe. The present study evaluated the pharmacokinetic (PK) bioequivalence of a single subcutaneous injection of fremanezumab 225 mg administered using an autoinjector compared to a prefilled syringe in healthy volunteers. Blood samples for PK and antidrug antibodies were collected before and after dosing. Safety and tolerability assessments included physical examinations, adverse event reporting, laboratory evaluations, and immunogenicity. Following single-dose administration, the mean concentration-time profiles for the 2 treatment groups (autoinjector, n = 106; and prefilled syringe, n = 110) were similar. The point estimates for the back-transformed ratio (autoinjector/prefilled syringe) of geometric least squares means of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the time of the last measurable drug concentration, and area under the plasma concentration-time curve from time 0 extrapolated to infinity were 1.03, 1.04, and 1.05, respectively, with the 90% confidence intervals entirely contained within bioequivalence margins of 0.8 to 1.25. For both groups, median time to maximum observed concentration was 5 days and mean terminal elimination half-life was approximately 29 days. Treatment-related adverse events were reported by 39 (36%) subjects in the autoinjector group and 26 (24%) in the prefilled syringe group, and the majority were nonserious injection site reactions. The incidence of treatment-emergent antidrug antibody response was low and evenly distributed between the autoinjector (n = 3; 3%) and prefilled syringe (n = 4; 4%) groups. These results indicate that the fremanezumab autoinjector presentation provides an easy-to-use bioequivalent PK profile with a similar safety and tolerability profile to that of the prefilled syringe.

Population pharmacokinetic modelling and simulation of fremanezumab in healthy subjects and patients with migraine.

AIMS: Fremanezumab is a fully humanized IgG2 Δa/κ monoclonal antibody specific for calcitonin gene-related peptide developed and approved for the preventive treatment of migraine in adults. The population pharmacokinetics (PK) of fremanezumab were characterized in healthy subjects and patients with chronic migraine and episodic migraine, including the effects of intrinsic and extrinsic factors on PK variability. METHODS: Nonlinear mixed effects modelling was performed using NONMEM with data from 7 phase 1-3 clinical trials evaluating selected intravenous and subcutaneous dose regimens. The influence of covariates on fremanezumab PK was assessed and model evaluation was performed through visual predictive checks. RESULTS: A 2-compartment model with first-order absorption and elimination described the PK data well. Typical values for fremanezumab central clearance (0.0902 L/d) and central distribution volume (1.88 L) for a 71-kg subject were consistent with previously reported values for IgG antibodies. Higher body weight was associated with increased central clearance and distribution volume. Effects of other covariates (age, albumin, renal function, sex, race, injection site, and acute, analgesic and preventive medication use for migraine) were not found to statistically significantly influence fremanezumab PK. There was no indication of reduced exposure in participants with positive anti-drug antibody status or with mild to moderate hepatic impairment. Absolute bioavailability was estimated at 0.658. CONCLUSIONS: A comprehensive population PK model was developed for fremanezumab following intravenous and subcutaneous administration in healthy subjects and patients with chronic migraine or episodic migraine, which will be used to further evaluate exposure-response relationships for efficacy and safety endpoints.