Migraine-Specific Biologics Treat Severe Headaches
Approved agents target calcitonin gene-related peptides to bring pain relief to affected patients.
Migraines are very common, with about 15.3% of Americans 18 years or older reporting a severe headache in the previous 3 months; that figure has remained stable for several decades.1
Migraines are recurrent headaches of moderate to severe intensity that tend to interfere with daily life functions.2 Symptoms include gastrointestinal problems, nausea, sensitivity to light, and vomiting. Migraines are caused by the activation of trigeminal sensory nerves leading to a release of neuropeptides, such as calcitonin gene-related peptide (CGRP), neurokinin A, pituitary adenylate cyclase-activating polypeptide, and substance P. In recent years, biologics have been introduced to the market that are approved for migraine prophylaxis by targeting CGRP. The approved agents (eptinezumab, erenumab, fremanezumab, and galcanezumab) work by binding directly to the CGRP ligand or receptor.
Eptinezumab (Vyepti) is a humanized IgG1 monoclonal antibody that is specific for a CGRP ligand and blocks its binding to the receptor.3 Eptinezumab's recommended dosing is 100 mg intravenous infusion every 3 months. A higher dose of 300 mg every 3 months may be considered for those who have a poor response with a 100-mg dose for chronic and episodic migraine.
Both 100- and 300-mg dosing regimens were studied via the PROMISE 1 trial (NCT02559895). The study enrolled adults with a history of episodic migraine (4-14 headache days per month, at least 4 migraine days); 665 individuals were randomized to receive a placebo, 100 mg, and 300 mg every 3 months for 12 months. The primary efficacy end point was defined as the change from baseline in mean monthly migraine days (MMD) over months 1 to 3. There were statistically significantly lower MMD with both the 100 mg (-0.7 MMD; P=.018) and the 300 mg (-1.1 MMD; P < .001) doses of eptinezumab compared with the placebo.
The PROMISE 2 study (NCT02974153) enrolled subjects with a history of chronic migraine (15-26 headache days per month, at least 8 migraine days), and 1072 individuals were randomized to receive a placebo or a 100-mg or 300-mg dose of eptinezumab every 3 months for 6 months. The primary end point was change from baseline in monthly migraine days over months 1 to 3. The 100- (-2.0 MMD; P < .001) and 300-mg doses (-2.6 MMD; P < .001) demonstrated statistically significant MMD reduction.
As the science community is gaining knowledge about CGRP pathology, clinicians are learning about the potential increased cardiovascular risk accompanied by a long-term blockade of the CGRP pathway. As a result, subgroup analyses were conducted on a 4 double-blind, placebo-controlled trials to assess the link between erenumab use and vascular adverse events (VEs).4 The subgroup analyses included 2443 subjects. Regardless of the dose received (70 mg/mo, 140 mg/mo), incidence of VE was not statistically difference from the individuals who received the placebo. Although this information is not directly applicable to eptinezumab, it offers value as a reference point.
There is not sufficient safety data to determine whether eptinezumab will or will not increase cardiovascular risk. Both the PROMISE 1 and PROMISE 2 studies set an inclusion criterion that excludes individuals with a history of cardiovascular disease.3 A cardiovascular event was not a significant adverse event reported in both trials. Safety data will continue to be monitored through postmarketing surveillance.
As the science community gathers more data on immunogenicity, it is important to differentiate between neutralizing antidrug antibodies (NAbs) and nonneutralizing antibodies (non-NAbs).5 NAbs bind to the biologic drug molecule and inhibit the pharmacologic activity. Although non-NAbs bind to biologic drug molecules without affecting pharmacologic activity, this may affect pharmacokinetics. It is also important to remember that clinical significance of immunogenicity is variable from one individual to another. To effectively apply immunogenicity in clinical practice, the science community will need to achieve standardization of immunogenic assays.
Immunogenicity formation with eptinezumab therapy is a potential concern as it is with 3 other biologic products that target CGRP. In the PROMISE 1 study, the antibody development rate was 20.6% with the 100-mg dose and 41.3% with the 300-mg dose.3 In the PROMISE 2 study, the antibody was developed in 18.3% with the 100-mg dose and 34.9% with the 300-mg dose. However, there is uncertainty about the clinical manifestations of eptinezumab's immunogenicity development. More data will need to be monitored through postmarketing surveillance.
As more therapy options targeting CGRP are introduced, class effects, such as a decrease in cardiovascular risk, immunogenicity, and MMD will be constantly monitored and evaluated. Although there therapies are great options for those experiencing migraines, interpreting immunogenicity data and applying them in clinical practice can be a challenge, not to mention that immunogenicity is an area of attention not only with the CGRP agents but also in other biologic products, as it can affect a product's effectiveness and safety. Immunogenicity will be a discussion topic among clinicians for many years. As pharmacists, it is important to understand the mechanism of CGRP agents and advise patients and prescribers accordingly.
ABOUT THE AUTHOR
David Kim, PharmD, MPH, is chief of pharmacy operations with the 92nd Medical Group, US Air Force. He is on military leave from Mayo Clinic in Rochester, Minnesota.
1. Burch R, Rizzoli P, Loder E. The prevalence and impact of migraine and severe headache in the United States: fi gures and trends from government health studies. Headache. 2018;58(4):496-505. doi:10.1111/head.13281
2. Headache: migraine and tension-type. In: DiPiro JT, DiPiro CV, Ellingrod V, Schwinghammer TL, eds. Pharmacotherapy Handbook. McGraw-Hill Professional Publishing; 2021.
3. Vyepti. Prescribing information. Lundbeck Seattle BioPharmaceuticals; 2020. Accessed June 14, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761119s000lbl.pdf
4. Kudrow D, Pascual J, Winner PK, et al. Vascular safety of erenumab for migraine prevention. Neurology. 2020;94(5):e497-e510. doi:10.1212/WNL.0000000000008743
5. Cohen JM, Ning X, Kessler Y, et al. Immunogenicity of biologic therapies for migraine: a review of current evidence. J Headache Pain. 2021;22(1):3. doi:10.1186/s10194-020-01211-5