Migraines are very common, with around 15.3% of Americans over the age of 18 reporting severe headaches in the past 3 months; this number has remained stable for several decades. 1
Migraines are recurrent headaches of moderate to severe intensity that tend to interfere with the functions of daily living.2 Symptoms include gastrointestinal problems, nausea, sensitivity to light, and vomiting. Migraines are caused by the activation of sensory trigeminal nerves that lead to the 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 on the market approved for migraine prophylaxis by targeting CGRP. The approved active ingredients (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 The recommended dose of eptinezumab is 100 mg intravenous infusion every 3 months. A higher dose of 300 mg every 3 months may be considered for those who respond poorly to a 100 mg dose for chronic and episodic migraines.
Both 100 and 300 mg dosage regimens were investigated via the PROMISE-1 study (NCT02559895). The study enrolled adults with a history of episodic migraine (4-14 headache days per month, at least 4 migraine days); 665 people were randomized to receive placebo, 100 mg and 300 mg every 3 months for 12 months. The primary efficacy endpoint was defined as the change from baseline in mean monthly migraine days (MMD) over months 1 through 3. For both the 100 mg (-0.7 MMD; P = .018) and the 300. there were statistically significantly lower MMD mg (-1.1 MMD; p <0.001) doses of eptinezumab compared to placebo.
The PROMISE 2 study (NCT02974153) enrolled patients with a history of chronic migraine (15-26 headache days per month, at least 8 migraine days), and 1,072 people were randomized to receive a placebo or a 100-mg or 300-mg – Receive dose of eptinezumab every 3 months for 6 months. The primary endpoint was the change in monthly migraine days from baseline over months 1 to 3. The doses of 100 (-2.0 MMD; p <0.001) and 300 mg (-2.6 MMD; p <0.001) were statistical significant MMD the discount.
As the scientific community learns about CGRP pathology, clinicians learn the potentially increased cardiovascular risk that is accompanied by long-term blockade of the CGRP pathway. As a result, subgroup analyzes were carried out in 4 double-blind, placebo-controlled studies to assess the relationship between the use of erenumab and vascular adverse events (VEs). 4 The subgroup analyzes included 2443 test subjects. Regardless of the dose received (70 mg / mo, 140 mg / mo), the VE incidence did not differ statistically from the people who received the placebo. While this information is not directly applicable to eptinezumab, it provides a guide value.
There are insufficient safety data to determine whether or not eptinezumab increases cardiovascular risk. Both the PROMISE 1 and PROMISE 2 studies established an inclusion criterion that excluded people with a history of cardiovascular disease.3 A cardiovascular event was not a significant adverse event in either study. The safety data will continue to be monitored through post-market surveillance.
As science continues to gather data on immunogenicity, it is important to distinguish between neutralizing antidrug antibodies (NAbs) and non-neutralizing antibodies (non-NAbs). NAbs bind to the biological drug molecule and inhibit pharmacological activity. Although non-NAbs bind to biological drug molecules without affecting pharmacological activity, it can affect pharmacokinetics. It is also important to remember that the clinical significance of immunogenicity varies from individual to individual. To apply immunogenicity effectively in clinical practice, the scientific community must achieve standardization of immunogenic assays.
The generation of immunogenicity in therapy with eptinezumab is a potential problem, as is the case with 3 other biological products targeting CGRP. In the PROMISE 1 study, the rate of antibody development was 20.6% for the 100 mg dose and 41.3% for the 300 mg dose.3 In the PROMISE 2 study, 18.3% of the antibodies were detected in the 100 mg dose. mg dose and 34.9% with the 300 mg dose. However, there is uncertainty about the clinical manifestations of the immunogenicity development of eptinezumab. Additional data must be monitored through post-market monitoring.
With the introduction of additional therapy options targeting CGRP, class effects such as cardiovascular risk reduction, immunogenicity, and MMD are constantly monitored and assessed. Although there are good therapeutic options for migraineurs, interpreting immunogenicity data and applying it in clinical practice can be challenging, not to mention that immunogenicity is an important issue not only with CGRP agents but also with other biological products, as it can affect the effectiveness and safety of a product. Immunogenicity will be a topic of discussion among clinicians for many years to come. As a pharmacist, it is important to understand how CGRP agents work and to advise patients and prescribing physicians accordingly.
ABOUT THE AUTHOR
David Kim, PharmD, MPH, is head of pharmacy operations for the US Air Force’s 92nd Medical Group. He is on military leave from Mayo Clinic in Rochester, Minnesota.
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2. Headache: migraine and tension type. In: DiPiro JT, DiPiro CV, Ellingrod V, Schwinghammer TL, ed. Handbook of Pharmacotherapy. McGraw-Hill Professional Publishing; 2021.
3. Vyepti. Prescribing information. Lundbeck Seattle BioPharmaceuticals; 2020. Retrieved 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 biological therapies for migraines: a review of the current evidence. J headache pain. 2021; 22 (1): 3. doi: 10.1186 / s10194-020-01211-5