The Holy Grail of Migraine Medications (3/3)

With the two newest migraine drugs specifically designed for migraine prevention released this year, is this new class of CGRP drugs the new holy grail of migraine medications? We have divided learning about the CGRP drug class into a three-part newsfeed series. Today we will look into deeper the differences between the two new FDA-approved CGRP drugs.

Monoclonal antibodies (mAbs) blocking CGRP activity have been introduced to the US market for the prevention of migraines. Aimovig™ (erenumab) was the first anti-CGRP mAb FDA approved treatment specifically developed to prevent migraines in May, 2018. Ajovy™ (fremanezumab) is the second anti-CGRP agent to gain FDA approval for migraine prophylaxis in September, 2018. The introduction of anti-CGRP medications mark a new era in the history of migraine preventive treatment. Despite similarities in the advantages and disadvantages in mAb therapy, there are some differences between erenumab and fremanezumab in the mechanism of action, the type of mAb, and the dosage.

Mechanism of action

Both erenumab and fremanezumab prevent migraines by blocking the CGRP pathway. However, there is a major difference in how they block the CGRP pathway. Erenumab binds to the CGRP receptor and blocks the CGRP receptor function. Fremanezumab binds directly to the CGRP molecule instead of its receptor and prevents CGRP from binding to the receptor. Despite their differences in how they block the CGRP system, both mechanisms of action ultimately lead to inhibiting the functions of CGRP in migraine headache.

The type of mAb

Both erenumab and fremanezumab are produced using recombinant DNA technology in Chinese hamster ovary cells. Erenumab is a fully human immunoglobulin mAb, while fremanezumab is a humanized immunoglobulin mAb. The distinction between a fully human mAb and a humanized mAb is humanized mAb is a combination of human and mouse antibody. The potential for the mAb to provoke an immune response by the body or “immunogenicity” is theoretically lower in fully human mAb than humanized mAb. Immunogenicity has many definitions but what makes it unique is that it occurs when our bodies treat a protein as if it is a foreign substance and try to attack the protein with antibodies.  Immunomic therapies have been around for years and have been used for developing vaccines.  As such, this type of drug is in essence a vaccine to prevent migraines.

Dosage regimen

The administration method for both drugs is monthly subcutaneous injections. The recommended dose of erenumab is 70 mg once monthly. Some patients may benefit from a higher dose of 140 mg once monthly, which is administered as two consecutive subcutaneous injections of 70 mg each. The recommended dosage for fremanezumab is 225 mg once monthly. Unlike erenumab, fremanezumab has the option for longer dosing intervals of 675 mg every 3 months (quarterly). This is administered as three consecutive subcutaneous injections of 225 mg each. Aimovig™ is available in a prefilled autoinjector or prefilled syringe while Ajovy™ is only available in prefilled syringe. Both Aimovig™ and Ajovy™ are intended for patient self-administration at home.

Adverse events

The most common adverse events for both drugs was injection site reactions. Fremanezumab seems to have a higher rate of injection site reactions than erenumab, with 43-45% vs. 38% (placebo) reporting injection site reactions for fremanezumab and 5-6% vs. 3% (placebo) for erenumab. For pharmacokinetics, the time to reach peak concentrations were similar for both drugs, approximately 6 days. However, the time to reach steady state was faster for erenumab (3 months) than fremanezumab (6 months).

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