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12 Articles in Volume 18, Issue #4
A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention
Assessment of Patients with Rheumatoid Arthritis or Osteoarthritis
Biosimilars in Rheumatology: How Popular Will They Be?
Case Studies in Regenerative Cellular Therapy: Tendinopathy and Osteoarthritis
Commentary: Make the Easy Choice for Care
Editorial: The Emergence of Trackable Pill Technology: Hype or Hope?
Editorial: The Practicality of Pain Acceptance
How to Avert Government Scrutiny When Prescribing Opioids
Letters to the Editor: DEA and Prescribing, the War on Statistics, Failing Treatments, Patients' Options
Meet the Migraine Game-Changers
Platelet-Rich Plasma and Stem Cell-Rich Prolotherapy for Musculoskeletal Pain
With concerns over opioids, could novel receptors be useful?

A New Frontier in Migraine Management: Inside CGRP Inhibitors & Migraine Prevention

With a series of calcitonin gene-related peptide antagonists that promise to prevent migraine now emerging from regulatory review, anticipation is growing across the healthcare and patient community. What can clinicians expect from this new class of monoclonal antibodies?

Calcitonin gene-related peptide (CGRP) is a vasoactive peptide. It is part of the “inflammatory soup” that is involved in dilation of cerebral and dural blood vessels. Widely distributed throughout the body, CGRP levels in serum increase during migraine or cluster headache. Triptans provide some migraine relief by modulating the CGRP.

Four companies have developed CGRP antagonists that are large molecule monoclonal antibodies (mAbs). Used to treat a number of conditions, mAbs work both indirectly, by activating host immune systems, and directly by binding to ligands or receptors. The migraine mAbs are subclasses of immunoglobulin G (IgG) and have very little potential for drug-drug interactions because they are metabolized through the reticuloendothelial system. They are also unlikely to cause liver or kidney irritations, but should not be confused with the CGRP medications referred to as “gepants,” which are small-molecule drugs being developed as migraine abortives. Gepants are metabolized through the liver.

What to Anticipate in 2018-19

The four mAbs targeting the CGRP pathway currently under or emerging from regulatory review are:

  • erenumab-aooe (Aimovig, Amgen/Novartis, a receptor antagonist with a 28-day half-life; to be administered monthly at-home via subcutaneous injection; FDA approved Aimovig in May, making it the first US-approved CGRP inhibitor for adult migraine prevention)
  • eptinezumab (ALD403, Alder Pharmaceuticals, a ligand antagonist with a 32-day half-life; to be administered quarterly via intravenous infusion)
  • fremanezumab (TEV-48125, Teva Pharmaceuticals, a ligand antagonist with an estimated 31- to 39-day half-life; to be administered monthly or quarterly via subcutaneous injection)
  • galcanezumab (LY2951742, Eli Lilly, a ligand antagonist with a 25- to 30-day half-life; to be administered monthly via subcutaneous injection).

The gepant molecules under development include: Biohaven Pharma’s rimegepant/BHV-3000 for acute migraine and BHV-3500 for migraine prevention, and Allergan’s ubrogepant for acute migraine and atogepant for migraine prevention. These latter investigative products are administered orally. Prior concerns with liver toxicity and oral administration are being analyzed. (See company perspectives on next page.)

Why all the Hype?

The buzz surrounding this new migraine management class has to do with the fact that anti-CGRP peptide and anti-CGRP receptor antibodies have been developed specifically for migraine pathophysiology. Current preventives are limited in efficacy, carry significant side effects, and were largely formulated to treat other conditions, such as high blood pressure.

All four mAbs have achieved similar results in Phase 3 trials to date for efficacy, tolerability, and safety. Upon injection, the mAbs are distributed in many tissues, with the highest concentrations occurring in the lung, kidneys, heart and spleen; very little crosses into the brain. The mAbs are expected to be indicated for chronic migraine and/or episodic migraine. It is possible that one or two may be approved for cluster headache or post-traumatic headache as well. In trials, many patients saw their migraine days decrease by 2 to 5 per month. For up to one-third of patients, headaches improved by 75% or more. A smaller minority (20% in an intravenous trial; and about the same percentage in a galcanezumab subcutaneous trial) experienced almost 100% improvement. There are important similarities between these mAb results, and those achieved by the administration of onabotulinumtoxinA (Botox) for migraine. Many patients may have very modest relief, while others may see their headaches drastically reduced.

How to Weigh in on Prescribing

Migraine preventive medications often lose effectiveness over time. Experts do not know yet whether this may be the case with the mAbs. Botox has been surprising in this regard; most patients who find Botox to be helpful do not experience a significant decline in efficacy. It is hoped that mAbs may yield similar sustained benefits.

As to side effects, they have been minimal in the short-term. Outside of local injection reactions, the mAbs have been surprisingly well tolerated and no cardiovascular or liver concerns have been raised. In the long-term, however, the medical community is concerned about cardiovascular risk. CGRP plays a role in cardiovascular homeostasis during ischemic events. It has vasodilatory effects and is important in the regulation of blood pressure. CGRP is also involved in wound healing; blocking it could, in theory, interfere. While the pending mAbs do not cross the blood brain barrier, the pituitary gland lies outside of this barrier; CGRP and its receptors are found in the anterior pituitary. CGRP is also present in the gastrointestinal (GI) tract and plays a role in GI motility. It is possible that blocking CGRP could contribute to inflammatory bowel disease. As long-term effects are unknown, clinicians may take caution in prescribing. Patients should be pre-screened for cardiovascular risk and sign informed consent forms. Recommending that patients try the new medication during a period of time off from work or other major stressors may be advisable as well.

Over time, those patients who have an excellent response to the mAbs may continue that trend for the long-term. It is possible that such responders may only be 20% of one’s migraine caseload, but for those migraineurs, the CGRP antagonists may be life-changing. With limited efficacy and significant side effects tied to currently available preventives, the CGRP monoclonal antibodies provide hope for many migraine sufferers.

 

See more of what's at stake from Dr. Robbins in a new paper on key questions clinicians and researchers need to address before prescribing CGRP antagonists for migraine and headache.

Last updated on: August 7, 2018
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