History and Review of anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: From Translational Research to Treatment

Abstract

Objective – To briefly describe the history of and available data on anti‐calcitonin gene‐related peptide (CGRP) therapies for headache. Background – CGRP was proposed as a target for primary headache therapies. Translational research involved moving from delineating the relationships between CGRP and primary headaches and the clinical development of anti‐CGRP treatments. The first anti‐CGRP treatment, an intravenous CGRP‐receptor antagonist or gepant, olcegepant, was described as effective in terminating migraines in humans in 2004. Methods – The author briefly reviews some of the pathophysiology and translational research that led to the development of the gepants initially and then subsequently to the anti‐CGRP and anti‐CGRP receptor monoclonal antibodies. All accessible randomized controlled trials, abstracts, platform presentations, and press releases on the monoclonal antibody trials are summarized. The trajectory from bench research to the approval of the first anti‐CGRP receptor monoclonal antibody for clinical use in migraine prevention, erenumab, is discussed, as well as potential clinical uses of the anti‐CGRP treatments. Results – The US Food and Drug Administration (FDA) approved erenumab, an anti‐CGRP receptor monoclonal antibody, for prevention of migraine May 17, 2018. At the time of this writing (May 2018), 2 other anti‐CGRP monoclonal antibodies have been submitted to the FDA for the indication of prevention of migraine, galcanezumab and fremanezumab. Galcanezumab has reportedly shown effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimegepant, have completed positive pivotal trials for acute treatment of migraine, but have not yet been submitted to the FDA for this indication. Conclusions – The development of anti‐CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders.

Anti‐Calcitonin Gene‐Related Peptide (CGRP) Therapies: Update on a Previous Review After the American Headache Society 60th Scientific Meeting, San Francisco, June 2018

“…The number of subjects studied was made more clear than before: the 301 study had 1084 EM patients evaluated for acute efficacy of rimegepant; the 302 study 1072. The effectiveness was the same as previously reported . However, increasing efficacy results across 8 hours presented at the meeting and described in the previous review raises the question as to whether gepants may behave more like ergots such as dihydroergotamine (DHE) in yielding slow but complete response, or whether they will be like naratriptan or frovatriptan.…”

“…In the previous review, the data on the first ubrogepant Phase 3 trial for the acute treatment of EM, ACHIEVE I, were described . The other Phase 3 trial results, Achieve II, provided in an AHS late breaking abstract, included 1355 patients in a modified intention‐to‐treat analysis.…”

“…In the previous review, fremanezumab data on conversion from chronic migraine (CM) to EM were cited . At the AHS meeting, conversion from CM to EM was presented for the erenumab pivotal CM prevention trial .…”

“…As noted in the previous review, 1 year of open label data on erenumab was published for safety and efficacy in EM prevention . At the AHS meeting, the investigators provided an interim analysis for what is planned as a 5‐year OLE for EM prevention in which 61.3% (235 patients) completed ≥3 years in the trial …”

“…The most frequent AEs, ≥4/100‐patient‐years, were respiratory (described variously as viral upper respiratory tract infection, upper respiratory tract infection, sinusitis, or influenza) and back pain . One death was described in the previous review and felt not to be due to erenumab treatment, a man with obesity, hypertension, elevated lipids, left anterior hemi‐block, and a family history of myocardial infarction, who had severe atherosclerosis and who had cardiac stimulants in the liver (phenylpropanolamine and norpseudoephedrine) . In the 3‐year report, “there was no increase in cardiovascular events over time and no meaningful changes in systolic/diastolic blood pressure or rate up to 3.3‐year follow up.”…”