August 29, 2019
Rimegepant and Inflammatory Neuropeptide Antagonism in Migraine
Background: Migraine is a chronic neurologic disease characterized by attacks of throbbing, often unilateral headache that are exacerbated by physical activity and associated with photophobia, phonophobia, nausea, vomiting, and, in many patients, cutaneous allodynia. Migraine is very common, and the burden of illness is substantial, with annual total costs estimated at $27 billion in the United States and ranking as the second most-disabling neurologic condition globally in terms of years lost to disability. Both preventive and abortive treatments have evolved alongside medicine’s improving understanding of the underlying pathophysiology of migraine and the discovery of new and effective therapies, however current treatments such as triptan therapy and neuroleptics are limited due to adverse effects (up to 52% in some cohorts) and contra-indications. Concerns about these effects were reported in one study to result in delays in treatment or avoidance of treatment in two thirds of patients. (Gallagher 2003).
The pathophysiology of migraine is complex, and much more complicated than the simple contribution of vasospasm that was once taught in medical schools and preclinical textbooks. Our understanding of migraine pathophysiology has improved rapidly, and recent studies have provided important new insights into genetic causes, anatomical and physiological features, and pharmacological targets. A synthesis of the latest literature suggests a complex and variable interplay between disordered thalamic and thalamo-cortical sensory processing, altered connectivity of different regions of the brain leading to disruption of normal brain functional connectivity, cervical neuropathies, and a strong role of neuropeptides as chronic and acute mediators for migraine. Accumulating evidence indicates a primary role for calcitonin gene-relate peptide (CGRP) as a mediator of migraine and as an important therapeutic target. Multiple studies have shown that CGRP is released into the circulation during migraine and cluster headache episodes, and that common therapies—including triptans, neuroleptics, and propofol, normalize these CGRP concentrations. (Importantly, non-specific opioid analgesia has no effect on CGRP concentrations).
The growing understanding of the specific neuroinflammatory process triggered by CGRP led to the development of a new and effective group of CGRP antagonists for the preventive treatment of migraine. Erenumab (brand name: Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality) are monoclonal antibodies approved by the FDA within the past year that have, in some ways, revolutionized the outpatient and preventive approach to migraine. Witnessing this success in migraine prevention, and recognizing the effectiveness of common migraine abortives in decreasing plasma CGRP levels, investigators (funded by industry) sought to examine the efficacy of rimegepant, an orally administered CGRP antagonist, for the abortive treatment of acute migraine.
Article: Lipton RB et al. Rimegepant, an Oral Calcitonin Gene–Related Peptide Receptor Antagonist, for Migraine. NEJM 2019. PMID: 31291516
Clinical Question: What is the efficacy and safety of rimegepant (at an oral dose of 75 mg) in acute migraine treatment.
Population: Men and women ≥ 18 years of age with at least:
- A one-year history of migraines (with or without aura) consistent with a diagnosis according to the International Classification of Headache Disorders, including:
- age of onset prior to 50,
- migraine attacks that last about 4 – 72 hours,
- not more than 8 attacks of moderate or severe intensity per month within the last 3 months and
- not less than 2 attacks per month
- Receiving preventive migraine meds and had to be receiving a stable dose for at least 3 months before trial entry
- Recruited by referral from physicians and other health care professionals and by standard methods of recruitment, including enrollment from clinical practices and through advertising. Treatment settings included clinics, institutions, and private office practices.
Primary Outcome: Freedom from pain (defined by the presence of no pain in a person who had had pain of moderate or severe intensity immediately before administration of the dose) and freedom from the patient’s most bothersome symptom associated with migraine (i.e., phonophobia, photophobia, or nausea), 2 hours after the dose.
Design: Multicenter, randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of rimegepant (at an oral dose of 75 mg) as compared with placebo, in acute migraine treatment. Patients were randomly assigned, in a 1:1 ratio, to the rimegepant group or the placebo group with the use of an interactive web-response system. They were given an electronic diary and were instructed on the proper use of the diary before they left the trial center. Patients were provided with one 75-mg dose of rimegepant or matching placebo and were instructed to take the tablet when a single migraine attack of moderate or severe intensity occurred.
Before taking the tablet, they answered questions in the electronic diary about their current pain and symptoms, and they identified and recorded their current most bothersome migraine-associated symptom, other than pain (i.e., phonophobia, photophobia, or nausea). Patients completed the electronic diary for up to 48 hours after taking the trial agent. Pain intensity, the presence or absence of associated symptoms, and ratings of functional disability were assessed at the onset of the treated attack, at 15, 30, 45, 60, and 90 minutes after the dose, and at 2, 3, 4, 6, 8, 24, and 48 hours after the dose.
Exclusions and Restrictions^:
- Patient history of basilar migraine or hemiplegic migraine*
- Patient history of HIV disease
- Patient with evidence of uncontrolled, unstable or recently diagnosed cardiovascular disease, such as ischemic heart disease, coronary artery vasospasm, and cerebral ischemia.
- Patients with Myocardial Infarction (MI), Acute Coronary Syndrome (ACS), Percutaneous Coronary Intervention (PCI), cardiac surgery, stroke or transient ischemic attack (TIA) during the 6 months prior to screening.
- Uncontrolled hypertension or uncontrolled diabetes.
- Current diagnosis of major depression, other pain syndromes, psychiatric conditions (eg, schizophrenia), dementia, or significant neurological disorders (other than migraine) that, in the Investigator’s opinion, might interfere with study assessments.
- History of gastric, or small intestinal surgery, or disease that causes malabsorption.
- History or current evidence of any significant and/or unstable medical conditions (eg, history of congenital heart disease or arrhythmia, known suspected infection, hepatitis B or C, or cancer) that, in the investigator’s opinion, would expose them to undue risk of a significant adverse event (AE) or interfere with assessments of safety or efficacy during the course of the trial.
- History of, treatment for, or evidence of, alcohol or drug abuse within the past 12 months or patients who have met DSM-V criteria for any significant substance use disorder within the past 12 months from the date of the screening visit.
- Positive drug screen for drugs of abuse that in the investigator’s judgment was medically significant, in that it would impact the safety of the patient or the interpretation of the study results.
- Detectable levels of cocaine, amphetamine, barbiturates and phencyclidine (PCP) in the drug screen.
- History of drug or other allergy which, in the opinion of the principal investigator, makes the subject unsuitable for participation in the study.
- Females of child-bearing potential who are unwilling or unable to use an acceptable contraceptive method or abstinence to avoid pregnancy for the entire study period and for up to 8 weeks after the study.
- Women who are pregnant or breastfeeding.
- Estimated glomerular filtration rate (eGFR) ≤ 40 ml/min.
- Corrected QT interval > 470 msec.
- Left Bundle Branch block.
- Right Bundle Branch Block with a QRS duration ≥ 150 msec.
- Intraventricular Conduction Defect with a QRS duration ≥ 150 msec.
- Serum bilirubin (Total, Direct and Indirect) > ULN.
- Neutrophil count ≤ 1000/µL.
- AST or ALT> ULN.
- John’s Wort taken 14 days prior to randomization or throughout the study.
- History of use of ergotamine medications on greater than/equal 10 days per month on a regular basis for greater than/equal 3 months.
- History of non-narcotic analgesic intake on greater than/equal 15 days per month for greater than/equal 3 months.
- Use of narcotic medication, such as barbiturates, heroin, opium in the form of morphine and codeine, oxycodone and hydrocodone in the 2 days prior to randomization.
- Use of acetaminophen or acetaminophen containing products after randomization except as rescue medication, or within 2 days of randomization.
- Use of marijuana was prohibited during the study.
^REBEL-EM Note: Many of these exclusion criteria suggest a future or planned comparison to triptan therapies.
*REBEL-EM Note: This is a common exclusion for migraine trials due to an older (and probably incorrect) presumption that basilar or hemiplegic migraine were primarily due to changes in blood flow through the basilar artery and that constriction of the basilar artery could be compounded by the vasoconstrictive action of triptans. Not only has such a pathophysiologic underpinning been disputed, but a magnetic resonance angiography study (Amin 2013) found that administration of sumatriptan to 19 patients during a migraine attack resulted in only 2% constriction of the basilar artery on average, a clinically insignificant vasoconstriction.
- Enrollment numbers
- 1499 patient assessed for eligibility
- 1186 randomized to treatment
- 594 assigned to rimegepant, 592 assigned to placebo
- 543 received rimegepant (51 withdrawn for various reasons).
- 543 received placebo (49 withdrawn for various reasons)
- Mean age 40.6 years
- 7% of patients were women
- 556 (51.9%) of patients reported photophobia as their most bothersome symptom
- No significant demographic differences identified between treatment and placebo arms
- Primary Outcomes:
- Freedom from pain 2 hours after dose favored rimegepant (19.6% vs 12.0%; ARR 7.6%, 95%CI 3.3 to 11.9), p<0.001.
- Freedom from the most bothersome symptom 2 hours after dose favored rimegepant (37.6% vs 25.2%; ARR 12.4, 95%CI 6.9 to 17.9), p<0.001.
- Adverse Events:
- Nausea (1.8% rimegepant vs 1.1% placebo)
- UTI (1.5% vs 1.1%)
- Study asks a clinically important and patient-centered question
- First trial to investigate oral CGRP antagonists for abortive treatment of migraine
- Reasonable clinical endpoints
- Baseline demographic and clinical characteristics of groups well-balanced
- Extensive effort to eliminate potential confounders
- Thorough data reporting, with only 3.3% missing data.
- No active comparator
- All authors of the trial have confidentiality agreements with Biohaven Pharmaceuticals
- Patients were screened for inclusion before being randomized which creates selection bias
- Majority of patients were white (74.0%) females (88.7%) limiting translation of results to populations outside of this
- Study conceived, funded, conducted, analyzed and reported by Biohaven Pharmaceuticals, the maker of rimegepant, introducing irreconcilable experimenter bias
- Extensively curated and non-pragmatic population with multiple exclusion criteria not reflective of most clinical environments
- Super-select group of patients with migraines creates a selection bias and limits generalizability of this medication to populations outside of this inclusion
- Not performed in ED patients
- Minimal efficacy overall.
- This study is the first large RCT to examine the role of oral CGRP antagonists in the abortive treatment of migraine, capitalizing on the progress and discoveries recently made in migraine pathophysiology and treatment.
- A similar study evaluating a rimegepant orally disintegrating tablet (ODT) was published in Lancet following this trial’s release in NEJM. The trial used a similar methodology and had nearly identical outcome data, with 21% of patients taking rimegepant ODT free from pain at 2 hours (Croop 2019).
- The use of placebo as a comparator for this trial is troublesome and drives significant questions about intent and IRB oversight. Phase III clinical trials test a new treatment that has worked well for patients in a phase II clinical trial against standard treatment. Standard migraine abortive therapy includes triptans, neuroleptics, or alternative treatments as previously discussed here on REBEL, and the use of placebo violates that fundamental scientific underpinning.
- Rimegepant led to freedom from pain at 2 hours in less than 20% of patients, an objectively dismal overall success rate and not comparable to standard ED-based therapies.
- The trial was planned to curate and create the most advantageous population and setting for response to rimegepant, with well-vetted disease and thoroughly-excluded confounders or potential limiters—a population neither reflective of nor similar to those seen in clinical practice.
- Industry design, funding, and influence must be recognized and placed into context in the interpretation of this trial. While not a disqualifier by any means, it should be noted as a potential source of irreconcilable bias. It is likely that this paper is a prequel to a future trial comparing rimegepant to triptan therapy or other typical abortives, and should be remembered and synthesized with future data.
- This trial shouldn’t, however, lead to deterrence or disappointment. These medications and their development embody the best of bench science being brought to the bedside. Migraine is a miserable and impactful disease, and touches nearly 20% of all women and about 6% of men. Even negative data helps us to learn.
“A single, oral, 75-mg dose of rimegepant was superior to placebo with respect to the primary end points of freedom from pain and freedom from the patient’s most bothersome symptom 2 hours after the dose; pain was eliminated in 19.6% of the patients who received rimegepant, as compared with 12.0% of the patients who received placebo.”
Our Conclusions: In this idealized cohort of patients experiencing acute migraine, rimegepant was minimally more effective than placebo in the primary endpoint of freedom from pain at 2 hours, and poorly effective overall.
Potential to Impact Current Practice: None.
Bottom Line: Injectable CGRP inhibitors have demonstrated efficacy in migraine prevention and represent a new horizon for migraine treatment, however this trial demonstrates little benefit over placebo for abortive therapy.
- Gallagher, R. Michael, and Robert Kunkel. “Migraine medication attributes important for patient compliance: concerns about side effects may delay treatment.” Headache: The Journal of Head and Face Pain1 (2003): 36-43. PMID: 12864756
- Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol 2013; 12: 454–61. PMID: 23578775
- Charles, Andrew. “The pathophysiology of migraine: implications for clinical management.” The Lancet Neurology 17.2 (2018): 174-182. PMID: 29229375
- American Headache Society. “The American Headache Society position statement on integrating new migraine treatments into clinical practice.” Headache: The Journal of Head and Face Pain 59.1 (2019): 1-18. PMID: 30536394
- Croop, Robert, et al. “Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial.” The Lancet(2019). PMID: 31311674
For More Thoughts on This Topic Checkout:
- EM Lit of Note: The New Cutting Edge Treatment for Migraines
- EM Lit of Note: Deja Vu – The New Cutting Edge Treatment for Migraines
- The SGEM: SGEM #279 – Do You really Want to Hurt Me and Use a Placebo Control for a Migraine Trial?
Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)
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