Ubrogepant (MK-1602)

Migraine overview and summary of current and emerging treatment options

Migraine is a leading cause of disability worldwide. Approximately 15% of Americans experience migraines. Most people who have migraines feel that people who do not have them often underestimate their condition. Migraines affect people's quality of life and ability to participate in work, family, and social events. A new class of medication, calcitonin gene-related peptide (CGRP) antagonists, has been approved for migraine prevention in adults. The newly approved CGRP antagonists are erenumab, fremanezumab, and galcanezumab, while eptinezumab looks to 2020 for approval. Lasmiditan, ubrogepant, and rimegepant are currently emerging acute migraine therapies that may be added to the arsenal of current migraine management.

Diagnosis and Management of Headache: A Review

Importance: Approximately 90% of people in the US experience headache during their lifetime. Migraine is the second leading cause of years lived with disability worldwide.
Observations: Primary headache disorders are defined as headaches that are unrelated to an underlying medical condition and are categorized into 4 groups: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Studies evaluating prevalence in more than 100 000 people reported that tension-type headache affected 38% of the population, while migraine affected 12% and was the most disabling. Secondary headache disorders are defined as headaches due to an underlying medical condition and are classified according to whether they are due to vascular, neoplastic, infectious, or intracranial pressure/volume causes. Patients presenting with headache should be evaluated to determine whether their headache is most likely a primary or a secondary headache disorder. They should be evaluated for symptoms or signs that suggest an urgent medical problem such as an abrupt onset, neurologic signs, age 50 years and older, presence of cancer or immunosuppression, and provocation by physical activities or postural changes. Acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs, and combination products that include caffeine. Patients not responsive to these treatments may require migraine-specific treatments including triptans (5-HT1B/D agonists), which eliminate pain in 20% to 30% of patients by 2 hours, but are accompanied by adverse effects such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Patients with or at high risk for cardiovascular disease should avoid triptans because of vasoconstrictive properties. Acute treatments with gepants, antagonists to receptors for the inflammatory neuropeptide calcitonin gene-related peptide, such as rimegepant or ubrogepant, can eliminate headache symptoms for 2 hours in 20% of patients but have adverse effects of nausea and dry mouth in 1% to 4% of patients. A 5-HT1F agonist, lasmiditan, is also available for acute migraine treatment and appears safe in patients with cardiovascular risk factors. Preventive treatments include antihypertensives, antiepileptics, antidepressants, calcitonin gene-related peptide monoclonal antibodies, and onabotulinumtoxinA, which reduce migraine by 1 to 3 days per month relative to placebo.
Conclusions and relevance: Headache disorders affect approximately 90% of people during their lifetime. Among primary headache disorders, migraine is most debilitating and can be treated acutely with analgesics, nonsteroidal anti-inflammatory drugs, triptans, gepants, and lasmiditan.

Ubrogepant for the Treatment of Migraine

Background: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment.
Methods: We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours.
Results: A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose.
Conclusions: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).

CGRP and migraine: from bench to bedside

Migraine treatment has reached a new era with the development of drugs that target the trigeminal neuropeptide calcitonin gene-related peptide (CGRP) or its receptor. The CGRP related therapies offer considerable improvements over existing drugs as they are the first to be designed to act on the trigeminal pain system, more specific and with few adverse events. Small molecule CGRP receptor antagonists, such as rimegepant and ubrogepant, are effective for the acute treatment of migraine headache. In contrast, monoclonal antibodies against CGRP or the CGRP receptor are beneficial for the prophylactic treatments in chronic migraine. Here I will provide a historical overview of the long path that led to their successful development. In addition, I will discuss aspects on the biology of CGRP signalling, the role of CGRP in migraine headache, the efficacy of CGRP targeted treatment, and synthesize what currently is known about the role of CGRP in the trigeminovascular system.