In December 2019, the US Food and Drug Administration (FDA) approved the first small molecule calcitonin gene-related peptide (CGRP) antagonist for the treatment of acute migraine, ubrogepant (Ubrelvy®),1 followed closely by rimegepant (Nurtec ODT®).2 A novel serotonin (5-HT)1F receptor agonist, lasmiditan (Reyvow®), was approved in October 2019 as a new oral agent for the acute treatment of migraine, with or without aura, in adults.3

The principal utility of these new abortive agents includes an alternative mechanism of action for those unable to tolerate or for whom treatment with triptans has been unsuccessful. Most importantly, the apparent lack of vascular risks (vasospastic cardiac or cerebrovascular) presents novel opportunities for treating acute migraine in older patients. Formerly this has been accomplished with unsatisfactory older analgesics or opioids.

Ubrogepant

Oral CGRP antagonists represent small molecule “-gepant” agents, which unlike the parenteral anti-CGRP monoclonal antibody agents, are approved for acute, abortive treatment of migraine. Ubrogepant was approved for the acute treatment of migraine with or without aura in adults.1 Ubrogepant is not indicated for the preventive treatment of migraine.

The effectiveness of ubrogepant for acute migraine was proven in 2 randomized, double-blind, placebo-controlled trials.4 In these studies, 1439 adult patients with a history of migraine, with and without aura, received ubrogepant. In both studies, the percentage of patients achieving 2-hour pain freedom was significantly greater  among patients receiving ubrogepant compared with those receiving placebo (20% at 50 mg vs 13% placebo), as was resolution of principal migraine symptom (nausea, light sensitivity, or sound sensitivity [38% at 50 mg vs 27% placebo]).1

The most common side effects that patients in the clinical trials reported were nausea, tiredness, and dry mouth. Ubrogepant is contraindicated for co-administration with strong CYP3A4 inhibitors.1

Rimegepant

Another gepant, rimegepant, was approved on February 27, 2020, as a rapidly dissolving tablet for aborting migraine in adults with acute migraine with or without aura.2 The 75-mg dose of rimegepant increased 2-hour postdose freedom from pain to 21% from a placebo rate of 10%; tolerability of active drug was similar to that seen with placebo. Rare significant unrelated transaminase elevations were observed. 

Lasmiditan

Anti-CGRP oral gepant agents are not the only recent new class of abortive agents. An alternative to traditional abortive triptan and ergot agents recently emerged for older patients and those with vascular risk, as well as treatment-intolerant individuals. 

Acute treatment of migraine has been approved with lasmiditan, a high-affinity, 5-HT1F receptor agonist without the 5‑HT1B/D-mediated vasoconstriction of older ergot and triptan agents. However, lasmiditan was placed in Schedule V as a non-opiate, nonbenzodiazepine sedating agent with a significant driving impairment.

Doses ranging from 50 mg to 200 mg, taken at onset of acute pain, achieve 2-hour complete elimination of pain in 28% to 39% of patients compared with 15% to 21% with placebo in 2 trials.3 Most common adverse events were dizziness, paresthesia, fatigue, and numbness, and were generally mild or moderate.5 Significant driving impairment occurred at 90 minutes and resolved by 8 hours. Driving impairment was similar to alcohol level of 0.05%.5

Click here for an overview of a novel class of preventive treatments for migraine.

References

  1. Ubrelvy [package insert]. Madison, NJ: Allergan USA, Inc; 2019.
  2. Scott LJ. Rimegepant: first approval. Drugs. 2020;80(7):741-746.
  3. Kuca B, Silberstein SD, Wietecha L, et al. Lasmiditan is an effective acute treatment for migraine: a phase 3 randomized study. Neurology. 2018;91(24):e2222-e2232.
  4. FDA approves new treatment for adults with migraine [news release]. US Food and Drug Administration. December 23, 2019. Accessed May 12, 2020.
  5. Krege JH, Rizzoli PB, Liffick E, et al. Safety findings from phase 3 lasmiditan studies for acute treatment of migraine: results from SAMURAI and SPARTAN. Cephalalgia. 2019;39(8):957-966.