Symbravo (previously AXS-07; Axsome Therapeutics), approved by the FDA on January 30, 2025, is a new medication for acute treatment of migraine in adults that combines the COX-2 preferential nonsteroidal anti-inflammatory drug (NSAID) meloxicam and the 5-HT1 receptor agonist rizatriptan.
In an Axsome Therapeutics Symbravo FDA approval call with institutional investors on January 31, Stewart Tepper, MD, principal investigator for the pivotal phase 3 clinical trials that led to the approval, answered questions about the multimechanistic action of the new combination, the features that make it unique, and how those features enhance the oral tablet’s efficacy.
Tepper: Migraine activation within the brain triggers the release of calcitonin gene-related peptide (CGRP) in the meninges. CGRP, a potent vasodilator, induces dilation of meningeal blood vessels, which in turn releases inflammatory mediators. This inflammatory cascade contributes to migraine pathophysiology, with pain signals traveling from the meninges to the brain, where they are processed, resulting in headache, nausea, and sensory sensitivities characteristic of migraine. Targeting CGRP is one approach to migraine treatment, but multiple mechanisms can be leveraged to interrupt the migraine process.
Symbravo combines rizatriptan and meloxicam in a novel formulation for acute migraine treatment. Rizatriptan acts early in the development of migraine by preventing CGRP release in the meninges and reversing CGRP-induced vasodilation. It also inhibits pain signal transmission from the meninges to the brain. Meloxicam mitigates meningeal inflammation and has been shown to modulate central pain processing. NSAIDs work both peripherally and centrally to interrupt migraine progression. The formulation uses MoSEIC technology, developed by Vertex Pharmaceuticals, which enhances the solubility of meloxicam and it’s absorption and that overcomes the limitations of conventional meloxicam, which has poor solubility and slow absorption. Overall, the improved drug dissolution and bioavailability creates rapid onset of therapeutic action.
The pharmacokinetic profile of Symbravo aligns with the temporal dynamics of migraine pathophysiology. CGRP peaks at approximately one hour after migraine onset, while prostaglandin E2 (PGE2), an inflammatory mediator, peaks at two hours. Rizatriptan is actually the oral triptan with the fastest onset of action and the highest 2-hour pain freedom scores. So, after taking Symbravo, rizatriptan reaches peak plasma concentration within 30 minutes, and Mosaic meloxicam peaks between 45 minutes and one hour—before CGRP and PGE2 reach their highest levels. By intervening early in different aspects of the migraine cascade, Symbravo quickly and effectively terminates the attack. For the FDA approval, the fixed dose Symbravo had to be evaluated against its individual components and placebo. The results demonstrated that the combination of MoSEIC meloxicam and rizatriptan in a single tablet produced superior efficacy compared to either component alone, confirming a synergistic effect and that the pill is greater than the sum of its parts.
Remember that the best acute treatment for migraine is 1 and done. Patient is pain free within 2 hours, without significant side effects, and most of the time without any headache recurrence after the successful treatment, one and done. Research has demonstrated, too, that optimal acute treatment was more than twice as likely to prevent this transformation from episodic to chronic migraine and that inadequate treatment significantly increased the risk of progression.
Tepper was asked about who should be prescribed Symbravo, including whether it was expected that a payer would need to see evidence of nonresponse to a previous acute medication. His response included details that should be considered in selecting patients appropriate for treatment with Symbravo, ie, those likely to benefit most from the dual mechanism of action.
The pivotal phase 3 clinical trials of Symbravo demonstrated low symptom recurrence rates, with sustained pain freedom documented at 24 and 48 hours. In the MOMENTUM trial, Symbravo was evaluated in patients who had not responded to previous acute treatments, representing a more difficult-to-treat population. Despite this, the medication showed excellent efficacy, supporting its role in managing patients with suboptimal response to prior therapies. Across clinical trials, the early onset and high efficacy was achieved with low rates of adverse events—only 1% above placebo.
Review details of the phase 3 MOMENTUM and INTERCEPT clinical trials
Tepper: The American Headache Society emphasizes that every patient with migraine needs an acute treatment. With that in mind, it is useful to consider which patients are most appropriate for Symbravo, independent of payer requirements, before circling back to those considerations.
For example, the ability of the NSAID component of Symbravo, the MoSEIC meloxicam, to reverse central sensitization makes it particularly effective for patients experiencing migraines at peak intensity, where a triptan or gepant alone may be insufficient. One common example is migraine upon awakening, a particularly severe type of migraine that accounts for nearly half of attacks. A triptan alone often fails to restore function in morning migraine, and gepants can be slow to take effect. Symbravo is going to be especially useful for the patients who awaken with a full-blown attack because of the speed of onset of the rizatriptan plus the rapid anti-inflammatory action of the MoSEIC meloxicam.
It is also well-suited for patients who experience quick time to peak migraine intensity, from the time they notice the pain to the time they are disabled. Gepants tend to act more slowly, whereas this combination therapy is designed for faster relief. Symbravo should also be used for people who need an anti-inflammatory component, such as women with menstrual migraine, may benefit significantly. Menstrual migraine affects two-thirds of women with migraine and tends to be prolonged. Since NSAIDs have demonstrated efficacy in menstrual pain, combining an anti-inflammatory with a triptan could extend the duration of symptom relief while also addressing central sensitization.
I also want to touch on the adolescent population. One of the defining characteristics of adolescent migraine is its rapid progression to peak intensity. When asked how quickly their migraine worsens, adolescents often say, "That fast," snapping their fingers. Rizatriptan is already FDA-approved for acute migraine treatment in adolescents, and the MoSEIC formulation allows for even earlier absorption of rizatriptan and meloxicam. This suggests that the combination could be particularly effective in this population, and I look forward to seeing the results of future studies.
We know that payers are likely to require prior trials of other treatments. The pivotal phase 3 MOMENTUM study demonstrated Symbravo efficacy in patients with various and inadequate responses to previous acute treatments. The late Matt Knight and colleagues published research showing that adding an NSAID to a triptan is often effective in patients for whom triptans alone have failed. Given this, there are numerous clinical scenarios in which this combination therapy could provide meaningful benefit.
