A novel formulation containing meloxicam and rizatriptan provides effective pain relief for patients with migraine, new research suggests.

Results from the phase 3 INTERCEPT trial show that the treatment, known as AXS-07 (Axsome Therapeutics), also provided greater relief from the patient’s most bothersome symptom (MBS) compared with placebo.

In addition, about 74% of patients who received AXS-07 experienced no progression of pain from 2 to 24 hours after dosing and were less than half as likely to use rescue medication through 24 hours than those who received placebo.

Similar to a previous formulation combining naproxen sodium and sumatriptan, AXS-07 combines a nonsteroidal anti-inflammatory drug (NSAID) with a triptan. The combination is synergistic, investigators note, because one drug addresses pain mechanisms that the other does not.

“Rizatriptan’s primary mechanism is peripheral, and NSAIDs have both peripheral and central benefit,” study investigator Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, told Medscape Medical News.

“That is why the whole is greater than the sum of the parts.” Tepper added.

The findings were presented at the virtual American Headache Society (AHS) Annual Meeting 2021.

Acute Treatments Needed

For many patients, current migraine treatments are inadequate. In addition, suboptimal acute treatment can increase risk for progression from episodic migraine to chronic migraine. It also increases the risk for medication-overuse headache.

The search for optimal acute treatments is therefore “really important for patients,” Tepper noted.

Because it contains rizatriptan, AXS-07 is believed to inhibit the release of calcitonin gene–related peptide, reverse the vasodilation that it causes, and decrease the transmission of pain signals. Meloxicam, on the other hand, is thought to reduce neuroinflammation and reverse central sensitization, which maintains chronic pain.

In the phase 3, double-blind INTERCEPT trial, the investigators examined AXS-07 for early treatment of migraine. Eligible patients were aged 18 to 65 years, had been diagnosed with migraine in accordance with ICHD-3 criteria, and averaged two to eight migraines per month.

The researchers randomly assigned a single dose of AXS-07 (n = 152) or placebo (n = 150). Participants were asked to administer treatment to themselves at the earliest sign of migraine pain.

The trial’s two primary endpoints were pain freedom and freedom from the MBS 2 hours after dosing. Secondary endpoints included sustained pain freedom, freedom from pain progression, functional disability, and use of rescue medication.

Demographic characteristics of the study population reflected those of the general population of people with migraine, according to the researchers. More than 85% of participants were women, and the study group’s mean age was 41 years. There were no demographic differences between the two treatment groups.

Reduced Pain Progression

Results showed that 2 hours after treatment, rate of pain freedom was 32.6% in the AXS-07 group and 16.3% in the placebo group (P = .002). At the same time point, rate of freedom from MBS was 43.9% and 26.7%, respectively (P = .003).

Approximately 64% of patients who received AXS-07 were pain free at 12 hours, and 69% were pain free at 24 hours. In contrast, 42% of the placebo group were pain free at 12 hours, and 47% were pain free at 24 hours (P < .001 for both comparisons).

The benefits AXS-07 provided were sustained; 22.7% of the active-treatment group achieved sustained pain freedom from 2 to 24 hours after treatment, compared with 12.6% of the placebo group (P = .03). Results were similar for sustained pain freedom from 2 to 48 hours after treatment (20.5% vs 9.6%; P = .013).

In addition, 73.5% of patients who received AXS-07 had freedom from pain progression from 2 to 24 hours after treatment, vs 47.4% of those who received placebo (P < .001). The rate of rescue medication use through 24 hours was 15.3% and 42.2%, respectively (P < .001).

AXS-07 was also linked to significant reductions in functional disability. About 74% of patients who received it reported no disability at 24 hours, compared with 47% of patients who received placebo (P < .001). Scores on the Patient Global Impression of Change scale were very much improved or much improved 2 hours after dosing for 52.4% of the AXS-07 group, vs 27.7% of the placebo group (P < .001).

The overall rate of treatment-emergent adverse events (AEs) was 17.9% in the active group and 7.7% among the control group. The rate of somnolence was 4.3%, vs 2.1%; the rate of dizziness was 2.9%, vs 1.4%; and the rate of paresthesia was 2.1%, vs 0%. There were no serious AEs.

“Unexpectedly, and it’s hard to interpret this, but the nausea associated with the use of AXS-07 is less than with either of the active components or the placebo,” said Tepper. “It’s not dramatically different for dizziness.”

Improved Adherence?

Meloxicam is generally used not as an acute medication but for prevention, Tepper noted. The drug is often administered to reduce inflammation in conditions such as chronic arthritis.

AXS-07 incorporates an altered pharmacokinetic delivery system to provide a quicker onset of effect for meloxicam.

“Most headache specialists would say that of all the oral triptans, rizatriptan is the fastest,” said Tepper.

The idea for the new agent was to hasten the onset of meloxicam’s effect so that both active components would work rapidly.

“We know that there is a synergy between NSAIDs and triptans, in terms of complete headache response,” Tepper said.

Data indicate that when neurologists recommend that patients take an NSAID and triptan together at the beginning of an attack, patients rarely comply.

“It’s a big adherence issue,” said Tepper. “They’re more likely to get a complete response if they take them together, especially if the tablet is designed to deliver the two products together in an optimal way.”

Uncertain Therapeutic Advantage

Commenting on the findings for Medscape Medical News, Robert Shapiro, MD, PhD, professor of neurologic science at the University of Vermont, in Burlington, Vermont, noted that because of favorable data from past studies for the combination of 85 mg of sumatriptan with 500 mg of naproxen sodium, the coadministration of a triptan with an NSAID has been a standard of care for the past decade.

“It’s therefore unsurprising that a combination of rizatriptan 10 mg plus meloxicam 20 mg in a proprietary MoSEIC formulation might also prove to be more effective than either individual medication taken alone for acute migraine attacks,” said Shapiro, who was not involved with the research.

It is not possible to compare the efficacy and tolerability of AXS-07 with those of sumatriptan–naproxen sodium without head-to-head trials. However, the available data suggest that the latter formulation is superior, he added.

In 2008, researchers conducted two parallel-group, placebo-controlled trials of sumatriptan–naproxen sodium taken early in a migraine attack. These trials had protocols comparable to that of the current INTERCEPT trial for AXS-07, said Shapiro.

For the key primary endpoint of 2-hour pain freedom, the two sumatriptan–naproxen sodium trials found therapeutic gains of 35% and 36%, respectively, vs 16.3% for the AXS-07 trial. The placebo response rates (17% and 15% for sumatriptan–naproxen sodium, vs 16.3% for the AXS-07 trial) were comparable.

Similarly, for the endpoint of 2- to 24-hour pain freedom, the sumatriptan–naproxen sodium trials found therapeutic gains of 33% and 26%, respectively, vs 15.1% for the AXS-07 trial. Again, response rates for placebo were comparable (12% and 14% for sumatriptan–naproxen sodium, vs 12.6% for AXS-07).

The placebo-adjusted differences for reporting any treatment-emergent AE, otherwise known as “therapeutic penalty,” was 10.2% for AXS-07 in the INTERCEPT trial, vs 7% and 5%, respectively, for participants in the two sumatriptan–naproxen sodium trials.

“In light of these data, it’s not immediately apparent what advantage AXS-07 might offer over sumatriptan–naproxen sodium,” said Shapiro.

“Furthermore, sumatriptan–naproxen sodium is currently available in generic form,” he added.

The study was funded by Axsome Therapeutics. Tepper is a consultant to Axsome Therapeutics. Shapiro has previously performed research consulting for Lilly and Lundbeck.

American Headache Society (AHS) Annual Meeting 2021. Abstract IOR-04, presented June 3, 2021.

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