ADAM Zolmitriptan Shows Efficacy in Acute Treatment of Difficult-to-Treat Migraines


The acute administration of adhesive dermally applied microarray zolmitriptan (Qytripta, Zosano Pharma) showed an almost uniform benefit across subgroups of patients with severe pain, delayed treatment, nausea, and who were awakening with headache.

Dr Stewart Tepper

Stewart Tepper, MD, the director of the Dartmouth Headache Clinic at Dartmouth-Hitchcock Medical Center, professor of neurology at the Geisel School of Medicine at Dartmouth Medical School

Stewart Tepper, MD

The acute administration of zolmitriptan (Qytripta, Zosano Pharma) via the adhesive dermally applied microarray (ADAM) platform is effective for patients with difficult-to-treat migraine, a post-hoc analysis of the phase 2/3 ZOTRIP study suggested.1

Patients with severe pain, whose treatment was delayed ≥2 hours, who were awakening with headache, and with nausea showed an almost uniformly better response in 2-hour headache freedom and 2-hour most-bothersome symptom freedom than patients who received placebo.

“We are pleased with the results of this retrospective analysis, which demonstrate that Qtrypta may be an effective acute treatment for patients exhibiting migraine characteristics that historically have been difficult to treat,” Stewart J. Tepper, MD, professor of neurology at the Geisel School of Medicine at Dartmouth, said in a statement.2

Ultimately, the analysis included 321 patients with nausea (n = 110) or severe pain (n = 72) at baseline, those whose treatment was delayed 2 or more hours after onset (n = 75), and those who awoke with migraine (n = 80). Patients had been randomized to either placebo or 3.8-mg zolmitriptan.

For those with nausea, 2-hour pain freedom was achieved in 26 of 59 patients (44%) in the zolmitriptan arm compared to 7 of 51 patients (14%) in the placebo arm (odds ratio [OR], 5.11; 95% CI, 1.96 to 13.30; P = .005), while 2-hour freedom from the most bothersome symptom was achieved in 40 patients (68%) compared to 23 patients (45%), respectively (OR, 2.86; 95% CI, 1.28 to 6.43; P = .009).

Meanwhile, 2-hour pain freedom was achieved in 10 of 39 patients who reported severe pain (26%) that were administered zolmitriptan compared to 5 of 33 (15%) of those given placebo (OR, 2.14; 95% CI, 0.60 to 7.62; P = .249). Freedom from the most bothersome symptom at 2 hours was achieved by 25 patients (64%) in the treatment group and 14 patients (42%) in the placebo group (OR, 2.86; 95% CI, 1.05 to 7.79; P = .038).

"There are a number of subtypes of acute migraine attacks that are less responsive to oral triptans. Our analysis suggests that intracutaneous delivery may effectively treat these subtypes," coauthor Pete Schmidt, MD, MSCI, the senior director of Medical Affiars at Zosano, told NeurologyLive. "Zolmitriptan has been a popular option in nasal, oral and oral dissolving forms because of its potency, efficacy and tolerability. We believe that the ADAM platform optimizes delivery of this molecule and will hopefully extend zolmitriptan’s favorable profile to difficult-to-treat migraine attacks."

Among those who awoke with migraine, 16 of 36 patients (44%) and 7 of 44 patients (16%) in the treatment and placebo arms, respectively, were pain‐free at 2 hours (OR, 4.29; 95% CI, 1.50 to 12.31; P = .006). With regard to 2-hour freedom from the most bothersome symptom, the zolmitriptan arm reported freedom in 26 of 36 patients (72%) compared with 17 of 44 patients (39%) in the placebo arm (OR, 4.40; 95% CI, 1.61 to 12.05; P = .003).

"I was most surprised that the ADAM zolmitriptan system appeared effective in treatments that were delayed greater than 2 hours. Typically, we consider this well outside of the 'treat early' paradigm of oral triptans," Schmidt said.

Of 36 patients whose treatment was delayed ≥2 hours in the treatment arm, 12 (33%) experienced pain freedom, compared to only 4 of 39 patients (10%) in the placebo group (OR, 4.33; 95% CI, 1.24 to 15.10; P = .017). Most-bothersome-symptom freedom was achieved in 25 of 36 patients (69%) and 16 of 39 patients (41%), respectively, in the delayed treatment cohort (OR, 3.37; 95% CI, 1.27 to 8.95; P = .014).

“Qtrypta was found to have clinically and statistically significant impact on pain freedom and most bothersome symptom freedom across the entire patient population in the ZOTRIP study,” Tepper said, “and the results from these subset analyses support the potential for Qtrypta to provide patients with a novel acute treatment that provides rapid relief of pain in patients with these more refractory migraine subtypes.”

No significant effects (overall interaction P = .353) were observed in the logistical regression models of treatment by subgroup interaction.

Zosano's ADAM technology consists of titanium microneedles coated with a drug, and in this case, its formulation of zolmitriptan. The therapy-coated microneedles penetrate through the epidermis, where the investigational treatment dissolves into the bloodstream.

Previously, results of the ZOTRIP study were announced in which the investigational agent met both co-primary end points of pain freedom (achieved by 41.5% of patients; P = .0001) and most bothersome symptom freedom (achieved by 68.3% of patients; P = .0009) at 2 hours with its 3.8-mg dose.3 In November 2017, Zosanos announced its long-term safety study with zolmitriptan, and the company has stated it plans to file a New Drug Application (NDA) with the FDA in the fourth quarter of 2019.


1. Tepper SJ, Dodick DW, Schmidt PC, Kellerman DJ. Efficacy of ADAM zolmitriptan for the acute treatment of difficult-to-treat migraine headaches. Headache. Published online January 30, 2019. Accessed January 31, 2019.

2. Zosano Pharma (ZSAN) Reports Publication of Positive Data on Qtrypta’s Potential as an Acute Treatment for Patients with Difficult-to-Treat Migraines [press release]. Fremont, CA: Zosano Pharma Corporation; Published January 31, 2019. Accessed January 31, 2019.

3. Spierings E, Kellerman D, Schmidt PC. Effectiveness and safety of a new zolmitriptan rapid absorption microneedle array (M207) for the acute treatment of migraine (The ZOTRIP Study). Neurology. 2018; 90 (15 Supplement). Published online April 9, 2018. Accessed January 31, 2019.

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