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Zosano Pharma noted that the DRL does not reflect the final FDA decision on the application, though the approval of zolmitriptan by its PDUFA action date of October 20, 2020, is no longer likely as a result.
The FDA has issued a discipline review letter (DRL) to Zosano Pharma in relation to its recent new drug application (NDA) for its zolmitriptan (Qtrypa) transdermal microneedle system—also known as its adhesive dermally applied microarray (ADAM) platform—conveying some preliminary deficiencies the agency highlighted during its review of the application.1
The FDA accepted the new drug application (NDA) for ADAM zolmitriptan in the acute treatment of migraine in March 2020. Zosano noted that as the comments are subject to change, the DRL does not reflect the final FDA decision on the application, though the approval of zolmitriptan by its Prescription Drug User Fee Act (PDUFA) action date of October 20, 2020, is no longer anticipated as a result.
“We are disappointed in this notification and are in the process of evaluating and addressing FDA’s comments,” said Steven Lo, president and chief executive, Zosano, in a statement. “We believe Qtrypta represents an attractive therapeutic alternative for patients suffering from migraines and look forward to working with [the] FDA through the NDA review process.”
Zosano confirmed in its announcement that the FDA cited 2 concerns, both related to the clinical pharmacology of the application: first, an unexpectedly high plasma concentration of the agent in 5 subjects from 2 pharmacokinetic (PK) studies; and second, differences in zolmitriptan exposure between lots administered to patients in the clinical trials. The PK data was noted as potentially impactful on the overall data in the aforementioned section of the application.
In July 2020, new post-hoc efficacy analyses of ADAM zolmitriptan from its open-label, long-term safety study were presented virtually at the 2020 American Headache Society (AHS) Annual Meeting, which suggest that the results were consistent with what was observed in the pivotal phase 2/3 study results.2
The data showed that across all 6 efficacy measurements—pain freedom at 2 hours, pain relief at 2 hours, sustained pain freedom for 2 to 24 hours, sustained pain freedom for 2 to 48 hours, sustained pain relief for 2 to 24 hours, and sustained pain relief for 2 to 48 hours—the migraine headaches treated with 3.8-mg ADAM zolmitriptan displayed meaningful clinical improvements compared to those treated with placebo. Over the course of the study, 5617 migraine attacks were observed. Pain freedom at 2 hours was reported for 44% of the migraine headaches treated, while pain relief at 2 hours was reported for 81%.
Sustained pain freedom at 2 to 24 hours and 2 to 48 hours was reported for 38% and 35% of the migraine headaches treated, respectively. Sustained pain relief at those same respective time points was reported for 70% and 65% of migraine headaches treated, as well.
As was the case in the pivotal study, the most common adverse events (AEs) observed in the open-label stud were redness and swelling at the application site, of which >95% were classified as mild, and 80% generally resolved within 48 hours. Patients treated with the Zosano agent reported less triptan-like neurological side effects than are typically found with the class, with <2% of patients in the long-term assessment reporting effects such as dizziness and paresthesia.
Overall, the pivotal phase 2/3 study 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.3