Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine

DOI: https://doi.org/10.1186/s10194-021-01249-z

Abstract-Summary M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks.

Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product dur- ing repeated use for the treatment of migraine attacks.

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In this 6–12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a qualifying attack with M207 3.8 mg (intracutaneous zolmitriptan).

Among 335 participants who treated ≥1 migraine attack, 257 completed 6 months

and 127 completed 1 year of treatment.

Most participants (96%) experienced at least 1 adverse event, the vast majority

of which concerned the application site, and > 95% of which were mild.

Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7

application site reactions, 6 of which were mild.

Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bother- some symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2 h post- dose in 4552/5617 (81%) of attacks.

The majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild.

These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of lon- ger-term repeated use.

Extended: We report here the methodology and key findings from this study that

support a well-characterized safety profile.

Background In a Phase 2b/3, double-blind, placebo-controlled trial (N = 365) in which M207 3.8 mg was used to treat a single migraine attack (ZOTRIP, NCT02745392), 2-h pain freedom was achieved by 41.5% of those on treatment compared to 14.3% of those on placebo [127].

M207 was well-tolerated in this trial, with 51.8% of M207-treated and 18.1% of placebo participants experiencing treatment emergent adverse events (TEAEs), the vast majority of which were considered mild [127].

A considerable percentage reported application site redness (26.5% in the M207 group and 10.8% in the placebo group) and bruising (14.5% M207 and 3.6% pla- cebo); both were mild and transient in most participants.

This combination of solicited, participant-reported, real-time assessment of application site observations, investigator- assessments, and conventional adverse event assessment was incorporated as a rigorous design for evaluating the safety and tolerability of this new, unique drug delivery system.

Methods Secondary outcomes included the percentage of migraine attacks for which pain freedom and MBS freedom were achieved at 2 h post-dose, and the percentage for which pain relief was achieved at 2 h post-dose.

Participants were instructed to use the eDiary to record migraine symptoms and application site observations pre-dose, and 30  min, 2  h, 12  h, 24  h, and 48  h post-dose.

Aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, and other medi- cations taken specifically for migraine symptoms were prohibited on the day of a

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confirmed migraine attack prior to M207 application and for 2  h after patch application.

Efficacy assessments at 30 min, 2, 12, 24, and 48 h post-dose included the pro- portion of attacks with pain freedom, the proportion with freedom from a partici- pant’s specified most bothersome migraine-associated symptom, and the proportion with pain relief.

Results A total of 96 participants treated at least 25 migraine attacks and had post-treatment assessments.

Investigators also reported discoloration at the application site at least once in 16% of participants, and this was the most common adverse event not captured by the eDiary.

All events occurred in the first 6 months of the study, and 4 participants withdrew

due to application site reactions.

Neurological adverse reactions that are often associated with triptans were reported by a small percentage of participants in this study; no event was reported in 2% or more of participants.

There was one serious and possibly treatment-related adverse event in the trial;

one participant became pregnant and had received one dose of study drug.

The proportion of attacks from which participants achieved pain freedom, MBS freedom, and pain relief at 2 h post-dose are very similar to what was observed in the pivotal ZOTRIP trial [127].

Discussion and Conclusions The microneedles for M207 are 340 μm in length and appear to penetrate less than 150 μm [128], which probably contributes to the transient nature of the application site effects and the lack of infections seen at the application sites.

Although application site TEAEs were generally mild, they were reported in the

majority of participants in this 12-month study.

Photographs from preclinical studies were provided to participants to assist in

assessing application site skin effects.

Except for observations of concern, photography or other imaging methods were

not used routinely to capture application site findings in this trial.

The adverse event profile of M207 is primarily related to mild skin reactions (particularly redness) that occur at the application site in a high percentage of participants.

Potential limitations of this study include the subjective nature of severity of participant-reported applications site reactions as well as the lack of contemporane- ous assessment by investigators.

Acknowledgement A machine generated summary based on the work of Nahas, Stephanie J.; Hindiyeh, Nada; Friedman, Deborah I.; Elbuluk, Nada; Kellerman, Donald J.; Foreman, Pamela K.; Schmidt, Peter. 2021 in The Journal of Headache and Pain.

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Efficacy of triptans for the treatment of acute migraines: a quantitative comparison based on the dose-effect and time-course characteristics