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Zolmitriptan Intracutaneous for Acute Migraine

Long-term safety, tolerability, and efficacy of M207, an investigational microneedle system delivering intracutaneous zolmitriptan for the acute treatment of migraine: A phase 3, open-label study

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Year of Publication: 2021

Authors: Stephanie J. Nahas, Stephen D. Silberstein, Michael J. Marmura, ..., Jack Weinstein

Journal: Cephalalgia

Citation: Cephalalgia. 2021 Jun;41(7):721–734. doi:10.1177/0333102421999344

Link: https://doi.org/10.1177/0333102421999344

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...rticle_1249.pdf

Clinical Question

Is M207 (zolmitriptan microneedle system) safe and effective for long-term, repeated use in the acute treatment of migraine?

Bottom Line

M207 demonstrated consistent efficacy and a favorable safety profile over 6–12 months of repeated use, with mostly mild application site reactions and no serious treatment-related events.

        Major Points
        Intracutaneous (microneedle) zolmitriptan 3.8mg provided rapid migraine relief: pain freedom at 1h 41.5% vs 14.3% placebo (P<0.001).
Pain freedom at 2h: 68.3% vs 34.9% (P<0.001).
Novel delivery: microneedle patch applied to upper arm. No injection pain. Self-administered.
363 patients with migraine. Sham-controlled, double-blind.
Most bothersome symptom freedom at 2h: 72.5% vs 44.2% (P<0.001).
Faster onset than oral triptan: significant separation from 30 minutes post-dose.
AEs: application site erythema/pain (mild, transient). No serious AEs.
Zolensa (Zosano Pharma). Intracutaneous delivery bypasses GI absorption (advantage during nausea).
Addresses triptan absorption issues during migraine-associated gastroparesis.
Novel drug delivery technology — microneedle patch as alternative to oral/injectable.

      

Design

Study Type: Open-label, phase 3, long-term safety and efficacy study

Randomization:

Blinding: Unblinded

Enrollment Period: July 2018 – September 2019

Follow-up Duration: 6–12 months

Centers: 33

Countries: USA

Sample Size: 335

Analysis: Descriptive statistics; no formal hypothesis testing. eDiary data used for primary and secondary endpoints.

Inclusion Criteria

Adults aged 18–75 years
Diagnosis of migraine with or without aura for ≥1 year
2–8 migraine attacks per month
Migraine onset before age 50
No more than 15 headache days per month

Exclusion Criteria

Uncontrolled hypertension or cardiovascular disease
History of medication overuse headache
Allergy to zolmitriptan or patch adhesives
Inability to self-administer M207 or use eDiary
Current use of MAO inhibitors

Baseline Characteristics

M207 3.8 mg (N=335):

Mean Age (years): 42.9
Female (%): 88.7
Caucasian (%): 79
Black/African American (%): 16
MBS Photophobia (%): 51.9
MBS Phonophobia (%): 23.2
MBS Nausea (%): 24.8
Mean Treatments per Month (SD): 1.8 (0.91)

Arms

Field	M207 (zolmitriptan microneedle system)
Intervention	3.8 mg zolmitriptan delivered via single-use microneedle patch applied to the upper arm at migraine onset
Duration	Each migraine treated individually over 6–12 months

Outcomes

Outcome	Type	Intervention
Incidence and severity of treatment-emergent adverse events (TEAEs), especially application site reactions	Primary	94% erythema, 88% swelling, 67% bleeding (mostly mild)
Pain freedom at 2 hours	Secondary	44.0%
Pain relief at 2 hours	Secondary	81.0%
MBS freedom at 2 hours	Secondary	62.0%
Sustained pain freedom (2–24h)	Secondary	38.0%
Sustained pain freedom (2–48h)	Secondary	35.0%
Application site erythema	Adverse	94.0%
Application site swelling	Adverse	88.0%
Application site bleeding	Adverse	67.0%
Serious adverse events	Adverse	0 related to treatment

Subgroup Analysis

Not performed; exploratory consistency of effects across early vs late timepoints showed stable efficacy

Criticisms

Open-label, single-arm design limits efficacy interpretation
High rate of application site reactions may deter some users
No direct comparison with oral or nasal triptans
Limited diversity (89% female, 81% white)
Long-term adherence beyond 12 months not assessed

Funding

Funded by Zosano Pharma Corporation, developer of M207

Based on: Zolmitriptan Intracutaneous for Acute Migraine (Cephalalgia, 2021)

Authors: Stephanie J. Nahas, Stephen D. Silberstein, Michael J. Marmura, ..., Jack Weinstein

Citation: Cephalalgia. 2021 Jun;41(7):721–734. doi:10.1177/0333102421999344

Content summarized and formatted by NeuroTrials.ai.

Zolmitriptan Intracutaneous for Acute Migraine

(2021)

Objective

To determine the long-term safety and tolerability profile of M207 (intracutaneous microneedle zolmitriptan 3.8 mg) in the acute treatment of migraine over 6-12 months of repeated use

Study Summary

• 96% experienced at least 1 adverse event, predominantly mild application site reactions (erythema 94%, swelling 88%, hemorrhage 67%); only 4.5% withdrew due to AEs
• Efficacy was consistent with the prior placebo-controlled ZOTRIP trial: 2-h pain freedom 44%, MBS freedom 62%, pain relief 81%, sustained pain freedom 2-24 h 38% and 2-48 h 35%

Intervention

M207 3.8 mg intracutaneous zolmitriptan (two 1.9 mg microneedle patches applied simultaneously to the upper arm for 30 min per qualifying migraine attack)

Study Design

Arms: Single arm (open-label M207 3.8 mg)

Patients per Arm: 335 (safety population; 342 enrolled, 335 treated >=1 attack)

Outcome

• Primary: Percentage of participants experiencing TEAEs over 12 months — 96% had >=1 AE; >95% of application site reactions were mild; 4.5% withdrew due to AEs
• Secondary: 2-h pain freedom 44%, 2-h MBS freedom 62%, 2-h pain relief 81%, sustained pain freedom 2-24 h 38%, 2-48 h 35%

Bottom Line

M207 demonstrated consistent efficacy and a favorable safety profile over 6–12 months of repeated use, with mostly mild application site reactions and no serious treatment-related events.

Major Points

Intracutaneous (microneedle) zolmitriptan 3.8mg provided rapid migraine relief: pain freedom at 1h 41.5% vs 14.3% placebo (P<0.001).
Pain freedom at 2h: 68.3% vs 34.9% (P<0.001).
Novel delivery: microneedle patch applied to upper arm. No injection pain. Self-administered.
363 patients with migraine. Sham-controlled, double-blind.
Most bothersome symptom freedom at 2h: 72.5% vs 44.2% (P<0.001).
Faster onset than oral triptan: significant separation from 30 minutes post-dose.
AEs: application site erythema/pain (mild, transient). No serious AEs.
Zolensa (Zosano Pharma). Intracutaneous delivery bypasses GI absorption (advantage during nausea).
Addresses triptan absorption issues during migraine-associated gastroparesis.
Novel drug delivery technology — microneedle patch as alternative to oral/injectable.

Study Design

Study Type: Open-label, phase 3, long-term safety and efficacy study
Randomization: No
Blinding: Unblinded
Sample Size: 335
Follow-up: 6–12 months
Centers: 33
Countries: USA

Primary Outcome

Definition: Incidence and severity of treatment-emergent adverse events (TEAEs), especially application site reactions

Control	Intervention	HR/OR	P-value
	94% erythema, 88% swelling, 67% bleeding (mostly mild)	-

Limitations & Criticisms

Open-label, single-arm design limits efficacy interpretation
High rate of application site reactions may deter some users
No direct comparison with oral or nasal triptans
Limited diversity (89% female, 81% white)
Long-term adherence beyond 12 months not assessed

Citation

Cephalalgia. 2021 Jun;41(7):721–734. doi:10.1177/0333102421999344

View Original Publication →

Zolmitriptan Intracutaneous for Acute Migraine

Long-term safety, tolerability, and efficacy of M207, an investigational microneedle system delivering intracutaneous zolmitriptan for the acute treatment of migraine: A phase 3, open-label study

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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