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Eptinezumab (Vyepti) for preventive treatment of both episodic and chronic migraine

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Migraines – A true pain to treat

Migraine is a complex neurobiological disorder that has been recognised since antiquity. Its core features include a throbbing and often unilateral headache that is exacerbated on movement, with associated features of nausea and sensitivity to light and sound. Migraine sufferers commonly report visual, sensory or language disturbances that comprise the aura phase just preceding the migraine headache.

Developments in migraine studies have now established that the calcitonin gene-related peptide (CGRP) appears to have a central role in migraine pathogenesis through both peripheral and central mechanisms. Research has found that CGRP is released during migraine attacks, and may trigger migraine in patients.

In the second half of the past decade alone, four anti-CGRP monoclonal antibodies have been developed for the prevention of episodic and chronic migraines: eptinezumab, erenumab, fremanezumab, and galcanezumab. All four are antagonists of the CGRP target. Specifically, eptinezumab binds to the CGRP ligand, thereby preventing binding to its receptor.

This issue of new HSA approvals is on eptinezumab, manufactured by Lundbeck Seattle Biopharmaceuticals. 

Dosing and administration

The recommended dose of Vypeti is 100mg every 3 months. The manufacturer suggests that some patients may benefit from a higher dose of 300 mg every 3 months. The drug is administered via an intravenous infusion.

Clinical trial experience

The efficacy and safety of eptineuzmab has been evaluated as preventive treatment of both episodic and chronic migraine patients in two randomised, multi-centre, placebo-controlled studies, both with 6-month double-blind periods. The PROMISE 1 trial studied patients with episodic migraine, whereas the PROMISE 2 trial evaluated the drug in chronic migraine patients. Another phase 3 trial, PREVAIL, evaluated the safety, immunogenicity and impact on patient-reported outcomes with a longer period of study in chronic migraine patients. The table below summarises the key efficacy findings of these landmark trials. 

Efficacy

Study Treatment arms Summary of primary and secondary efficacy endpoints
PROMISE 1

N=665, patients with history of episodic migraine (4-14 headache days per month)

Eptinezumab 100mg 

VS

Eptinezumab 300mg

VS 

Placebo

Administered every 3 months for 12 months

  • The mean difference in monthly migraine days for eptinezumab 100 mg compared with placebo was −0.7 days (P = 0.0179) over Months 1-3.
  • The mean difference in monthly migraine days for eptinezumab 300 mg compared with placebo was −1.1 days (P = 0.0001) over Months 1-3.
  • Secondary endpoints included the proportion of patients with 50% or greater, and 75% or greater reductions from baseline in monthly migraine days over Months 1-3
    • Compared with placebo, the difference in proportion of patients with 50% or greater reductions from baseline in monthly migraine days over Months 1-3 was statistically significant for both 100mg and 300mg treatment groups.
    • Only the 300mg treatment group showed a statistically significant difference compared with placebo in the proportion of patients with 75% or greater reductions from baseline in monthly migraine days over Months 1-3.
PROMISE 2

N=1072, patients with history of chronic migraine (15 to 26 headache days per month, of which at least 8 were migraine days). 

  • The mean difference in monthly migraine days for eptinezumab 100 mg compared with placebo was −2 days (P <0.001) over Months 1-3.
  • The mean difference in monthly migraine days for eptinezumab 300 mg compared with placebo was −2.6 days (P <0.001) over Months 1-3.
  • For the same secondary endpoints as in PROMISE 1, both 100mg and 300mg groups showed a statistically significant difference as compared with placebo in achieving 50% and 75% or greater reductions from baseline in monthly migraine days.
PREVAIL

N = 480, adults with chronic migraine for ≥12 months

Eptinezumab 300 mg 

Administered once every 12 weeks (a total of 8 doses)

  • Nasopharyngitis (14%) and URTI (8%) were the most frequent adverse events. 
  • The drug was discontinued in 6.3% of patients due to adverse events. 
  • Anti-Drug antibodies peaked at week 24 and declined to non-detectable levels at week 104 despite continued dosing. 
  • The patient reported outcomes improved at first assessment and were sustained throughout.

Safety

The most common (defined as: incidence at least 2% and at least 2% greater than placebo) adverse reactions in the PROMISE 1 and 2 trials for the preventive treatment of migraine were nasopharyngitis and hypersensitivity. 1.9% of patients treated with Vyepti discontinued treatment because of adverse reactions, the large majority of which were infusion-related reactions and included anaphylaxis and angioedema. In the PREVAIL trial, at least one treatment emergent adverse event (TEAE) was seen in 71% of eptinezumab recipients, with the most common being nasopharyngitis.

Guidelines

At present, only the American Headache Society has published a guidance on incorporating new migraine treatment modalities into clinical practice. Its consensus statement (updated June 2021) outlines criteria for initiating treatment with CGRP inhibitors, which includes the inability to tolerate or inadequate response to an 8-week trial of at least 2 or more of current standard treatment with beta blockers, selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), topiramate or onabotulinum toxin A. Ultimately, the anti-CGRP monoclonal antibodies are recommended as third-line agents

Vyepti – The Unknowns

While optimistic, it should be noted that the efficacy and safety of Vyepti has only been studied up to a duration of 48 weeks. In comparison, other anti-CGRP monoclonal antibodies such as the older erenumab and fremanezumab have supporting data over longer study periods. Therefore, it remains to be seen if eptinezumab (Vyepti) will continue to be useful treatment past this period, or if the drug is amenable to tolerance or plateauing of therapeutic effect. More longitudinal studies are likely needed to guide physicians on how long patients may receive Vyepti if treatment is started and effective. 

Additionally, the drug is administered via an intravenous infusion, which may deter patients predisposed to needle phobia. While there have been other trials evaluating the efficacy of eptinezumab during an acute migraine attack, its feasibility of use in the acute clinical context is limited by its route of administration. Additional costs such as clinic visits for drug administration should also be considered on top of the already hefty price tag of the drug (average cost of the drug is 1500 USD in international market). 

At present, it appears unlikely that Vyepti will surpass current first-line treatment options in the management of migraine. However, for patients who suffer from debilitating migraine refractory to treatment with no barriers to access, the drug may be an attractive alternative that may alter their disease course. However, more studies are still required to gain insight of the use of the drug in different migraine populations and clinical settings (acute treatment vs prophylaxis). Comparison studies with other anti-CGRP monoclonal antibodies as well as onabotulinum toxin A would also be pertinent to distinguish one agent from another in the prevailing treatment algorithm.

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