Migraine headache is a complex neurobiological disorder that is debilitating for many of its sufferers. Despite its long history, it remains an unmet medical need that is often inadequately recognized and undertreated. Current treatment options are centered on aborting acute episodes, as well preventive treatments to minimize the frequency of the migraine attacks.
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. This article sheds light on fremanezumab (Ajovy), a monoclonal antibody against CGRP.
How it works
Fremanezumab selectively binds to and blocks the CGRP ligand, thereby inhibiting downstream cascade of events and preventing the activation of the trigeminovascular pain pathway.
Dosing and administration
The recommended dose of Ajovy is 225mg monthly, or 675mg every 3 months. The drug is administered subcutaneously and comes in a pre-filled syringe or autoinjector. The higher dose is administered as three consecutive injections of 225mg.
Clinical trial experience
Efficacy
| Study | Treatment arms | Summary of key primary and secondary efficacy endpoints |
| HALO-EM
N=875, patients with history of episodic migraine (6-14 headache days with at least 4 migraine days in 28-day pre-treatment period) |
Fremanezumab 225mg
VS VS Placebo Administered at 0, 4 and 8 weeks (higher dose was administered at week 0 followed by 2 placebo injections) |
Primary Endpoints
Secondary Endpoints
|
| HALO-CM
N=1130, patients with history of chronic migraine (At least 15 headache days per month, of which at least 8 were migraine days). |
Fremanezumab Monthly (n=379)
VS VS Placebo (n=375) Monthly dose administered as 675mg at week 0, then 225mg at weeks 4 and 8. Quarterly dose administered as 675mg at week 0 followed by 2 placebo injections at weeks 4 and 8. |
Primary Endpoints
Secondary Endpoints
|
| FOCUS
N=838, patients with episodic migraine (EM) or chronic migraine (CM) across 104 sites |
Fremanezumab Monthly (n=283)
VS VS Placebo (n=279) Quarterly dose administered as 675mg at week 0 followed by monthly placebo injections for 2 months. EM dosing Monthly dose administered as 225mg plus two placebo injections at week 0, then monthly 225mg for 2 months. CM dosing Monthly dose administered as 675mg once, followed by 225mg monthly for 2 months. |
Primary endpoint
Secondary endpoints
|
It should be considered that patients who had previously not responded to two or more migraine preventive medications were excluded from the HALO trials. Results from these studies may hence differ from real world practice, given that Ajovy is recommended and likely to be prescribed in refractory cases. The FOCUS trial provides insight on this patient profile.
Safety
Severe adverse events, serious adverse events, and adverse events leading to discontinuation were infrequent and had similar incidences (≤2%) across the treatment groups in both HALO trials. The most common adverse events in patients treated with fremanezumab were injection site reactions: pain, induration and erythema, which occurred more frequently than in patients with placebo. Nasopharyngitis was included in the most common adverse events in the FOCUS trial.
Likewise, adverse events were similar for placebo and fremanezumab groups in the FOCUS study. The incidence of serious adverse events were reported to be low (<1%-1%) across all treatment groups, and no serious adverse events were considered treatment related by the investigators.
Of worthwhile mention, the HALO-CM trial reported events of possible trial-agent–induced liver injury (aspartate aminotransferase or alanine transaminase level ≥3 times the upper limit of the normal range, total bilirubin level ≥2 times the upper limit of the normal range, or international normalized ratio >1.5) in 3 patients from the placebo group and 5 patients from each of the fremanezumab groups. The difference was not found to be statistically significant, and none of the events led to discontinuation of the trial. The phenomenon was associated with concomitant use of nonsteroidal anti-inflammatory drugs or acetaminophen as well as antidepressants. All events were transient and resolved without discontinuation of the trial regimen.
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 OnabotulinumtoxinA. Ultimately, the anti-CGRP monoclonal antibodies are recommended as third-line agents.
Framanezumab – the road ahead
Unlike eptinezumab that requires admission to medical facilities for intravenous administration, Ajovy may be self-administered via an auto-injector and hence be a more attractive option for patients. However, the monthly injection schedule for some could be an equally deterrent trade-off. Further, having to administer three consecutive injections to make the quarterly dose of 675mg appears to be counterintuitive for the needle-phobic patient who may prefer the lower frequency injection schedule.
At present, there are no head-to-head comparison trials between the various CGRP antagonists, as well as any cost effectiveness studies to differentiate the agents.
Ultimately, with stiff competition in the market, any preference for a particular anti-CGRP agent may come down to the accessibility depending on cost and geographical region.
