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Fremanezumab (Ajovy): Migraines – A True Pain to Treat

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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
Fremanezumab  675mg

VS

Placebo

Administered at 0, 4 and 8 weeks (higher dose was administered at week 0 followed by 2 placebo injections)

Primary Endpoints

  • The mean difference in monthly migraine days for fremanezumab 225mg monthly dose compared with placebo was −1.5 days (95% CI, –2.01 to –0.93 days; P <0.01) from baseline to week 12.
  • The mean difference in monthly migraine days for fremanezumab 675mg single dose compared with placebo was 1.3 days (95% CI, –1.79 to –0.72 days; P < .001) from baseline to week 12.
  • During the 12-week period after the first dose, he mean numbers of migraine days per month were 4.9 days for the monthly fremanezumab dosing group, 5.3 days for the fremanezumab single higher dose group and 6.5 days in the placebo group. 

Secondary Endpoints

  • Secondary endpoints included the proportion of patients with at least 50% reduction from baseline in mean monthly migraine days from baseline to week 12
  • Compared with placebo (27.9%), the difference in proportion of patients with at least 50% reduction from baseline in monthly migraine days from baseline to week 12 was statistically significant for both fremanezumab monthly (47.4%) and single higher dose (44.4%)groups, favouring the treatment arms.
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
Fremanezumab Quarterly (n=376)

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

  • The mean number of headache days per month for the fremanezumab quarterly group was reduced by 4.30.3 days over Months 1-3.
  • The mean number of headache days per month for the fremanezumab monthly group was reduced by 4.60.3 days over Months 1-3.
  • The mean number of headache days per month for the placebo group was reduced by 2.50.3 days over Months 1-3. Both comparisons (quarterly and monthly fremanezumab) with placebo were statistically different (P <0.001)
  • For the 12 weeks of the intervention period, patients receiving placebo had an average of 10.4±6.4 headache days, as compared with 8.5±6.3 days for those receiving fremanezumab quarterly and 8.0±6.3 days for those receiving fremanezumab monthly.

Secondary Endpoints

  • Secondary endpoints included the proportion of patients with at least 50% reduction from baseline in mean monthly migraine days from baseline to week 12 and mean change from baseline in average number of days per month in which acute headache medication was used during the 12-week period after the first dose.
  • 41% patients in the monthly regimen, 38% of patients in the quarterly regimen and 18% patients in the placebo group had a reduction of at least 50% in the average number of headache days per month (P<0.001 for both comparisons with placebo) 
  • Statistically significant treatment effects were also seen in the 4 week and 12 week period after first dose of fremanezumab, favouring the treatment arms over placebo. 
FOCUS

N=838, patients with episodic migraine (EM) or chronic migraine (CM) across 104 sites

Fremanezumab Monthly (n=283)

VS
Fremanezumab Quarterly (n=276)

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

  • Reductions from baseline in monthly average migraine days over 12 weeks were greater with quarterly fremanezumab as compared to placebo (least-squares mean [LSM] change -0.6 [SE 0.3]) (LSM change -3.7 [0.3]; LSM difference vs placebo -3.1 [95% CI -3.8 to -2.4]; p<0.0001) 
  • Reductions from baseline in monthly average migraine days were greater with monthly fremanezumab (LSM change -4.1 [0.34]; LSM difference vs placebo -3.5 [-4.2 to -2.8]; p<0.0001) over the same period.
  • The mean percentage change from baseline in the monthly average number of migraine days during the 12-week treatment period was −8·5% (SD 31.3) in the placebo group, −34·9% (31.7) in the fremanezumab quarterly group, and −36.8 (32.1) in the fremanezumab monthly group.

Secondary endpoints

  • Reductions from baseline in the monthly average number of migraine days were greater with quarterly fremanezumab versus placebo as early as 4 weeks after starting study treatment (−3.5 [95% CI −4.2 to −2.8]; p<0·0001) and monthly fremanezumab (−3.6 [−4.3 to −2.8]; p<0.0001).
  • The proportions of participants with a 50% or greater response were higher versus placebo over 12 weeks with quarterly fremanezumab (9% vs 34%; OR 5.8 [95% CI 3.6 – 9.6]; p<0·0001 and with monthly fremanezumab (9% vs 34%; OR 5.8 [3.6 – 9.5]; p<0·0001
  • The proportions of participants with a 50% or greater response were higher versus placebo at 4 weeks with quarterly fremanezumab (10% vs 38%; OR 5.8 [95% CI 3.6 – 9.3]; p<0·0001 and with monthly fremanezumab (10% vs 36%; OR 5.3 [3.3 – 8.4]; p<0.0001

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.

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