Update on CGRP inhibitors in migraine

 

SPECIAL REPORT

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Calcitonin gene-related peptide (CGRP) inhibitors are emerging as an important class of agents for the prevention of episodic and chronic migraine (See Targeting CGRP in migraine, NeuroSens, March 28, 2018). Four monoclonal antibodies are currently in development: erenumab, a fully-human MAb targeting the CGRP receptor; and three humanized MAbs targeting the CGRP ligand (fremanezumab, eptinezumab, galcanezumab). Erenumab received FDA approval for the treatment of migraine this week.

The following summarizes key studies of CGRP inhibitors presented at this year’s American Academy of Neurology (AAN) annual meeting.

Erenumab: The 12-week LIBERTY trial evaluated erenumab 140 mg SC versus placebo in refractory migraine patients who had failed 2-4 prior preventive agents (Reuter et al. AAN 2018; abstract ES009). The most common prior prophylactic agents were topiramate, amitriptyline, propranolol and metoprolol. The proportion of patients who achieved >50% reduction from baseline in monthly migraine days (MMD) was significantly greater with erenumab beginning at week 4 (23.5% vs. 4.8%), with benefits sustained at week 8 (31.1% vs. 12.1%) and week 12 (30.3% vs. 13.7%),

Two analyses demonstrated that the efficacy of erenumab was comparable in migraine patients with and without aura. The first study compared erenumab versus placebo in patients with episodic migraine with or without aura (McAllister et al. AAN 2018; abstract P4.094). The mean change from baseline in MMD with erenumab 140 mg was -3.5 with aura, and -3.8 without aura (vs. -2.1 and -1.5 with placebo). The responder rates (>50% reduction in MMD) were 51% and 49% in patients with and without aura (vs. 30% and 23% with placebo). Efficacy in chronic migraine with and without aura was also comparable in an analysis of phase II data (Messoud et al. AAN 2018; abstract S32 006). The mean reduction in MMD with erenumab 140 mg was -7.1 and -6.1 in patients with and without aura (vs. -4.5 and -3.8 with placebo).

An analysis of the phase III STRIVE trial reported that the number of acute migraine-specific medication days per month was significantly reduced (treatment difference -2.30 averaged over months 4-6) with erenumab 140 mg versus placebo (Reuter et al. AAN 2018; abstract P4.118). A separate analysis from STRIVE found that erenumab was equally effective in women with and without a history of menstruation-related migraine (MRM) (Pavlovic et al. AAN 2018; abstract P4.096). The mean change in MMD was -3.6 with erenumab in both subgroups versus -1.5 and -1.9 with and without MRM in the placebo group.

Three safety studies were also noteworthy. An integrated safety analysis reported that the incidence of serious adverse events was similar with erenumab and placebo in patients who used triptans/ergotamine (erenumab 1.7%, placebo 1.9%) compared to non-users (0.5% and 0.6%, respectively) (Winner et al. AAN 2018; abstract P4.100). The incidence of serious cardiac or vascular adverse events was low (< 2% for both groups). Continuous 24-hour blood pressure monitoring revealed no increase in blood pressure and no effect on diurnal rhythm during erenumab treatment (Tepper et al. AAN 2018; abstract P4.103).

A pooled analysis of immunogenicity data reported that the incidence of binding antibodies with erenumab 140 mg was 2.6%; no patient developed neutralizing antibodies (Vargas et al. AAN 2018; abstract P4.098). With continued treatment, >50% of BAb-positive subjects reverted to BAb-negative status. The presence of BAbs did not significantly affect efficacy: the mean change in MMD was -3.8 in BAb-negative and -5.2 in BAb-positive subjects.

Fremanezumab: A 12-week phase III trial of fremanezumab SC in chronic migraine found that a  significantly higher proportion of patients achieved a ≥50% reduction in MMD for headaches of at least moderate severity (monthly dosing 40.8% vs. placebo 18.1%) (Winner et al. AAN 2018; abstract P4.113). A separate analysis reported a reduction in the number of days of acute headache medication use with fremanezumab compared to placebo (-3.7 to -4.2 vs. -1.9) (Aycardi et al. AAN 2018; abstract P4.101).

Two dosing regimens are being investigated in chronic and episodic migraine: monthly dosing (225 mg per month); and quarterly dosing (675 in month 1, with a second injection in month 4). An initial loading dose of 675 mg was used for the monthly regimen in the chronic migraine trial. A 12-week trial reported comparable efficacy with the two regimens in chronic migraine (Silberstein et al. AAN 2018; abstract S32 005). The two regimens were similarly effective in episodic migraine (Dodick et al. AAN 2018; abstract P4.093). There were significant reductions in the number of monthly headache days of at least moderate severity (monthly -2.9 days; quarterly -3.0 days vs placebo -1.5 days). There were also comparable reductions in the number of days of acute headache medication use (-3.0 and -2.9 vs. -1.6) with the two regimens (Brandes et al. AAN 2018; abstract P4.106).

An analysis of phase II data reported a reduction in the number of days with nausea, vomiting, photophobia and phonophobia with fremanezumab 225 mg/month in patients with high-frequency episodic migraine (Bigal et al. AAN 2018; abstract P4.111). Improvements in associated migraine symptoms were observed in the first week of treatment.

Eptinezumab: The PROMISE-1 placebo-controlled trial evaluated three doses (30, 100 and 300 mg) of eptinezumab, the only anti-CGRP MAb administered by IV infusion ever should be every 12 weeks, in patients with frequent episodic migraine (Saper et al. AAN 2018; abstract S20 001). MMD was reduced from baseline -4.0, -3.9 and -4.3 days with the three doses versus -3.2 days with placebo. The response rate (>75% reduction in MMD) was 24.7%, 22.2% and 29.7% with eptinezumab versus 16.2% with placebo. A total of 56.3% (pooled) achieved a ≥50% reduction in MMD at 12 weeks compared to 37.4% with placebo. The pooled response rate was 63.1% in weeks 21-24 versus 52.3% with placebo following a second quarterly infusion (Egilius et al. AAN 2018; abstract P4.108). The mean number of migraine hours was reduced by 35.2-42.9 hours (versus 23.8 hours with placebo) in weeks 1-4, and by 33.6-42.8 hours (versus 26.9 hours with placebo) in weeks 21-24 (Silberstein et al. AAN 2018; abstract P4.91).

Survey:

What proportion of your migraine patients are currently taking a preventive medication?

What proportion of your migraine patients could be considered for a preventive medication?

How do you assess the success of a preventive treatment in practice? (pick one)

Do you expect that how you assess the success of preventive therapy will change once anti-CGRP MAbs become available?

How would you rate your level of awareness of the efficacy and safety data for the CGRP MAbs?

Once CGRP inhibitors are available, what would be your first choice for migraine prophylaxis?

Once CGRP inhibitors are available, what would be your second choice for migraine prophylaxis in a patient with an inadequate response to a first-choice agent?

Once CGRP inhibitors are available, what would be your third choice for migraine prophylaxis in a patient with an inadequate response to two prior agents?

Which drug attribute do you view most favourably with respect to CGRP inhibitors? (pick one)

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