60th Annual Scientific Meeting of the American Headache Society, San Francisco CA, 29 June – 1 July 2018 – Erenumab, the first in a new class of monoclonal antibodies that inhibit calcitonin gene-related peptide (CGRP), has now been approved in the U.S. Other agents in development are fremanezumab, eptinezumab and galcanezumab. The following is a summary of new data on these agents presented at the 60th annual meeting of the American Headache Society.
Erenumab: The LIBERTY trial was a 12-week phase IIIb study that compared erenumab 140 mg SC versus placebo in refractory migraine patients who had failed 2-4 prior prophylactic agents. Results were presented at AAN 2018 (see Update on CGRP inhibitors in migraine, NeuroSens, May 18, 2018). At baseline, the proportion of patients who had failed two, three and four prior therapies was 38.6%, 37.8%, and 22.8%, respectively; the mean monthly migraine days (MMD) was 9.3 (Goadsby et al. AHS 2018; abstract IOR08). The proportion of patients who achieved a >50% reduction in MMD at week 12 was 30.3% with erenumab 140 mg versus 13.7% with placebo (odds ratio 2.73).
Long-term safety is being evaluated in an ongoing five-year open-label extension involving patients with episodic migraine (Ashina et al. AHS 2018; abstract IOR01). The three-year interim analysis included 235 patients who had received erenumab 140 mg for >1 year; median drug exposure was 3.2 years. The overall rate of adverse events was 132.0 per 100 patient-years. The rate of serious adverse events was 4.2 per 100 PY. The most common adverse events were viral upper respiratory tract infection, sinusitis, influenza and back pain. There were no meaningful changes in blood pressure or heart rate at 3.3-year follow-up, and no increase in cardiovascular events over time.
Cardiovascular safety was further evaluated in a separate study of 81 migraine patients with stable angina (Depre et al. AHS 2018; abstract PS45). About 40% of patients had a history of myocardial infarction, and 24% had a history of cerebrovascular or peripheral arterial disease. Subjects received a single 140-mg dose of erenumab or placebo followed by exercise treadmill testing. Baseline mean BP was comparable in the erenumab (129/77) and placebo (132/80) groups. Mean heart rate in the erenumab and placebo groups was 69.6 and 70.5 beats/minute. During treadmill testing, the peak BP was comparable with erenumab (172/90) and placebo (172/90). Peak heart rate during exercise testing was also similar (122.2 vs. 122.6). No serious adverse events were reported in the erenumab group; one serious event (atrial fibrillation) occurred in the placebo group over the 12-week period.
Four studies reported on the use of erenumab in patients with chronic migraine. A post-hoc analysis of data from a randomized controlled trial (n=656) reported that the proportion of patients converting from chronic migraine (>15 headache days/month) to episodic migraine (<15 days/month) over the 12-week period was 54.8% and 52.4% with erenumab 70 mg and 140 mg versus 34.9% with placebo (odds ratio 2.31 for the 70-mg dose, OR 2.10 for the 140-mg dose). (Lipton et al. AHS 2018; abstract PS25). A subgroup analysis of chronic migraine patients who had previously failed prior prophylaxis demonstrated greater improvement in patient-reported outcomes (Headache Impact Test [HIT-6], Migraine Disability Assessment Test [MIDAS]) with erenumab versus placebo (Lanteri-Minet et al. AHS 2018; abstract PS36). A separate analysis of the subgroup of chronic migraine patients who had previously failed at least one prophylactic medication reported that the efficacy of erenumab was sustained during a 52-week open-label extension (Ashina et al. AHS 2018; abstract PF108LB). At week 52, the proportion achieving >50% reduction from baseline in MMD was 63.3% for the erenumab 140 mg group and 49.3% with erenumab 70 mg. Treatment was well tolerated and was associated with a low rate of discontinuation (2.6%) due to adverse events over the one-year period. Improvements in PROs were also found in a subgroup analysis of patients with chronic migraine and acute medication overdose (Tepper et al. AHS 2018; abstract PS24). Improvements were shown in measures of social and psychological domains of functioning, disability and quality of life in migraine patients with medication overuse.
Fremanezumab: A phase III trial randomized patients with chronic migraine to placebo or fremanezumab administered monthly (675 mg at week 0, 225 mg at weeks 4 and 8) or quarterly (675 mg at week 0) (Winner et al. AHS 2018; abstract IOR11). The proportion of patients with >50% reduction in MMD was 37.6% and 40.8% with fremanezumab quarterly or monthly versus 18.1% with placebo. A post-hoc analysis reported that the proportion of patients converting from chronic to episodic migraine (i.e. to <15 headache days/month) was 32% with quarterly dosing, 35% with monthly dosing and 23% with placebo (Halker Singh et al. AHS 2018; abstract OR15). A separate report found that fremanezumab significantly reduced the number of days with nausea or vomiting as early as week 4 (McAllister et al. AHS 2018; abstract PF15). Treatment was also associated with fewer days with photophobia and phonophobia during the 12-week study period.
Long-term data were also reported. A one-year study enrolled subjects from two prior studies as well as 312 new subjects with chronic or episodic migraine (Goadsby et al. AHS 2018; abstract PS30). For the interim analysis, the mean change from baseline to month 6 in MMD was -27.9 days and -26.5 days with monthly and quarterly dosing for the chronic migraine cohort, and -24.9 and -25.0 days, respectively, for the episodic migraine cohort. The most common adverse events were injection-site reactions and pruritus. Four percent of patients withdrew due to adverse events.
Eptinezumab: PROMISE-2 is a phase III trial of placebo versus eptinezumab 100 or 300 mg administered by infusion every 12 weeks. MMD at baseline was 16.1 days for the eptinezumab groups and 16.2 days for placebo (Winner et al. AHS 2018; abstract IOR03). Over weeks 1-12, the reduction in MMD was -27.7 and -28.2 days for eptinezumab 100 mg and 300 mg, respectively, compared to -25.6 days with placebo. Overall, 57.6-61.4% of eptinezumab-treated patients achieved >50% reduction in MMD versus 39.3% with placebo. The proportion achieving >75% reduction in MMD was 26.7% and 33.1% with active therapy versus 15.0% with placebo.
Reductions in migraine activity were seen as early as day 1 of therapy (Kudrow et al. AHS 2018; abstract IOR04). The proportion of patients with a migraine on day 1 after the infusion was 28.6% and 27.8% with the two eptinezumab doses compared to 42.3% with placebo. A separate analysis reported that mean number of days per month of triptan or ergotamine use was reduced from 6.6 and 6.7 days for the two dosing groups to 3.3 and 3.2 days/month, respectively (Silberstein et al. AHS 2018; abstract PF20). Triptan/ergotamine use decreased from 6.2 to 4.3 days/month with placebo.
Galcanezumab: Three phase III studies have evaluated galcanezumab in episodic (EVOLVE-1 and -2) and chronic (REGAIN) migraine. A subgroup analysis was performed in patients who had previously failed two or more prophylactic agents (Zhang et al. AHS 2018; abstract PS29). In episodic migraine, a greater reduction in MMD was observed with galcanezumab 120 mg and 240 mg SC (-3.45 and -3.85 days) versus placebo (-0.81 days). A reduction in MMD was also seen in the chronic migraine cohort with the two doses (–5.91 and -3.30 days) versus placebo (-1.44).
A post-hoc analysis of the three trials examined factors associated with a reduction in migraine days (Aurora et al. AHS 2018; abstract PS26). For the 120-mg dose, there was a greater treatment effect in patients with a history of failing one or more prior prophylactic agents, and for those who used a triptan at baseline. A migraine diagnosis of >20 years was predictive of a response to the 120-mg dose but not to the 240-mg dose.
A separate post-hoc analysis of the EVOLVE studies examined the onset of effect, defined as the earliest week in which there was separation from placebo in the number of migraine headache days (Aurora et al. AHS 2018; abstract IOR05). There was a significant reduction in MHD at week 1 (odds ratio 2.71 for EVOLVE-1, OR 2.88 for EVOLVE-2). Reductions in MHD remained significant for each week of the four-week study period (OR 1.56 and 2.57 for the two studies at week 4).