Atogepant

Anti-Calcitonin Gene-Related Peptide (CGRP) Therapies: Update on a Previous Review After the American Headache Society 60th Scientific

Objective.—To briefly update and correct the available data on anti-calcitonin gene-related peptide (CGRP) therapies for headache since the American Headache Society 60th Scientific Meeting, San Francisco, June 2018.

Background.—CGRP is a target for primary headache therapies.

Methods.—The author briefly reviews the new data and publications on gepants and anti-CGRP and anti-CGRP receptor monoclonal antibodies since the writing of his previous review in May 2018, with an emphasis on data provided at the American Headache Society 60th Scientific Meeting, San Francisco, June 2018.

Results.—The US Food and Drug Administration (FDA) approved erenumab-aooe, an anti-CGRP receptor monoclonal antibody, for the prevention of migraine on May 17, 2018. On September 14, 2018, the FDA approved fremanezumab-vfrm and on September 26, 2018, the FDA approved galcanezumab-gnlm, both anti-CGRP ligand monoclonal antibodies for the prevention of migraine. Galcanezumab showed effectiveness in preventing episodic cluster headache as well, although has not yet been submitted to the FDA for this indication. Both galcanezumab and fremanezumab failed to prevent chronic cluster headache. Eptinezumab will likely be submitted to the FDA for prevention of migraine later in 2018. Two gepants, ubrogepant and rimege- pant, have completed positive pivotal trials for the acute treatment of migraine, but have not yet been submitted to the FDA for this indication. A press release with data on the effectiveness of daily atogepant in migraine prevention provides some details. An announcement at the meeting suggests daily rimegepant will be tested for prevention as well.

Conclusions.—The development of anti-CGRP therapies opens a new era in the acute and preventive treatment of primary headache disorders.

Key words: calcitonin gene-related peptide, CGRP, gepants, monoclonal antibodies, migraine, cluster headache

GEPANTS

Rimegepant.—The data from the Phase 3 studies of rimegepant 75 mg for the acute treatment of episodic migraine (EM) were published as Late Breaking Abstracts at the AHS meeting. The provided abstracts, which will be fully published later in the journal Headache, did not list the authors, so the references here list only a poster and the title. The number of subjects studied was made more clear than before: the 301 study had 1084 EM patients evaluated for acute efficacy of rimegepant; the 302 study 1072. The effectiveness was the same as previously reported.1 However, increasing efficacy results across 8 hours presented at the meeting and described in the previous review raises the question as to whether gepants may behave more like ergots such as dihydroergotamine (DHE) in yielding slow but complete response, or whether they will be like naratriptan or frovatriptan. Additionally, a bioequivalence study on the oral tablet of rimegepant and an orally dissolving tab- let (ODT) was presented. “Median time to maximal serum concentration (Tmax) was about 1.5 hours for rimegepant ODT administered sublingually vs 2 hours for rimegepant oral tablet.” The clinical question as to whether this will result in either faster onset or a higher 2-hour pain-free response will be answered in a current randomized controlled trial of the rimegepant ODT for the acute treatment of EM.2-4 Traditionally, acute medications are studied in as-needed treatment for episodic migraine attacks, but the FDA has ap- proved these medications in the acute treatment of migraine, without specifying migraine sub-type.

Both rimegepant and the follow-on gepant BHV- 3500 were studied for their vasoconstrictive properties on explanted human coronary and cerebral arteries and compared with sumatriptan. Sumatriptan did show “progressive, concentration-dependent contrac- tion” of both artery types; the gepants showed no va- soconstriction, hence more reassuring data.5

An announcement at the AHS meeting on rimege- pant was that the company studying it will be evaluating this compound in daily use for migraine prevention.6 This press release means that a decision on how their other gepant, BHV-3500, will be studied is currently un- resolved as of the time of this writing (July 2018).

Ubrogepant.—In the previous review, the data on the first ubrogepant Phase 3 trial for the acute treatment of EM, ACHIEVE I, were described.1 The other Phase 3 trial results, Achieve II, provided in an AHS late breaking abstract, included 1355 patients in a modified intention-to-treat analysis. Two-hour pain freedom was 14.3% for placebo, 20.7% for the 25 mg dose (P = .0285 vs placebo), and 21.8% for the 50 mg ubrogepant dose (P = .0129 vs placebo). “At 2 hours, the absence of most bothersome symptom (MBS) was significantly greater for the ubrogepant 50 mg dose than placebo (38.9% vs 27.4%; (P = .0129) but not for the 25 mg.” The most common MBS, as in all of the acute migraine trials so far, was photophobia. The most frequent adverse events (AEs) were nausea and dizziness, each ≤2.5%, but the actual rates and the placebo rates were not provided in the abstract.

Additional data from ACHIEVE II were:

• 2-hour headache relief for the 50 mg was 62.7%, for placebo 48.2%, P = .0129.
• Sustained 2-24 hour pain relief was 36.7% for the 50 mg dose, placebo 21%, P =.0129.7

Atogepant.—A press release in June 2018 anno- unced positive results for another gepant, atogepant, in a Phase 2 trial of daily use for EM prevention, study CGP-MD-01.8 The study was a typical randomized placebo-controlled dose ranging study, with mean monthly migraine days (MMD) compared with placebo across 12 weeks as the primary endpoint.
The study consisted of 795 patients, and atoge- pant doses ranged from 10 mg QD to 60 mg BID. The mean baseline monthly migraine days was about 7.6- 7.8 days. See Table 1 for the details on the different doses and effects on MMDs.

Atogepant appeared to show no significant liver toxicity signal at any dose despite daily dosing for 3 months. This is very important, and if confirmed in Phase 3 trials suggests a way forward for use of this medication and class in migraine prophylaxis. See Table 2 for the details provided on the liver function tests for the atogepant trial.

MIGRAINE MONOCLONAL ANTIBODIES

Erenumab-aooe (Note: for convenience, erenumab- aooe will be referred to as erenumab in this review).— Erenumab Pivotal Chronic Migraine Prevention Registration Trial : Medication overuse.—As noted in the previous review, erenumab appeared to work as well in chronic migraine with and without medication overuse for the major outcome measures, MMDs and responder rates, bearing in mind that opioid and barbiturate overuse patients were excluded. Acute medication overuse was present in 41% of those in the erenumab chronic migraine pivotal trial.9
An additional evaluation of the randomized con- trolled data to 12 weeks reported on patient-reported outcomes (PROs) in the presence of acute medica- tion overuse and was presented as an ePoster at the AHS meeting.10 Acute medication overuse (AMO) was determined by the patients meeting International Classification of Headache Disorders, 3rd Edition (ICHD-3) criteria11 during the baseline month, as well as the patients adhering to data collection in the diary each week and manifesting medication overuse each week of the baseline, so the demonstration of medication overuse was quite secure. The PROs eval- uated were the Headache Impact Test (HIT-6), the Migraine Disability Assessment scale (MIDAS), and the Migraine-Specific Quality-of-Life Questionnaire (MSQ).

HIT-6 scores in chronic migraine patients with and without AMO treated with either 70 or 140 mg of erenumab dropped from the severely impacted range of >60 to the moderately impacted range of 50-59. Placebo dropped to 60.9 in the AMO group, still in the severe range.
As noted in the previous review, a drop of >3 points is considered clinically significant for HIT-6. The erenumab groups dropped −5.3 to −6.1 points from baseline, numerically more than placebo (−2.9 for AMO and −3.2 for non-AMO). There was a slightly greater numerical drop in the non-AMO erenumab groups compared with the AMO erenumab doses.10 These HIT-6 scores are seen in Table 3.

MIDAS scores again began in a very severely dis- abled range and dropped disproportionately in the erenumab-treated patients compared to the placebo. MIDAS scores of >5 days improvement over the last 3 months are considered a clinically meaningful change.12 For this PRO endpoint, the non-AMO erenumab group did considerably better at the 140 mg dose than either the placebo or the AMO groups, although as noted, both active erenumab doses dropped much more numerically than placebo. Table 4 shows the MIDAS PRO numbers.

Erenumab groups all showed lower MSQ scores numerically than placebo. Minimally important dif- ferences from placebo in change from baseline were observed for the MSQ-RFR [role function-restric- tive] (≥3.2) and MSQ-EF [emotional functioning] (>7.5) domain scales in both the AMO and non-AMO subgroups.10

Erenumab Pivotal Chronic Migraine Prevention Registration Trial: Open Label Extension Data on Conversion from Chronic Migraine to Episodic Migraine.—In the previous review, fremanezumab data on conversion from chronic migraine (CM) to EM were cited.1 At the AHS meeting, conversion from CM to EM was presented for the erenumab pivotal CM prevention trial.13 This was a post hoc analysis, and over the 12 weeks, erenumab use was associated with greater rates of conversion from CM to EM than placebo, with a statistically significant odds ratio of >2 for both the doses (see Table 5).

Erenumab Pivotal Chronic Migraine Prevention Registration Trial: Open Label Extension Primary Data.—The open label extension (OLE) phase data of the erenumab chronic migraine pivotal trial were presented in an abstract form at the AHS meeting. The authors state, “609 subjects were enrolled to the OLE study and 451 (74.1%) completed the study.”14

Since the purpose of an OLE is to evaluate for safety and tolerability, Table 6 lists the most frequent AEs, which were respiratory, from the 12-week ran- domized controlled trial (RCT) and from the OLE. The investigators stated, “no differences were observed in these safety events between erenumab and placebo

… There were no clinically meaningful changes from baseline in laboratory values, vital signs, electrocar- diographic (EKG) findings, blood pressure, or heart rate and any postbaseline time point.”14One of the limitations of the OLE studies is the fact that, generally, only responders continue for the duration, ensuring a positive bias for effi- cacy. The investigators did note that, “based on the last dose received, a numerically greater benefit in terms of efficacy was observed with erenumab 140- mg compared with the 70-mg dose at both weeks 40 and 52 in completers.” At 12 weeks, both the 70 and 140 mg erenumab dose groups dropped −6.6 days from baseline.9 At 52 weeks, allowing for the bias of responders staying in, the 70 mg dropped −8.5 days and the 140 mg group dropped −10.5 days from baseline.14 group dropped −10.5 days from baseline.14 Subdividing, for the non-AMO group at 1 year, the 70 mg dose dropped −8.2 days, and the 140 mg group dropped −10.8 days. The AMO group showed similar results at 1 year, as the 70 mg dose dropped −8.9 days, and the 140 mg group dropped −10 days. Again, medication overuse did not seem to make much difference in MMD reduction.15

The ≥50% responder rates at 52 weeks were 67% for both the doses and all comers.14 Sixty-one percent of the non-AMO group and 56% of the AMO group man- ifested ≥50% responder rates for reduction in MMDs.15 One difference in the two groups was in the reduc- tion of acute migraine-specific medication intake per month. This is linked to the fact that the AMO group was using more acute medications to begin with. The non-AMO group dropped triptan or ergot use by −3.7 days per month from baseline, while the AMO group dropped acute migraine-specific acute medica- tion use by −6.7 days.15

Erenumab Effects on Human Isolated Internal Mammary Artery.—As with rimegepant and BHV- 3500, erenumab was studied for its effects on internal mammary artery segments obtained perioperatively. DHE induced concentration-dependent contraction. CGRP dilated the vessels; erenumab inhibited that effect, but did not cause vasoconstriction.16

Erenumab 3-Year Open Label Extension Data in Episodic Migraine Prevention.—As noted in the previous review, 1 year of open label data on erenumab was published for safety and efficacy in EM prevention.1,17 At the AHS meeting, the investigators provided an interim analysis for what is planned as a 5-year OLE for EM prevention in which 61.3% (235 patients) completed ≥3 years in the trial.18

The most frequent AEs, ≥4/100-patient-years, were respiratory (described variously as viral upper respiratory tract infection, upper respiratory tract in- fection, sinusitis, or influenza) and back pain.18 One death was described in the previous review and felt not to be due to erenumab treatment, a man with obe- sity, hypertension, elevated lipids, left anterior hemi- block, and a family history of myocardial infarction, who had severe atherosclerosis and who had cardiac stimulants in the liver (phenylpropanolamine and norpseudoephedrine).1,17 In the 3-year report, “there was no increase in cardiovascular events over time and no meaningful changes in systolic/diastolic blood pressure or rate up to 3.3-year follow up.”18

Fremanezumab-vfrm (Note: for convenience, fremanezumab-vfrm will be referred to as fremanezumab in this review).—1-Year Fremanezumab Open Label Extension Data.—At the AHS meeting, the investigators reported on 1-year OLE data from the two Phase 3 trials of fremanezumab for migraine prevention, CM and EM, and 312 new patients. The patients were assigned to receive fremanezumab monthly or quarterly.19
The most common AEs were injection site reac- tions. Withdrawal rate from the study due to AEs was 4%. No deaths occurred during the 1-year OLE.19

Again, as discussed above, the OLE data on ef- ficacy must be reviewed with the understanding that responders are the patients who stay in the trial, thus there is a positive bias. However, in these data, which were only for 6 months, there was no improvement in the MMD reduction compared with the 12 week ran- domized controlled data (see Table 7).

The investigators also evaluated ≥50% responder rates, change in any acute headache medication use per month, and MIDAS, all at 6 months for the fre- manezumab EM OLE. The ≥50% responder rates did go up from week 12 to 6 months (see Table 8).20There was also a continued drop in the acute headache medication days per month across time seen in the EM OLE and compared with baseline and 12 weeks (see Table 9).

Finally, MIDAS continued to drop in the fre- manezumab monthly dose group across 6 months, al- though not in the quarterly dose group. However, all MIDAS scores from 12 weeks dramatically dropped from the baseline severely disabled numbers (see Table 10).

Fremanezumab and Adverse Events.—The investigators pooled safety data from placebo- controlled Phase 2 and Phase 3 fremanezumab prevention studies and reported on this at AHS. There were 1702 patients who received fremanezumab and 861 placebo comparison patients.23
The most common AE was injection site reaction. Respiratory symptoms occurred at the same rate with fremanezumab and placebo. There was no hepatotox- icity signal and no anaphylaxis. “Only 3 patients (2 on placebo, and 1 on fremanezumab) had adverse events of drug hypersensitivity of mild or moderate severity. Each of these events was not serious and resolved with steroid and/or antihistamine treatment. Incidence of anti-drug antibodies formation as of the data cut-off date was low.”23

Fremanezumab and Cardiovascular Risk Factors.— The investigators reported on cardiovascular risk factors and AEs from 4 placebo-controlled studies of fremanezumab in migraine prevention. The investigators stated, “patients with cardiovascular or cerebrovascular risk factors (1398 patients [56%]) were included. These risk factors included pre- existing cardiovascular medical history (314 patients [13%]), obesity (689 patients [27%]), hypertension (259 patients [10%]), lipid metabolism disorders (225 patients [9%]), and diabetes mellitus (43 patients [2%]) … Cardiovascular adverse events occurred infrequently and with similar frequency between placebo and fremanezumab-treated patients. The most common (≥10 patients) cardiovascular adverse events in all fremanezumab treated patients were hypertension (2%), palpitations (<1%), and hot flushes (<1%). There were no notable trends in blood pressure, and ECG parameters … with no cardiovascular safety signal.”24 In addition, the investigators noted in a sepa- rate abstract a lack of relationship between freman- ezumab exposure and cardiovascular adverse events in the Phase 2 and Phase 3 data from all of the EM and CM studies of migraine prevention. Extensive phamacokinetic modeling and evaluation of high dia- stolic or systolic blood pressure readings or abnormal heart rate were evaluated, and none of the exposure measures was found to be a statistically significant predictor of abnormal blood pressure or heart rate.25 Fremanezumab and Cluster Headache.—There was an announcement in June 2018 that the clinical trial of fremanezumab for prevention of chronic cluster headache was discontinued for futility, that is, that the biologic did not appear to work in chronic cluster headache prophylaxis.26 The trial of fremanezumab for episodic cluster headache prevention is continuing at the time of this writing (July 2018). Fremanezumab-vfrm FDA Approval.—Freman- ezumab-vfrm was approved by the FDA for preven- tion of migraine on September 14, 2018. The biologic comes in subcutaneous prefilled syringes of 225 mg. The drug can be injected in one of two dosage regi- mens, either 225 mg subcutaneous monthly or three injections of the 225 mg, so 675 mg quarterly, to be chosen by the health care provider in consultation with the patient. Galcanezumab-gnlm (Note: for convenience, galcanezumab-gnlm will be referred to as galca- nezumab in this review).—Galcanezumab Pivotal Episodic Migraine Prevention Registration Phase 3 Trial, EVOLVE-1.—Since the previous review, the first of the two Phase 3 galcanezumab prevention of EM studies, EVOLVE-1, was fully published.27 Eight hundred and sixty-two patients were randomized for this 6-month placebo-controlled EM prevention study of 120 or 240 mg of monthly subcutaneous galacanezumab, 703 completed the double-blind pe- riod, and 155 discontinued the treatment. The trial was conducted at 90 sites in North America, with EM defined as 4-14 migraine days per month. As in the erenumab pivotal trials, a migraine was defined as meeting ICHD-3 criteria,11 but with a duration as short as 30 minutes, due to the potential for intervention with the acute treatment. The base- line MMDs in this trial were 9.1 days for placebo and the 240 mg dose and 9.2 days for the 120 mg group.27 The primary outcome “was to assess whether at least 1 dose of galcanezumab was superior to placebo in overall mean change from baseline of monthly MMDs during double-blind treatment.” For placebo, the drop was −2.8 to 6.3 days from 9.1 days. For the 120 mg group, the drop was −4.7 to 4.5 days from 9.2 days (P < .001 vs placebo). For the 240 mg dose, the drop was −4.6 to 4.5 days from 9.1 days (P < .001 vs placebo).27 Secondary outcomes were: 1. Responder rates for ≥50%, ≥75%, and 100% reduction in MMDs. 2. MMDs with acute medication use. This included “triptans, ergots, nonsteroidal anti-inflammatory drugs, aspirin, and acetaminophen without limita- tions; opioid- and barbiturate containing medica- tions limited to 3 days monthly, and only one corticosteroid injection was allowed during any pe- riod.”27 Therefore, this collection of data was dif- ferent than the erenumab and eptinezumab secondary endpoints, which were migraine-specific acute medication intake, meaning triptans or ergots. 3. PROs including MSQ, Patient Global Impression of Severity (PGI-S), and MIDAS. 1. The ≥50% responder rate for reduction in MMDs for placebo was 38.6%, for 120 mg 62.3%, and for 240 mg 60.9% (both galcanezumab doses P < .001 vs placebo). The ≥75% responder rate was 19.3% for placebo, for 120 mg 38.8%, and for 240 mg 38.5% (both galcanezumab doses P < .001 vs placebo). The 100% responder rate was 6.2% for placebo, for 120 mg 15.6%, and for 240 mg 14.6% (both galcane- zumab doses P < .001 vs placebo).27 2. MMDs with acute medication use were 7.4 days/ month for placebo and the 120 mg dose, and 7.5 days for the 240 mg group. Acute medication days dropped by −2.2 to 5.2 days per month for pla- cebo, by −4 to 3.4 days per month for the 120 mg dose, and by −3.8 to 3.7 days per month for the 240 mg group (both galcanezumab doses P <.001 vs placebo).27 3. The authors state that MSQ domains were im- proved for both galcanezumab doses vs placebo. PGI-S improved months 4-6 for both galcane- zumab doses vs placebo. MIDAS was improved at month 6 for both active doses vs placebo. The investigators further stated, “Although not part of the multiplicity adjustment, there were no statistically significant differences between gal- canezumab dose groups for any of the efficacy measures.”27 The most common treatment-emergent AEs were injection site reactions. Respiratory AEs occurred at the same rate as placebo. There were no deaths.Other Analyses of Galcanezumab Data.— Factors Associated With MMD Reduction in Galcanezumab Migraine Prevention Trials, Post Hoc Analysis.—In a post hoc analysis, the investigators on the galcanezumab migraine prevention trials attempted to find factors that predicted reduction in MMDs. They used the three Phase 3 randomized controlled migraine prevention studies, one 3-month CM trial and two 6-month EM trials. Three factors were evaluated: prior triptan use, migraine history of ≥20 years, and lack of success with previous prophylaxis. The positive outcome measure they chose was the ≥50% responder rate for reduction in MMDs.28 The results were equivocal. The authors stated, “For the 120 mg dose vs placebo in the EM and CM studies, a greater treatment effect was seen for those with vs without history of failure of ≥1 preventive treatment (treatment-by-subgroup interaction EM: P = .012; CM: P < .001), and for those who used vs did not use a triptan at baseline (EM: P < .001; CM: P = .062). Migraine diagnosis ≥20 years previously was predictive of response to the 120 mg dose for indi- viduals with EM (P = .056) but not for those with CM (P = .206).”28 It is possible that the most important factors predicting the response have yet to be deter- mined and tested. Galcanezumab Non-Responders, Post Hoc Analysis.—In the only evaluation like this so far done on the anti-CGRP therapies, the investigators reported at the AHS meeting on those patients without initial treatment response.29 Lack of response was defined as not showing ≥50% fewer MMDs for EM or ≥30% for CM at months 1 and 2. The patients were categorized as • modest response (>30% to <50% for EM; >10% to <30% for CM) • minimal/no response (≤10% reduction in MMDs for EM and CM) • worsening response (>10% more MMDs for both)

The investigators then evaluated what happened across the remaining time to 6 months for the EM patients and to the third month for the CM patients. This is summarized in Table 11.The investigators concluded, “Galcanezumab- treated patients with episodic or chronic migraine who had not responded after 1 or 2 months of treat- ment appear to have a reasonable likelihood of im- provement in the months following initial treatment, with a greater likelihood seen in patients that showed modest improvement with initial treatment. While the small percentage of patients with episodic or chronic migraine who experienced worsening MMDs fol- lowing initial treatment did respond with continued dosing, most patients did not show substantial benefit with continued treatment. Factors contributing to re- sponse/nonresponse have yet to be elucidated.”29

Galcanezumab Pivotal Episodic Migraine Prevention Registration Phase 3 Trial, EVOLVE-2.— The second pivotal galcanezumab 6-month trial for prevention of AM was fully published as this review was being readied for publication. Most of the data were previously reported,1 but the reference is listed for the reader.30

Galcanezumab for Patients With Lack of Success With Previous Prophylaxis.—In the previous review, the erenumab prospective LIBERTY trial was cited with positive results for patients who had had a lack of success with previous prevention. Also, the investi- gators reported erenumab success in the randomized controlled studies in those with previous prophylaxis trials. In addition, fremanezumab was effective in those with previous treatments with topiramate and onabotulinumtoxinA.1

At the AHS meeting, the investigators probed the three pivotal galcanezumab randomized controlled trials, two for EM, one for CM, for treatment effects in patients who had failed to respond to ≥2 preventive migraine medications previously. They reported that both the doses significantly improved the overall re- duction in MMDs (P < .001) and ≥50% responder rates compared with the placebo (statistics not provided) in both the patient subgroup who had a lack of prophy- lactic success and those who did not have this history.31 As was seen in the erenumab exploratory analysis, pla- cebo rates were lower in those who had a history of lack of success with preventive migraine medications.” Galcanezumab Pivotal Episodic Cluster Headache Prevention Registration Trial.—The pivotal galcanezumab trial for the prevention of episodic cluster headache (ECH) was presented at the AHS meeting. This was a study of patients with ECH randomized to placebo (N = 57) or galcanezumab 300 mg subcutaneous (N = 49).32 The baseline number of CH attacks per week was 17.3 for the placebo and 17.8 for the galcanezumab group. There was an 8-week double-blind place- bo-controlled treatment period. During this period, 12 patients in the placebo group and 4 in the active group dropped out of the study. The primary outcome was “the overall mean change from baseline in weekly cluster headache attack frequency across Weeks 1 to 3.”32 For the placebo, CH attacks went down by −5.2 to 12.1 attacks per week. For galcanezumab, CH attacks went down by −8.7 to 9.1 attacks per week (galcanezumab vs placebo, P = .036). The key (gated) secondary endpoints were: 1. The ≥50% responder rate for patients for reduction in weekly CH attacks at week 3. 2. PGI-S at weeks 4 and 8. The ≥50% responder rate for placebo was 57%, and for galcanezumab was 76% (P = .04). PGI-S was signifi- cant for galcanezumab vs placebo at week 4, but not at week 8. The only AE greater in the active than pla- cebo group was injection site pain.32 As noted previously in the previous review, the trial of galcanezumab for the prevention of chronic cluster headache was negative.33 This was also true for the trial of fremanezumab for the prevention of chronic cluster headache, which as described above was discontinued for futility.26 OLE Galcanezumab Data.—Galcanezumab Self- Injector.—The investigators at the AHS meeting compared migraine patients who self-injected galcanezumab monthly with an autoinjector vs a prefilled syringe in a 12-month OLE trial, and this study has subsequently been fully published in a peer-reviewed journal.34,35 The patients were given a Subcutaneous Administration Assessment Questionnaire and also queried as to AEs. There were 170 patients who used both injection methods at least once. The investigators stated, “the majority of these patients (91% to 97%) found the autoinjector to be an improvement or was comparable to the prefilled syringe. Positive patient-reported experiences were more common for the autoinjector (93% to 98%) than the prefilled syringe (86% to 94%) … Of 179 patents, 7 patients experienced an injection site-related AE with their first self-administration of the prefilled syringe, but not with their first use of the autoinjector; while 16 patients experienced an injection site-related AE during their first use of the autoinjector, but not with their first use of the prefilled syringe.”34 Thus, the two options appear similar. Galcanezumab-gnlm FDA Approval.—Galcanezumab-gnlm was approved by the FDA for pre- vention of migraine on September 26, 2018. The biologic comes both in subcutaneous prefilled syringes of 120 mg and autoinjectors of 120 mg. The prescribing information states that the medi- cation should be given with a “240 mg loading dose (administered as two consecutive injections of 120 mg each), followed by monthly doses of 120 mg.” Note that the monthly dose is only 120 mg, and the 240 mg dose is only for loading purposes, not a mainte- nance dose. Thus, to summarize on currently available MABs, erenumab-aooe has two doses from which to choose, 70 mg or 140 mg subcutaneous monthly with an auto- injector. Fremanezumab-vfrm has what amounts to a 225 mg dose per month either administered monthly or in a quarterly combination dose of 675 mg, with prefilled syringes of 225 mg. Galcanezumab-gnlm is the only MAB with a loading dose of 240 mg and a subsequent monthly dose of 120 mg, available either with an autoinjector or prefilled syringe. Eptinezumab.—Eptinezumab Pivotal Phase 3 Episodic Migraine Prevention Trial, PROMISE-1.— In the previous review, the primary and secondary endpoints from weeks 1-12 for the eptinezumab Phase 3 EM randomized, placebo-controlled, planned 1-year prevention trial were described, as well as some data up to 24 weeks.1 At the AHS meeting, the investigators reported on 1-year data from the eptinezumab PROMISE-1 EM prevention study.36 This was a 1-year placebo-controlled study of in- travenous infusions of placebo or eptinezumab 30, 100, or 300 mg every 12 weeks for a total of 4 doses. As noted in the previous review, the primary endpoint was reduction in MMDs for weeks 1-12.The investigators provided some additional data. The primary and key secondary endpoint results for the 30 mg dose were stated to be not statistically significant. MMD reduction continued across time for the 100 and 300 mg doses (see Table 12). The placebo numbers for the MMD reduction across the year were not provided in the abstract. The investigators further reported, “overall Treatment Emergent Adverse Event (TEAE) rates were similar to placebo, and the safety profile was consistent with previous eptinezumab studies.”36 The secondary endpoint of ≥75% MMD reduc- tion responder rates was statistically significant for eptinezumab doses 100 and 300 mg at weeks 1-4, and is described in the previous review.1 The 100 mg eptinezumab dose failed to separate from placebo for this endpoint and also the endpoint of ≥50% MMD reduction responder rates at weeks 1-12, but the 300 mg dose was significantly better than placebo for both the endpoints during this time. By the end of the year, both the ≥50% MMD reduction responder rates and the ≥75% MMD re- duction responder rates showed increases in pla- cebo and both eptinezumab doses (see Tables 13 and 14).36 Remembering that this is a placebo-controlled trial, the ≥75% MMD reduction responder rates of 54.1% for the 300 mg eptinezumab dose is a high re- sponder rate that is unprecedented, and is evidence for the paradigm shift that these treatments augur. The ≥75% responder rate is tightly linked to reduced disability and impact. Eptinezumab Pivotal Phase 3 Chronic Migraine Prevention Trial, PROMISE-2.—In the previous review, the primary and secondary endpoints from weeks 1-12 for the eptinezumab Phase 3 CM randomized, placebo-controlled, planned 1-year prevention trial were described.1 At the AHS meeting, additional information on the study was provided. The demographics were that 59.8% of the chronic migraine subjects had medication overuse; 43.1% of the participants had been on ≥1 preventive medication in the previous 3 months. Anxiety was reported in 18.4% and depression in 16.3%.37 The investigators described changes in the PRO Short Form Health Survey (SF-36) with treatment vs placebo, which was a secondary endpoint. They pro- vided data which confirmed their conclusions, “SF-36 scores improved in all domains at Week 4 and were sustained through Week 12, particularly in those domains most affected by migraine in this study. Improvements in every domain were greater with ep- tinezumab vs placebo.”38 CONCLUSIONS This update was to correct and add to the review of anti-CGRP therapies previously published in Headache. Among the important new information, as of July 2018: • Daily atogepant was effective in a Phase 2 epi- sodic migraine prevention study without a hepa- totoxicity signal.
• Daily rimegepant will be studied for migraine prevention.
• All Phase 3 randomized controlled trials on ubrogepant and rimegepant for the acute treat- ment of episodic migraine have now been pre- sented in abstract form.
• Erenumab appears to work about equally in chronic migraine patients with and without med- ication overuse.
• Both erenumab and fremanezumab treatment can convert patients from chronic migraine to episodic migraine.
• Open label data suggest that erenumab can con- vert acute medication overusers who stay on the biologic to non-overusers across time.
• Open label data on erenumab (3 years), fremane- zumab (6 months to 1 year), 6-month randomized controlled data for galcanezumab, as well as 1-year randomized controlled data on eptinezumab con- tinue to be reassuring on safety and tolerability.
• Open label data on erenumab (1 year) and fre- manezumab (6 months to 1 year), 6-month and 3-month randomized controlled data for galcane- zumab, and 1-year eptinezumab episodic migraine randomized controlled trial data all show continu- ing clinical improvement by various outcome mea- sures in those staying in the studies over time.
• Rimegepant, BHV-3500, and erenumab all failed to manifest vasoconstrictive effects when tested on explanted arteries. Data reviews of erenumab and fremanezumab failed to turn up additional risk in patients with cardiovascular risk factors. There is no warning for erenumab, fremane- zumab, or galcanezumab use in patients with vascular disease in the US erenumab prescribing information for these approved biologics.
• Galcanezumab was effective in preventing epi- sodic cluster headache.
• Neither galcanezumab nor fremanezumab was effective in preventing chronic cluster headache.
• The three erenumab pivotal trials, both fremanezumabpivotaltrialsandtwoofthethreePhase 3 galcanezumab trials are now fully published. The pivotal Chronic Migraine preventive galcanezumab trial and both eptinezumab registration trials are not yet fully published as of this writing.
• Prospective placebo-controlled data showing effectiveness in patients who have had a lack of success with multiple migraine preventive treatments were presented for erenumab. Exploratory analysis data on randomized controlled trials also suggest the effectiveness of erenumab and galcanezumab in patients with a lack of effective previous prophylaxis. Fremanezumab is effective in patients with previous trials of topiramate and onabotulinumtoxinA.
There are now three monoclonal antibodies FDA ap- proved and available in the US. They are:
• Erenumab-aooe, which is a fully human MAB, targets the canonical CGRP receptor, and is avail- able in autoinjectors with monthly subcutaneous doses of 70 or 140 mg.
• Fremanezumab-vfrm, which is a fully humanized MAB, targets the CGRP ligand, and is available in prefilled syringes of 225 mg, with dosage regimens of a monthly subcutaneous dose of 225 mg or quarterly dose of 675 mg (three injections of 225 mg at one time).
• Galcanezumab-gnlm, which is a humanized MAB, targets the CGRP ligand, and is available both in autoinjector or prefilled syringe of a 120 mg dose. This MAB is administered with a sub- cutaneous loading dose of 240 mg (two injections of 120 mg at one time), and then 120 mg monthly subcutaneous thereafter.