Anti-Calcitonin Gene-Related Peptide
`Monoclonal Antibodies: Adverse Effects.
`What Do We Really Know? A Literature Review
`
`Authors:
`
`Theodoros Mavridis,1,2 Chrysa Koniari,1,2 Nikolaos Fakas,2
`*Dimos D. Mitsikostas1
`
`Disclosure:
`
`Received:
`
`Accepted:
`
`Keywords:
`
`1. 1st Neurology Department, Aeginition Hospital, School of Medicine,
`National and Kapodistrian University of Athens, Athens, Greece
`2. Neurology Department, 401 General Army Hospital, Athens, Greece
`*Correspondence to dmitsikostas@med.uoa.gr
`
`The authors have declared no conflicts of interest.
`
`17.09.18
`
`23.10.18
`
`Adverse events (AE), calcitonin gene-related peptide (CGRP), eptinezumab,
`erenumab, fremanezumab, galcanezumab, headache, migraine, monoclonal
`antibodies (mAb).
`
`Citation:
`
`EMJ Innov. 2019;3[1]:64-72.
`
`Abstract
`individuals worldwide.
`Migraine
`is a chronic and disabling disorder affecting >1 billion
`Current treatments for the prevention of migraine include antihypertensives, antiepileptics,
`and antidepressants, and all share limited tolerability and adherence, highlighting the need for the
`development of new disease-specific and mechanism-based agents. In this context, four novel
`anti-calcitonin gene-related peptide monoclonal antibodies have been investigated in a large
`Phase II–III clinical programme and showed similar efficacy to the currently used drugs for migraine
`prevention but with a significantly improved safety profile, as highlighted in this review. It is
`expected that patient compliance with treatment will increase with the use of these therapies,
`improving the long-term overall outcome of migraine. However, real-world evidence is needed to
`confirm the tolerability and safety of anti-calcitonin gene-related peptide monoclonal antibodies
`before the drugs can be established as first-line agents in the prophylactic treatment of migraine.
`
`INTRODUCTION
`
`Migraine is a pervasive brain disorder that is
`ranked as the second most disabling condition1-3
`and has the third highest prevalence among all
`medical illnesses.4 The common understanding
`that has guided the management of people
`with migraine is pharmacological intervention to
`prevent disease chronification.5 Pharmacological
`agents approved for the prevention of episodic
`migraine (EM)6 span different drug classes
`
`tricyclic
`(e.g., antihypertensive compounds,
`antidepressants, and antiepileptic drugs).7 Due
`to the prolonged administration required for
`migraine prevention and drug nonspecificity,
`these drugs can cause numerous adverse events
`(AE), and the agents interact with many other
`medications in comorbid patients.8 Furthermore,
`only one medication (onabotulinumtoxinA) is
`approved for the prevention of chronic migraine
`(CM).9-15 The suboptimal efficacy and tolerability
`of current treatments contribute to poor patient
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`treatment compliance and adherence (up to
`68% of patients stopped using preventative
`medication within 6 months).16-18 As patients cycle
`through preventative therapies, discontinuation
`rates
`increase and
`the augmented need
`for abortive medication
`leads
`to disease
`chronification.19 All of the above, in addition
`to pharmacophobia (fear of medication) and
`the nocebo effect (experience of AE related
`to patients’ negative expectations
`that a
`treatment will most likely cause harm instead
`of
`improving disease),20 suggest the need
`for novel treatments that are better tolerated
`and have fewer contraindications, not only for
`patients who have failed existing preventative
`treatments but also
`for
`treatment naïve
`patients, especially those who fluctuate in the
`prechronic phase.6,21,22 Among the available
`molecular
`targets,
`calcitonin gene-related
`peptide (CGRP) has the best base of evidence
`for controlling migraine.23 CGRP, a 37 amino acid
`long neurotransmitter, is part of the calcitonin
`family of peptides, together with calcitonin,
`amylin, and adrenomedullin, and is the most
`potent microvascular dilator currently known.24-26
`CGRP acts on an unusual receptor family that
`is located at sites crucial to the triggering of
`migraine,
`including
`the cerebrovasculature,
`the trigeminocervical complex in the brainstem,
`and the trigeminal ganglion (Table 1).24,27,28
`Small molecule CGRP receptor antagonists,
`the gepants, are under development for the
`treatment of migraine, with three (rimegepant,
`ubrogepant, and atogepant) such agents
`currently in a Phase III clinical trial programme.29-36
`
`ANTIMIGRAINE
`MONOCLONAL ANTIBODIES
`
`Monoclonal antibodies (mAb) against CGRP
`share several pharmacokinetic advantages over
`
`small anti-CGRP molecules (e.g., greater target
`specificity and prolonged half-life, making them
`suitable for monthly administration to prevent
`migraine). Three of
`these macromolecules
`target
`the CGRP
`ligand
`(fremanezumab,
`galcanezumab, and eptinezumab), while a fourth
`(erenumab) targets the CGRP receptor.14,37,38
`All four require parenteral administration and
`have a preferential peripheral site of action,
`since only 0.1–0.5% of the mAb cross the blood–
`brain barrier due to their large size (molecular
`weight around 150 kDa).14,39,40 These four mAb
`have shown particular effectiveness for the
`prevention of both EM and CM.41,42
`
`Erenumab
`Erenumab (AMG 334) is a fully human IgG2
`mAb that prevents native CGRP ligand binding
`to the CGRP receptor.6 At 70 mg, the estimated
`elimination half-life of erenumab is 21 days,
`supporting monthly subcutaneous dosing and,
`thus, bettering patient compliance.43,44 Even in
`the early phases, studies showed no significant
`differences among healthy
`subjects and
`patients with migraine in least squares mean
`24-hour or nocturnal diastolic blood pressure
`(BP) measurements between placebo and
`erenumab-treated groups.6 Similar results were
`found from studying the coadministration of
`erenumab and sumatriptan and their effect on
`resting BP in healthy subjects (no additional
`effect on resting BP beyond the effects of
`sumatriptan monotherapy, without affecting the
`pharmacokinetic of sumatriptan).45 The AE that
`were most commonly reported in the single-
`dose study (in ≥20% of subjects
`in the
`erenumab group) were headache in healthy
`subjects (erenumab: 25.0%; placebo: 25.0%) and
`nasopharyngitis (erenumab: 50.0%; placebo:
`50.0%), arthralgia (erenumab: 33.3%; placebo:
`0%), and
`influenza-like
`illness
`(erenumab:
`33.3%; placebo: 16.7%) in patients with migraine.
`
`Table 1: The calcitonin gene-related peptide receptor family.
`
`Ligand/receptor
`Receptor
`composition
`Name
`
`CGRP
`CLR+
`RAMP1
`CGRP
`
`Adrenomedullin
`CLR+
`RAMP2
`ADM1
`
`Adrenomedullin
`CLR+
`RAMP3
`ADM2
`
`Amylin
`CT+
`RAMP1
`AMY1
`
`Amylin
`CT+
`RAMP2
`AMY2
`
`Amylin
`CT+
`RAMP3
`AMY3
`
`CGRP binds to both CGRP and AMY1 receptors.24
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`No deaths or serious AE (SAE) were reported
`in the Phase I studies. Most AE were mild or
`moderate in severity and there were no clinically
`meaningful changes in laboratory assessments
`or vital signs.6
`
`Again, in Phase II clinical trials for prevention
`of both EM and CM, the number of patients with
`AE was similar between the treatment groups.
`In EM, 95% of the patients in the erenumab
`treatment groups experienced AE that were
`mild or moderate
`in severity (similar
`in
`all different doses) versus 98%
`in
`the
`placebo group. The most common AE was
`nasopharyngitis, and the reported SAE were
`considered to be unrelated to treatment. A small
`percentage of participants developed binding
`and neutralising anti-erenumab antibodies,
`with no apparent association recorded among
`these patients in terms of AE, safety, or efficacy.
`The incidence of injection-site reactions was
`low (5%) and all reactions were mild in severity.
`No notable findings were recorded following
`the collection of clinical and laboratory results,
`vital signs, BP, or ECG changes. One death
`was noted: a 52-year-old man with a history of
`migraine with aura, and this was confounded
`by pre-existing cardiovascular
`risk
`factors
`(3-year history of diagnosed hypertension,
`obesity, a
`lipoprotein
`level of 153 mg/dL,
`left anterior hemiblock on baseline ECG, and
`a
`family history of myocardial
`infarction).
`The patient’s autopsy showed evidence of
`severe coronary atherosclerosis and the presence
`of cardiac stimulants (phenylpropanolamine
`and norpseudoephedrine)
`in the
`liver. The
`myocardial ischaemia event was based on results
`of an exercise treadmill test, which showed
`transient exercise-induced myocardial ischaemia,
`confounded by sumatriptan administration 4
`hours prior to the event. It was considered not
`related to treatment by the investigator.17,44
`
`In studies of CM, the most frequent AE,
`reported by ≥2% of erenumab-treated patients,
`were injection-site pain, upper respiratory tract
`infection, nausea, nasopharyngitis, constipation,
`muscle spasms, and migraine.46 Taking into
`consideration
`the
`individuality of patients
`and the nocebo effect, with the common
`denominator being the AE associated with prior
`medication failure, the incidence of AE was
`broadly comparable within each group (placebo
`and different doses of erenumab).15
`
`study of
`a placebo-controlled
`Notably,
`erenumab in a high-risk population of patients
`with stable angina with a median age of
`65 years showed that intravenous erenumab
`140 mg did not lead to significant changes
`in exercise time compared to placebo. The
`change in treadmill exercise time from baseline
`was noninferior for erenumab compared to
`placebo, no difference was observed in the
`time to onset of ≥1 mm ST-segment depression
`or exercise-induced angina, and there were
`no significant differences between treatment
`groups in reported AE through the 12-week
`safety follow-up.47
`
`The most common AE reported in Phase III
`clinical trials are fatigue, nasopharyngitis and
`upper respiratory tract infection, injection-site
`pain, headache, vertigo, and nausea.14 Once
`more,
`the development of anti-erenumab
`binding and transient neutralising antibodies
`was observed, but with no clinical or other
`association. No clinically meaningful differences
`between
`the erenumab groups and
`the
`placebo group were observed with regard
`to the results of hepatic function testing,
`creatinine levels, total neutrophil counts, vital
`signs, or ECG findings.14,42,48,49
`
`Fremanezumab
`Fremanezumab (TEV 48125) is a fully humanised
`IgG2a/kappa mAb that potently and selectively
`binds to both α and β isoforms of CGRP.50
`The mean half-life values range from 32–36
`days.51
`In early clinical studies, treatment-
`related AE occurred
`in 21.2% of subjects
`receiving fremanezumab (no association pattern
`regarding the dosage), compared with 17.7%
`in those receiving the placebo. The most
`common treatment-emerging AE reported were
`headache, nasopharyngitis, gastroenteritis, and
`back pain, while the two SAE, thoracic aortic
`aneurysm (patient had an unreported history
`of Ehlers–Danlos syndrome) and glaucoma,
`in individuals receiving fremanezumab, were not
`treatment related. Fremanezumab was also not
`associated with any clinically relevant patterns
`of change in vital signs (including systolic
`and diastolic BP, temperature, and heart rate),
`ECG parameters, or laboratory findings.50 Similar
`results were reported in Phase I studies comparing
`the prevalence of safety
`issues between
`Caucasian and Japanese healthy subjects.51
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`In Phase II clinical trials of both CM and high
`frequency EM,52,53 despite having different doses,
`the AE (treatment-emerging and treatment-
`related) reported had consistency regarding the
`type and frequency. In the CM Phase II study,53
`40% of patients in the placebo group, 53% in
`the 675/225 mg dose group (675 mg in the first
`treatment cycle and 225 mg in the second and
`third treatment cycles), and 47% in the 900 mg
`dose group had treatment emergent AE. In the
`Phase II trial of high frequency EM, the rates of
`treatment-emergent AE were 56% (placebo),
`46%
`(225 mg
`fremanezumab), and 59%
`(675 mg fremanezumab).52 The most common
`AE in both studies were mild injection-site pain
`and pruritus. The SAE that occurred were not
`treatment-related and, again, there were no
`relevant changes in BP or other vital signs.
`The prevalence of patients with detectable
`concentrations of
`fremanezumab antibodies
`(1% in both studies) was much lower than that
`detected with other monoclonal anti-CGRP
`antibodies (19% with galcanezumab and 14%
`with eptinezumab).52,53 In a post-hoc analysis
`of the previous studies, it was found that
`fremanezumab was compatible with most of
`the major classes of migraine preventative
`therapies, which suggests that it will be a useful
`and safe agent as an add-on therapy for patients
`requiring additional preventative
`treatment.
`Also, results suggest that fremanezumab can
`be started immediately, without requiring other
`preventatives to be titrated or washed out first,
`giving patients the opportunity for a more
`rapid clinical improvement.54
`
`In Phase III studies regarding CM, AE were
`reported
`in 64% of the patients receiving
`placebo, 70% of those receiving fremanezumab
`quarterly,
`and 71% of
`those
`receiving
`fremanezumab monthly; the reported AE were
`mild-to-moderate
`in severity
`in 95–96% of
`patients in all three groups. Again, the most
`common AE were
`injection-site
`reactions
`(40% placebo, 47% fremanezumab quarterly,
`and 47% fremanezumab monthly), the severity
`of which did not differ significantly among
`the trial groups. SAE occurred in 2% of the
`patients given placebo, 1% of those given
`fremanezumab monthly, and <1% of those given
`fremanezumab quarterly, and no participants
`had anaphylaxis or a severe hypersensitivity
`reaction. Abnormalities
`in hepatic
`function
`
`occurred in 1% of patients in the fremanezumab
`groups and <1% in the placebo group, which
`can be attributed to the use of nonsteroidal
`anti-inflammatory drugs. As
`in previous
`studies, antidrug antibodies developed in two
`patients who received fremanezumab quarterly.
`No clinically significant changes in vital signs,
`physical examination findings, or ECG results
`occurred in any of the trial groups.55
`
`In a Phase III study of EM,56 66%, 66%, and
`58% of patients who received fremanezumab
`monthly, fremanezumab once (higher dose),
`and placebo, respectively, reported at least one
`AE. Treatment-related AE were higher in the
`fremanezumab groups (48% in the monthly
`group and 47%
`in the single-higher-dose
`group) compared with placebo (37%), with the
`most common being injection-site reactions
`(pain, induration, and erythema). No relevant
`changes in vital signs (BP, pulse, temperature,
`and respiratory rate), physical examination
`measurements (including weight), or ECG
`findings were noted in patients in any of the
`treatment groups. There were no clinically
`significant changes in any laboratory parameters,
`including liver function tests. Again, a small
`percentage of patients in the fremanezumab
`monthly dosing group developed antidrug
`antibodies against
`fremanezumab, without
`any significant AE. It should be noted that one
`patient died 109 days after receiving a single
`higher dose of fremanezumab. The patient
`had withdrawn from the study 38 days earlier
`because of a family emergency and the cause
`of death noted in the autopsy report was
`suicide by diphenhydramine overdose; this death
`was considered unrelated to the treatment.56
`
`Galcanezumab
`Galcanezumab (LY 2951742) is a humanised
`mAb with a long half-life (time to maximum
`serum concentration ranges from 7–13 days
`and elimination half-life is about 28 days) that
`binds to both α and β CGRP isoforms with
`approximately equal affinity.57 AE reported
`in a Phase I clinical trial were transient, with
`no apparent relationship with the prolonged
`systemic drug exposure (indicated by the long
`half-life of galcanezumab). In subjects receiving
`galcanezumab, the most common AE were
`headache, nasopharyngitis, haematuria, and
`contact dermatitis; the frequencies of these
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`AE were similar to placebo. Other frequently
`reported AE in subjects receiving galcanezumab
`were diarrhoea, toothache, and increased alanine
`aminotransferase. There were no apparent
`differences among galcanezumab dose groups
`or between galcanezumab dose groups and
`placebo in terms of frequency of any AE.
`This observation
`included changes
`from
`baseline in vital signs, laboratory values, and
`ECG parameters. It was reported that 26% of
`the galcanezumab-treated subjects produced
`antidrug antibodies, the presence of which had
`no obvious effect on pharmacokinetics and
`pharmacodynamics compared with subjects
`who had no detectable antidrug antibody titres.4
`
`In a Phase IIa study58 (galcanezumab 150 mg
`administrated subcutaneously twice a month),
`AE were reported by 72% of patients in the
`galcanezumab group and by 67%
`in the
`placebo group (no significant difference). AE
`that occurred more frequently in galcanezumab
`versus placebo
`included
`injection-site pain,
`erythema, or both (21 [20%] of 107 patients
`versus 7 [6%] of 110 patients), upper respiratory
`tract infections (18 [17%] versus 10 [9%]), and
`abdominal pain (6 [6%] versus 3 [3%]). There
`were two SAE reported in the treatment arm
`and four in the placebo arm, none of which
`were deemed to be related to the study drug.
`Once more, there were no clinically important
`changes in laboratory parameters, ECG results,
`or vital signs between the groups. Antidrug
`antibodies were detected
`in 8 patients at
`screening and in 20 patients at the end of the
`study; nevertheless, there was no association
`in
`terms of efficacy and AE with
`the
`antidrug antibodies.58
`
`In a Phase IIb study (galcanezumab 120 mg
`once per month),59 a similar frequency of AE
`was reported in both the placebo (70 [51.1%])
`and galcanezumab-treated (140 [53.1%]) patients.
`The most common AE
`for galcanezumab
`were injection-site pain, which had a dose-
`dependent response, upper respiratory tract
`infections, nasopharyngitis, dysmenorrhoea, and
`nausea, without any dosage correlation; most
`AE were mild-to-moderate in intensity. None
`of the SAE were considered to be related to
`galcanezumab.59 Taking into account the vital
`signs during treatment and post-treatment
`periods, mean changes in systolic BP, diastolic
`BP, and pulse were not clinically meaningful,
`
`and there were no trends to show that
`galcanezumab
`treatment
`increased
`BP.
`Also, mean baseline-to-endpoint changes
`in
`ECG intervals (PR, QRS, and QTcF) and heart
`rate showed no clinically meaningful differences
`between individual or pooled galcanezumab
`dose groups and placebo. In addition, changes
`in temperature were small and not clinically
`meaningful; weight changes were also similar
`across treatment groups.59,60
`
`EVOLVE-161
`III
`(Phase
`studies
`Larger
`and EVOLVE-218) have corroborated
`the
`aforementioned
`findings.
`In
`EVOLVE-1,61
`5 participants in the placebo group and 6 in
`the galcanezumab 120 mg group reported a
`total of 12 SAE, none of which were considered
`by the
`investigator to be associated with
`the treatment. Similarly,
`in EVOLVE-2,18 the
`percentages of SAE, which were 1.1%, 2.2%,
`and 3.1% for the placebo, galcanezumab 120 mg,
`and galcanezumab 240 mg groups, respectively,
`did not differ
`significantly.
`Injection-site
`erythema, injection-site pruritus, and injection-
`site
`reactions were
`the most
`frequently
`reported AE related to the injection site for
`galcanezumab compared with placebo
`in
`both Phase III clinical trials, but most AE were
`mild-to-moderate in severity. Discontinuations
`owing to AE in galcanezumab-treated patients
`were low (2.2–4.0%). The most common post-
`treatment emergent AE was upper respiratory
`tract infection, which occurred at a similar rate
`across treatment groups. Other post-treatment
`emergent AE that occurred in ≥1% of patients
`in the combined galcanezumab group were
`viral upper respiratory tract infection, sinusitis,
`and influenza, and these events occurred at a
`rate similar to placebo. Again, there were no
`statistically significant differences between
`galcanezumab dose groups and placebo on
`mean change from baseline of systolic BP and
`pulse at any visit. For temperature, statistically
`(≤17.6°C) were
`significant mean
`increases
`observed only in EVOLVE-1, and these were
`transient and not sustained. Body weight
`was measured at Month 6 only and the mean
`change from baseline to last observation carried
`forward endpoint was small (<1 kg) and not
`statistically
`significant between
`treatment
`groups. Regarding
`the development of
`anti-galcanezumab antibodies, at baseline,
`in EVOLVE-1, 5.9% of patients in the placebo
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`group (n=25) and 8.9% (n=18; 120 mg group)
`and 10.8% (n=23; 240 mg group)
`in the
`galcanezumab dose groups had antidrug
`antibodies present. With consistency,
`the
`respective percentages in EVOLVE 2 were 8.4%
`(placebo), 8.1% (galcanezumab 120 mg), and
`11.2% (galcanezumab 240 mg). The percentage
`of patients with antidrug antibodies during the
`double-blind treatment phase was low, and the
`number of patients with neutralising antibodies
`was even less. No antidrug antibodies were
`associated with changes in efficacy or safety.18,61
`
`Eptinezumab
`is a humanised
`Eptinezumab
`(ALD403)
`anti-CGRP IgG1 antibody that potently and
`selectively binds to both the α and β forms
`of human CGRP. The plasma half-life of
`eptinezumab after an intravenous infusion of
`1,000 mg is 31 days. In a Phase II clinical trial,62
`during which patients with frequent EM were
`given one intravenous dose of 1,000 mg of
`eptinezumab, AE were experienced by 52% of
`patients in the placebo group and 57% in the
`eptinezumab group. The most frequent AE
`in both groups were upper respiratory tract
`infection, urinary tract infection, fatigue, back
`pain, nausea, vomiting, and arthralgia. During
`the study, 55% of patients experienced ≥1 AE.
`No infusion reactions were reported during
`the study and most AE were transient and
`mild-to-moderate in severity. Six SAE were
`reported by three patients; all of these events
`were deemed to be unrelated to the study drug
`(fractured fibula, pyelonephritis, non-cardiac
`chest pain, and transient ischaemic attack).
`There were no clinically significant differences
`
`in vital signs, 12-lead ECG results, or laboratory
`safety data between patients treated with
`eptinezumab or placebo at any time during the
`study. Furthermore, in antidrug antibody assays,
`14% of patients in the eptinezumab group who
`were tested had positive results, suggesting the
`potential formation of eptinezumab antibodies
`during the study. However, the corresponding
`antidrug titres were low and no obvious effects
`of
`immunogenicity on the pharmacokinetic
`parameters or efficacy were noted.62
`
`In all succeeding clinical trials, Phase II and III
`for CM and PROMISE 1 and 2, the observed
`safety profile of eptinezumab was similar
`to placebo. PROMISE 163 is a double-blind,
`randomised, placebo-controlled Phase
`III
`study evaluating the efficacy and safety of
`eptinezumab
`in patients with frequent EM.
`Both the safety profile and the placebo rates
`were consistent with previously
`reported
`eptinezumab studies.63,64 On the other hand,
`the Phase III trial, PROMISE 2,65 is a evaluating
`the safety and efficacy of eptinezumab for
`CM prevention. As previously mentioned,
`AE rates among eptinezumab-treated subjects
`were similar
`to placebo-treated subjects.
`Likewise, the most commonly reported AE for
`eptinezumab, occurring at an incidence of ≥2%,
`were nasopharyngitis (6.3%), upper respiratory
`infection (4.0%), nausea (3.4%) and urinary
`tract infection (3.1%), arthralgia (2.3%), dizziness
`(2.6%), anxiety (2.0%), and fatigue (2%).65
`
`Table 2: The most common adverse events that have been reported more frequently in the active anti-calcitonin
`gene-related peptide monoclonal antibody arms versus placebo arms.6,14,18,40,41,42,44-49,52-60
`
`Monoclonal antibody
`Erenumab (AMG 334)
`
`Galcanezumab (LY 2951742)
`
`Eptinezumab (ALD 403)
`
`Fremanezumab (TEV 48125)
`
`Adverse events
`Injection-site pain, upper respiratory infection, nasopharyngitis, influenza, fatigue,
`nausea, joint pain, back pain, and headache.
`Injection-site pain, erythema, respiratory infection, nasopharyngitis, abdominal pain,
`nausea, and dysmenorrhoea.
`Respiratory infection, sinusitis, urinary infection, fatigue, dizziness, nausea,
`vomiting, back pain, joint pain, dry mouth, and ECG changes.
`Injection-site pain, erythema, pruritus, sinusitis, urinary infection, dizziness,
`back pain, dry mouth, ECG changes, and tooth abscess.
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`CONCLUSION
`
`Monoclonal antibodies against CGRP and its
`receptor have passed all clinical phases and
`are becoming available in the USA and Europe.
`Unlike
`formerly
`available
`prophylactic
`treatments
`for migraine, anti-CGRP mAb
`have been developed specifically
`for
`the
`prophylaxis of migraine following a mechanism-
`based design. Their profile regarding dosage,
`pharmacokinetics,
`and distribution makes
`anti-CGRP mAb attractive
`in
`terms of
`adherence and patient compliance. Many safety
`questions were raised due to preclinical data
`that came from studying and blocking CGRP,66
`but no safety flags occurred during the large
`programme of their development and all four
`CGRP mAb have shown similar tolerability
`
`and safety in Phase II and III trials. The most
`common adverse events are
`reported
`in
`Table 2. No interactions with other preventative
`drugs have been reported. The major scepticism
`regarding their use was related to the potential
`cardiovascular effects and liver toxicity. While
`existing data do not confirm any cardiovascular
`effect, animal studies and long-term Phase IV
`trials are needed to further evaluate the safety
`of anti-CGRP mAb. As far as liver toxicity is
`concerned, mAb elimination is mainly the result
`of proteolysis and does not involve metabolism
`by liver enzymes, making drug–drug interactions
`and hepatotoxicity unlikely. Thus, the overall
`safety profile of anti-CGRP mAb
`for the
`prevention of migraine has been reported to be
`more than satisfactory so far.
`
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