Expert Review of Neurotherapeutics

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iern20

Targeting CGRP for migraine treatment:

mechanisms, antibodies, small molecules,
perspectives

Eleonora De Matteis , Martina Guglielmetti , Raffaele Ornello , Valerio

Spuntarelli , Paolo Martelletti & Simona Sacco

To cite this article: Eleonora De Matteis , Martina Guglielmetti , Raffaele Ornello , Valerio
Spuntarelli , Paolo Martelletti & Simona Sacco (2020): Targeting CGRP for migraine treatment:
mechanisms, antibodies, small molecules, perspectives, Expert Review of Neurotherapeutics, DOI:
10.1080/14737175.2020.1772758

To link to this article: https://doi.org/10.1080/14737175.2020.1772758

Accepted author version posted online: 20

May 2020.

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Review of Neurotherapeutics

DOI: 10.1080/14737175.2020.1772758
Targeting CGRP for migraine treatment:
mechanisms, antibodies, small molecules, perspectives

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Eleonora De Matteis 1,2 , Martina Guglielmetti 3,4, Raffaele Ornello 1,2, Valerio Spuntarelli3,4,

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Paolo Martelletti3,4* and Simona Sacco1,2

1. Neuroscience section, Department of Applied Clinical Sciences and Biotechnology,

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University of L’Aquila, L’Aquila, Italy

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2. Regional Referral Headache Center of the Abruzzo region, ASL Avezzano-Sulmona-
L’Aquila, L’Aquila, Italy

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3. Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome,
Italy
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4. Regional Referral Headache Center of the Lazio region, Sant’Andrea Hospital, Rome,
Italy
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*Corresponding author:
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Paolo Martelletti
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Address: Department of Clinical and Molecular Medicine, Sapienza University of Rome,

Rome, Italy
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Email: paolo.martelletti@uniroma1.it
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Abstract
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Introduction: Calcitonin Gene-Related Peptide (CGRP) has gradually emerged as a

suitable therapeutic target to treat migraine. Considering the social and economic burden

of migraine, it is fundamental to optimize the disease management with efficacious and

safe treatments. In this scenario, drugs targeting GCRP, monoclonal antibodies (MoAbs)

and gepants, represent new therapeutic strategies.

Areas covered: In the present work, the authors aim at appraising the main insights and

implications of those treatments targeting CGRP by reviewing pathophysiology and clinical

information.

Expert opinion: Anti-CGRP MoAbs are the first migraine-specific preventive treatments

representing a suitable option especially for difficult-to-treat patients. They can be safely

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administered for long periods even in association with preventatives acting on different

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targets. Gepants are a safe alternative to triptans for the acute management of migraine

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and are currently being tested for prevention, thus representing the first transitional

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molecules for disease therapy. In the future, it might be possible to adapt the treatment

according to patients’ characteristics and disease phenotype even combining the two

treatments targeting the CGRP pathway.

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Keywords: migraine, Calcitonin Gene-Related Peptide, GCRP, erenumab,

galcanezumab, fremanezumab, eptinezumab, atogepant, rimegepant, ubrogepant.

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Article highlights
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• Calcitonin Gene-Related Peptide (CGRP) is a neuromodulator and vasodilator peptide

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playing a key role in migraine genesis. Gepants and monoclonal antibodies are specific
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migraine treatments, which act peripherally at the levels of trigeminal ganglion and

afferents.
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• Monoclonal antibodies targeting the CGRP pathway achieved good results in migraine
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prevention, even in the most difficult-to-treat patients and in those with medication

overuse. Indeed, they are particularly indicated in who suffers from high-frequency

episodic migraine and chronic migraine.

• Monoclonal antibodies proved to have several advantages compared to old oral

preventatives, such as ease of use and a high safety and tolerability profile, which

might ensure greater therapeutic adherence rate.

• Gepants induce a blockade of CGRP pathway binding to its receptor and have a short

half-life and a good tolerability profile. The new generation of these drugs, rimegepant

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and ubrogepant proved to be effective in controlling acute migraine symptoms,

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whereas atogepant is under study as a preventive treatment.

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• Gepants might be transitional molecules leading to a completely new therapeutic

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strategy. Their ease of use in prevention and during the acute attacks of migraine could

allow a patient self-regulated treatment.

•
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Further studies are needed to deeper understand the mechanisms at the basis of

disease, as well as the CGRP pathway itself. They are fundamental to explain the
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partial or absent response of some patients to these treatments opening up new

therapeutic strategies.
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• For difficult-to-treat patients, a possible therapeutic approach is the add-on therapy with

treatments acting on peripheral and central targets combining new and old
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preventatives. In the future, it might even be possible to combine gepants and

monoclonal antibodies and/or switching the antibody class used.

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• The treatment duration of anti-CGRP treatments has not been defined yet. Even if the

guidelines suggest discontinuing the therapy after 6-12 months, a longer timespan

might be necessary to downregulate the pathogenetic mechanisms and subsequently

avoid rebound after drug discontinuation. Further data are necessary to clarify this

issue. Long treatment durations are justified by the excellent tolerability profile of those

drugs.
1. Introduction

Migraine is a primary headache disorder ranked as the second cause of disability

worldwide, affecting mostly young adults and middle-age women with a global prevalence

of 14.4% (1.04 billion of people) [1,2]. The Global Burden of Disease (GBD) committee

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estimated that it is the sixth most prevalent disease [1], whose two main clinical forms are

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migraine with aura and without aura. This classification is based on the presence of focal

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neurological symptoms preceding the headache. Considering the monthly frequency of the

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attacks, an episodic form can be distinguished from a chronic type, which is characterized

by a minimum of 15 headache days/per month [3]. Patients with severe and disabling

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attacks and/or having more than 4 episodes per month and/or at high risk of medications
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overuse represent the best candidates to a preventive treatment [4]. Multiple and not yet

completely defined factors play a role in the disease development and evolution [5]. This
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lack of knowledge reflects the complexity of the therapeutic scenario, whose main goals
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are remission of acute attacks and prevention. A wide range of nonspecific treatments
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have been used as standard therapies for migraine prevention including antidepressants,

anticonvulsants, blood-pressure lowering drugs and onabotulinumtoxinA [5,6]. All those

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treatments were originally developed for other conditions. The only treatments specifically
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released for migraine were triptans and ergot-derived drugs, the latter no longer used [7].
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More recently, new migraine-specific treatments have been developed; they include drugs

acting on the Calcitonin Gene-Related Peptide (CGRP) pathway, namely monoclonal

antibodies (MoAbs), small molecules (gepants) and serotonin acting drugs such as ditans.

Indeed, CGRP is a molecule acting as a pain mediator directly involved in the genesis of

patients’ pain [8]. This work aims at focusing on the therapeutic importance of this

mediator and on mechanisms of action of therapies that target it. A search on the PubMed
Website and ClinicalTrials.gov database was carried out using keywords and MeSH

(Medical Subject Headings) terms for the concepts “migraine”, “CGRP”, “monoclonal

antibodies”, “gepants”, “erenumab”, “galcanezumab”, “fremanezumab”, “eptinezumab”,

“atogepant”, “rimegepant”, “ubrogepant”. Results were limited to articles written in English.

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2. Mechanisms - the role of CGRP and CGRP antagonism in migraine

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Migraine has a wide, extremely complex and still unclarified pathogenesis: despite many

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uncertainties, the central role of CGRP in its underlying mechanisms is well-defined [9].

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There are two similar forms of this molecule encoded by two different genes, the α-CGRP

and the β-CGRP. The α-CGRP is the transcript of calcitonin-related α gene (CALCA) in the
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nervous system [10,11] and contributes to migraine pathogenesis. Its role in the disease
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was firstly investigated in the early ‘80s [12,13], but targeted therapies had not been
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available for the following 20 years [14]. The existing migraine treatments were important

in the comprehension of the CGRP pathway. Indeed, 5-hydroxytryptamine (5-HT)

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receptors 5-HT1B, 5-HT1D [15] and 5-HT1F [16] agonists such as triptans and ditans
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demonstrated to inhibit the CGRP release from the trigeminal presynaptic neurons during
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migraine episodes [17,18]. However, these drugs do not fully explain the whole

connections between CGRP and the serotoninergic system, which has a dual and not
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completely understood action in migraine pain [19,20]. CGRP-containing cell bodies are
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located in several central nervous system (CNS) sites such as some cerebellar,

hypothalamic, thalamic, limbic and mesencephalic areas [21]; whereas, peripherally,

CGRP is produced and released by the C-type sensory pain fibers of the trigeminal

ganglion [22] and trigeminal nerves [23]. In the trigeminovascular system, CGRP receptor

(CGRPr) does not colocalize with CGRP and is indeed expressed on Aδ-type fibers of

central and peripheral afferents [24]. Aδ-neurons are responsible for nociception, thus
playing a key role in the genesis of migraine pain. However, other cell-types expressing

CGRPr are involved in disease pathophysiology through different CGRP-mediated actions.

Indeed, CGRP causes neuron-glia crosstalk due to the activation of satellite glial cells,

arterial vasodilation through the relaxation of cerebrovascular smooth muscle cells and

mast cell degranulation (Figure 1a) [25].

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CGRPr is a complex of several proteins, whose main components are the transmembrane

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Gαs coupled receptor calcitonin receptor-like receptor (CALCRL) and receptor activity-

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modifying protein 1 (RAMP1). CGRP binding to its receptor causes the Gαs-mediated

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activation of adenylyl cyclase and the consequent increase of intracellular cyclic

adenosine monophosphate (cAMP), which activates protein kinase A. The latter

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phosphorylates multiple targets, including ATP-sensitive potassium channels (KATP)s,
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extracellular signal-related kinases (ERKs) and transcription factors [9,26] (Figure 1b). In

the Aδ-type fibers, cAMP-dependent intracellular signaling mechanisms lead to hyper-

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excitability and to the hypothetical opening of hyperpolarization-activated cyclic nucleotide-

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gated (HCN) channels involved in neuropathic pain [25]. Besides, these mechanisms
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cause the upregulation of various receptor proteins such as functional purinergic receptors

(P2X3), possibly involved in crosstalk between neurons and glia [27-29], which results in
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enhanced CGRP release [28]. This crosstalk is a strategic mechanism yet not unique for

the signaling among C and Aδ-type fibers in trigeminal ganglion and trigeminal nerves.
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Indeed, recent evidences showed that there is also an axon-axon interaction between the
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fibers. Specifically, CGRP could be released not only from neurons’ soma but even from

the fiber itself and that C-fibers present CGRP-positive boutons in paranodal areas of the

CGRPr-positive Aδ-fibers [30].

In the CNS, CGRPr is widely present in sites devoted to pain processioning and functions

associated with migraine-related symptoms such as nausea, phonophobia and

photophobia. According to the current insights into premonitory symptoms, the putative

migraine generator is thought to be the limbic system and, specifically, the hypothalamus.

This structure has connections with the thalamus, which is responsible for multimodal

sensory integration and with the brainstem, where the trigeminal nucleus caudalis is

located. The latter plays a key role in migraine pathogenesis activating the trigeminal

ganglion with the subsequent CGRP release [9,25,37]. Differently from all the above-

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mentioned structures, the trigeminal ganglion is part of the peripheral nervous system

(PNS) and is outside the blood-brain barrier (BBB). Thus, it is one the main targets of anti-

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CGRP treatments together with the area postrema and the sphenopalatine ganglion,

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which might be involved in the crosstalk between the sensory and parasympathetic system

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[21,37]. All these structures are part of descending and ascending pathways. Indeed, the
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pain signal can run from the PNS to the CNS and in the opposite direction creating a cycle

where the trigeminal ganglion acts as a signal-amplifier due to the communication between
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C fibers and Aδ-fiber (Figure 1a) [38].

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The primary role of the CNS in triggering a migraine attack in susceptible subjects led to
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the current view of migraine as a neural disorder. However, migraine pain is a

consequence of neurovascular mechanisms [36], thus, the role of intracranial vasculature

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remains significant. Early studies showed that direct stimulation of dura mater surrounding

dural and cerebral blood vessels is able to evoke a pain sensation in humans [36,39].
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This phenomenon is related to the rich innervation of dural blood vessels by trigeminal C
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and Aδ-type fibers, responsible for nociception [23]. Once activated the fibers release

CGRP and substance P causing the so-called “sterile neurogenic inflammation”, which

consists on capillary permeability, plasma protein extravasation, arterial vasodilatation,

and mast cell activation [40-43], with the consequent release of mediators which further

activate meningeal nociceptors [44]. Even if the role of neurogenic inflammation in

conjunction with acute migraine attacks is still debated, it is not possible to exclude the

potential involvement of inflammatory processes in migraine chronification [45].

3. Overview of treatments targeting the CGRP pathway

In the last decade, two main types of targeted treatments were developed: gepants, which

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are small molecules blocking CGRPr and MoAbs binding to the CGRP or its receptor

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[9,50]. They represent a further proof of the importance of the CGRP pathway in migraine

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pathogenesis. Indeed, it has been demonstrated that they hardly pass the BBB: their

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efficacy is explained by their peripheral action on structures located outside the BBB,

including the trigeminal ganglion and meninges.

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Specifically, four MoAbs have been released for migraine prevention: erenumab is the sole

binding to the extracellular domain of CGRPr, whereas, fremanezumab, galcanezumab,

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and eptinezumab have affinity for the soluble molecule, preventing it from reaching and

activating the receptor (Figure 1b).

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At present, two gepants are available for the symptomatic treatment of disease, namely

ubrogepant and rimegepant. In terms of preventative options, atogepant is the only

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available, while the efficacy of rimegepant is still under evaluation. Even though gepants

are much smaller than MoAbs, they act peripherally binding to the extracellular domain of
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CGRPr in a similar way to erenumab [51]. However, differently from MoAbs, they are
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internalized together with CGRPr [52], blocking its endosomal residual action [53].

In the following sections, we will summarize the efficacy and safety results of randomized

clinical trials (RCTs) on anti-CGRP targeted treatments together with their limitations. We

will also discuss some practical issues regarding the use of these drugs, including

therapeutic adherence, treatment duration, cost-effectiveness and their possible role in

treating conditions such as aura and medication overuse. Finally, we will present some

suitable therapeutic strategies as add-on approaches and the combination of gepants with

MoAbs.

3.1. Monoclonal antibodies

3.1.1. Types of antibodies and dosage

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Erenumab and galcanezumab are administered in subcutaneous monthly doses,

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fremanezumab in subcutaneous monthly or quarterly doses, and eptinezumab in

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intravenous quarterly doses. Erenumab is commercially available in 70 and 140 mg doses

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[54], fremanezumab can be administered either in three quarterly doses or in one monthly

dose of 225 mg [55] and galcanezumab in a loading dose of 240 mg followed by monthly
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120 mg. There is no evidence of superior efficacy or safety of one of the two available
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dosages for neither of the drugs. Evidence suggests that erenumab 140 mg monthly dose
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might confer an advantage over the 70 mg monthly dose in patients with multiple prior

preventive treatment failures [56]; however, this suggestion should be confirmed by more
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in-depth studies.
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3.1.2. Clinical trials

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Available RCTs have shown reduction in monthly migraine days (MMDs) over 3 to 6

months with the use of MoAbs compared to placebo in patients with episodic [57-61] and
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chronic migraine (Figure 2a ) [62-65], without any increase in adverse events. The main
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design characteristics of these RCTs are reported in Table 1 and further details have been

summarized in previous reviews [66-70].

Open-label extensions of the available trials [75-77] confirmed the safety of erenumab in

the long term. Similarly, a phase 3 long-term safety study on galcanezumab demonstrated

a good safety and tolerability profile of the drug [78].

3.1.3. Medication overuse

Medication overuse (MO) is a common condition occurring in patients with regular overuse

of symptomatic headache medications [3]. All the trials on MoAbs enrolled patients with

MO, who had not previously undergone detoxification treatments. The results highlight an

overall efficacy of these treatments in reducing MMDs and in reverting MO, suggesting

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that they could play a role in the detoxification process itself [67]. Currently, the sole study

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analyzing the efficacy of erenumab on MO is a double-blind placebo-controlled study. It

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registered a twofold reduction of MMDs (mean -6.6) both with dosages 140 and 70 mg of

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the MoAbs compared to placebo (mean -3.5) [79].

3.1.4. Monoclonal antibodies efficacy in difficult-to treat patients

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Among all the RCTs on MoAbs, five evaluated their efficacy in difficult-to-treat patients,
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who have failed two to four preventive treatments. Specifically, the LIBERTY trial of
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erenumab in episodic migraine [71], the FOCUS trial of fremanezumab in episodic and

chronic migraine [63] and subgroup analyses of the EVOLVE [72], REGAIN [73] and
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CONQUER [74] trials of galcanezumab in episodic and chronic migraine showed that anti-
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CGRP MoAbs effectively reduces MMDs in these patients, while the placebo effect did not
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result significant (Figure 2b)[63,71,72,74].

3.1.5. Therapeutic adherence

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A further advantage of preventive therapy with MoAbs might be the increased compliance
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to the treatment. Indeed, after 12 months from treatment start, the adherence to oral

preventive therapies in migraine was 35%-56%, while the persistence was 57%-77%,

mostly due to adverse events [80]. The compliance of the new injectables is supposed to

be much higher compared with the traditional oral drugs, while the persistence could also

be higher due to their safety. However, real-life data are required to more accurately

compare patients’ compliance to new and old preventatives

3.1.6. Limitations of the current trials

In the above-mentioned RCTs, anti-CGRP MoAbs were compared with placebo instead of

active comparators. There are several implications of the exclusive use of a passive

comparator as placebo. Primarily, it is not known if the new drugs are more effective than

the available preventive treatments. Indirect comparisons and clinical experience are not

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helpful to understand this issue. To our knowledge, there is only one ongoing trial so far,

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performing a head-to-head comparison between erenumab and topiramate

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(NCT03828539).

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A further limit of current studies is the choice of the efficacy outcomes. Indeed, the

response to MoAbs is assessed in terms of MMDs decrease and symptomatic medication

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use. However, a significant proportion of patients might experience relevant improvements
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in other outcomes, including severity of the attacks, response to symptomatic medications,

and psychiatric and cognitive symptoms. Real-life data are required for a more rigorous
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assessment of patients’ response to MoAbs, to benchmark their efficacy and safety with
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other agents and to test possible add-on approaches.

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3.2. Gepants
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3.2.1. Types and pharmacokinetic of gepants

Previously developed gepants, telcagepant, MK-3207 and BI 44370 TA, caused liver
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toxicity and olcegepant was also not available in an oral formulation, hence, they all have
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been abandoned [51,81]. The new generation of these drugs, rimegepant, ubrogepant and

atogepant, showed a good safety profile and can be administrated orally. Ubrogepant and

rimegepant both have a short half-life: measured as Tmax 0.7-1,5 hours [82,83], and 1-4

hours respectively [84], which suits for the treatment of acute migraine episodes.
3.2.2. Clinical trials

The efficacy and safety of rimegepant were tested in a phase 2 double-blind, dose ranging

RCT compared with placebo. Different dosages of the drug were considered: 10 mg, 25

mg, 75 mg, 150 mg, 300 mg and 600 mg. Results proved the superiority of rimegepant

over placebo in leading to pain freedom at two hours as well as total migraine freedom at

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two hours (defined as freedom from pain, photophobia, phonophobia and nausea) and

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sustained pain freedom (from 2 to 24 hours post-dose). With respect to all these

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outcomes, the difference between drug and placebo was statistically significant for three

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dosages: 75 mg, 150 mg and 300 mg. Specifically, rimegepant 150 mg demonstrated to

be the best dosage in inducing pain freedom at two hours compared with placebo (32.9%

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vs 15.3%; P<0.001); whereas, rimegepant 75 mg was superior in leading to total migraine
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freedom at two hours compared with placebo (27.9% vs 11.8%, P<0.001). The trial used

sumatriptan 100 mg as an active control, however, there was not statistical power to
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compare the two symptomatic treatments [85]. Three multicenter, double-blind clinical
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trials on rimegepant 75 mg have been completed, all comparing the drug with placebo.
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Particularly, NCT03237845 and NCT03461757 results demonstrated a higher proportion

of pain-free subjects at two hours post-dose of rimegepant 75 mg compared with placebo

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(19.6% vs 12%, P<0.001; 21% vs 11%, P<0.0001). Furthermore, both RCTs demonstrated

a significant reduction in the other migraine-related bothersome symptoms at two hours,

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such as photophobia and phonophobia, in the group of patients treated with rimegepant
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compared with placebo (NCT03237845: 37.6% vs 25.2% P<0.001; NCT03461757: 35% vs

27%, P=0.0009) (Figure 3a) [86,87]. The patients enrolled in both studies had similar

demographics and baseline characteristics: the main difference was the formulation of the

drug used. Indeed, the second trial, NCT03461757, used an orally disintegrating tablet,

whose slightly different pharmacokinetic might explain its better results, especially in terms
of relatively rapid onset of relief [87]. A further phase 3 RCT registered on

ClinicalTrials.gov (NCT03235479) was completed in 2019, but results have not been

published yet. At present, there is an ongoing RCT (NCT03732638) investigating the

efficacy of rimegepant as a preventive treatment.

The efficacy, safety and tolerability of ubrogepant have been studied by a phase 2 RCT

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and two phase 3 RCTs. The phase 2 double-blind RCT compared different drug dosages

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and showed the efficacy of the 100 mg dose in terms of two-hour pain freedom compared

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with placebo (25.5% vs 8.9%; P<0.001). The same dosage led to a higher headache

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response rate compared with placebo for the two-hour headache response (defined as

reduction in headache severity from grade 2 or 3 at baseline to grade 1 or 0 on a pain

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scale from 0 to 3), but this difference was not statistically significant [88]. The two phase 3
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trials, ACHIEVE I and ACHIEVE II, ran similar analyses comparing ubrogepant with

placebo [89,90]. Specifically, ACHIEVE I investigated the efficacy of the 50 and 100 mg
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dosages, while ACHIEVE II investigated that of 25 and 50 mg dosages. Both studies

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confirmed the superiority of ubrogepant over placebo, with better results for the higher
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dosages (100 mg in ACHIEVE I and 50 mg in ACHIEVE II) in terms of the principal

endpoints of freedom from pain and from the most bothersome migraine symptoms at two
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hours. In ACHIEVE I, 19.2% of patients were free from pain within two hours from the 50

mg ubrogepant administration; this proportion increased to 21.2% in patients who received

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the 100 mg dosage [89]. Similarly, in ACHIEVE II, 20.7% patients receiving the 25 mg
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dosage were free from pain at two hours compared to 21.8% patients who was treated

with the 50 mg ubrogepant (Figure 3a) [90].

Atogepant is a second-generation gepant indicated in migraine prophylaxis. Currently,

there are five ongoing RCTs (NCT02848326, NCT03855137, NCT03777059,

NCT03700320, NCT03939312); four of them are assessing the safety, tolerability and
efficacy of different dosages of the drug, while one (NCT03700320) is comparing the

efficacy of this treatment with other preventive drugs considered the standard of care for

migraine. NCT02848326 is the only phase 2b/3 RCT, whose results have been published:

this trial enrolled adults with a history of episodic migraine with or without aura and

compared the efficacy of different dosages of atogepant (10 mg QD, 30 mg QD, 30 mg

BID, 60 mg QD, or 60 mg BID) with placebo in reducing MMDs. After the 12-week

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treatment, patients reported a statistically significant MMDs reduction for all the atogepant

dosages compared with placebo (P<0.05 for all comparisons). Furthermore, the mean

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percentage of patients who achieved at least 25%, 50%, or 75%, or a complete 100%

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MMDs reduction across all the atogepant dosages were 77%, 57%, 34%, and 10%,

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respectively (Figure 3b) [91,92] . Further details on RCTs designs and outcomes are
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summarized in Table 2.

3.2.3. Limitations of the current trials

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One of the main issues limiting a precise estimate of clinical advantages of gepants as
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symptomatic treatments for migraine is the lack of comparative studies. The only RCT
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using an active comparator, sumatriptan, was the phase 2 RCT of rimegepant, which,

however, was not aiming at comparing the two drugs [85]. In the future, it might be useful
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to directly compare gepants not only to triptans, but also to other new targeted treatments
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such as ditans. Concerning migraine prevention, a direct comparison between gepants

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and MoAbs could provide interesting data on the efficacy of these drugs and could

contribute to identifying the subset of patients who might benefit more from one treatment

rather than the other.

4. Safety and tolerability

Studies on the CGRP targeted treatments have showed overall good safety and tolerability

profiles. With respect of their mechanisms of action on CGRP pathway, their major
concern is the blockade of CGRP-mediated vasodilation. Several preclinical studies have

been carried out on the coronary action of these drugs. Both gepants and MoAbs seem to

exert their effect mainly on distal coronary arteries, preventing vasodilation when exposed

to CGRP; however, they are unlikely to induce coronary side effects under normal

cardiovascular conditions. [77,80,93,94].

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The most common adverse event related to the use of anti-CGRP MoAbs was injection

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site pain due to the subcutaneous administration [67]. The use of autoinjectors instead of

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classical subcutaneous administration will likely decrease the prevalence of injection site

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pain in the transition from trials to clinical practice. The incidence of serious adverse

events in the available trials of anti-CGRP MoAbs was low, ranging from 0.4% to 5.8%;

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most serious adverse events were likely unrelated to the drugs [95]. Open-label studies
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confirmed the safety of anti-CGRP MoAbs beyond the duration of the clinical trials, up to 3

years of ongoing treatment [75,78]. Notably, anti-CGRP MoAbs do not act as

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immunomodulatory agents and can therefore be combined with immunomodulatory

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treatments, such as immunoglobulin [96] .

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With respect to the safety profile of gepants, the main concern for the first generation of

these drugs was liver toxicity, which has been reduced in the new generation according to
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the available RCTs. Indeed, few cases of transaminase pathological increase were
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reported [85-88,90]. Conversely, the most common side effects were somnolence,
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dizziness, dry mouth, urinary and respiratory traits-infections and dose-dependent nausea.

A phase 2/3 open label clinical trial, NCT03266588, evaluated the safety of rimegepant

and its possible hepatotoxicity, but results have not been published yet. As far as

ubrogepant is concerned, a phase 3 open-label RCT showed its overall long-term safety

and tolerability. A high proportion of patients treated with ubrogepant presented treatment-

emergent adverse events (66% of patients treated with the 50 mg dosage and 73%
receiving the 100 mg dosage). However, a remarkably lower proportion was directly

related to the drug (10% in patients receiving the 50 mg dose and 11% in those receiving

the 100 mg dose). Besides, just 2-3% of patients reported serious adverse events and

about the same proportion of ubrogepant-treated participants discontinued the treatment

due to adverse events. Only 20 patients out of 813 reported ALT/AST levels increase more

than threefold: 4/398 (1.0%) in the usual care arm, 5/399 (1.3%) in the ubrogepant 50 mg

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arm, and 11/406 (2.7%) in the ubrogepant 100 mg arm. However, only one case was

judged probably related to ubrogepant 100 mg. Notably, all cases resolved without the

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need to discontinue ubrogepant. [97].

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5. Aura and treatments acting on the CGRP pathway

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The novel drugs acting on the CGRP pathway will provide new insights in the current
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understanding of migraine mechanisms and aura genesis. The RCTs, testing the efficacy

and safety of MoAbs, enrolled also patients suffering from migraine with aura, thus
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extending the benefits of the drugs also to this subgroup of patients. At present, there are
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no clinical studies describing possible modifications of aura in patients treated with drugs
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targeting the CGRP pathway. Based on the central mechanisms causing the aura, these

drugs are expected to be effective on the sole headache pain. Therefore, it can be
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theoretically predicted that patients treated with preventive treatments acting on the CGRP
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pathway may experience episodes of aura without migraine. So far, this possible
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phenomenon has not been observed and reported, subsequently, we can speculate that

these drugs may also prevent aura occurrence. This idea is supported by preclinical

studies, which demonstrated the CGRP involvement in the cortical spreading depression,

a key pathogenetic step in migraine with aura [98,99]. However, real-life data are needed

to demonstrate the action of anti-CGRP treatments on this type of migraine and to provide
deeper understanding of connections between central and peripheral systems involved in

the disease.

6. Treatment duration and cost-effectiveness analysis

One of the main strengths of both MoAbs and gepants is their good safety profile: the

paucity of side effects, mostly mild, guarantees a good compliance and allows an

T
extended-regimen treatment. With respect to preventive treatments and particularly

IP
MoAbs, the European guidelines, based on the RCTs data, suggest to discontinue the

R
treatment after 6-12 months to evaluate whether the response is sustained even after

SC
withdrawal [100]. However further data are needed to confirm this suggestion and to

define the most effective treatment duration, especially in some specific categories of

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patients. For instance, it has been showed the importance to treat partial responders for at
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least three months and up to 6 months [101]. From the biological and molecular

perspective, the effect of the long-term blockade of the CGRP pathway with targeted
M

treatments has not been completely understood. Indeed, it is unknown if it is possible to

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induce a long-lasting downregulation of the CGRP pathway as well as neuroplasticity of

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dysfunctional migraine circuits and, eventually, how long the blockade has to be to achieve

these results. The need to establish a time limit to the old, poorly tolerated preventive
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treatments was due to improve their compliance, while time limits are established to anti-
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CGRP treatments mostly due to their high economic cost. For instance, the United States
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annual cost of erenumab is $6900, however, it ultimately proves itself cost-effective,

particularly in patients with chronic migraine, when considering also the social burden of

disease and its direct and indirect costs [102]. To our knowledge, there are no similar

analyses for the other MoAbs and gepants, but it is not excluded that a broader usage

might reveal a similar cost-effectiveness. At present, it is recommended to accurately

select patients who might benefit from targeted treatments. To attain this selection, a
personalized approach to patients’ comorbidities and response to previous treatments is

paramount [103]. The multifactorial nature of the disease suggests the need for a tailored

approach to the patients’ characteristics, proving the criticality of Headache Centers

expertise.

7. Conclusions

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MoAbs and gepants acting on the CGRP pathway represent an emergent approach to

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migraine therapy due to their specificity for migraine pathophysiology. RCTs evaluating

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their efficacy and safety demonstrated promising results and provided relevant insights

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both on disease pathogenesis and clinical phenotypes of migraine. However, real-life data

are necessary to confirm these results and clarify further questions, namely the efficacy of

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those drugs compared with the old preventatives/symptomatic treatments, the subgroup of
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patients which can most benefit from them, treatment duration and therapeutic adherence.
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8. Expert opinion

The advent of targeted treatments for migraine marked the beginning of a new era. Due to
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their safety, tolerability profiles and significant results in terms of efficacy, these drugs
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represent a major therapeutic advance compared to previous migraine treatments.

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Moreover, they offer a new therapeutic opportunity for patients who suffer from aggressive

disease phenotypes and have unsuccessfully tried several other prior drugs. If promptly
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used, anti-CGRP treatments can slow down, freeze or even revert the natural course of
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migraine with a great impact on patients’ quality of life, thus, they can be defined as

Disease-Modifying-Migraine-Drugs (DMMDs) [104].

8.1. Monoclonal Antibodies

MoAbs are versatile drugs of proven efficacy, suitable for almost every migraine patient

who needs prevention. They do not require dose titration and their monthly or quarterly
administration ensures a much higher therapeutic adherence compared to traditional oral

drugs, partly due to their tolerability. They ideally represent the first-choice treatment in

patients who are eligible for migraine prevention. However, direct costs of these drugs are

higher than costs of the old oral preventatives. Consequently, they should be selectively

offered to a group of migraineurs who mostly need them, keeping them affordable for

national health systems and insurance companies [105]. Available guidelines have

T
IP
identified the most suitable candidates in patients who have failed or have not tolerated at

least two migraine preventive treatments [100,106]. However, it is important to highlight

R
that some patients fulfilling these criteria may have room to try a third or even more drugs

SC
before switching to MoAbs. Conversely, there are some patients who, due to their

U
comorbidities and characteristics, can be considered eligible to MoAbs before failing two
AN
oral preventatives. New European Headache Federation (EHF) criteria to define difficult to

treat migraine, resistant and refractory migraine, may be relevant to select patients who
M

are most in need of more expensive treatments such as MoAbs [107].

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Referring to migraine types, it is noteworthy that the new treatments should not be
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restricted to patients suffering from chronic migraine. Indeed, episodic migraine is also a

very disabling condition: several studies have shown that there is no substantial difference
EP

in terms of impairment among patients with chronic migraine and with high frequency

episodic migraine [108]. This latter form of disease, defined on a minimum of 8 monthly
C

headache days, has a similar disability burden in patients’ life compared to chronic
AC

migraine [109]. Treatment of high frequency episodic migraine may reduce both patients’

impairment and risk of MO, possibly even slowing down the natural progress to a chronic

form of disease [110,111].

Despite proved efficacy of MoAbs, clinical trials and real-life data demonstrated that there

are patients who experience no change in their migraine attacks with the administration of
the treatment. We can speculate that these patients’ migraine is mainly caused by

mechanisms independent of CGRP. There are also patients who report a partial response

to the treatment, who may contemporaneously have different pathways involved in their

disease genesis. Further experimental studies should clarify the mechanisms and the

reasons for partial or absent response to those drugs improving disease management. For

instance, a suitable therapeutic option for patients with inadequate response to MoAbs,

T
IP
might be polytherapy with drugs acting on different targets such as treatments which act

on the CNS. Otherwise, it could be possible to add on onabotulinumtoxinA, which exerts

R
its action peripherally with different mechanisms from MoAbs. Indeed, there is some

SC
evidence showing that patients who had a poor response to onabotulinumtoxinA may

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favorably respond to MoAbs [101]. Additionally, the lack of response to MoAbs could also
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be explained by the category of antibody used. Apart from erenumab, which is specific for

the CGRPr, the other MoAbs bind to the soluble CGRP, thus interfering with its possible
M

binding to other receptors (e.g. Adrenomedullin 1 (AM1), AM2, Amylin 1 (AMY1) and
D

AMY2). Conversely, it is possible that CGRPr is activated by peptides different from its
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specific ligand [112]. A deeper understanding of these processes could lead to a better

choice of the antibody type, to switch from one to another or even to combine them.
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Notably, according to a case report, three patients who did not respond to erenumab had a

positive response to galcanezumab [113]. Another point yet to be clarified is if a combined

C

targeting of the CGRP and the CGRPr with different types of antibodies may yield benefits
AC

in very selected difficult-to-treat patients. Further larger and comparative studies are

required to evaluate the real efficacy of these therapeutic strategies.

8.2. Gepants

After the initial safety concern, gepants have gradually regained importance and new

molecules have been developed for acute and preventive migraine treatment. Due to their
usage in both migraine prevention and acute treatment, these drugs could lead to a novel

therapeutic approach. In the future, patients might be able to self-regulate the therapy

assuming the same treatment in a continuous or acute fashion according to their needs.

However, their limited usage in clinical practice still leaves uncertainties on some

therapeutic aspects such as the possibility of overuse headache, similar to triptans and

non-steroidal anti-inflammatory drugs (NSAIDs). The mechanism of action directed on

T
IP
CGRPr ensures the specificity of gepants for trigeminal fibers and does not cause direct

vasoconstriction. Hence, these drugs might be associated with a lower cardiovascular risk

R
compared with triptans, representing a suitable alternative in the symptomatic treatment of

SC
patients with contraindications for triptans. Furthermore, the different mechanism of action

U
makes gepants an additional option for non-responders to triptans. Their efficacy as a
AN
symptomatic treatment was assessed as the proportion of patients free from pain at two

hours. RCTs demonstrated the statistical superiority of rimegepant and ubrogepant over
M

placebo [51,114]. Nonetheless, from a clinical perspective, gepants seem not to show a
D

meaningful therapeutic gain compared with other common acute treatments [115],
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supporting the hypothesis that these drugs should be administered to specific categories

of patients.
EP

With respect to the usage of gepants in migraine prevention, the only molecule developed

for this indication is atogepant, which achieved good results, measured as MMDs
C

reduction, compared with placebo. Further studies are required to confirm these data and
AC

to identify the subset of patients that could benefit more from this treatment. Notably,

rimegepant, which has been successfully tested as a symptomatic treatment, might find

indications in migraine prevention in the future, as an ongoing RCT is comparing its

efficacy against placebo in reducing the monthly attack frequency (NCT03732638).

8.3. Monoclonal antibodies versus or plus gepants

The choice of atogepant instead of MoAbs in migraine prevention is related to patients’

needs and preferences. Currently, atogepant is considered an alternative to MoAbs for

migraineurs who prefer a less invasive administration route or might benefit from a non-

long-lasting block of the CGRP pathway such as fertile women desiring a pregnancy or

T
patients with cardiovascular risks factors.

IP
The different pharmacodynamics of the two types of anti-CGRP treatments opens up new

R
therapeutic strategies such as the combined administration of gepants with MoAbs to

SC
induce a more effective CGRP pathway blockade. There are no literature data available in

support of this combined targeted therapy to prevent migraine. However, according to a

U
case report, two patients responding to erenumab were able to quickly control their acute
AN
attacks with rimegepant 75 mg [116]. These results support the idea that MoAbs and

gepants have slightly different mechanisms of action, partly related to the dimension of the
M

therapeutic molecule, resulting in different pharmacodynamics. The incomplete blockade

D

of the GCRP pathway exerted by MoAbs could, indeed, benefit from the combination with
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a different CGRP specific molecule, such as rimegepant, which is internalized together

with the CGRPr into the target cell and inhibits its intracellular signaling [52,117]. A further
EP

possibility might be the combination of MoAbs and gepants in migraine prevention in those
C

patients who have an absent or a partial response to the single treatment to obtain a boost
AC

effect.

The upcoming years will likely see a great development of headache medicine, to whom

the study of the CGRP pathway will provide a great contribution. The peripheral action of

anti-CGRP treatments will lead to unprecedented understandings into migraine

pathophysiology, revealing the role of the trigeminal ganglion and its interactions with

other neurovascular structures in generating and perpetuating migraine pain.

The clinical aspect will also be enriched by a plethora of real-life data on the efficacy and

safety of anti-CGRP therapies, contributing to new guidelines. Future large collaborative

studies could also provide insights on the best moments to start, stop, and how to assess

the response to these treatments.

T
Funding

IP
This paper was not funded.

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Declaration of interests

SC
R Ornello has received sponsorship to attend meetings from Novartis and Teva. S Sacco

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has received speaking honoraria from and has served on Advisory Boards of Abbott,
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Allergan, Eli-Lilly, Medscape, Novartis, Teva. P Martelletti has received speaking honoraria

from and has served on the Advisory Board of Eli-Lilly, Allergan, Novartis, Teva. The
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authors have no other relevant affiliations or financial involvement with any organization or
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entity with a financial interest in or conflict with the subject matter or materials discussed in
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this manuscript apart from those disclosed.

Reviewer disclosures
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Peer reviewers on this manuscript have no relevant financial or other relationships to

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disclose.
AC

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Figure legends
Figure 1.

a) Migraine pathogenesis - from left to right: the activation of cortical areas, specifically of

hypothalamus and thalamus leads to the subsequent activation of trigeminal nucleus caudalis and

trigeminal ganglion, which are part of the trigeminovascular system. The consequent calcitonin

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gene-related peptide release from trigeminal C-type fibers causes arterial vasodilation through the

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relaxation of cerebrovascular smooth muscle cells, pain input transmission through Aδ-fibers

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activation, and neurogenic inflammation due to mast cell degranulation. All these mechanisms are

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involved in generating and perpetuating migraine pain. Notably, the pain signal can run from

central to peripheral structures and vice versa making the trigeminal ganglion an amplifier of

migraine headache.
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Abbreviations: CGRP Calcitonin Gene-Related Peptide, TNC trigeminal nucleus caudalis, BBB

blood-brain barrier.
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b) Calcitonin Gene-Related Peptide release from the trigeminovascular system – Once released
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from trigeminal C-type fibers, the calcitonin gene-related peptide binds to its Gαs coupled receptor

activating the adenylate cyclase, which converts Adenosine triphosphate in 3',5'-cyclic Adenosine
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monophosphate. The latter activates protein kinase A, responsible for the phosphorylation of

multiple intracellular targets. The receptor is a complex of several proteins: the receptor coupling
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protein together with the α- subunit of the GS protein forms the intracellular domain; whereas,
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receptor activity-modifying protein 1 and a seven-transmembrane domain form the extracellular

domain. Anti-calcitonin gene-related peptide treatments exert their action at different levels. Indeed,

triptans inhibit the pre-synaptic calcitonin gene-related peptide release binding to 5-HT1D or 1F. A

type of anti-calcitonin gene-related peptide monoclonal antibody binds to the soluble calcitonin

gene-related peptide interfering with the binding of the molecule to its post-synaptic receptor. The
other type of anti-caalcitonin geene-related peptide mo
onoclonal antibody
a ass well as gepants actss

binding dirrectly to thee extracellullar domain oof calcitonin gene-relatted peptide receptor.

Abbreviatiions: CGRP
P Calcitonin
n Gene-Relaated Peptid
de, 5-HT 5-h
hydroxytrypptamine recceptor, AC
C

adenylate cyclase, cA
AMP 3',5'-ccyclic Adennosine mon
nophosphate, ATP Addenosine triphosphate,,

PKA proteein kinase A,

A RCP receptor couplinng protein, RAMP1 recceptor activvity- modify
ying proteinn

1.

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Figure 2.

a) Efficacyy of anti-C
Calcitonin Gene-Relatted Peptide monoclonal antiboddies in preevention off

episodic aand chronicc migraine - mean moonthly migrraine days reduction annd proportio
ons of 50%
%

responderss in the avaailable phasee 2b/3 randdomized clin

nical trials of monocloonal antibod
dies againstt

the calcitoonin gene-rrelated pepttide or its receptor for

fo the prev
vention of episodic and
a chronicc

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migraine. D
Data are froom the pooleed analyses of the Euro
opean Head
dache Federaation guidellines [100].

b) Efficacyy of in antii-Calcitonin
n Gene-Rellated Peptiide monoclo
onal antiboodies in preevention off

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episodic aand chronicc migraine - mean moonthly migrraine days reduction inn the availab
ble phase 3

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randomized controlledd trials of monoclonal
m antibodies against
a the calcitonin ggene-related
d peptide orr

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its receptorr for the preevention off episodic annd chronic migraine
m in patients wiith ≥2 priorr preventivee
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treatment ffailures.

Error bars indicate 95% confiden

nce intervalss. Asterisks indicate sig
gnificant diffferences.
M

Abbreviatiions: MMD
Ds mean monthly
m miggraine dayss reduction
n, M monthhly administration; Q

quarterly aadministratioon.
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Figure 3

a) Efficacyy of rimegeepant and ubrogepan migraine - percentagee

nt in sympttomatic treatment of m

of patients, who reporrted pain freeedom at tw

wo hours and
d reduction of the mostt migraine bothersome
b e

symptoms in the availlable phase 3 randomizzed clinical trials on rim

megepant aand ubrogep
pant [86-87,,

89-90].
b) Efficacy of atogepant in migraine prevention of episodic migraine = mean monthly migraine

days reduction in patients with a frequency of 4–14 monthly migraine days [91-92].

Asterisks indicate significant differences

Abbreviations: MMD mean monthly migraine days, QD once a day dosing, BID twice a day dosing

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Table 1: randomized
d clinical trials on mon
noclonal an
ntibodies fo
or migrainee preventio
on
Episodic m
migraine
U % wiith prior
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Duration NNo. of Ag
ge % withh concurrent
Trial Phase preventiv
ve treatment
(months) ppatients ran
nge preventiive treatmentss
faiilures
Eptinezumabb
M

18
8-
NCT017772524 2 3 174 0 0
55
Erenumab
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NCT019552574 (70 mg 8-
18
2 3 483 0 32
2-38
M) 60
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18
8-
STRIVE ((70/140 mg M)
M 3 6 955 2-3 36
6-40
65
18
8-
ARISE (770 mg M) 3 3 577 6-7 83
65
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Fremanezum
mab
NCT020225556 (225 mgg 8-
18
2 3 297 27-34 NR
N
M) 65
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HALO-EMM (225 mg M / 18
8-
3 3 875 20-21 NR
N
675 mg Q) 70
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Galcanezumaab
EVOLVE E-1 (120 mg M 8-
18
3 6 858 0 18
8-19
+ 240 mg LD
D) 65
EVOLVE E-2 (120 mg M 18
8-
3 6 922 0 14
4-15*
+ 240 mg LDD) 65
*≥2 treatmennts
Chronic m
migraine
% witith
% with prior
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Duration No
o. of Age concurrrent
Trial Phase preventive
p
months)
(m patiients rangee preventtive
treattment failures
treatmeents
Erenumab
NCT02066415 (70/140 mg M) 2 3 667 18-65 0 66-70
Fremanezumab
NCT02021773 (225 mg M + 675
2 3 264 18-65 38-43 NR
mg LD)
38-31
HALO-CM (225 mg M + 675 mg (topiramate)
3 3 1130 18-70 20-22
LD / 675 mg Q) 13-18 (botulinum
toxin)
Galcanezumab

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REGAIN (120 mg M + 240 mg LD) 3 3 1117 18-65 13-16 24-35
NR = not reported

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Table 2: randomized clinical trials on gepants

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 Completion Duration No. of Age Primary Secondary
Trial Phase State
date (months) patients range outcomes outcomes

Rimegepant
Cmax,
6
September >18 Tmax,
NCT01445067* 1 Completed 11 48 pharmacokinetic
2012 18- AUC (0-
2b Completed 8 885 endpoints
May 2012 65 24)
NCT01430442 Total MSF
2h PF
3 Completed January 7 1485 >18 2h PF and 11 clinical
NCT03235479* 2018 MSF endpoints (SPF

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3 Completed 7 14991811 >18
3 Completed January 8 1909 >18 2h PF and etc.)

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NCT03237845 2/3 Completed 2018 11 1629 >18 MSF 11 clinical
October 2h PF and endpoints (SPF
2/3 Ongoing 25 >18
NCT03461757 2018 MSF etc.)

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July 2019 AEs 21 clinical
NCT03266588* January (frequency, endpoints (SPF
834

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2021 severity) etc.)
2 Completed 6 195 18- Liver function
NCT03732638* MMDs
2 Completed 5 1672 65 reduction 50% MMDs
3 Completed 17 1254 18- reduction, AEs,
Ubrogepant 3
3
Completed
Completed
December
2012 U
23
7
1686
40
65
18-
liver toxicity,
MIDAS, MQS,
No. of rescue
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75
NCT01613248 1 Completed December 4 2h PF and
18- medications
2012 MSF
76
NCT01657370* December 834 2h PF and
>18
ACHIEVE I 2/3 Completed 2017 5 PR 5 clinical
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18- endpoints (SPF

August 750 2h P and
50 etc.)
NCT02873221* 3 Ongoing 2018 29 MS
ACHIEVE II August 872 freedom 7 clinical
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2018 AEs endpoints (SPF

3 Ongoing 26 18- etc.)
NCT04179474 December 700 2h PF and
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75 MSF 6 clinical
2019 750
3 Ongoing 25 endpoints (SPF
Atogepant AUC0-t,
3 Ongoing 18 18- AUC0-∞, etc.)
80 Cmax ECG, laboratory
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NCT02848326* April 2018 data, C-SSRS

18- 21 clinical
August 80 endpoints
NCT03855137* 2021 MMDs
reduction 10
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8-80 pharmacokinetic
February endpoints
18-
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NCT03777059* 2020 MMDs

80 reduction
November MMDs > and <
NCT03700320* 2020 MMDs
12 weeks, 50%
reduction
November MMDs reduction
NCT03939312* 2020 50% MMDs
AEs reduction, MSQ,
AEs medication use,
AIM-D
50% MMDs
reduction, AIM-
D, No. of rescue
medications
ECG, laboratory
data, C-SSRS
 ECG, laboratory
data, C-SSRS

AEs = Adverse Events; AIM-D = Activity Impairment in Migraine - Diary; AUC = Area Under the Curve; Cmax =
Maximum Concentration; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; MIDAS =
Migraine Disability Assessment Score; MMDs = Monthly Migraine Days; MSF = Migraine Symptoms Freedom; MSQ
= Migraine-Specific Quality of Life; NCT = National Clinical Trial identifier on www.clinicaltrials.gov; No. = number;
PF = Pain Freedom; PR = Pain Relief; SPF = Sustained Pain Freedom; * data not published.

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