Positioning the new drugs for migraine

KEYWORDS:

• CGRP(r) monoclonal antibodies
• combination therapy
• ditans
• drug-drug interactions
• gepants
• migraine
• precision medicine
• safety

1. Introduction

The importance of migraine as a biopsychosocial disease with its impressive global burden, which arises from the detrimental effects on patients’ personal, professional, and social performances of and causes huge public health expenditure, is now fully established.

Notwithstanding the easy-to-go diagnostic workout and a general population prevalence exceeding 11%, the management of migraine and its multi-faceted biopsychosocial consequences is still far from optimal [1].

Up to date, guidelines strongly push therapeutic innovation mainly based on inhibiting the pathways involving a key peptide in the pathophysiology of headaches, the Calcitonin Gene-Related Peptide (CGRP) [2].

2. Toward new therapeutic approaches

Currently, there are innovative preventive drugs that act on specific mechanisms of migraine genesis, monoclonal antibodies (MAbs), eptinezumab, erenumab, galcanezumab, fremanezumab, targeting CGRP or its receptor (CGRP (r)). This new pharmacological class has shown high efficacy and an optimal safety profile. However, the therapeutic management of migraine is not yet definable as optimal over time [2]. Unfortunately, erenumab, galcanezumab, fremanezumab seem to have not precisely reached the neediest group of migraine patients, those with countless preventive failures [^3–6].

Similarly, the botulinum toxin type A (BTX-A), which has been available for more than ten years to treat chronic migraine, despite showing overtime progressive increasing efficacy in patients, has not reached the majority of target patients. As a matter of fact, either for organizational reasons or for the easier prescription [7], patients continued to be treated with the so-called Standard of Care (SOC), miscellaneous small molecule drugs that represented the sole therapeutic option before BTX-A advent, indeed.

While moving from the SOC to the new therapies, combined, either ab initio or because of an add-on process, therapeutic regimens should be discouraged, as MAbs have shown to be an efficacious treatment for patients with previous therapeutic failures of SOC [8–10]. In addition, combination therapy increases the risk of possible Adverse Drug Reactions (ADR) with an uncertain causal relationship and the consequent impossibility of a selective drug withdrawal [11].

3. A risk analysis prescription model

The positioning of new drug classes in the therapeutic flow is based on the efficacy, safety, and tolerability profile of the single molecules, on their interaction potential, and on the administration route and posology, which determine the ease of use by patients and, finally, their adherence and persistence. These dimensions and parameters are carefully investigated during the clinical development of drugs and increasingly clarified through the real-world evidence accumulating over time. Importantly, in the last decades, in addition to the abovementioned classical dimensions of clinical pharmacology, the pharmacoeconomic profile of drugs has been receiving increasing attention.

Today, there is a wide choice of new molecules for the prevention and acute treatment of migraine attacks (Table 1). Currently, CGRP(r) MAbs are placed in therapy with their different routes and timing of administration, monthly subcutaneous (erenumab, fremanezumab, galcanezumab) or quarterly intravenous (eptinezumab) [3–6]. Considering possible characteristics exploitable to optimize the prescription of the different CGRP(r) MAbs, which all target CGRP or its receptor with superimposable potency and selectivity, we may focus on the route and frequency of administration, but also the peak serum concentration (Cmax) and the time to reach it (Tmax) (https://go.drugbank.com). Table 1 reports, together with the similar volume of distribution (Vd) values, the significant differences in Tmax: current eptinezumab intravenous formulation ensures a full (100%) bioavailability, with a Tmax of less than 5 hours from the start of the 1-hour infusion, while for other MAbs, the time-lag between subcutaneous administration and reaching Cmax ranges between 5 and 11 days (https://go.drugbank.com). According to the differential pharmacokinetics profiles, no objection may be theoretically raised against the use of eptinezumab to treat attacks in selected settings, such as of refractory/resistant migraine accessing the Emergency Department (ED).

Table 1. Tmax and distribution volume (VD) of anti-CGRP(r) MAbs

	Tmax	DISTRIBUTION VOLUME
DRUG
EPTINEZUMAB	3–4,8 hours	3,7 L
ERENUMAB	6 days	3,6 L
FREMANEZUMAB	5–11 days	6 L
GALCANEZUMAB	5 days	7,3 L

Tmax: time to reach maximum concentration

VD: distribution volume

In the EU, headaches, mostly due to resistant/refractory migraine and only in a few cases to secondary headaches such as subarachnoid hemorrhage, stroke, head trauma, or brain tumors, account for 4% of all accesses to the ED [12]. After a diagnosis of migraine, evidence-based specific treatments are rarely prescribed, preferring nonspecific analgesia with the most disparate and often only transiently effective approaches [12]. In addition, the referral to the Headache Centers for the possible evaluation of a de novo or a changed prevention therapy is not a standard process, being often exquisitely physician expertise-dependent, with unavoidable delay in the therapeutic process [13].

Based on the abovementioned pharmacokinetics and clinical considerations, it is rational to hypothesize the use of eptinezumab in the ED as a transitional acute treatment for resistant/refractory migraine to be then continued as a preventative [14–16]. Importantly, the intravenous administration will ensure a fast and reliable (bioavailability is not impaired by migraine-related gastrointestinal disturbances) targeting a migraine-specific mechanism that currently cannot be ensured by any other drug, except for subcutaneous sumatriptan.

Currently, clinical medicine is oriented toward combination therapies including drugs targeting the same pathophysiological route, but at different levels. As for the new oral small molecules which all target CGRP receptor as antagonists, the gepants for attack treatment (ubrogepant, rimegepant, zavegepant) and prevention (atogepant, rimegepant) [17–20], a simple criterion of prudence may be usefully kept in mind. Combination therapies for migraine, including both transient association of SOC and CGRP(r) MAbs and combined administration of drugs directly targeting the same mechanism (i.e. CGRP), should be avoided [8–10]. In the first case, if SOC has failed, there is no rational reason to co-prescribe it with CGRP(r) MAbs; in the second case, at least theoretically, there is an increased risk of ADR (11). For acute migraine, lasmitidan, because of its different therapeutic target (5HT_1F), although possible modulation of CGRP pathway should be considered [21], should guarantee a non-cross influence [22].

4. Conclusions

In the parterre of migraine drugs, now including CGRP(r) MAbs, gepants and ditans, it is still wise to optimize the positioning of these new drugs according to their clinical pharmacology [23]. Without specific evidence of clinical efficacy, it is advisable to limit empirical combination therapy only to drugs targeting different process of pathophysiological mechanisms to minimize the risk of ADR [24]. Importantly, some pharmacokinetics peculiarities may be considered the rationale to test the use of specific drugs in specific settings (i.e. intravenous eptinezumab as rescue treatment in the emergency department to be then continued as preventative). Further properly sized clinical studies are needed to define optimal positioning of specific migraine drugs, in terms of both efficacy and safety.

5. Expert opinion

Due to the paucity of head-to-head trials between different pharmacological classes, it is still impossible to properly confer them their relative therapeutic value. Nowadays, the prescription of combination therapy for prophylaxis is not evidence based and, in everyday practice, some settings (i.e. acute treatment in the emergency room) still remain somehow orphan.

According to the recent introduction of new pharmacological approaches (i.e. CGRP targeting therapy), one of the ultimate goal in the field of migraine treatment is to find the appropriate positioning of different drug classes (combination therapy?) and active principles (eptinezumab for acute treatment in the emergency room) and, in the coming years, clinical research should move in this direction.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed receiving a consulting fee from Trillen Medical Inc. in the past 2 years. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The paper was not funded.