Emerging experimental drugs in clinical trials for migraine: observations and key talking points

ABSTRACT

Introduction

There have been significant advances in the treatment of migraine. In response to the clinical success of monoclonal antibodies targeting calcitonin gene-related peptide, there is interest in the clinical trial outcomes of alternative emerging drugs that act on novel targets associated with migraine pathophysiology. As approximately 50% of patients do not respond to CGRP therapies, there is significant value in future drug innovation. Emerging drugs in clinical trials for the treatment of migraine aim to fill this need.

Areas covered

The emerging drugs that will be discussed in this review include zavegepant, lasmiditan, delta opioid receptor agonists, neuronal nitric oxide synthase inhibitors, monoclonal antibodies targeting pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor, dual orexin receptor antagonists, metabotropic glutamate receptor 5 antagonists, and inducers of ketosis.

Expert opinion

When considering the preclinical and clinical research related to the emerging drug classes discussed in this review, most therapies are derived from highly supported targets of migraine pathogenesis. Although the individual drugs discussed in this review may be of dubious clinical value, the importance of the therapeutic targets on which they act cannot be understated. Future research is necessary to appropriately target the pathways elucidated by preclinical studies.

KEYWORDS:

• CGRP
• Lasmiditan
• Migraine
• PACAP
• Zavegepant

Article highlights

• Zavegepant has become the first intranasally administered gepant to gain FDA approval for the acute treatment of migraine. Zavegepant has a favorable safety profile, a rapid time to maximum concentration, and is not associated with medication overuse headache.

• Lasmiditan, the only FDA approved ditan (5-HT1F agonist), may be valuable in the acute treatment of migraine when triptans are contraindicated due to cardiovascular comorbidities. Lasmiditan is conducting further clinical trials that aim to demonstrate efficacy and safety in the pediatric population.

• Although there are few recent clinical trials investigating the efficacy of the delta-opioid receptor agonists and neuronal nitric oxide synthase inhibitors, results from preclinical studies greatly support these emerging drug classes as future treatments of acute migraine episodes.

• Little information remains available concerning the safety and efficacy of monoclonal antibodies targeting PACAP or PAC1. Although supported by significant preclinical research, previous clinical studies of AMG 301 failed to demonstrate efficacy. Lu AG09222 recently completed a phase 2 trial, the results of which are highly anticipated.

• An inducer of ketosis, tricaprilin, completed a phase II clinical trial aiming to demonstrate efficacy in the preventative treatment of migraine. Although the role of ketosis in migraine remains debated, the results of this study are anticipated.

• There have been few recent clinical trials studying the efficacy of dual orexin receptor antagonists or metabotropic glutamate receptor 5 antagonists in the preventative treatment of migraine. Although the clinical trials studying readily available drugs targeting these pathways either resulted in a lack of efficacy or termination due to an increase in adverse events, these targets are supported by significant preclinical studies. Novel drug innovation targeting these pathways may be of great clinical value.

Declaration of interests

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 that within the past 24 months, they have received funding from NIH; institutional support for serving as an investigator from Teva, AbbVie, Trillen, Thermaquil; consultant fees from Salvia, Pfizer, Cerenovus; and royalties from Cambridge University Press and MedLink. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.