Anti-CGRP monoclonal antibodies emerged as the most promising peptide-targeted migraine therapy in phase III trials, while substance P and nitric oxide-targeting approaches failed, and PACAP and kynurenic acid analogs show future promise.
CGRP success, SP failureOf all neuropeptide targets tested for migraine, only CGRP-targeting monoclonal antibodies reached Phase III with positive results, while substance P and NOS-targeting drugs were terminated — demonstrating the challenge of translating neuropeptide biology into effective therapies.
What the researchers found
The review assessed therapeutic strategies targeting neurogenic inflammation mediators in migraine:
- CGRP pathway: Phase III clinical trials of monoclonal antibodies against CGRP and the CGRP receptor showed the most promise — these would later become approved drugs (erenumab, fremanezumab, galcanezumab)
- Substance P: Preclinical and clinical studies targeting SP were all terminated with no significant benefit over placebo
- Nitric oxide synthase (NOS): Clinical trials targeting NOS were similarly terminated without significant results
- PACAP and PAC1 receptor: Identified as a promising new therapeutic target based on emerging evidence of PACAP's role in migraine
- Kynurenic acid (KYNA) analogs: Highlighted as another novel approach worth pursuing
Why it matters
This review captures a pivotal moment in migraine pharmacology — the transition from failed neuropeptide-targeting strategies (substance P, nitric oxide) to the successful development of anti-CGRP therapies that would soon revolutionize migraine treatment. Understanding which neuropeptide targets succeeded and which failed informs the next generation of drug development, particularly for PACAP-targeted therapies that are now in clinical development.
How the study worked
The authors conducted a systematic literature search of PubMed for studies published through January 2017 on therapeutic strategies in migraine related to neurogenic inflammation. The review focused on substances and cytokines released during neurogenic inflammation, covering preclinical and clinical drug development across multiple neuropeptide and neurotransmitter targets.
What this study cannot tell us
The literature search was limited to PubMed and studies published through January 2017, missing subsequent developments including the approval of anti-CGRP drugs (2018) and the advancement of PACAP-targeting therapies. The review primarily covers pharmacological approaches and may not fully address non-peptide targets or device-based treatments for migraine. As a review focused on neurogenic inflammation, it may underrepresent other migraine mechanisms like cortical spreading depression.
How to read the evidence
This is a systematic review of the drug development landscape for migraine neuropeptide therapies, covering preclinical through Phase III clinical data. It provides a high-level synthesis of evidence across multiple therapeutic targets, though it is limited by its 2017 search date.
When this study was published
Published in 2017, this review predates the approval of anti-CGRP drugs (erenumab approved 2018) that validated its main finding. The PACAP and kynurenic acid directions identified remain active areas of research. The substance P and NOS failure conclusions remain unchanged.
The bigger picture
The migraine neuropeptide story is one of the great drug development narratives in modern medicine. Despite decades of knowing that substance P, CGRP, and other neuropeptides were involved in migraine, only CGRP-targeted therapies proved clinically effective. This illustrates that understanding a peptide's involvement in disease does not guarantee it's a viable drug target. The review's identification of PACAP as a next-generation target has proven prescient — anti-PACAP antibodies are now being tested in clinical trials years after this review was published.
Questions still open
- Why did CGRP-targeted therapies succeed where substance P-targeted approaches failed, despite both peptides being involved in migraine?
- Will anti-PACAP therapies prove effective for migraine patients who don't respond to anti-CGRP drugs?
- Could combination therapies targeting multiple neuropeptides simultaneously provide better migraine relief than single-target approaches?
Common questions
Which neuropeptides are involved in migraine, and which are we targeting with drugs?
Why didn't substance P drugs work for migraine even though substance P is involved in migraine pain?
Read the original research
Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects.
Current medicinal chemistry, 24(33), 3649-3665
Citation
Lukacs, Melinda; Tajti, Janos; Fulop, Ferenc; Toldi, Jozsef; Edvinsson, Lars; Vecsei, Laszlo. (2017). Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects.. Current medicinal chemistry, 24(33), 3649-3665. https://doi.org/10.2174/0929867324666170712163437