Pyoderma gangrenosum: proposed pathogenesis and current use of biologics with an emphasis on complement C5a inhibitor IFX-1

ABSTRACT

Introduction

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis with no FDA-approved treatment. The complement pathway has received renewed attention because it is elevated in inflammatory cutaneous conditions such as hidradenitis suppurativa (HS) and psoriasis. IFX-1 is a complement C5a inhibitor which inhibits neutrophil activation, chemotaxis, and reduces inflammatory signaling and complement driven tissue damage in various diseases.

Areas covered

The article discusses a proposed pathogenesis of PG, early clinical investigations of IFX-1 for the treatment of HS and PG, its potential as a treatment for PG, and those other biologics currently under investigation.

Expert opinion

Further studies should explore how patients with PG and other neutrophilic conditions may respond to complement inhibitors such as IFX-1. C5a blockade led to a reduction in inflammatory tunnels in HS, and alteration in neutrophil migration and activation supports the role of this pathway in the development of PG. The main challenges to the approval of IFX-1 are the identification of the optimal dose, duration, and stage-dependent factors in cutaneous inflammatory disorders. Further studies are required; however, complement inhibitors such as IFX-1 could find a place in clinical practice in years to come for severe, resistant PG that does not respond to conventional therapies.

KEYWORDS:

• C5a
• pyoderma gangrenosum
• IFX-1
• clinical trial
• hidradenitis suppurativa
• complement
• neutrophilic dermatoses
• pathophysiology

Box 1. Drug summary

Article highlights

• PG is a rare neutrophilic dermatosis that presents as an inflammatory ulcerative disorder.

• We review the current clinical trials and a proposed pathogenesis model for PG.

• There are no FDA-approved drugs for the treatment of PG and most biologics under investigation for PG are limited to small case reports or cohort studies.

• IFX-1 is a complement C5a inhibitor which has demonstrated complete remission in 2 out of 5 patients with PG in a recent Phase IIa open-label trial, with no reported serious adverse events.

• IFX-1 also showed an acceptable safety profile in hidradenitis suppurativa (HS) but did not achieve significant clinical response vs. placebo in a phase IIb study. However, there was a significant reduction in draining fistulas and IHS4 scores.

• Although more studies are required, complement inhibitors such as IFX-1 could find a place in clinical practice in the following years for severe, resistant PG that does not respond to conventional therapies.

This box summarizes key points contained in the article.

Declarations of interest

A Alavi has received honoraria as a consultant, speaker, or advisory board participant from AbbVie, Galderma, Janssen, LEO, Novartis, Sanofi, and Valeant; received grants from AbbVie; and was a research investigator with AbbVie, Aristea, Asana, Boehringer-Ingelheim, Bristol-Myers Squibb, Dermavant, Eli Lilly, Genetech, Glenmark, Incyte, Infla Rx, Janssen, Kyowa, LEO, Novartis, Pfizer, Regeneron, and UCB. A Ortega-Loayza was part of the advisory board for Janssen Inc. The authors have no other 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.

Disclosure statement

AA has acted as a consultant, advisor, and/or received research funding from Abbvie, Galderma, Janssen, LEO Pharma, Novartis, Sanofi Aventis, Valeant, Boehringer-Ingelheim, DSBiopharma, Eli Lilly, Kymera, Kyowa Glenmark, Incyte,InflaRx , Ilkos, Merck Serono, Pfizer, Regeneron, Roche, Xenon, and Xoma.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.