Inhibition of KIT for chronic urticaria: a status update on drugs in early clinical development

ABSTRACT

Introduction

Chronic urticaria (CU), including chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), is a prevalent, enduring, mast-cell driven condition that presents challenges in its management. There is a clear need for additional approved treatment options beyond H1 receptor antagonists and the anti-IgE monoclonal antibody (mAb), omalizumab. One of the latest therapeutic strategies targets KIT, which is considered the primary master regulator for mast cell-related disorders.

Areas covered

This review provides a status update on KIT inhibiting drugs in early clinical development for CU.

Expert opinion

Whereas multi-targeted tyrosine kinase KIT inhibitors carry the risk of off-target toxicities, initial data from anti-KIT mAbs indicate significant potential in CSU and CIndU. The prolonged depletion of mast cells over several weeks by barzolvolimab could effectively control urticarial symptoms. Regarding safety, based on theoretical considerations and the available preliminary results, it is already evident that there may be more side effects compared to omalizumab. However, long-term safety data beyond 12 weeks are still lacking. The outcome of ongoing or planned clinical trials with several anti-KIT mAbs will need to demonstrate benefits compared to anti-IgE in CU or whether one approach is better suited for specific urticaria endotypes.

KEYWORDS:

• Barzolvolimab
• briquilimab
• chronic urticaria
• chronic inducible urticaria
• chronic spontaneous urticaria
• KIT
• mast cell
• tyrosine kinases

Article highlights

• Chronic urticaria, including chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU), is characterized by the activation and degranulation of skin mast cells.

• Approximately 20% of patients do not respond to the currently approved and guideline-recommended treatments. For CIndU, there are currently no approved therapies beyond H1-RA.

• KIT is a master regulator of mast cells, which are the primary effector cells in CU.

• In contrast to small molecules that inhibit KIT, anti-KIT mAbs like barzolvolimab and briquilimab do not inhibit unrelated tyrosine kinases and are therefore expected to have fewer side effects.

• CSU and CIndU are the first non-cancer indications in which anti-KIT mAbs are being investigated.

• Preliminary clinical data of barzolvolimab in CSU and CIndU demonstrated a profound and durable reduction of skin mast cells associated with excellent control of urticaria activity.

• Adverse events associated with the intravenous application of barzolvolimab included infusion reactions, mild hematologic abnormalities, hair color changes, taste alterations, headaches, and infections.

• The following clinical trials of anti-KIT mAbs are either ongoing or planned:- Phase 3 clinical trials of subcutaneous barzolvolimab in CSU and CIndU (Celldex, recruiting)- Clinical trials of subcutaneous briquilimab in CSU and CIndU (Jasper, upcoming in 2024)- Clinical trial of SLRN-517 in CU is announced (Acelyrin, upcoming not specified)

Declaration of interest

The author has received honoraria for lectures and/or advisory boards from ALK-Abelló, Bencard, CSL Behring, Biocryst, Novartis, Sanofi-Aventis, Takeda, ThermoFisherScientific; all outside this work. The author has 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 apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.