Factor XII(a) inhibitors: a review of the patent literature

ABSTRACT

Introduction: Blood coagulation factor XII (FXII) is an emerging and potentially safe drug target, which dysregulation is associated with thrombosis, hereditary angioedema, and (neuro)inflammation. At the same time, FXII-deficiency is practically asymptomatic. Industrial and academic institutions have developed a number of potential therapeutic agents targeting either FXII zymogen or its active form FXIIa for the treatment of thrombotic and inflammatory conditions associated with the activity of this enzyme.

Areas covered: A short overview of the FXII(a) structure and function, underlining its suitability as a drug target, is given. The article reviews patents reported over the last three decades on FXII(a)-targeting therapeutic agents. These agents include small molecules, proteins, peptides, oligonucleotides, siRNAs, and monoclonal antibodies.

Expert opinion: The performed analysis of patents revealed that many FXII(a) inhibitors are in the early preclinical stage, while several already showed efficacy in vivo animal models of thrombosis, sepsis, hereditary angioedema, and multiple sclerosis. Two anti-FXIIa agents namely tick protein Ir-CPI and monoclonal antibody CSL312 are currently in human clinical trials. The results of these trials and further studies of FXII(a) pathophysiological functions will encourage the development of new FXII(a) inhibitors.

KEYWORDS:

• Factor XII
• thrombosis
• drug discovery
• safe anticoagulants
• hereditary angioedema
• serine proteinase inhibitors
• contact pathway
• monoclonal antibodies
• covalent inhibitors
• neuroinflammation

Article highlights

• Factor XIIa is a serine protease, which initiates the intrinsic blood coagulation pathway and the kallikrein/kinin system, dysregulation of this enzyme is associated with thrombosis, hereditary angioedema, and (neuro)inflammation.

• Considering FXII(a) as a promising drug target, a number of patents disclosing potential therapeutic agents targeting either FXII zymogen or its active form have been issued over the past three decades.

• New inhibitors of FXII(a) are structurally diverse and include small molecules, proteins, peptides, oligonucleotides, siRNAs, and monoclonal antibodies.

• Although many FXII(a)-targeting agents are in the early preclinical stage, several already showed their high efficacy in animal models of thrombosis, sepsis, hereditary angioedema, multiple sclerosis, and even progressed into human clinical trials.

This box summarizes key points contained in the article.

Declaration of interest

The author has 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

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

Additional information

Funding

The author states no conflict of interest and has received no payment for the preparation of this manuscript.