Factor XI(a) inhibitors for thrombosis: an updated patent review (2016-present)

ABSTRACT

Introduction: Anticoagulation without bleeding is an ideal goal in treating thrombosis, however, this goal has not been achieved. All current anticoagulants are associated with significant bleeding which limits their safe use. Genetic and pharmacological findings indicate that factor XIa is a key player in thrombosis, yet it is a relatively marginal one in hemostasis. Thus, factor XIa and its zymogen offer a unique opportunity to develop anticoagulants with low bleeding risk.

Areas covered: A survey of patent literature has retrieved more than 50 patents on the discovery of novel therapeutics targeting factor XI(a) since 2016. Small molecules, monoclonal antibodies, oligonucleotides, and polypeptides have been developed to inhibit factor XI(a). Many inhibitors are in early development and few have been evaluated in clinical trials.

Expert opinion: Factor XI(a) is being actively pursued as a drug target for the development of effective and safer anticoagulants. Although many patents claiming factor XI(a) inhibitors were filed prior to 2016, recent literature reveals a moderately declining trend. Nevertheless, more agents have entered different levels of clinical trials. These agents exploit diverse mechanistic strategies for inhibition. Although further development is warranted, reaching one or more of these agents to the clinic will transform the anticoagulation therapy.

KEYWORDS:

• Thrombosis
• safe anticoagulants
• factor XIa
• active site inhibitors
• pyridine-N-oxide
• oxopyridine
• macrocyclic
• β-lactam
• monoclonal antibodies
• aptamers

Article highlights

• Factor XIa is a homodimeric coagulation serine protease which continues to be an attractive drug target for effective and relatively safer anticoagulants.

• Small molecules and monoclonal antibodies dominate the drug development arena for factor XI(a) inhibition.

• The past 3 years have witnessed an increase in the number of clinical trials that evaluate the efficacy and safety of factor XI(a) inhibitors.

• Small molecules offer the convenience of oral administration, whereas monoclonal antibodies provide the benefits of monthly dosing and the independence of the drug clearance process from hepatic and renal systems.

This box summarizes key points contained in the article.

Declaration of interest

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

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

Additional information

Funding

This work was supported by NIGMS under award number [SC3GM131986] and by IDeA program from NIGMS under grant number [P20GM103424]. The content is solely the responsibility of the author and does not necessarily represent the official views of NIH.