Tropomyosin receptor kinase inhibitors: an updated patent review for 2016–2019

ABSTRACT

Introduction: Tropomyosin receptor kinases (Trks) control processes in the fields of growth, survival, and differentiation of neuronal processes. They also play a crucial role in neurodegenerative diseases as well as different types of cancer. Interest in developing Trk inhibitors to target NTRK fusion-driven cancers has escalated in the last decade, leading to the FDA approval of the pan-Trk inhibitors entrectinib and larotrectinib. The development of next-generation inhibitors that overcome resistance mutations arising from treatment with these first generation inhibitors has been the focus in recent years.

Area covered: In this updated patent review for 2016–2019, patents covering inhibitors targeting the Trk family are discussed as a continuation of the previous reviews, Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – Parts 1 & 2. The status of Trk inhibitors in clinical trials is also evaluated. For the identification of relevant patents and clinical trials, Web of Science, Google, Google Patents, and patent referencing were used.

Expert opinion: The FDA approval of larotrectinib and entrectinib is a prime example of how basket clinical trial design targeting oncogenic drivers, regardless of tumor histology, is a viable approach to drug discovery and embodies the shift toward personalized medicine.

KEYWORDS:

• Tropomyosin receptor kinase
• TrkA
• TrkB
• TrkC
• NTRK
• Trk inhibitor
• cancer treatment
• chronic pain
• entrectinib
• larotrectinib
• targeted therapy
• selitrectinib
• resistance mutations
• allosteric inhibitors

Article Highlights

• Structural diversification of Trk inhibitors has been in decline compared to previous years where novel drug classes were developed and drugs were repurposed.

• Interest in personalized medicine and tissue-agnostic drug development has increased in light of the FDA approval of larotrectinib and entrectinib as first-generation inhibitors for Trk fusion-positive cancers.

• The anticipated development of secondary resistances after treatment with first-generation Trk inhibitors has driven the development of next-generation inhibitors to overcome treatment acquired resistance mutations.

• Basket clinical trial design and next-generation sequencing reinforce the era of personalized medicine.

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 paper was not funded.