Investigational Janus kinase inhibitors in development for myelofibrosis

ABSTRACT

Introduction: Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development.

Areas covered: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail. NS-018 and INCB039110, selective inhibitors of JAK2 and JAK1, respectively, are also discussed. Finally, the JAK2 inhibitors no longer in clinical development are summarized in tabular form.

Expert opinion: The different agents evaluated clearly differ in their kinomes, toxicity profiles and potential for myelosuppression. If approved, the JAK2-specific non-myelosuppressive inhibitor pacritinib could fulfill a major unmet need, that of patients with significant cytopenias. However, toxicity concerns persist. The data from the pivotal trials of momelotinib do not support its approval, although improvement of anemia is an important benefit. Selective JAK1 inhibition alone is unlikely to succeed in myelofibrosis. In these circumstances, rational ruxolitinib-based combinations may represent the best way forward.

KEYWORDS:

• Myelofibrosis
• momelotinib
• pacritinib
• NS-018
• RUXOLITINIB
• INCB039110
• CHZ868
• JAK inhibitors

Article highlights

• Among the many JAK2 inhibitors tested, ruxolitinib remains the only one approved for the treatment of patients with myelofibrosis.

• The development of momelotinib has been halted based on the results of phase 3 studies in MF.

• The FDA’s ‘full clinical hold’ on pacritinib has been lifted, but further dose exploration studies will be required.

• The development of NS-018, a JAK2-selective inhibitor, for myelofibrosis continues.

• A number of investigational JAK2 inhibitors have been discontinued due to toxicity.

• Ruxolitinib-based combinations may represent the best way forward in the treatment of MF.

This box summarizes key points contained in the article.

Declaration of interest

P. Bose has received honoraria from Incyte Corporation for advisory board participation. S Vervovstek receives research funding from Incyte Corporation, Roche, Astra Zeneca, Lilly Oncology, Geron, NS Pharma, Bristol Myers Squibb, Celgene, Gilead, Seattle Genetics, Promedior, CTI BioPharma Corp., Galena BioPharma, Pfizer, Genentech and Blueprint Medicines Corp. 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 apart from those disclosed.

Additional information

Funding

This work was supported in part by the MD Anderson Cancer Center support grant [P30 CA016672] from the National Cancer Institute.