Ixazomib: First Global Approval

Abstract

Ixazomib (Ninlaro(®)) is an orally bioavailable, reversible proteasome inhibitor developed by Millennium Pharmaceuticals, Inc. (now Takeda Oncology). Ixazomib acts by binding to and inhibiting the β5 subunit of the 20S proteasome. In November 2015, the US FDA approved ixazomib for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. Ixazomib is under regulatory review for this indication in the EU. Phase III development of ixazomib is underway worldwide for newly-diagnosed multiple myeloma (in patients who are not eligible for stem cell transplant, or as maintenance therapy) and for relapsed or refractory systemic light chain (AL) amyloidosis. Ixazomib is also under phase I-II development for the treatment of several other haematological and non-haematological malignancies, graft-versus-host disease and lupus nephritis. This article summarizes the milestones in the development of ixazomib leading to this first approval for multiple myeloma.

Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

“…The UPS is essential, ensuring orderly cell cycle progression, signal transduction, clearance of damaged proteins and maintenance of general protein homeostasis. Dysfunction in the UPS is associated with various diseases, as reviewed in refs 4, 5, with hyperactivation of proteasome function often invoked by cancer cells467 and inhibitors specifically targeting the CP (bortezomib, carfilzomib and ixazomib) used clinically to treat haematological cancers8910.…”

The Proteasome Ubiquitin Receptor hRpn13 and Its Interacting Deubiquitinating Enzyme Uch37 Are Required for Proper Cell Cycle Progression

“…Dysfunction in this pathway is associated with human diseases, and it has emerged as a major pharmaceutical target for cancer and neurodegenerative diseases (4). The proteasome inhibitors bortezomib (Velcade), carfilzomib (Kyprolis TM ), and ixazomib (Ninlaro) are approved to treat certain hematological cancers, and other inhibitors are in clinical trials (5)(6)(7)(8). Bortezomib resistance and the toxicity of approved proteasome inhibitors motivates efforts to find alternative approaches to target the ubiquitin-proteasome pathway (5,6).…”

Acute Pancreatitis Associated with Ixazomib in a Multiple Myeloma Patient

“…No details of any potential relationship between ixazomib and acute pancreatitis in this patient were given. There have, however, been several case reports on bortezomib-induced acute pancreatitis [6,7,8], and the lack of reported cases of ixazomib- and carfilzomib-associated acute pancreatitis may be in part due to their relatively recent regulatory approval in 2015 [9] and 2012 [10], respectively, compared to that of bortezomib in 2003 [11]. Alternatively, the relative risk for acute pancreatitis could also be influenced by the difference in the boronic-acid active moiety of bortezomib and ixazomib versus the epoxyketone active moiety of carfilzomib as well as differences in proteasome inhibitor specificity, as bortezomib also has activity against nonproteasomal serine and cysteine proteases [12].…”