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Published online: 4 February 2016
© Springer International Publishing Switzerland 2016
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.
1 Introduction
Proteasome inhibitors, together with immunomodulatory drugs, now form the basis of many treatment regimens for multiple myeloma, in first-line therapy (in the transplant and nontransplant settings) as well as for the treatment of relapsed disease [1-3]. Combination therapy has become a standard-of-care in many situations because of synergistic properties of agents with different mechanisms of action [1, 2].
The first-in-class proteasome inhibitor bortezomib [4], and the second generation agent carfilzomib [5], are both limited by their requirement for parenteral administration (intravenous or subcutaneous injection for bortezomib; intravenous injection for carfilzomib) [3, 6]. Ixazomib (Ninlaro^) is a once-weekly, orally-bioavailable proteasome inhibitor [7]. It was originally selected from a large pool of boron-containing proteasome inhibitors with physicochemical properties distinct from bortezomib [8], and has since progressed through clinical development.
Based on interim results of the pivotal phase III TOURMALINE-MM1 trial [9], ixazomib received its first global approval, in the USA, on 20 November 2015, for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy [10]. Ixazomib is the first, and to date only, orally-administered proteasome inhibitor to be approved in the treatment of multiple myeloma. The recommended dosage regimen for ixazomib in combination with lenalidomide and dexamethasone is...