Ixazomib: the First Oral Proteasome Inhibitor for the Treatment of Multiple Myeloma

PHARMACOTHERAPY 229

Ixazomib: the first oral proteasome inhibitor for the treatment of multiple myeloma

K.L. Wu, MD, PhD

SUMMARY The ubiquitin-proteasome system is a major pathway for the degradation of most intracellular proteins and therefore plays an essential regulatory role in cellular processes including cell cycle progression, proliferation, differentiation and apoptosis. The recognition of its importance in tumorigenesis has led to the development of agents that target this pathway as cancer therapeutics. Bortezomib is the first proteasome inhibitor approved for clinical use and has a profound impact on the survival of patients with multiple myeloma. Ixazomib is a promising second generation proteasome inhibitor. (BELG J HEMATOL 2017;8(6):229-31)

INTRODUCTION Ixazomib is a second-generation proteasome inhibitor and The treatment landscape for multiple myeloma (MM) patients the first oral compound. In November 2015, the US Food and is constantly evolving. In the past decade, the introduction Drug Administration (FDA) approved ixazomib (Ninlaro®) of novel agents such as bortezomib and immunomodulatory in combination with lenalidomide and dexamethasone for drugs (thalidomide and lenalidomide) has resulted in notable the treatment of MM patients who have received at least one changes in therapeutic strategy and improvements in survival. prior therapy. This first all-oral, proteasome inhibitor-con- Combining agents with different mechanisms of action and taining, triplet combination is highly effective and overall prolonging duration of therapy are new strategic approaches. well tolerated.

A B

FIGURE 1. Chemical structure of bortezomib (A) and ixazomib (B).

Department of Haematology, ZNA Stuivenberg, Antwerp, Belgium. Please send all correspondence to: K.L. Wu, MD, PhD, Department of Haematology, ZNA Stuivenberg, Lange Beeldekensstraat 267, 2060 Antwerp, Belgium, tel: +32 3 217 73 92, email: [email protected]. Conflict of interest:The author has nothing to disclose and indicates no potential conflict of interest. Keywords: ixazomib, multiple myeloma, pharmacotherapy, proteasome inhibitor.

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IXAZOMIB: CHEMICAL STRUCTURE AND PFS was 20.6 months in patients receiving the ixazomib MECHANISM OF ACTION combination and 14.7 months in the placebo plus lenalido- Ixazomib is a reversible proteasome inhibitor with structural mide and dexamethasone group. The hazard-ratio for disease similarity to bortezomib (Figure 1). It has an alanine-leucine progression was 0.74, representing a 40% longer PFS with dipeptide core with a citrate-protected boric acid. After ex- ixazomib combination as compared with placebo plus posure to aqueous solution, the citrate ester core hydrolyses lenalidomide and dexamethasone. The superior PFS with and the free boric acid metabolite MLN2238 targets the the ixazomib combination was consistent in all subgroups, beta 5 chymotrypsin-like subunit of the 20S proteasome. including patients with high-risk cytogenetic features. Ixazomib has a short proteasome dissociation half-life (18 The overall response rate (ORR) was 78% in the ixazomib minutes) compared to bortezomib (110 minutes).1 group and 72% in the placebo group. After a median follow- Studies in human MM cells showed that various concentra- up of 23 months, the median overall survival was not reached tions of ixazomib can induce caspase-dependent apoptosis in either study group. of MM cell lines which are sensitive and resistant to conven- Overall, the toxicity rate was similar in both groups. The most tional therapy, and in MM cells obtained from bortezomib- common adverse reactions (grade ≥3) were neutropenia and lenalidomide-resistant patients.2 (23%), thrombocytopenia (19%), diarrhoea (6%), rash (7%), fatigue (4%) and nausea (2%). The incidence of peripheral PHARMACOKINETICS neuropathy was 27% and were almost all low-grade (2% A phase I dose-escalation study of twice-weekly oral ixazomib grade ≥3). determined that the maximum tolerated dose (MTD) was The oral triplet combination of ixazomib, lenalidomide and 2.0mg/m2.3 Ixazomib was rapidly absorbed (Tmax of 1 hour) dexamethasone is being assessed in patients with newly and there was a dose dependent increase of plasma exposure. diagnosed MM (TOURMALINE-MM2). Ixazomib is also The dose limited toxicities were grade 3 rash and grade 4 being evaluated as maintenance therapy in MM patients thrombocytopenia. after autologous stem cell transplantation (TOURMALINE- With once-weekly dosing, the MTD was determined at MM3). 2.97mg/m2.4 The terminal half-life was long (3.6- 11.3 days), supporting the once-weekly dosing. Based on a population CONCLUSION pharmacokinetic analysis, the 2.97 mg/m2 MTD of once- The introduction of proteasome inhibitors has a major im- weekly dosing can be converted into a fixed-dose equivalent pact on the survival of MM patients. Ixazomib is a second- of 4.0 mg.5 generation proteasome inhibitor. Major advantages of ixazomib are the ability to overcome bortezomib resistance, the IXAZOMIB IN CLINICAL TRIALS favourable tolerability and the oral formulation. The addition Phase I/II studies with ixazomib, as a single agent or in of ixazomib to a regimen of lenalidomide and dexametha- combination with dexamethasone, demonstrated the anti- sone, improves the progression free survival in MM patients tumour activity in MM patients with relapsed and refractory with relapsed or refractory disease and has limited additio- disease.3,4,6 More promising results were obtained with the nal toxicity. combination of ixazomib, lenalidomide and dexamethasone in patients with newly diagnosed MM. Early phase study of REFERENCES this triplet combination showed an overall response rate of 1. Kupperman E, Lee EC, Cao Y, et al. Evaluations of proteasome inhibitor 90%, with 62% of the patients achieved a very good partial MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70(5):1970-80. response or better.7 2. Chauhan D, Tian Z, Zhou B, et al. 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KEY MESSAGES FOR CLINICAL PRACTICE

1 Ixazomib (Ninlaro®) is a second-generation and the first oral proteasome inhibitor.

2 Side effects of ixazomib are infrequent and easy manageable.

3 The oral-triplet combination ixazomib, lenalidomide, and dexamethasone for relapsed/refractory multiple myeloma is approved by the FDA in November 2015.

4 Ixazomib received a positive opinion on the marketing authorisation by the Committee for Medical Products for Human Use (CHMP) in September 2016.

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