Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML

Abstract

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.

Neddylation inhibition upregulates PD‐L1 expression and enhances the efficacy of immune checkpoint blockade in glioblastoma

“…6,7 Pevonedistat treatment largely blocks cullin neddylation and inhibits cullin-RING E3 ligase activity, and in turn leads to the accumulation of tumor suppressor substrates to induce cell-cycle arrest, senescence or apoptosis in GBM cells. [8][9][10][11][12] Thus, developing a rational combination therapy with pevonedistat may improve anticancer strategy. 5 Several combinations of pevonedistat and anticancer agents have been proposed to enhance the cytotoxic effect of pevonedistat.…”

“…5 Several combinations of pevonedistat and anticancer agents have been proposed to enhance the cytotoxic effect of pevonedistat. [8][9][10][11][12] Thus, developing a rational combination therapy with pevonedistat may improve anticancer strategy.…”

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

“…Soucy et al reported potent inhibition of Uba3 in the single-digit nanomolar range with cross-reactivity against other E1s in the low micromolar range (Soucy et al, 2009). Pevonedistat is currently being tested in clinical trials of patients with acute myeloid leukemia, where the principal side effect seems to be liver toxicity and sepsis due to disruptions in the GTPase RhoA cytoskeleton protein and tumor necrosis factor (TNF)-α (Swords et al, 2017;Swords et al, 2018).…”

Breaking the Fourth Wall: Modulating Quaternary Associations for Protein Regulation and Drug Discovery

“…An example of this mechanism is the NEDD8-E1 enzymei nhibitor (MLN4924;S cheme 1), which is in clinical trials for the treatment of chronic myelomonocytic leukemia anda cute myeloid leukemia. [30] Thism olecule forms ac ovalent complex with Nedd8, which has high affinity for aN EDD8-specific activating enzyme,U BA3 [31] (Figure 2). Alternatively,PPI inducers can stimulate gain-of-function behavior.O ne example of this behavior is the approved acute promyelocytic leukemia drug, arsenic tri-oxide.…”

“…The resulting modifiedprotein is apotent inhibitoro fU BA3, forming as table modified NEDD8-UBA3complex. [30,31,46] UBA3 is typically complexedtot he regulatory factor, NEDD8-activating enzymeE 1r egulatory subunit (NAE1); however,NAE1 is omitted here for clarity. ChemBioChem 2019ChemBioChem , 20,1091ChemBioChem -1104 www.chembiochem.org the BCLX L -specific inhibitor A-1331852 has been the subject of severalstudies, but has not yetreached clinicaltrials.…”