Pevonedistat could spell the end for a rare anticancer mechanism

One of the interesting facts about Takeda’s pevonedistat is that it is the industry’s only NEDD8-activating enzyme inhibitor in clinical development, according to Evaluate Pharma and Whether it remains in trials for much longer is the next question, in light of yesterday’s failure of its key phase 3 study, Panther. In this trial, in high-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia and low-blast AML, pevonedistat failed in terms of event-free survival to beat Vidaza, an approved chemotherapy for MDS. Inhibition of NEDD8-activating enzyme is said to disrupt protein homeostasis and bring about cancer cell death, and pevonedistat combo and monotherapy had shown promise in terms of remission rates in early, uncontrolled studies. The only other NEDD8-activating enzyme inhibitor to have made it to the clinic appears to be Otsuka’s TAS4464, but this was put on hold and then scrapped after meeting Hy’s Law, indicating risk of drug-induced liver injury. reveals numerous ongoing academic-sponsored pevonedistat trials, most significantly Beat-AML, but Takeda’s remaining efforts amount effectively to one phase 2 test. Another phase 2 study – in MDS – is due to start next month, but given Panther’s failure it must now be seen as a long shot.

Selected studies of NEDD8 activating enzyme regulators
Project Company Trial Setting Data
Pevonedistat Millennium (Takeda)/ Ligand Panther (ph3) High-risk MDS, CMML & low-blast AML Failed to beat Vidaza on EFS, the primary endpoint
Pevanza (ph2) Chemo-unfit AML, Venetoclax + Vidaza combo Ends May 2023
Pevobine (ph2) High-risk MDS, decitabine + cedazuridine combo Set to begin Oct 2021
Uncontrolled ph1 Blood cancers or solid tumours with kidney/liver problems Ends Feb 2022
Uncontrolled ph1 East Asia study in AML & MDS 50% ORR as Vidaza combo (Ash 2018)
TAS4464 Taiho (Otsuka) Uncontrolled ph1 Multiple myeloma/lymphoma Trial terminated after meeting criteria for Hy's Law

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