Pevonedistat (MLN4924): A Comprehensive Review of a First-in-Class NEDD8-Activating Enzyme Inhibitor from Preclinical Promise to Pivotal Trial Outcomes

Executive Summary

Pevonedistat (MLN4924) is an investigational, first-in-class small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a critical upstream regulator of the ubiquitin-proteasome system. By targeting the neddylation pathway, Pevonedistat disrupts the activity of Cullin-RING E3 ubiquitin ligases (CRLs), leading to the accumulation of specific CRL substrate proteins. This accumulation induces a state of proteotoxic stress characterized by cell cycle disruption, DNA damage, and ultimately, apoptosis in malignant cells. This novel mechanism of action positioned Pevonedistat as a promising therapeutic agent for hematologic malignancies, particularly for older, transplant-ineligible patients with higher-risk myelodysplastic syndromes (HR-MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), where the standard of care has long been limited to hypomethylating agents (HMAs) with suboptimal outcomes.

The clinical development of Pevonedistat followed a trajectory of significant promise followed by profound disappointment. Early phase studies established a manageable safety profile and a recommended Phase 2 dose when combined with azacitidine. A randomized Phase 2 trial (NCT02610777) generated compelling evidence of clinical activity, particularly in the HR-MDS subgroup, where the combination of Pevonedistat and azacitidine nearly doubled the complete remission rate and significantly improved event-free survival compared to azacitidine alone. These highly encouraging results led the U.S. Food and Drug Administration (FDA) to grant Pevonedistat a Breakthrough Therapy Designation in 2020, signaling its potential to be the first novel treatment for this patient population in over a decade.