Takeda's First-in-Class NAE Inhibitor Pevonedistat Receives FDA Breakthrough Therapy Designation for Higher-Risk Myelodysplastic Syndromes

Takeda Announces FDA Breakthrough Therapy Designation for Investigational Drug Pevonedistat in High-Risk Myelodysplastic Syndromes (HR-MDS)Takeda announced today that the U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to its investigational drug pevonedistat for the treatment of patients with high-risk myelodysplastic syndromes (HR-MDS). Pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor and has the potential to become the first innovative therapy for HR-MDS patients in over a decade. Currently, treatment options for these patients are limited to hypomethylating agents (HMAs), and prognosis remains poor even with existing therapies.

MDS is a rare bone marrow-related cancer caused by abnormal blood cell production in the bone marrow. This cancer most commonly affects elderly patients, with a median age at diagnosis ranging from 60 to 74 years. Due to abnormal blood cell production, MDS patients do not have sufficient normal red blood cells, white blood cells, and/or platelets in their circulation.

Based on blood cell counts, blast counts, mutations, and cytogenetics, MDS can be classified into several categories ranging from very low risk to very high risk. Approximately 40% of patients with high-risk MDS (HR-MDS) progress to acute myeloid leukemia (AML), another aggressive cancer with a poor prognosis.

Pevonedistat is a “first-in-class” NEDD8-activating enzyme (NAE) inhibitor. In preclinical studies, pevonedistat’s inhibition of NAE blocks the modification of specific proteins, thereby disrupting cell cycle progression and cell survival, leading to cancer cell death.

▲Molecular structure of Pevonedistat (Image source: PubChem)

This Breakthrough Therapy designation is based on the final data analysis of the Phase 2 clinical trial named Pevonedistat-2001. The study evaluated the efficacy of pevonedistat in combination with azacitidine versus azacitidine monotherapy in patients with rare leukemias, including those with higher-risk myelodysplastic syndromes (HR-MDS). Takeda presented the results of the Pevonedistat-2001 trial at the 56th American Society of Clinical Oncology (ASCO) Virtual Annual Meeting and the 25th European Hematology Association (EHA) Virtual Congress. In the treatment of patients with HR-MDS, the pevonedistat combination therapy achieved a median overall survival (OS) of 23.9 months, compared to 19.1 months for azacitidine monotherapy.

“High-risk MDS is associated with poor prognosis, reduced quality of life, and a higher likelihood of transformation to acute myeloid leukemia. These patients have few treatment options. The combination of pevonedistat and azacitidine represents a promising therapeutic approach that could become the first novel treatment advancement for high-risk MDS in over a decade,” said Dr. Christopher Arendt, Head of the Oncology Therapeutic Area at Takeda. “We appreciate the FDA’s recognition of the efficacy of pevonedistat and the urgent need to develop innovative therapies to address the treatment needs of patients with high-risk MDS.”

References:

[1] Takeda Announces U.S. FDA Breakthrough Therapy Designation Granted for Pevonedistat for the Treatment of Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS). Retrieved July 30, 2020, from https://www.businesswire.com/news/home/20200730005233/en

Original Title: Express | Takeda’s “first-in-class” NAE inhibitor receives FDA Breakthrough Therapy Designation for treating high-risk myeloid-related cancers

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