FDA Grants Eprenetapopt Fast Track Status in TP53-Mutant AML

November 30, 2020 - The FDA has granted a fast track designation to eprenetapopt as a treatment for patients with TP53-mutant acute myeloid leukemia.

The FDA has granted a fast track designation to eprenetapopt (APR-246) as a treatment for patients with TP53-mutant acute myeloid leukemia (AML).

“We are pleased to have received fast track designation for eprenetapopt in the treatment of [patients with] TP53-mutant AML, a cancer for which outcomes are poor and there are no current therapeutic options specifically for these patients,” said Eyal C. Attar, MD, chief medical officer of Aprea Therapeutics Inc., the developer of eprenetapopt.

“Emerging data from our AML trials evaluating eprenetapopt with azacitidine, and with eprenetapopt, azacitidine and venetoclax [Venclexta], are promising and we continue to enroll patients to identify the best treatment regimen,” Attar added. “As these data mature in 2021, we look forward to continued interaction with FDA as we map out opportunities for an accelerated pathway to potential approval.”

p53 is said to be the most frequently mutated gene in human cancer, as it occurs in approximately 50% of all malignancies, and is often linked with resistance to anticancer drugs and poor survival, representing an unmet need in cancer treatment.

Eprenetapopt is a small molecule that has shown reactivation of mutant and inactivated p53 protein through restoration of wild-type p53 conformation and function, which then induces programmed cell death in human cancer cells. Preclinical data have shown that eprenetapopt does elicit antitumor activity in AML, as well as myelodysplastic syndromes (MDS) and ovarian cancer.

Previously, eprenetapopt received breakthrough therapy, orphan drug, and fast track designations for the treatment of patients with TP53-mutant MDS.

Results from a phase 2 trial that were presented during the 2020 European Hematology Association Congress showed promising response rates with the eprenetapopt plus azacitidine in a very high-risk population of patients with TP53-mutated MDS and AML.

Specifically, in response-evaluable patients, the regimen elicited a 77% objective response rate, which included a 49% complete response (CR) rate. Patients with AML, who had 20% to 30% blasts, had an ORR of 78% and a CR rate of 33%. 

In a subset of patients with MDS (n = 28), the response rate was 75%, with more than half, or 57%, of patients achieving a CR. In the intent-to-treat population, the response seen with the combination was 58%, which included a 33% CR rate.

In the AML cohort, 39% of patients (n = 7) had greater than 30% blasts, and 61% of patients (n = 11) had 20% to 30% blasts. Additionally, 89% of patients (n = 16) had complex karyotype, monosomal karyotype (n = 9; 50%), and del5q (n = 12; 67%).

Investigators are examining the same combination in an open-label, phase 3 study of patients with TP53-mutant MDS (NCT03745716), which recently completed enrollment.Results are expected by the end of 2020 and will be incorporated into new drug applications to the FDA and the European Medicines Agency in 2021.

The phase 3 trial, which was fully enrolled as of June 3, 2020, comprises 154 patients in 28 study locations. Participants are expected to receive treatment for an average of 1 year. Data will be stratified by patients’ age (younger than 65 years vs 65 years or older). The primary end point is CR rate, which is defined as the proportion of patients who achieve complete remission and duration of CR.


1. Aprea Therapeutics receives FDA fast track designation for eprenetapopt in the treatment of TP53 mutant acute myeloid leukemia (AML). News release. Aprea Therapeutics, Inc. November 30, 2020. Accessed November 30, 2020. https://yhoo.it/3oaW4w0

2. Cluzeau T, Serbert M, Rahme R, et al. APR-246 with azacitidine in TP53 mutated myelodysplastic syndromes and acute myeloid leukemia: a phase 2 study by Francophone Des Myelodysplasies. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S181. bit.ly/3fsqKVz.

3. APR-246 & azacitidine for the treatment of TP53 mutant myelodysplastic syndromes (MDS). ClinicalTrials.gov. Updated June 4, 2020. Accessed September 1, 2020. https:// bit.ly/2DiK1uA