FDA Grants Fast Track and Orphan Drug Designations to Novel Agent Targeting P53 in MDS

The FDA has granted a fast track designation and an orphan drug designation to APR-246, a novel agent targeting p53 for the treatment of patients with myelodysplastic syndromes.

The FDA has granted a fast track designation and an orphan drug designation to APR-246, a novel agent targeting p53 for the treatment of patients with myelodysplastic syndromes (MDS).1

Aprea Therapeutics, the company developing the novel agent, announced that the orphan drug designation was granted to APR-246 for the treatment of patients with MDS, and the fast track designation for patients with MDS who harbor aTP53mutation.

“The granting of Fast Track designation and Orphan Drug Designation by FDA for APR-246 inTP53-mutated MDS underscores the significant unmet medical need in this disease,” said Christian S. Schade, president and CEO of Aprea, in a statement. “With our Phase III clinical study in MDS underway, we look forward to continuing our productive dialogue with FDA and bringing APR-246 to patients as soon as possible.”

The FDA’s fast track program is intended for drugs that are designated to treat a serious condition and may fill a current unmet medical need. The orphan drug designation is for medicines that are intended to treat rare diseases that affect <200,000 people in the United States. Both allow for additional FDA assistance in the accelerated development and review of the drug. Approximately 20% of patients with MDS and AML harbor a mutation in p53, which is associated with a poor prognosis. APR-246 reactivates mutant and inactivated p53 proteins which leads to programmed cell death in cancer cells.

The agent is currently being studied in a number of early-stage clinical trials investigating the agent in various solid tumors and hematologic malignancies, including a phase I/II study of APR-246 in combination with azacitidine in patients with myeloid neoplasms who have aTP53mutation (NCT03588078). The combination is also being studied in a randomized, multicenter phase III trial of patients withTP53-mutant MDS (NCT03745716). Patients with adequate organ function and an ECOG performance status of 0 to 2 will be randomized to either the combination or azacitidine alone and stratified by age (<65 versus ≥65 years). The primary endpoint of the study is complete response.

Preliminary findings from a phase Ib/II trial of APR-246 plus azacitidine in patients withTP53-mutant MDS or AML who had not received prior treatment with a hypomethylating agent were presented at the 2018 EHA Annual Meeting.2APR-214 was administered in varying doses intravenously daily over 4 days as a lead-in phase prior to combination treatment with azacitidine at 75 mg/m2over 7 days in 28-day cycles. The maximum tolerated dose was not reached.

Of the 9 patients included in the phase Ib portion of the trial, 6 had MDS and 3 had AML with myelodysplasia-related changes. All of the 5 evaluable patients achieved a response, consisting of 4 complete responses and 1 durable marrow complete response. All of the patients that achieved a complete response had high p53 positivity (55%-70%) at baseline by immunohistochemistry.

Adverse events (≥1) in the study included nausea and neutropenia in 6 patients; infection and neuropathy in 4; dizziness, thrombocytopenia, pain, and falls in 3 each; and headache, weakness, xerostomia, mucositis, and ataxia in 2 patients each. To treatment-related serious adverse events or dose-limiting toxicities had occurred at the time of treatment cutoff.


  1. Aprea Therapeutics Receives FDA Fast Track Designation and Orphan Drug Designation for APR-246 for the Treatment of Myelodysplastic Syndromes (MDS) [news release]. Boston, MA and Stockholm, Sweden: Aprea Therapeutics; April 16, 2019. https://bit.ly/2IsKSKa. Accessed April 18, 2019.
  2. Sallman D, Dezern A, Sweet K, et al. Phase 1b/2 combination study of APR-246 and azacitidine (aza) in patients with TP53 mutant myelodysplastic syndromes (mds) and acute myeloid leukemia (aml). Presented at: 2018 EHA Annual Meeting; June 14-17, 2018; Stockholm, Sweden. Abstract S1558.