p53 target new drug! Aprea’s Blood Cancer Combination Therapy Receives FDA Breakthrough Therapy Designation

Aprea Therapeutics is a Boston-based biopharmaceutical company focused on developing and commercializing innovative cancer therapies that reactivate the tumor suppressor protein p53. Recently, the company announced that the U.S. food and drug administration (FDA) has awarded apr-246 combined with azacitidine as a breakthrough therapy designation (BTD) for myelodysplastic syndrome (MDS), which carries a susceptible TP53 mutation.

Drugs that receive BTD can receive closer guidance, including senior FDA officials, during research and development to ensure that new treatment options are provided to patients in the shortest possible time. BTD is a new drug review pathway created by the FDA in 2012 to accelerate the development and review of new drugs to treat serious or life-threatening diseases that have preliminary clinical evidence of substantial improvement over existing treatments.

Figure 1 APR-426 molecular structure

MDS is cancer that fails to produce enough healthy blood cells due to the mature defects of blood cells in the bone marrow. Its symptoms include severe or even fatal anemia. About 30% to 40% of patients with MDS will progress to acute myeloid leukemia (AML).

p53 was discovered at the peak of tumor virus research, and it was originally thought to be an oncoprotein. p53 tumor suppressor gene is the most common mutant gene in human cancer, accounting for about 50% of all human tumors. However, subsequent studies found that wild type p53 inhibited tumor growth and cell canceration in a cell culture environment. Inactive mutations in the TP53 gene encoding p53 are very common in human tumors. In many cancers, mutations in the TP53 gene are associated with poor patient prognosis, often with anticancer drug resistance and poor overall survival. Currently, no treatment option exists for this group of patients with MDS.

APR-246 is a small molecule drug that “reactivates” the p53 protein that has been mutated and inactivated, and induces apoptosis. APR-246 is a prodrug that can be converted into the active compound methylene quinuclidinone (MQ), a Michael receptor that binds to mutant p53 via cysteine and restores p53 wild-type conformation and function. APR-246 has been shown to reactivate mutant and inactivated p53 proteins, thereby inducing programmed cell death in human cancer cells.

APR-246 has been observed in many preclinical studies in solid tumors and hematological cancers, including MDS, AML and ovarian cancer. In addition, it has shown strong synergy in combination with traditional anticancer therapies (such as chemotherapy), new anticancer drugs, and immune tumor checkpoint inhibitors. In a phase 1/2 clinical study, Aprea demonstrated the safety of Apr-246 and the clinical remission of malignant hematologic tumors and solid tumors carrying mutations in the TP53 gene. The combination of APR-246 and azacitidine as a first-line therapy in a pivotal phase 3 clinical study of patients with TP53 mutant MDS is ongoing. Earlier, APlR-246 has been granted FDA orphan drug and fast-track status for patients with MDS, and the European Medicines Agency (EMA) for orphan drugs for patients with MDS, AML, and ovarian cancer.

Data from two French and American Phase I / II clinical trials announced at the American Society of Hematology (ASH) Annual Meeting in December 2019 showed: APR-246 combined with azacitidine has shown strong efficacy in patients with TP53 mutant MDS and AML.

“This breakthrough therapy is identified as further supporting the development of APR-246 in combination with azacitidine in the treatment of patients with TP53 mutant MDS,” Aprea CEO Christian S. Schade said, “The prognosis for patients with MDS carrying the TP53 mutation is poor and no treatment options are currently available for these patients. We hope to continue working with the FDA to further advance the clinical development plan for APR-246. ”


  1. Aprea Therapeutics Receives FDA Breakthrough Therapy Designation for APR-246 in Combination with Azacitidine for the Treatment of Myelodysplastic Syndromes (MDS) with a TP53 Mutation,Retrieved January 30, 2020, from https://ir.aprea.com/news-releases/news-release-details/aprea-therapeutics-receives-fda-breakthrough-therapy-designation