Myelodysplastic Syndromes (MDS)
Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal
stem cell malignancies in which bone marrow fails to produce healthy blood cells. MDS is characterised by ineffective and dysplastic myeloid cell differentiation and a high rate of progression (30-40%) to acute myeloid leukaemia (AML).
AML and MDS are generally manifested by an excess of immature or dysfunctional blood cells. Therapeutic options for these diseases are aimed at restoring normal blood cell counts. Some treatments are referred to curative-intent option (intensive), such as the cytotoxic “7 + 3” chemotherapy regimen, or not curative-intent (less intensive) option, such as the hypomethylating drug, Vidaza (azacytidine: an inhibitor for DNA methyltransferase), thereby restoring normal hematopoiesis. In many cancers (e.g., MDS), DNA hypermethylation is known to silence the genes responsible for cell differentiation and apoptosis.
The most common mutations detected in MDS patients include RNA splicing machinery, DNA methylation, chromatin modification, transcription regulation, and DNA damage response as shown below.
The somatic mutations shown above are available at https://emj.emg-health.com/wp-content/uploads/sites/2/2016/11/Somatic-Mutations-in-Myelodysplastic-Syndrome-Patients-in-the-Context-of-Allogeneic-Stem-Cell-Transplantation.pdf.
p53 and APR-246 (eprenetapopt)
It is believed that the mutant p53 tumor suppressor protein is directly associated with disease progression and a poor overall prognosis.
“Breakthrough Therapy Designation further supports our development program for APR-246 in combination with azacitidine in MDS patients with a TP53 mutation,” said Christian S. Schade, Chief Executive Officer of Aprea Therapeutics. “Outcomes for MDS patients with a TP53 mutation are poor and there are no current therapeutic options for these patients. We look forward to continued interaction with FDA regarding our ongoing Phase 3 clinical study and our clinical development program to advance APR-246.”
A phase III clinical trial is expected to be completed in November, 2020 entitled “A Phase III Multicenter, Randomized, Open Label Study of APR-246 in Combination With Azacitidine Versus Azacitidine Alone for the Treatment of (Tumor Protein) TP53 Mutant Myelodysplastic Syndromes.”
Primary endpoint outcome measures are to compare the complete response rate (CR) with APR 246 + azacitidine treatment vs. azacitidine only. [ Time Frame: Through study completion, an average of 1 year ]
ClinicalTrials.gov Identifier: NCT03745716 at https://clinicaltrials.gov/ct2/show/NCT03745716
Company: Pharmion Corporation
Application No.: 050794
Approval Date: 05/19/2004
VIDAZA* is a nucleoside metabolic inhibitor indicated for the treatment of
patients with the following FAB myelodysplastic syndrome (MDS) subtypes:
Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring
transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).
*: VIDAZA (azacitidine for injection) contains azacitidine, which is a pyrimidine nucleoside analog of cytidine. Azacitidine is 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The empirical formula is C8H12N4O5. The molecular weight is 244. Azacitidine is a white to off-white solid.
FDA review and approval: Vidaza (Azacitidine): NDA No. 050794
Last Updated: 2020-07-03
Comments are closed.