Oral Azacitidine and Cedazuridine Approximate Parenteral Azacitidine Efficacy in Murine Model

Abstract

Background DNA methyltransferase inhibitors (DNMTis) improve survival for patients with myelodysplastic syndromes (MDS) and those with acute myeloid leukemia (AML) unable to receive standard cytotoxic chemotherapy and are, accordingly, the backbone of standard-of-care treatment for these conditions. Standard regimens with DNMTIs, decitabine (DEC) or azacitidine (AZA) include daily subcutaneous (s.c.) or intravenous (i.v.) administration for 5-7 consecutive days. Attempts to provide the therapy orally have been limited given rapid clearance of the agents by the enzyme cytidine deaminase (CDA), which is ubiquitous in the gut and liver as part of first-pass metabolism. Recently, cedazuridine (CDZ), an oral inhibitor of CDA, was successfully combined with DEC to approximate the pharmacokinetics of i.v. DEC in patients. Objective To determine if an oral dosing strategy might be feasible in the clinic with AZA, we attempted to increase the bioavailability of oral AZA through the use of CDZ, in a murine model. Methods Following pharmacokinetic and pharmacodynamic assessment of oral AZA dosed with CDZ in murine and monkey models, we tested this regimen in vivo with a human cell line-derived xenograft transplantation experiment (CDX). Following this we combined the regimen with venetoclax (VEN) to test the efficacy of an all-oral regimen in a patient-derived xenograft (PDX) model. Results Parenteral AZA and oral AZA + CDZ exhibited similar pharmacokinetic profiles, and efficacy against human AML cells. Tumor regression was seen with AZA + CDZ in MOLM-13 CDX and PDX models. Conclusions We conclude that oral AZA when combined with CDZ achieves successful tumor regression in both CDX and PDX models. Furthermore, the combination of AZA + CDZ with VEN in a PDX model emulated responses seen with VEN + AZA in the clinic, implying a potential all-oral VEN-based therapy opportunity in myeloid diseases. Key PointsOral azacitidine + cedazuridine achieved similar dosedependent responses to those achieved with intraperitoneal azacitidine.The addition of venetoclax to oral azacitidine + cedazuridine resulted in significant decreases in tumor expansion in an acute myeloid leukemia patient-derived xenograft model.

Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

“…Apart from its successful combination with decitabine, the novel CDA inhibitor cedazuridine has also been studied in combination with CC-486, an oral formulation of azacitidine. In animal models, the combination of oral azacitidine and cedazuridine was shown to have similar bioavailability as parenteral azacitidine [78]. Moreover, oral azacitidine and cedazuridine as well as an oral triple therapy comprising this combination plus venetoclax resulted in decreased leukemic expansion in an AML patient-derived xenograft model [78].…”

“…In animal models, the combination of oral azacitidine and cedazuridine was shown to have similar bioavailability as parenteral azacitidine [78]. Moreover, oral azacitidine and cedazuridine as well as an oral triple therapy comprising this combination plus venetoclax resulted in decreased leukemic expansion in an AML patient-derived xenograft model [78].…”

Decitabine/Cedazuridine: First Approval

“…Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of the bone marrow haematopoietic stem cells, characterized by impaired haematopoiesis, peripheral blood cytopenias, increased blast populations in the peripheral blood and/or bone marrow and a higher risk of developing acute myeloid leukaemia (AML) [ 1 , 2 ]. While allogeneic hematopoietic stem cell transplant is the only potentially curative option for MDS (and other advanced haematological malignancies), many patients are not eligible for the procedure and the hypomethylating agents (HMAs) azacitidine and decitabine are the mainstay of therapy to alleviate cytopenia, control disease and prolong survival in these patients [ 1 , 3 – 5 ]. HMAs are cytidine-nucleoside analogues that incorporate into DNA during the S-phase of the cell cycle and covalently bind DNA methyltransferase 1, which is then degraded and depleted within the cell, resulting in reduced methylation of CpG residues in genomic DNA, altered epigenetic pattern and modified gene expression [ 3 , 6 ].…”

Oral Azacitidine (CC-486) for the Treatment of Myeloid Malignancies

“…A preclinical PK/PD assessment of oral co-administration of AZA and cedazuridine (CDZ)-a CDA inhibitor-increased AZA exposure in vivo by >1000% in animal models. 97 Methylation decreases with this combination were comparable to those of intraperitoneal administration of AZA alone. AML cell line and primary patient-derived xenograft (PDX) models showed oral administration of AZA plus CDZ led to decreases in leukemic burden and improved survival.…”