Azacitidine
- Generic Name
- Azacitidine
- Brand Names
- Onureg, Vidaza, Azacitidine Accord, Azacitidine betapharm, Azacitidine Mylan, Azacitidine Kabi
- Drug Type
- Small Molecule
- Chemical Formula
- C8H12N4O5
- CAS Number
- 320-67-2
- Unique Ingredient Identifier
- M801H13NRU
- Background
Azacitidine is a pyrimidine nucleoside analogue with anti-neoplastic activity. It differs from cytosine by the presence of nitrogen in the C5-position, key in its hypomethylating activity. Two main mechanisms of action have been proposed for azacitidine. One of them is the induction of cytotoxicity. As an analogue of cytidine, it is able to incorporate into RNA and DNA, disrupting RNA metabolism and inhibiting protein and DNA synthesis. The other one is through the inhibition of DNA methyltransferase, impairing DNA methylation. Due to its anti-neoplastic activity and its ability to inhibit methylation in replicating DNA, azacytidine has been used mainly used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), two types of cancer characterized by the presence of aberrant DNA methylation.
In May 2004, the FDA approved the use of azacitidine administered subcutaneously for the treatment of MDS of all French-American-British (FAB) subtypes. In January 2007, the FDA approved the intravenous administration of azacitidine. The use of oral azacitidine for the treatment of AML in patients in complete remission was approved by the FDA in September 2020.
- Indication
Azacitidine (for subcutaneous or intravenous use) is indicated for the treatment of adult patients with the following French-American-British (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). Azacitidine is also indicated for the treatment of pediatric patients aged 1 month and older with newly diagnosed Juvenile Myelomonocytic Leukemia (JMML).
Azacitidine (for oral use) is indicated for continued treatment of adult patients with acute myeloid leukemia (AML) who achieved first complete remission or complete remission with incomplete blood count recovery following intensive induction chemotherapy and are not able to complete intensive curative therapy.
- Associated Conditions
- Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Refractory Anemia, Refractory Anemia With Excess Blasts in Transformation, Refractory Anemia With Excess of Blasts (RAEB), Refractory Anemia With Ringed Sideroblasts, Newly diagnosed Juvenile Myelomonocytic Leukaemias (JMML)
EMA Grants Orphan Drug Designation to AB8939 for Acute Myeloid Leukemia Treatment
• The European Medicines Agency has granted orphan drug designation to AB8939, developed by AB Science, for treating acute myeloid leukemia, following a similar designation from the US FDA.
• Preclinical studies demonstrate AB8939's efficacy against resistant AML cells, showing advantages over current therapies like cytarabine, azacitidine, and venetoclax without causing serious hematotoxicity.
• The orphan designation acknowledges AB8939's potential significant benefits for AML patients with limited treatment options, providing AB Science with scientific advice, reduced fees, and 10 years of marketing exclusivity if approved.
Omeros Forms Elite Clinical Steering Committee to Advance Novel AML Therapeutic Program
• Omeros Corporation has established an Oncology Clinical Steering Committee comprising eight distinguished leukemia experts from leading cancer centers to guide its OncotoX-AML program development.
• The OncotoX-AML therapeutic has demonstrated superior efficacy to current standard treatments in preclinical studies, effectively targeting 90% of common AML mutations while showing excellent tolerability at high doses.
• The novel engineered molecules, approximately half the size of antibodies, selectively kill dividing cancer cells including treatment-resistant leukemia stem cells, addressing a significant unmet need in AML treatment.
Personalized Treatment Approaches Show Promise in T-Cell Lymphoma Therapy
• Recent advances in molecular classification of T-cell lymphomas are shifting treatment paradigms from histology-based to genetically-informed approaches, potentially improving outcomes for this aggressive cancer.
• Standard CHOP chemotherapy shows limited efficacy in T-cell lymphomas with response rates of only 50-70%, highlighting the urgent need for novel targeted therapies tailored to specific genetic mutations.
• Emerging treatments including epigenetic therapies, CAR T-cell adaptations, and combination approaches show promising results in clinical trials, particularly for patients with relapsed or refractory disease.
FDA Grants Orphan Drug Designation to Bexmarilimab for Myelodysplastic Syndrome Treatment
• Faron Pharmaceuticals' lead candidate bexmarilimab receives FDA Orphan Drug Designation for myelodysplastic syndromes treatment, offering development incentives and seven-year marketing exclusivity upon approval.
• The novel immunotherapy targets the Clever-1 receptor on macrophages, reprogramming them from immunosuppressive to immunostimulatory states to enhance anti-tumor immune responses.
• Top-line efficacy results for bexmarilimab in both frontline and HMA-failed MDS patients are expected to be reported in April 2025.
Emavusertib Shows Promise in FLT3-Mutated AML Patients Resistant to Prior Therapies
• Phase 1/2 TakeAim Leukemia trial demonstrates significant efficacy of emavusertib in relapsed/refractory AML patients, with 6 complete remissions observed among 19 evaluable FLT3-mutated patients.
• The IRAK4 inhibitor showed effectiveness in patients previously treated with FLT3 inhibitors like midostaurin and gilteritinib, suggesting potential to overcome existing resistance mechanisms.
• Clinical responses were also observed in patients with spliceosome factor mutations, including those heavily pretreated with hypomethylating agents plus venetoclax.
FDA Places Partial Clinical Hold on Gilead's Magrolimab Trials
• The FDA has placed a partial clinical hold on trials of Gilead's magrolimab when used with azacitidine due to an imbalance in serious adverse events.
• The hold affects Phase 3 trials in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as Phase 2 and Phase 1b studies in myeloid malignancies.
• Gilead is investigating the safety signal, but patients already enrolled in the trials can continue treatment with the magrolimab combination.
• Magrolimab, a CD47-directed antibody, is a key asset in Gilead's oncology pipeline, and this hold could significantly impact its development.
Study Reveals Varying HMA Treatment Outcomes in MDS Patients Based on Cytogenetic Risk Profiles
• New research from ASH 2024 demonstrates that myelodysplastic syndrome patients with very complex karyotype have significantly shorter survival (12.6 months) compared to those with non-complex karyotype (36.1 months) when treated with hypomethylating agents.
• TP53 mutations were found to be substantially more prevalent in very complex karyotype MDS (75%) compared to complex karyotype (40%) and non-complex karyotype (7%), impacting treatment outcomes.
• Novel single-cell sequencing analysis identifies shared splicing neoantigens as potential immunotargets, offering new insights into HMA resistance mechanisms in MDS treatment.
Menin Inhibitors Show Promise in Frontline AML Treatment, Highlighted at EHA Congress
Recent findings presented at the 2024 EHA Congress reveal that menin inhibitors, particularly in combination therapies, are showing high efficacy in treating newly diagnosed acute myeloid leukemia (AML). With a composite complete remission rate of 96% and a 92% MRD-negative status in a phase 1/2 trial, these inhibitors could significantly improve patient outcomes. Ongoing research aims to further establish their safety and efficacy in frontline settings.
Oryzon's Iadademstat Enters Phase I Trial for Myelodysplastic Syndrome
• Oryzon Genomics has announced the dosing of the first patient in a Phase I trial of iadademstat for myelodysplastic syndrome (MDS).
• The trial, led by the Medical College of Wisconsin, will assess the safety, tolerability, and optimal dose of iadademstat with azacitidine.
• Iadademstat, a selective LSD1 inhibitor, aims to address the differentiation block in hematopoietic progenitor cells characteristic of MDS.
• The study hopes to improve outcomes for MDS patients, where current treatments have limited efficacy, especially in higher-risk cases.
Aptose's Tuspetinib-Based Triple Therapy Shows Promise in Newly Diagnosed AML Patients
• Aptose Biosciences' TUSCANY trial evaluates tuspetinib (TUS) with venetoclax (VEN) and azacitidine (AZA) for newly diagnosed AML patients.
• Early data from the trial's first cohort show complete remissions in patients with TP53 mutations and FLT3-wildtype AML.
• The triplet therapy demonstrates a favorable safety profile, with no dose-limiting toxicities or prolonged myelosuppression observed.
• The Cohort Safety Review Committee (CSRC) has approved dose escalation to 80 mg of tuspetinib based on the encouraging safety data.
Luspatercept Plus Lenalidomide Shows Promise in Non-del(5q) Myelodysplastic Syndrome
• A phase 1b trial combining luspatercept and lenalidomide demonstrates safety and preliminary efficacy in patients with non-del(5q) myelodysplastic syndrome (MDS).
• The combination therapy showed a 50% hematologic improvement rate among evaluable patients, with notable red blood cell transfusion independence.
• The study established a recommended phase 2 dose (RP2D) of lenalidomide at 10 mg daily and luspatercept at 1.0 mg/kg every 21 days.
• These findings support further investigation of this combination to improve outcomes for lower-risk MDS patients lacking the del(5q) abnormality.
BeiGene Launches Global Phase 2 Trial of Zanubrutinib for Relapsed or Refractory Marginal Zone Lymphoma
BeiGene has initiated a global Phase 2 trial, named MAGNOLIA, to evaluate the efficacy and safety of zanubrutinib in patients with relapsed or refractory marginal zone lymphoma (MZL). The trial aims to enroll approximately 65 patients, focusing on overall response rate as the primary endpoint.
Sana Biotechnology's HIP Technology Shows Promise in Type 1 Diabetes Islet Cell Transplant Study
• Sana Biotechnology's UP421 demonstrates survival and function of transplanted islet cells in a type 1 diabetes patient without immunosuppression.
• The first-in-human study shows HIP-engineered cells evade immune detection, producing insulin as indicated by increased C-peptide levels.
• MRI scans confirm graft survival 28 days post-transplantation, with no reported safety issues, suggesting potential for a curative T1D treatment.
• These results support the development of Sana's SC451, a stem cell-derived islet cell program, offering hope for scalable T1D therapies.
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Ziftomenib Shows Promise in Treatment of Relapsed/Refractory AML
• Ziftomenib, a selective menin inhibitor, demonstrates promising clinical activity in relapsed/refractory AML patients, especially those with _NPM1_ mutations or _KMT2A_ rearrangements.
• The KOMET-001 trial revealed a 25% complete remission rate in patients with _KMT2A_ rearrangement or _NPM1_ mutations at the 600 mg dose, with a 35% complete remission rate in _NPM1_ mutated patients.
• Ziftomenib exhibits a manageable safety profile, with the most common severe adverse events including anemia, febrile neutropenia, and pneumonia, and a low incidence of _MEN1_ mutation development.
• Ongoing clinical studies are exploring ziftomenib in combination with other therapies, such as 7+3 induction chemotherapy and azacytidine/venetoclax, to enhance its effectiveness in AML treatment.
Revumenib Demonstrates Sustained Responses in Relapsed/Refractory KMT2Ar Acute Leukemia
• Revumenib shows continued clinically meaningful responses in patients with relapsed/refractory _KMT2Ar_ acute leukemia.
• The Phase 2 AUGMENT-101 trial update reveals higher minimal residual disease negativity rates with revumenib.
• Treatment with revumenib led to a significant percentage of patients proceeding to hematopoietic stem cell transplant.
• The safety profile of revumenib remains manageable, with no discontinuations due to differentiation syndrome or QTc prolongation.
PMV Pharmaceuticals Provides Update on PC14586 (Rezatapopt) Clinical Trials and Financial Status
• PMV Pharmaceuticals is advancing PC14586 (rezatapopt) in a Phase 2 monotherapy trial (PYNNACLE) for solid tumors with p53 Y220C mutations, with interim data expected by mid-2025.
• The company discontinued the Phase 1b combination arm of the PYNNACLE trial, which evaluated rezatapopt with pembrolizumab (KEYTRUDA®).
• Collaborations with MD Anderson and Memorial Sloan Kettering will support a Phase 1b study combining rezatapopt with azacytidine, starting in Q1 2025.
• PMV's current funds should support operations through 2026, focusing on PC14586's clinical development and regulatory milestones.
myeloMATCH Trials Open to Accelerate Precision Medicine for AML and MDS
• myeloMATCH, a collaborative effort by leading cancer research organizations, launches clinical trials to advance precision medicine for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
• The program offers advanced biomarker testing to identify genomic and molecular features, matching patients with targeted treatments in a tiered approach across their treatment journey.
• Three treatment trials are now open, focusing on initial induction, residual disease, and consolidation therapy, with the goal of improving outcomes and developing new therapies for myeloid malignancies.
• The initiative aims to enroll 5,000 patients, tracking their progress and clonal evolution to refine treatments and address unmet needs in AML and MDS management.
AB Science Provides Update on Masitinib and AB8939 Clinical Programs
• AB Science is re-examining the marketing authorization application for masitinib in amyotrophic lateral sclerosis (ALS) with the EMA and Health Canada.
• Phase 1 trial of AB8939 shows promising activity against MECOM-rearranged acute myeloid leukemia (AML), with potential for accelerated FDA approval.
• Masitinib demonstrates potential as an alternative to BTK inhibitors in progressive forms of multiple sclerosis, based on ECTRIMS 2024 data.
Epigenetic Drug Development Sees Record $342M Series A Funding Surge in Early 2024
• Series A venture financing for epigenetic drug development has reached $342M in early 2024, marking a dramatic 375% increase from 2023 and setting a five-year record.
• Avenzo Therapeutics secured the largest Series A round of $150M to advance CDK2 inhibitor ARTS-021, currently in Phase I/II trials for solid tumors and metastatic breast cancer.
• The surge in investment follows FDA's approval of Vertex's Casgevy, highlighting growing confidence in epigenetic approaches as safer alternatives to traditional gene editing.
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