SUMMARY: The FDA on October 24, 2023, approved Ivosidenib (TIBSOVO®) for adult patients with Relapsed or Refractory MyeloDysplastic Syndromes (MDS) with a susceptible Isocitrate DeHydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for Ivosidenib.
It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).
The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.
Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as Azacitidine and Decitabine and these agents can favorably modify the natural history of the disease, and have been shown to improve survival. However, outcomes are poor and no therapies currently exist for patients with Isocitrate Dehydrogenase 1-mutant Relapsed or Refractory MDS, following failure on a hypomethylating agent.
Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.
Ivosidenib is a first-in-class, oral, potent, targeted, small-molecule inhibitor of mutant IDH1. The FDA in 2018, approved Ivosidenib for adult patients with Relapsed or Refractory AML with a susceptible IDH1 mutation, and in 2019 approved Ivosidenib for newly diagnosed AML with a susceptible IDH1 (Isocitrate DeHydrogenase-1) mutation, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction.
The present FDA approval is supported by a pivotal Phase 1, open-label, multinational study, in which the safety, tolerability, and clinical activity of Ivosidenib was evaluated among patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. In this study 18 eligible patients (N=18) received Ivosidenib 500 mg orally daily, continuous for 28-day cycles, until disease progression, unacceptable toxicity, or Hematopoietic Stem Cell Transplantation. The median treatment duration was 9.3 months. One patient underwent a Stem Cell Transplantation following Ivosidenib. IDH1 mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by the Abbott RealTime IDH1 Assay. The median age was 73 years and majority of patients had intermediate or high IPSS-R score at the time of screening for the study. The Primary efficacy end point was the Complete Response (CR) plus Partial Response (PR) rate. Secondary endpoints included duration of CR plus PR, duration of transfusion independence, and time to transfusion independence.
All observed responses were Complete Responses. The CR rate was 38.9%. The median time to Complete Response was 1.9 months and at the time of data cutoff, the median duration of Complete Responses was not estimable and ranged from 1.9 to 80.8+ months. Additionally, of the 9 patients who were transfusion dependent with Red Blood Cells or platelets at baseline, 67% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 9 patients independent of both RBC and platelet transfusions at baseline, 78% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions included GI toxicities such as mucositis, diarrhea, constipation and nausea, fatigue, arthralgia, myalgia, cough, and rash. Differentiation syndrome was rare and manageable. It should be noted that Ivosidenib can also cause QTc prolongation.
It was concluded from this study that Ivosidenib induced durable remissions including a substantial proportion of Complete Remissions with an acceptable safety profile, in patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. Further, a significant proportion of patients became or remained transfusion independent. This is the first targeted therapy approved for this indication.
UPDATED SUBSTUDY RESULTS FOR IVOSIDENIB IN IDH1-MUTANT RELAPSED/REFRACTORY MYELODYSPLASTIC SYNDROME. Dinardo C, Roboz G, Watts JM, et al. Hemasphere. 2023 Aug; 7(Suppl): e75740ab. DOI: 10.1097/01.HS9.0000969800.75740.ab.
