Ivosidenib Receives FDA Approval for Myelodysplastic Syndromes

On October 24, 2023, the US Food and Drug Administration (FDA) approved treatment for adults with relapsed or refractory myelodysplastic syndromes (MDS) carrying an isocitrate dehydrogenase-1 (IDH1) mutation: ivosidenib (Tibsovo, Servier Pharmaceuticals), an oral medicine.

The FDA also approved the Abbott RealTime IDH1 test to select patients for ivosidenib.

What Are Myelodysplastic Syndromes?

Myelodysplastic syndromes (MDS) are disorders causing abnormal cells in the bone marrow and blood. The marrow cannot produce enough healthy blood cells. MDS generally affects older people and may progress to acute myeloid leukemia (AML). Abnormal cells accumulate in the marrow and hinder healthy cell production, causing low blood counts and potentially various health problems.

FDA Approval Based on AG120-C-001

Approval was based on AG120-C-001, an open-label, single-arm, multicenter study in 18 adults with relapsed or refractory MDS and IDH1 mutations. IDH1 mutations were detected in peripheral blood or bone marrow using local or central diagnostic testing and retrospectively confirmed with the Abbott RealTime IDH1 Assay.

Ivosidenib was given orally until disease progression, unacceptable toxicity or hematopoietic stem cell transplantation , starting at 500 mg daily in 28-day cycles. Median treatment duration was 9.3 months. One patient underwent stem cell transplantation after ivosidenib.

Effectiveness was assessed by complete remission (CR) or partial remission (PR) rates using the 2006 International Working Group MDS response criteria, CR+PR duration and conversion from transfusion dependence to independence.

Results

• All observed responses were complete remissions (CR).
• The CR rate was 38.9% (95% CI: 17.3, 64.3).
• Median time to CR was 1.9 months (range, 1.0 to 5.6 months), and median CR duration was not estimable (range, 1.9 to 80.8+ months).

Of 9 patients dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 6 (67%) became independent of both during any 56-day period after baseline. Of 9 initially independent of both RBC and platelet transfusions, 7 (78%) maintained independence during any 56-day postbaseline period.

The most common adverse reactions resembled those seen with ivosidenib monotherapy in AML. They included gastrointestinal toxicities (diarrhea, constipation, mucositis and nausea), arthralgia, fatigue, cough, myalgia and rash. Tibsovo can also prolong the QTc interval on an ECG.

The prescribing information includes a Boxed Warning alerting healthcare professionals and patients to potentially life-threatening differentiation syndrome. This complication can occur with certain medicines used for cancers, particularly acute promyelocytic leukemia (APL). Medicines trigger cancer cells to differentiate or mature rapidly, provoking an inflammatory response. Symptoms may include fever, respiratory distress, chest pain, weight gain or fluid accumulation, low blood pressure and a rapid heartbeat. Because it can be serious and life-threatening, early recognition and intervention are important. Patients are generally managed with anti-inflammatory medicines such as corticosteroids and other supportive care.

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How Does Ivosidenib Work?

Ivosidenib inhibits mutant isocitrate dehydrogenase 1 (IDH1), suppressing its activity. IDH1 normally converts isocitrate, a type of energy molecule, into alpha-ketoglutarate. Mutant IDH1, however, converts alpha-ketoglutarate into the abnormal metabolite 2-hydroxyglutarate (2-HG). Accumulated 2-HG blocks cellular differentiation and promotes the formation and growth of malignant cells.

By suppressing mutant IDH1 activity, ivosidenib lowers 2-HG levels. This reduction in 2-HG promotes myeloid differentiation and increases mature myeloid cell numbers.

This mechanism explains its use in IDH1-mutated diseases such as AML, MDS and cholangiocarcinoma. Reducing abnormal 2-HG production allows malignant cells to differentiate, helping control and treat disease.

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Ivosidenib FDA Approval History:

1. First Approval: July 20, 2018: Tibsovo (ivosidenib) was approved for relapsed or refractory IDH1-mutated acute myeloid leukemia (AML).
2. May 2, 2019 Approval: Tibsovo monotherapy was approved for newly diagnosed IDH1-mutated AML in adults ineligible for intensive chemotherapy.
3. August 25, 2021 Approval: Tibsovo received approval for IDH1-mutated cholangiocarcinoma (bile duct cancer).
4. May 25, 2022 Approval: Tibsovo plus azacitidine was approved for newly diagnosed IDH1-mutated acute myeloid leukemia.
5. October 24, 2023 Approval: Tibsovo was approved for relapsed or refractory IDH1-mutated myelodysplastic syndromes (MDS).