On October 24, 2023, the U.S. Food and Drug Administration (FDA) approved ivosidenib (Tibsovo®) for the treatment of adult patients with relapsed or refractory myelodysplastic syndrome (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) variant, as detected by an FDA-approved test. The agency also approved the Abbott RealTime IDH1 assay as a companion diagnostic device to select patients for ivosidenib treatment.

FDA update

FDA’s approvals center around results from AG120-C-001 (NCT02074839), an open-label, single-arm, multicenter trial of 18 adult patients with relapsed or refractory MDS with an IDH1 variant that was detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by the Abbott RealTime IDH1 assay.

Ivosidenib was administered orally at a starting dose of 500 mg daily continuously for 28-day cycles until patients experienced disease progression or unacceptable toxicity or required hematopoietic stem cell transplantation. The median treatment duration was 9.3 months. One patient underwent a stem cell transplantation following their ivosidenib treatment.

Efficacy was established by rates of complete (CR) or partial remission (PR), CR+PR duration, and conversion from transfusion dependence to independence. All of the observed responses were CRs at a 38.9% rate (95% CI = 17.3, 64.3). The median time-to-CR was 1.9 months (range = 1.0–5.6 months), and the median CR duration was not estimable (range = 1.9, 80.8+ months).

Among the 9 patients dependent on red blood cell or platelet transfusions at baseline, 6 (67%) became transfusion independent during a 56-day post-baseline period. Of the 9 patients independent of both red blood cell and platelet transfusions at baseline, 7 (78%) remained transfusion independent during a 56-day post-baseline period.

Ivosidenib’s prescribing information contains a boxed warning for differentiation syndrome, which may be life threatening or fatal. The most common adverse reactions were similar to those observed with ivosidenib monotherapy for acute myeloid leukemia, including gastrointestinal toxicities (e.g., diarrhea, constipation, mucositis, nausea), arthralgia, fatigue, cough, myalgia, and rash. Ivosidenib may also cause QTc prolongation.

The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. It was also granted priority review, breakthrough designation, and orphan drug designation. FDA-expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.

For assistance with single-patient investigable new drug applications, healthcare professionals may contact the Oncology Center of Excellence’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.