FDA Grants Ivosidenib Breakthrough Status for Relapsed/Refractory IDH1+ MDS


The FDA has granted a breakthrough therapy designation to ivosidenib for the treatment of adult patients with relapsed/refractory myelodysplastic syndromes who harbor IDH1 mutations.

Chris Bowden, MD

The FDA has granted a breakthrough therapy designation to ivosidenib (Tibsovo) for the treatment of adult patients with relapsed/refractory myelodysplastic syndromes (MDS) who harbor IDH1 mutations.1

The designation is based on results from an MDS substudy of a phase I trial (NCT02074839) looking at ivosidenib in patients with advanced hematologic malignancies who have IDH1 mutations. In the MDS cohort, findings showed an overall response rate (ORR) of 75%, which included a 42% complete response (CR) rate, with ivosidenib in this patient population.2 Additionally, the median duration of CR had not been reached (95% CI, 2.8 months—not estimable), and of the patients who achieved a CR, 60% were relapse-free at 1 year.

"There is a significant need for new targeted therapeutic approaches for individuals with MDS whose disease continues to progress despite treatment with standard of care," Chris Bowden, MD, chief medical officer at Agios, the developer of ivosidenib, stated in a press release. "The Breakthrough Therapy designation is based on results from the initial 12 patients in the MDS arm of our phase 1 study in advanced hematologic malignancies with an IDH1 mutation and recognizes the potential for single-agent treatment with Tibsovo to make an impact on these patients. We recently re-opened the MDS arm of this study with the goal of generating sufficient data to pursue a regulatory filing in this indication."

In the phase I dose-escalation and expansion study, investigators are evaluating the clinical activity, safety, tolerability, pharmacokinetics, and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies. The expected enrollment for the overall trial is 291 patients.

To be eligible for enrollment, patients must be ≥18 years old, harbor an IDH1 mutation, have an ECOG performance status of 0 to 2, platelet count of ≥20,000 µL, and have an adequate renal and hepatic function. Some of the exclusion criteria included those who underwent hematopoietic stem cell transplant within 60 days of the first ivosidenib dose, received systemic therapy or radiation <14 days prior to the first day of study treatment, and having a history of myocardial infarction within 6 months of screening.

In one of the cohorts, 12 patients with relapsed/refractory MDS that harbor IDH1 mutations received 500 mg of ivosidenib monotherapy daily. The median duration of treatment was 11.4 months; the median age was 72.5 years, and 42% of patients were ≥75 years old.

The coprimary endpoints were safety and tolerability, maximum-tolerated dose and recommended phase II dose of ivosidenib, clinical activity in the expansion phase, and clinical activity as well as safety and tolerability in the relapsed/refractory MDS substudy. Secondary endpoints include dose-limiting toxicities, pharmacokinetics, pharmacodynamics, serial blood sampling, and blood and bone marrow sampling.

Results of the MDS substudy also showed that single-agent ivosidenib was well tolerated and associated with durable remissions. At the November 2, 2018 data cutoff, 75% achieved a response (n = 9); results also showed that 9 (75%) patients were transfusion-independent for ≥56 days during study treatment.

Regarding safety, the most common any-grade adverse events (AEs) were back pain, diarrhea, fatigue, and rash. Moreover, grade 2 IDH differentiation syndrome was observed in 1 patient. No AEs resulted in permanent discontinuation of treatment.

In October 2019, the MDS arm of patients was reopened, and investigators will enroll ≤25 patients to generate enough data for a potential regulatory filing for ivosidenib in this setting. Recruitment is ongoing in 22 sites in both the United States and France, Agios concluded in the press release.


  1. Agios receives FDA breakthrough therapy designation for Tibsovo (ivosidenib) for the treatment of adult patients with relapsed or refractory myelodysplastic syndrome with an IDH1 mutation [news release]. Agios Pharmaceuticals. Published December 16, 2019. https://bit.ly/2PucvEW. Accessed December 16, 2019.
  2. Foran JM, DiNardo CD, Watts JM, et al. Ivosidenib (AG-120) in patients with IDH1-mutant relapsed/refractory myelodysplastic syndrome: updated enrollment of a phase 1 dose escalation and expansion study. Blood. 2019;134(suppl_1):4254. doi: 10.1182/blood-2019-123946.
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