Ivosidenib Granted Priority Review by FDA for IDH1+ R/R Myelodysplastic Syndromes

• A priority review for ivosidenib tablets is based on the drug's ability to fill an unmet need for patient with IDH1-positive, relpased or refractory (R/R) myelodysplastic syndrome (MDS).

• If later granted FDA approval , ivosidenib tablets would be a first-in-class targeted therapy option for patients with IDH1-positive MDS.

• Previsouldy, the this therapy received breakthrough therapy designationfor the treatment of adult patients with R/R MDS with a susceptible IDH1 mutation, as detected by an FDA-approved test.

Accepting the supplemental new drug application (sNDA), the FDA has granted priority review for ivosidenib tablets (Tibsovo) in the treatment of isocitrate dehydrogenase 1 (IDH1)-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS) according to a press release by the French pharmaceutical company, Servier.¹

The basis for the sNDA comes from a Phase 1 trial (NCT02074839), which showed a complete response (CR) of 38.9% and an objective response rate of 83.3%.

"Servier continues to drive our leadership in the scientific innovation behind targeted mutant IDH inhibition, transforming the treatment landscape for thousands of patients living with difficult and hard-to-treat cancers," said Susan Pandya, MD, vice president clinical development and head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier, in a press release. "This filing acceptance and Priority Review for Tibsovo in patients with relapsed or refractory myelodysplastic syndromes underscores our continued work to advance therapeutic progress across IDH-mutated cancers, and if approved in this setting, will bring the first and only targeted therapy to patients living with a significant unmet need."

The CR was reached with a median duration of 1.87 months (range, 1.0-5.6) with the data end point revealing that the median duration of CR remained beyond the determined end point (range, 1.9-80.8). The median overall survival was at 35.7 months (range, 3.7-88.7). Among the 9 patients who initially required transfusions of red blood cells or platelets, 66.7% achieved transfusion independence during any period of 56 days or more post-baseline. The safety profile remained consistent, with treatment-related adverse events aligning with known information. The study did not identify any new safety concerns or signals.

The phase 1 trial, consisting of 291 patients, set out to evaluate safety, pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in advanced hematologic malignancies that harbor an IDH1 mutation.² The study was separated into phases with the first phase as the dose escalation phase. The experimental arm in phase 1 received an initial oral dose of the ivosidenib daily in a 28-day cycle. The second phase focused on dose expansion and study participates could proceed further with treatment until the following events occurred: disease progression, other intolerable toxicity developed, or experiencing a hematopoietic stem cell transplant.

To qualify for the trial, patients had to achieve and agree to the following: they had to be 18 years of age or older, had documented IDH1 R132 gene-mutated advanced hematologic malignancy based on local or central evaluation, and be able to undergo bone marrow biopsies, peripheral blood sampling and urine sampling throughout the study.²

Ivosidenib has been FDA approved, prior, as a monotherapy treatment for patients with IDH1-mutant relapsed or refractory acute myeloid leukemia (AML) or for patients with newly diagnosed IDH1-mutant AML through monotherapy or combined with azacytidine.¹

"While the novel use of targeted IDH inhibition has been proven across a number of difficult-to-treat cancers, there continues to be a significant unmet need for MDS patients within this molecularly defined subset, especially for those who experience disease progression," said Amir Fathi, MD, program director, Center for Leukemia at Massachusetts General Hospital and Associate Professor of Medicine at Harvard Medical School, in the press release. "Today's filing acceptance provides further support for the potential efficacy and acceptable safety profile of Tibsovo in relapsed or refractory MDS and reinforces the importance of mutational testing in this patient population."

_REFERENCES:

_{1. Pharmaceuticals S. Servier Announces FDA filing acceptance and priority review for Tbsovo® (ivosidenib tablets) in the treatment of IDH1-mutated relapsed or refractory (R/R) myelodysplastic syndromes (MDS). Published August 15, 2023. Accessed August 15, 2023. https://tinyurl.com/z58zuv3x}

_{2. Study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation. ClinicalTrials.gov. Accessed August 15, 2023. https://classic.clinicaltrials.gov/ct2/show/study/NCT02074839}