Ivosidenib as Monotherapy Granted FDA Approval for Certain Patients with IDH1 Mutant AML


The sNDA was granted Priority Review and accepted under the agency's Real-Time Oncology Review pilot program, which aims to make the review of oncology drugs more efficient by allowing the FDA access to clinical trial data before the information is formally submitted to the agency.

Officials with the FDA have approved a supplemental New Drug Application (sNDA) to update the US Prescribing Information for Agios Pharmaceuticals’ ivosidenib (Tibsovo), an isocitrate dehydrogenase-1 (IDH1) inhibitor, to include adult patients with newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. The update is indicated for these patients who are age 75 years and older or who have comorbidities that preclude use of intensive induction chemotherapy.

The sNDA was granted Priority Review and accepted under the agency's Real-Time Oncology Review pilot program, which aims to make the review of oncology drugs more efficient by allowing the FDA access to clinical trial data before the information is formally submitted to the agency. Ivosidenib received initial FDA approval in July 2018 for adult patients with relapsed or refractory (R/R) AML and an IDH1 mutation, according to Agios.

“Despite several new AML medicines approved in the last two years, many newly diagnosed patients are still not eligible for existing therapies or combination regimens because of age and other comorbidities,” said Chris Bowden, MD, chief medical officer at Agios, in a prepared statement. “With today’s additional Tibsovo approval, we are now able to provide a targeted, oral therapy to patients with an IDH1 mutation who may not have other treatment options. In addition, we are continuing our work to expand the utility of Tibsovo in newly diagnosed AML patients in ongoing Phase 3 trials in combination with both intensive chemotherapy and azacitidine.”

AML patients are typically older or have comorbidities that preclude the use of intensive chemotherapy. These patients typically have a worse prognosis and poor outcomes. The majority of patients with AML eventually relapse. The 5-year survival rate is approximately 28%. For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia7. IDH1 mutations have been associated with negative prognosis in AML.

According to Gail J. Roboz, MD, Professor of Medicine, Director of the Leukemia Program and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center, the Phase 1 results for Agios’ ivosidenib demonstrated that this oral, single agent therapy can induce durable responses in newly diagnosed AML patients with an IDH1 mutation.

“Many patients included in the study had features associated with particularly aggressive and challenging forms of AML, including secondary disease, adverse risk genetics and prior treatment with hypomethylating agents,” said Roboz, in a prepared statement.

The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation who were assigned to receive a 500 mg daily dose. The cohort included patients who were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy (baseline Eastern Cooperative Oncology Group [ECOG] performance status of ≥2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, or creatinine clearance <45 mL/min). Patients had a median age of 77 years (range of 64 to 87) and 68% had AML with myelodysplasia-related changes.

The primary endpoint is the combined complete remission (CR) and complete remission with partial hematologic improvement (CRh) rate. CRh is defined as <5% of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

The safety profile of single-agent ivosidenib was evaluated in 28 patients with newly diagnosed AML with an IDH1 mutation treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 4.3 months (range, 0.3 to 40.9 months).

In the clinical trial, 25% of patients treated with ivosidenib experienced differentiation syndrome, which can be fatal if not treated. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 patients recovered. QTc interval prolongation occurred in patients treated with ivosidenib.

The most common adverse reactions (≥20%) of any grade in patients with newly diagnosed AML were diarrhea, fatigue, decreased appetite, edema, nausea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia, constipation, differentiation syndrome, dizziness, electrocardiogram QT prolonged, mucositis and vomiting.


Agios announces FDA approval of Supplemental New Drug Application (sNDA) for TIBSOVO as monotherapy for newly diagnosed adult patients with IDH1 mutant acute myeloid leukemia (AML) not eligible for intensive chemotherapy [news release]. Cambridge, MA; May 2, 2019: Agios Pharmaceuticals. https://www.globenewswire.com/news-release/2019/05/02/1815567/0/en/Agios-Announces-FDA-Approval-of-Supplemental-New-Drug-Application-sNDA-for-TIBSOVO-as-Monotherapy-for-Newly-Diagnosed-Adult-Patients-with-IDH1-Mutant-Acute-Myeloid-Leukemia-AML-Not.html. Accessed May 2, 2019.

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