On December 16, 2021 Forma Therapeutics Holdings, Inc. (Nasdaq: FMTX), a clinical-stage biopharmaceutical company focused on sickle cell disease, prostate cancer and other rare hematologic diseases and cancers, reported the company’s investigational oral, selective mIDH1 inhibitor combined with azacitidine yielded durable complete remission (CR) or CR with partial hematologic recovery (CRh) responses with favorable tolerability in patients with the mIDH1 form of acute myeloid leukemia (AML) (Press release, Forma Therapeutics, DEC 16, 2021, View Source [SID1234597301]).

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These positive findings, the first Phase 2 results of olutasidenib used in combination with a chemotherapy, were presented in an oral session on Dec. 13, 2021, at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. The findings support the potential of olutasidenib as the basis of combination therapy in patients with AML who have not achieved a durable response from prior therapy. In addition, a poster, presented on Dec. 12 at ASH (Free ASH Whitepaper), reported on the molecular characteristics of the mIDH1 of patients in the trial who responded to olutasidenib when administered as monotherapy.

"AML is a cancer that returns in about half of patients following initial treatment. Patients who are not achieving remission or suffer from an AML relapse are in need of new therapies with more durable outcomes. The data presented today at ASH (Free ASH Whitepaper) increase our understanding of olutasidenib’s potential to achieve durable complete responses when used as either first-line or second-line therapy along with a standard therapy for patients with mIDH1 AML," said Patrick Kelly, M.D., chief medical officer of Forma Therapeutics.

The oral presentation reports an analysis of four patient cohorts from the pivotal open-label Phase 2 arm of an ongoing Phase 1/2 study, (2102-HEM-101, NCT02719574), who received olutasidenib dosed 150 milligrams (mg) twice daily continuously during 28-day cycles plus azacitidine, as of June 16, 2021. Azacitidine, a hypomethylating agent (HMA), was administered daily as an intravenous or subcutaneous injection therapy for days one to seven of each cycle.

Investigators enrolled patients into one of the four groups based on their disease status and prior therapy and recorded the best overall response for the primary endpoint of a composite complete remission (CR) plus CR with partial hematologic recovery (CRh) rate (CR/CRh). The group of patients who had not yet received therapy for their AML and were candidates for azacitidine as a first-line treatment had CR/CRh rate of 45% (5 out of 11). The other three groups enrolled patients who had relapsed/refractory AML (R/R AML) that, respectively, had prior HMA therapy; had prior therapy with an IDH1 inhibitor, including olutasidenib monotherapy; and were candidates for azacitidine as a first-line treatment. The CR/CRh rates for these groups were 38% (5 of 13), 30% (6 of 20), and 47% (9 of 19), respectively.

Olutasidenib with Azacitidine Well Tolerated

Olutasidenib was well tolerated in the trial in combination with azacitidine and the combination had a safety profile largely consistent with that of olutasidenib alone. Treatment-emergent adverse events (TEAEs) occurring in 25 percent or more of the participants included nausea (49 percent), constipation (40 percent), vomiting (35 percent), thrombocytopenia (32 percent), diarrhea (28 percent), and neutropenia (26 percent). TEAEs of grade 3 or 4 in more than 10 percent of participants included neutropenia (26 percent), thrombocytopenia (25 percent), anemia (19 percent), and febrile neutropenia (14 percent). TEAEs of QTc prolongation occurred in five participants (7 percent), of whom two experienced grade 3 QTc prolongation, and none discontinued olutasidenib.

TEAEs associated with liver enzyme abnormalities occurred in 15 participants (21 percent), with grade 3/4 in six (8 percent). Investigator-assessed IDH1 differentiation syndrome in six (8 percent) patients, of whom most resolved with treatment interruption, dexamethasone, and/or supportive treatment, while two patients had concomitant leukocytosis.

Molecular Characteristics of Response to Olutasidenib in Patients with R/R AML

A poster presentation reported findings from a planned interim analysis of the trial’s cohort of patients with R/R AML receiving olutasidenib alone, dosed 150 mg twice daily. The analysis examined expression of IDH1m variant allele frequency, prevalence of other genetic co-mutations in the trial’s pivotal cohort, and associations between mutations and response. Responses were observed across all IDH1 mutation subtypes and response rates were lower amongst patients with concurrent FLT3 co-mutations. Patients with higher co-mutations at baseline had lower rates of response than those with low mutational burden. Similarly, patients with lower baseline IDH1 expression were more likely to respond than those with high expression.

Olutasidenib Presentations Details

Abstract 698: Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia.

Session 616 on Monday, Dec. 13, at 3:00 PM ET

Presenter: Jorge E. Cortes, M.D.

Abstract 2351: Molecular Characteristics of Response to Olutasidenib (FT-2102) in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia

Session: 616 on Sunday, Dec. 12, at 6:00 PM ET

Presenter: Stéphane de Botton, M.D., Ph.D.

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About AML

Acute myeloid leukemia (AML) is a cancer that starts in a person’s bone marrow but often quickly moves into the blood. AML develops from immature blood cells, known as myeloid cells, that are supposed to mature into white blood cells. However, the diseased myeloid cells do not function properly. They instead multiply rapidly, which causes normal blood cell production to fail. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that about 20,940 new cases, most in adults, arose in 2021 in the United States alone.1

Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.2 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.3

About Olutasidenib

Olutasidenib is an oral, potent and small molecule investigational agent designed to selectively bind to and inhibit mutated IDH1 enzymes. This targeted treatment has the potential to provide therapeutic benefit by reducing 2-HG levels and restoring normal cellular differentiation. IDH1 is a natural enzyme that is part of the normal metabolism of all cells. When mutated, IDH1 activity can promote blood malignancies and solid tumors. IDH1 mutations are present in 6 to 8 percent of patients with AML.