On November 10, 2022 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL) reported the publication of data in The Lancet Haematology, which summarizes the Phase 1 results of the Phase 1/2 study of olutasidenib, an investigational, oral, small molecule inhibitor of mutant isocitrate dehydrogenase-1 (mIDH1) (Press release, Rigel, NOV 10, 2022, View Source [SID1234623710]). Olutasidenib was assessed as a monotherapy or in combination with azacitidine, in patients with mIDH1 acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The published data suggest that olutasidenib, with or without azacitidine, was well-tolerated and was associated with improvements in clinical efficacy endpoints in patients with mIDH1 AML.
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"These data from the first phase of the Phase 1/2 study suggest that olutasidenib may be both efficacious and well-tolerated, findings that are reinforced by the subsequently reported data from the Phase 2 registrational trial, which generated compelling efficacy and safety data that highlight olutasidenib as a potential treatment option for mIDH1 relapsed/refractory AML," said Wolfgang Dummer, M.D., Ph.D., Rigel’s chief medical officer. "The NDA for olutasidenib, submitted by Forma Therapeutics, is under FDA review and we look forward to a potential approval in early 2023."
The objectives of the first phase of the multi-center, open-label Phase 1/2 study were to assess the safety, pharmacokinetic and pharmacodynamic profile, and clinical activity of olutasidenib, both as monotherapy and in combination with azacitidine, in patients with treatment-naïve or relapsed/refractory (R/R) AML or MDS harboring IDH1 mutations.
Key findings from the study are summarized below:
Among patients receiving combination therapy, treatment-naïve AML patients saw a 77% overall response rate (ORR) and a 54% complete response (CR) plus CR with partial hematological recovery (CR/CRh). These results provide strong rationale for future evaluation of either sequential or triplet therapy in this setting.
In the MDS cohort, 4 of 9 responding patients achieved mutation clearance. CRs were observed with both monotherapy and combination therapy, including an 86% ORR and 57% CR rate in the combination arm. The investigators noted, "To our knowledge, we also report the first available data on patients with myelodysplastic syndrome treated with an IDH1 inhibitor plus azacitidine, where we observed a strong preliminary activity signal."
Olutasidenib was well-tolerated in patients with AML and MDS, either as monotherapy or in combination with azacitidine. No dose limiting toxicities occurred in the dose escalation cohorts. Overall, adverse events were similar and manageable across the monotherapy and combination arms. Transient QT prolongation was observed in 3 patients (4%).
This study showed that olutasidenib has the potential to provide an additional treatment option for mIDH1 AML.
A link to the online publication at The Lancet Haematology can be found here.
Last week, Rigel announced updated interim data from the Phase 2 pivotal cohort of this trial. This data will be presented in a poster at the 64th ASH (Free ASH Whitepaper) Meeting in New Orleans on December 11, 2022. A link to the press release can be found here.
On August 2, 2022, Rigel and Forma Therapeutics, Inc. announced they entered into an exclusive, worldwide license agreement to develop, manufacture and commercialize olutasidenib for the treatment of relapsed/refractory AML (R/R AML) and other malignancies. Forma’s New Drug Application (NDA) for olutasidenib is currently under review by the U.S. Food and Drug Administration (FDA) and the Prescription Drug User Fee Act (PDUFA) target action date is February 15, 2023.
About Olutasidenib and AML
Olutasidenib is an oral, 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 9 percent of patients with AML1.
AML is a rapidly progressing cancer of the bone marrow and blood2. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that in the United States, there will be about 20,050 new cases of AML in 2022, mostly in adults.3 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need.