FORMA Therapeutics’ Olutasidenib Shows Promising Activity Against IDH1-Mutated AML

Treatment with FORMA Therapeutics’ investigational agent olutasidenib has shown promising efficacy and safety in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and mutations in isocitrate dehydrogenase 1 (IDH1m), according to topline data from the Phase II FT2102-HEM-101 clinical trial.

Olutasidenib was discovered by clinical-stage biopharmaceutical company FORMA Therapeutics through a drug discovery platform. The platform uses “high throughput screening with DNA-encoded library screens for lead identification” in addition to a “technology-leveraged parallel optimization process to develop lead candidates,” according to the company.

In regard to its primary mechanism of action, olutasidenib is a selective inhibitor of IDH1m. The IDH1 is an enzyme that, when mutated, can promote blood cancers and solid tumors. Olutasidenib, a potent small-molecule agent, also potentially reduces levels of 2-hydroxyglutarate, a metabolite produced by IDH1m that may play a role in AML pathogenesis. The therapy may also restore normal cellular differentiation in the presence of these mutations.

FORMA’s 500-patient Phase II open-label, fixed-dose FT2102-HEM-101 study is currently enrolling. The study is examining olutasidenib monotherapy in not only patients with IDH1m AML, but also in cohorts combining olutasidenib with azacitidine or cytarabine in patients with IDH1m AML or myelodysplastic syndrome (MDS).

Olutasidenib monotherapy in this trial has so far been associated with a complete remission (CR) rate of 30% in the 123 enrolled patients with IDH1m R/R AML. The data from FT2102-HEM-101 also show that 3% of patients achieved a CR plus CR with partial hematologic recovery (CRh). According to investigators of the ongoing trial, the median duration of CR/CRh has not been reached. A sensitivity analysis demonstrates the median duration of CR/CRh is 13.8 months.

Topline data from the Phase II study, which will be submitted at a future medical meeting, also demonstrate that olutasidenib featured a “favorable tolerability profile as a monotherapy” in this patient population. The most frequently reported adverse events associated with olutasidenib in this study included nausea, constipation, increased white blood cell count, decreased red blood cell count, fever, febrile neutropenia and fatigue.

“The safety profile and the duration of the response we’re seeing supports the potential for olutasidenib to become a leading therapy for R/R IDH1m AML patients,” according to a statement made by Patrick Kelly, MD, FORMA’s chief medical officer. “While the multi-cohort Phase II trial is ongoing, this specific cohort was designed to serve as a pivotal study; these efficacy data support an early stop in enrollment in favor of moving the program forward.”

Positive preliminary data from FORMA’s Phase I/II study of olutasidenib previously showed that the IDH1m inhibitor produced rapid clinical remissions and clearance of mutations in patients with AML and MDS.

“In the U.S. alone, more than 20,000 new cases of AML are diagnosed each year, with about one-third of those evolving from patients with MDS,” FORMA’s chief executive officer, Frank Lee, said in a statement. “Despite recent advances in the field, the low median five-year survival rate for AML patients is only 28%, so the need for a new therapy to transform patient outcomes remains significant.”

Mutated AML isn’t the only indication for which FORMA is seeking to attribute to olutasidenib. In late 2019, the company showed that the therapy effectively penetrates the blood-brain barrier and results in disease response in patients with IDH1m glioma.

“In patients with a predominantly enhancing relapsed/refractory glioma, we achieved a clinical response with half of the patients still on study treatment at four months,” Kelly said. “Particularly for patients with late-stage gliomas where the disease progresses quickly, maintaining disease control holds promise.”

In May 2020, FORMA presented two abstract presentations on olutasidenib at the American Society of Clinical Oncology 2020 Virtual Scientific Program. One of the presentations included safety and efficacy data from the Phase Ib/II study of the small-molecule inhibitor in patients with relapsed-refractory IDH1 mutant gliomas. Another presentation presented by FORMA included safety and efficacy day of a Phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1m solid tumors, including patients with confirmed IDH1m advanced glioma. Both studies demonstrate that the therapy may hold a clinical benefit for these patients.

In December 2019, FORMA closed a $100 million Series D financing round, which was led by RA Capital Management in collaboration with other major investors. A statement made by FORMA says the funding is being used to support further development of olutasidenib for gliomas, R/R AML, MDS, and other IDH1m solid tumors.