Arog Pharmaceuticals presented new results from a Phase III trial at the American Society of Hematology (ASH) Annual Meeting 2025, held in Orlando, Florida and online from 6 to 9 December. The placebo-controlled, randomised, double-blind study (NCT03250338) investigated crenolanib in relapsed or refractory (R/R) FLT3-mutated adult acute myeloid leukaemia (AML) patients.
Crenolanib + salvage chemotherapy demonstrated encouraging antitumour activity and met the primary endpoint. At a data cut-off of 37.3 months, the median event-free survival (EFS) improved to 3.4 months for crenolanib, compared with 0.0 months for placebo (hazard ratio [HR] 0.64; p=0.013). For the secondary outcomes, among 106 enrolled patients, crenolanib was associated with a substantially higher overall response rate (ORR) of 60% (31/52) compared with 39% (21/54) in the placebo arm, and a marked reduction in refractory disease to 40% (21/52) versus 61% (33/54) with placebo. Median overall survival (OS) increased from 8.7 months with placebo to 10.4 months with crenolanib (HR 0.83); however, this difference did not reach statistical significance (p=0.39).
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A stronger response was observed in a subset of patients with NPM1/FLT3 co-mutated disease. NPM1 alterations occur in around 60% of FLT3-mutated cases. In this group, median EFS increased to 6.1 months with crenolanib, from 0.0 months with placebo (HR 0.53; p=0.01). Median OS improved from 6.3 months for placebo to 12.4 months for crenolanib (HR 0.53; p=0.03). These findings support continued development of crenolanib for NPM1/FLT3 co‑mutated AML. Arog is also advancing the agent for newly diagnosed FLT3-mutated AML.
The safety profile was consistent with that previously reported and acceptable, given the intensity of the treatment regimen. Crenolanib or placebo were administered in three phases: induction alongside salvage chemotherapy, consolidation with cytarabine and hematopoietic stem cell transplantation (HSCT) for eligible patients, and maintenance for up to one year. Among 52 patients receiving chemotherapy + crenolanib, grade 3 and higher adverse events included elevations in liver function tests in 12 (23%), nausea in 10 (19%), gastrointestinal bleeding in nine (17%), and diarrhoea in two (4%). Eight patients required dose reductions. Importantly, the addition of crenolanib did not impact graft-versus-host disease in patients undergoing HSCT.
Crenolanib is a small molecule type I FLT3 inhibitor. FLT3 mutation is associated with poor prognosis in AML. Internal tandem duplications (ITD) occur in approximately 25% of patients, and point mutations in the tyrosine kinase domain (TKD) account for 5%. Crenolanib targets FLT3‑mutated AML irrespective of ITD or TKD subtype. If approved, it would become the fourth targeted therapy for FLT3‑mutated AML and the second option for R/R disease. Physicians’ familiarity with FLT3 inhibitors and established genetic testing will support the uptake, particularly if crenolanib demonstrates a clinical advantage over existing therapies. Within the current competitive FLT3 inhibitors landscape, Astellas’ Xospata (gilteritinib), a type I inhibitor approved in 2018, remains the main treatment for patients with R/R AML.
In newly diagnosed AML, Novartis’ type I agent Rydapt (midostaurin) was approved by the FDA in 2017, while Daiichi Sankyo’s Vanflyta (quizartinib), the type II inhibitor selectively targeting FLT3-ITD, was approved in 2023. The second-generation agents Xospata and Vanflyta are more specific and potent and have fewer off-target toxicities. However, limited durability of response and safety concerns remain, particularly cardiovascular toxicity and myelosuppression for Vanflyta and differentiation syndrome for Xospata. As a result, a meaningful opportunity remains to develop more effective and safer FLT3 inhibitors. AML is an aggressive haematologic malignancy, with a five-year OS rate of 35% in the general population and below 10% in individuals above 65 years old. GlobalData estimates that AML diagnosed incident cases will rise from 75,758 in 2022 to 95,654 by 2032 at a compound annual growth rate (CAGR) of 2.6% across the eight major pharmaceutical markets (8MM: Australia, Canada, France, Germany, Italy, Spain, the UK and the US). Sales of AML products are projected to grow at a CAGR of 4.7%, reaching $4.1 billion in 2030. FLT3 inhibitors in AML will generate $600 million, with crenolanib projected to contribute around $140 million. Arog Pharmaceuticals, located in Dallas, Texas, was formed primarily to acquire crenolanib, originally developed by Pfizer in partnership with OSI Pharmaceuticals. Crenolanib remains Arog’s sole disclosed development asset, making the success of this programme critical for the company.
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