Dihydroorotate dehydrogenase (DHODH), catalyzing the ubiquinone-mediated oxidation of dihydroorotate to orotate, is the rate-limiting enzyme in the de novo synthesis of pyrimidines, and as such may control the rate of cell division. The enzyme is localised on the outer side of the inner mitochondrial membrane, and links both the electron transport chain to pyrimidine production and thus to the maintenance of cell viability. DHODH inhibitors were identified in a myeloid differentiation screen using an ER-HoxA9 GMP cell line, and ASLAN003, a novel small molecule DHODH oral inhibitor, has been found to be a potent inducer of myeloid differentiation in AML cell lines. ASLAN003 also demonstrated the ability to reduce leukemic burden and extend survival in AML xenograft models. ASLAN003 has previously been shown to exhibit a safe and tolerable profile in prior phase I studies in healthy volunteers.


A multicenter, single arm phase IIA study was initiated to evaluate ASLAN003 monotherapy administered as a 28-day cycle in patients with AML who are ineligible for standard therapy. The primary objective is to determine the optimum dose of ASLAN003 in this AML cohort based on efficacy (Overall Complete Remission Rate, % of complete remission [CR] + CR with incomplete hematologic recovery [CRi]), tolerability and safety. The secondary objective is to assess the pharmacokinetics (PK) of ASLAN003 and its metabolites and to further assess the efficacy based on relapse-free survival and clinical benefit rate (CBR, % of partial remission + CR + CRi). Exploratory objectives are to examine the myeloid differentiation effects of ASLAN003 ex vivo and explore possible relationships between the clinical response and molecular profile of leukemic cells. The study contains 3 cohorts for the optimum dose determination (100 mg, 200 mg, and 300 mg once daily [QD], with planned enrollment for 6 patients for each cohort), and an additional expansion cohort with the selected optimum dose (20 patients).


Enrollment started in December 2017. As of 12 July 2018, 10 patients were enrolled and treated (6 in the 100 mg QD cohort and 4 in the 200 mg QD cohort). Although the data are immature, two patients to date have exhibited some evidence of clinical activity (one per cohort). A patient in the 100 mg QD cohort, with a baseline peripheral blood blast of 27%, experienced a reduction to 6% on Cycle 3 Day 10 (C3D10), coupled with an upward trend in the percentage of neutrophils (16% at baseline, 64% on C3D10). The patient had underlying chronic lung infection, but also showed suspected symptoms of differentiation syndrome (dyspnea, leukocytosis). After 126 days of ASLAN003 initiation, the patient expired due to AML related clinical deterioration. The second patient in the 200 mg QD cohort experienced a decrease in bone marrow blasts from 26% at baseline, to 12% on C2D1. Concomitantly, there was a slight decrease in peripheral blood blasts with an increase in neutrophil percentages from 7% to 51%. The patient remains on study with further efficacy data awaited. To date, the safety profile is consistent with the previous healthy volunteer studies. Treatment-related adverse events (AEs) are listed in Table 1. The most frequent treatment-related AEs include nausea (n=2, 20%) and leukocytosis (n=2, 20%). Two treatment-related Grade ≥ 3 AEs were observed (Grade 3 anaemia and Grade 3 leukocytosis). The study continues and is currently enrolling to the 200 mg cohort.


At the date of submission, this is the first report of clinical activity of a DHODH inhibitor in AML patients. Monotherapy with ASLAN003 was well tolerated and has showed encouraging signs of clinical activity in AML patients. This study is on-going and the optimal dose for AML has not yet been determined. Safety, PK and efficacy data will be updated at the time of presentation. Clinical trial information: NCT03451084


Chng:ASLAN Pharmaceuticals: Research Funding. McHale:ASLAN Pharmaceuticals: Employment, Equity Ownership. Hsieh:ASLAN Pharmaceuticals: Employment, Equity Ownership. Shih:ASLAN Pharmaceuticals: Employment; AstraZeneca Taiwan: Employment. McIntyre:ASLAN Pharmaceuticals: Consultancy. Kwek:ASLAN Pharmaceuticals: Employment. Chang:ASLAN Pharmaceuticals: Employment. Lindmark:ASLAN Pharmaceuticals: Employment, Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.