EP0042 Wins FDA Orphan Drug Status for Acute Myeloid Leukemia

The FDA has granted an orphan drug designation to EP0042 for use as a potential therapeutic option in patients with acute myeloid leukemia with acquired resistance to FLT3 inhibitors.

Image Credit: ©immimagery / Adobe Stock Images

Image Credit: ©immimagery / Adobe Stock Images

The FDA has granted an orphan drug designation to EP0042 for use as a potential therapeutic option in patients with acute myeloid leukemia (AML) with acquired resistance to FLT3 inhibitors, according to an announcement from Ellipses Pharma.1

EP0042 binds to and inhibits the Aurora kinase and FLT3, which hinders the activation of Aurora kinase– and FLT3-mediated signal transduction pathways.2 This process could lead to the disruption of the assembly of the mitotic spindle apparatus and chromosome segregation, as well as the inhibition of cell proliferation in cancer cells that overexpress either or both targets.

Preclinical data have suggested that dual inhibition of the Aurora/FLT3 kinase can overcome acquired resistance to selective FLT3 inhibition.3,4 Moreover, in FLT3-ITD and FLT3-ITD-TKD human cancer xenograft models and in quizartinib-resistant primary AML samples, the investigative agent inhibited cancer growth.5 The safety and tolerability of EP0042 is under evaluation in a phase 1/2 trial (NCT04581512) in patients with relapsed or refractory AML.5

“Receiving an FDA orphan drug designation for EP0042 validates this compound’s potential in a currently underserved area of medicine,” Rajan Jethwa, MA, MRCS, chief executive officer and co-founder of Ellipses Pharma, stated in a press release.1 “The designation is an important milestone in the development of EP0042 and underscores the work we are already undertaking toward accelerating its potential access to patients. We believe its early clinical data merit its continued study, and this FDA decision further focuses our vision as we continue our drive toward bringing EP0042 to more patients.”

The early-phase trial enrolled patients with a histologically or cytologically confirmed advanced cancer who were at least 18 years of age.6 They were required to have an ECOG performance status of 0 to 2 and a sufficient life expectancy to permit the patient to complete at least 1 cycle of study treatment. They could not have suspected brain and/or leptomeningeal metastases that were symptomatic, untreated, or needed therapy, nor could they have acute promyelocytic leukemia.

Study participants were given oral EP0042 at doses ranging from 20 mg to 50 mg. The primary outcome measure of the research is the incidence of dose-limiting toxicities (DLTs) from the first dose through the end of the DLT observation period.

Early data from the dose-ranging portion of the trial were presented at the 2022 ASH Annual Meeting.7,8 These data were based on a total of 25 patients who were enrolled across 6 dosing cohorts. The population included those with tumors harboring FLT3 mutations and those with wild-type AML at the time of enrollment. Notably, the median number of prior therapies received in this group was 2 (range, 1-6). Several participants had previously received a FLT3 inhibitor.

Findings indicated that EP0042 had acceptable safety and tolerability. Moreover, investigators noted prolonged disease control in several patients with AML who were heavily pretreated. Notably, no DLTs were reported with the agent. Common adverse effects observed with EP4002 included febrile neutropenia, fatigue, diarrhea, peripheral edema, dizziness, and ataxia.

Once a phase 2 dose of EP4002 is confirmed, Ellipses Pharma shared plans to further examine the agent as a single agent and in combination with standard drugs.1


  1. Ellipses Pharma: EP0042 receives orphan drug designation from the US Food and Drug Administration. News release. Ellipses Pharma. https://www.businesswire.com/news/home/
  2. Aurora kinase/FLT3 inhibitor EP0042. National Cancer Institute website. Accessed March 14, 2023. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/aurora-kinase-flt3-inhibitor-ep0042
  3. Moore AS, Faisal A, Gonzalez de Castro D, et al. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia. 2012;26(7):1462-1470. doi:10.1038/leu.2012.52
  4. Tariq MU, Furqan M, Parveen H, et al. CCT245718, a dual FLT3/Aurora A inhibitor overcomes D835Y-mediated resistance to FLT3 inhibitors in acute myeloid leukaemia cells. Br J Cancer. 2021;125(7):966-974. doi:10.1038/s41416-021-01527-2
  5. Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736. Blood Adv. 2020;4(7):1478-1491. doi:10.1182/bloodadvances.2019000986
  6. Study to evaluate the safety and tolerability of EP0042. ClinicalTrials.gov. Updated February 8, 2023. Accessed March 14, 2023. https://clinicaltrials.gov/ct2/show/NCT04581512
  7. Ellipses Pharma presents preliminary data from the first in human phase-1/2 trial of EP0042, a dual FLT-3 and Aurora kinase inhibitor, at ASH. Press release. Ellipses Pharma Limited. December 12, 2022. Accessed March 14, 2023. https://www.businesswire.com/news/home/
  8. Taussig D, O’Nions J, Jongen-Lavrencic M, et al. EP0042, a dual FLT3 and Aurora kinase inhibitor: preliminary results of an ongoing phase I/IIa first in human study in patients with relapsed/refractory acute myeloid leukemia. Blood. 2022;140(suppl 1):6222-6223. doi:10.1182/blood-2022-166400
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