FDA Awards Orphan Drug Designation to EP0042 for AML Treatment


Preclinical and phase 1/2a data evaluating the safety and tolerability of EP0042 in patients with relapsed or refractory acute myeloid leukemia has led the FDA to grant an orphan drug designation to the agent.

The FDA has granted an orphan drug designation to EP0042, a dual FLT3 and Aurora kinase inhibitor, for patients with acute myeloid leukemia (AML) who have acquired resistance to FLT3 inhibitors, according to Ellipses Pharma.1

"EP0042 works to block two enzymes, aurora kinase and FLT3. FLT3 drives leukaemia cells to proliferate rapidly and inhibiting it can lead to remissions. However leukaemia cells get resistant to current FLT3 inhibitors. They can use the enzyme aurora kinase to resist the FLT3 inhibitors. By inhibiting both pathways we hope to improve outcomes," David Taussig, MD, consultant hematologist at The Royal Marsden, told Targeted OncologyTM.

This agent is being developed to combat acquired resistance to FLT3 inhibitors in patients with AML as one third of patients diagnosed with AML also harbor FLT3-mutations. These mutations are associated with a higher risk of relapse and poor clinical outcomes, leaving an unmet need for more treatment options for patients with this disease.

According to preclinical data, dual inhibition of the Aurora/FLT3 kinase was able to overcome acquired resistance to selective FLT3 inhibition.2 FLT3-ITD and FLT3-ITD-TKD human cancer xenograft models and quizartinib-resistant primary AML samples also showed that EP0042 led to the inhibition of cancer growth.

The safety and tolerability of EP0042 is being evaluated in a phase 1/2a trial (NCT04581512) in patients with relapsed or refractory AML.3

“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.”

In the phase 1/2a multicenter, early-phase trial, patients were administered EP0042 as monotherapy or in combination with established standard treatments to determine the maximum tolerated dose and optimal dose of the agent in this patient population.

Patients enrolled in the study were aged 18 years and older, required to have a histologically or cytologically confirmed advanced cancer, 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.

Oral EP0042 at doses ranging from 20 mg to 50 mg were administered to those enrolled in the study and investigators assessed the primary end point of incidence of dose-limiting toxicities (DLT) from the first dose through the end of the DLT observation period.

During the 2022 ASH Annual Meeting, early data were presented based on 25 patients enrolled across 6 dosing cohorts. Patients had a median age of 73 years old (range, 28-83), and 23 presented with AML while 2 had myelodysplastic syndrome.2

Among those enrolled in the study were patients with FLT3-mutatedAML and those with wild-type AML at the time of enrollment, and the median number of prior therapies received in this group was 2 (range, 1-6). Additionally, participants had previously received a FLT3 inhibitor.

Findings indicated that EP0042 had acceptable safety and tolerability in patients with AML at the doses studied in the trial. There was prolonged disease control in several heavily pretreated patients with AML.

Regarding safety, there were no DLTs reported with the agent. The most common adverse events seen with EP4002 treatment included febrile neutropenia, fatigue, diarrhea, peripheral edema, dizziness, and ataxia.

The dose-escalation portion of the trial is underway to establish the maximum tolerated dose of the agent. Once a phase 2 dose of EP4002 is confirmed, the agent will be further examined as a monotherapy and in combination with standard drugs for this patient population.1

"I am excited that the FDA has an granted orphan designation to EP0042. While some forms of AML are curable with standard therapies many are not, and the FLT3 mutants are a particular challenge. We are establishing the optimal dose and then will move into combination therapy," added Taussig.

  1. Ellipses Pharma: EP0042 receives orphan drug designation from the US Food and Drug Administration. News release. Ellipses Pharma. March 14, 2023. Accessed March 15, 2023. https://bwnews.pr/3Ltvmxk
  2. 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
  3. Study to evaluate the safety and tolerability of EP0042. ClinicalTrials.gov. Updated February 8, 2023. Accessed March 15, 2023. https://clinicaltrials.gov/ct2/show/NCT04581512
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