Complete Bone Response Observed in Trial of AB8939 for AML

A patient who received AB8939, a microtubule inhibitor, in a phase 1 study, had a significant reduction in bone marrow blasts, showing its potential to treat drug-resistant acute myeloid leukemia.

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Treatment with AB8939, a microtubule destabilizer, resulted in a complete bone response in a patient with relapsed and refractory acute myeloid leukemia (AML) in a phase 1/2 study (AB18001; NCT05211570], according to a press release from AB Science.1

The patient had a reduction from 55% to 5% in bone marrow blast cells 1 month after receiving the second-lowest dose increment used in the trial. They also experienced no treatment-related toxicities.

“It is remarkable that we rapidly observed a response in what is typically a difficult-to-treat patient population of refractory AML. We observe a clear blast count reduction for this patient and excellent tolerance so far,” Pau Montesinos, MD, hematologist at the La Fe University Hospital and coordinator of the Spanish group of acute myeloblastic leukemia (PETHEMA), stated in the press release. “It is all the more noteworthy because the initial disappearance of leukemic cells was obtained after only 3 days of AB8939 treatment at a very low dose, with a good response maintained after a second 3-day cycle at this dose.”

The microtubule destabilizer AB8939 has broad antitumor activity with the capability to overcome P-glycoprotein– and myeloperoxidase-mediated resistance that reduces the efficacy of microtubule-targeting chemotherapies. In preclinical studies, it showed activity across all AML subtypes and in AML that displays resistance to azacitidine (Onureg).2 It was granted orphan drug designation for AML by the FDA.1

“AML is a serious life-threatening condition and the most common cause of leukemia-related mortality, in large part because patients develop chemoresistance to existing frontline AML drugs,” Olivier Hermine, MD, president of the Scientific Committee of AB Science and member of the Académie des Sciences in France, said in the press release.1

The AB18001 trial is a phase 1/2, open-label, multi-center, non-randomized, 2-part study that is planned to enroll an estimated 78 patients with relapsed or refractory AML or refractory myelodysplastic syndrome. The first part is a dose escalation study with a primary end point of safety, tolerability, and pharmacokinetic profiles of AB8939. The second part is a dose expansion study using a recommended phase 2 dose to study the schedule for a phase 2 trial and assess efficacy.

Patients are ineligible for the study if they are eligible for standard of care or hematopoietic stem cell transplantation, have active central nervous system leukemia, or acute promyelocytic leukemia.

The patient who had the bone marrow response was 65 years old and previously failed treatment with azacitidine and had a MECOM gene rearrangement which is a biomarker associated with resistance to standard chemotherapies and is linked to disease progression.1,3 Overexpression of MECOM occurs in approximately 10% of patients with AML, and they have poor prognosis. AB Science has submitted a provisional patent application for this subpopulation of patients with AML.

The patient received a 1.8 mg/m2 intravenous dose for 3 consecutive days on a 28-day cycle.3 They were noted for benefiting at the second lowest of 13 potential dose levels in the dose escalation part of the trial. They received further treatment with AB8939 at the request of the investigator. One month after the second treatment cycle of 3 consecutive days at the same dose, they maintained a good response of 10% bone marrow blasts, and a third treatment cycle was initiated.

The patient also had an increase in neutrophils from 200/μLto 260/μL after the first cycle and 480/μL after the end of the second cycle. They had an increase in platelet count from 3000/μL to 11000/μL after 1 cycle and 12000/μL after 2 cycles of treatment.

Investigators reported that overall, there have been no signs of moderate, severe, or serious toxicities in the trial.1,3 Approximately 50% of patients enrolled have requested further treatment cycles after receiving the first cycle and a measurement at day 28. In addition, 70% of patients had an increase in platelets and 90% had an increase in neutrophils.3 The first 4 dose levels have been completed, with the fifth dose level cohort of 9.0 mg/m2 being ongoing.

AB Science is planning to complete phase 1 in 2023 and initiate phase 2 in 2023 or 2024. The planned design for phase 2 may involve patient selection based on MECOM and other genetic factors and will enroll fewer than 100 patients. “[The] AML indication fits the criteria for accelerated approval pathway based on compelling phase 2 (FDA), hematological response being a validated surrogate endpoint of efficacy,” they stated in the webcast.3

“This preliminary clinical data provides the most encouraging signs to date that AB8939 may be well-suited for treatment of high-risk relapsed/refractory AML,” said Hermine.1


1. AB Science reports a first complete bone marrow response in a relapsed refractory acute myeloid leukemia patient from the very low dose arm of its AB8939 Phase I/II clinical trial (AB18001). News release. March 13, 2023. Accessed March 22, 2023.

2. Hermine O, Humbert M, Goubard A, et al. B8939, a novel microtubule-destabilizing agent for the treatment of acute myeloid leukemia. Presented at: 2020 Annual Congress of the European Hematology Association; June 11-20, 2020; virtual. Accessed March 23, 2023.

3. AB Science Webconference microtubule destabilizer agents (MDA). March 16, 2023. Accessed March 23, 2023. AB Science.

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