AB Science's AB8939 Plus Venetoclax Achieves 67% ORR in Phase 1 Trial for High-Risk Relapsed/Refractory AML
Key Insights
AB Science (search) completed Step 3 of its Phase 1 trial evaluating AB8939 combined with venetoclax in six heavily pre-treated patients with relapsed/refractory AML and adverse genetics.
The combination achieved a 67% overall response rate and 100% disease control rate after a single 14-day cycle, with no dose-limiting toxicities observed.
Responses were seen in patients with TP53 mutations, MECOM rearrangements, complex karyotypes, and monosomy 5/7 — genetic profiles typically associated with poor prognosis.
AB Science (search) SA announced on June 29, 2026 the completion of Step 3 of its Phase 1 clinical trial (NCT05211570), evaluating the combination of its investigational agent AB8939 with venetoclax in patients with relapsed or refractory acute myeloid leukemia (search) (AML) harboring highly unfavorable genetic profiles. The combination generated a 67% overall response rate (ORR) and a 100% disease control rate (DCR), with no dose-limiting toxicities (DLT) observed across two dose levels.
The data represent an early but striking signal in a patient population where standard-of-care therapies typically achieve ORR of only 10–30% in adverse-risk, multiply pre-treated AML, as referenced from Gill H, et al. (Cancer Med. 2020).
Trial Design and Safety Profile
Step 3 enrolled six patients treated across two dose levels of AB8939 — 16 mg/m² and 21.3 mg/m² — each administered over a 14-day cycle in combination with venetoclax. The combination was well-tolerated at both dose levels, with no DLT and no hematological toxicity observed, enabling selection of the recommended Phase 2 dose (RP2D).
The first two steps of the Phase 1 study had previously established the maximum tolerated dose (MTD) of AB8939 monotherapy at 21.3 mg/m², following both 3-day and 14-day consecutive dosing schedules.
Efficacy in a High-Risk Population
Of the six patients treated, four achieved an objective response: one complete remission with incomplete hematologic recovery (CRi) and three partial responses (PR), yielding the 67% ORR. The two remaining patients achieved stable disease (SD), resulting in a 100% disease control rate. All responses were observed after a single 14-day treatment cycle in patients receiving second- to fourth-line therapy.
Notably, two of the responding patients had previously progressed on venetoclax in combination with other chemotherapies, suggesting AB8939 may overcome resistance mechanisms that limit venetoclax-based regimens.
The patients treated carried some of the most challenging cytogenetic and molecular abnormalities in AML, including TP53 mutations, NRAS mutations, MECOM rearrangements, complex karyotypes, and monosomy 5 and 7. Among the six patients, four harbored TP53 mutations — a subgroup with a median overall survival of just 5.5 months in the relapsed or refractory setting.
The patient-level response data showed: Patient 1 (16 mg/m², second-line, RUNX1 and NRAS mutations) achieved CRi; Patient 2 (16 mg/m², second-line, MECOM rearrangement, complex karyotype, monosomy 5 and 7) achieved PR; Patient 3 (16 mg/m², fourth-line, TP53 mutation, complex karyotype, monosomy 5 and 7) achieved PR; Patient 4 (21.3 mg/m², third-line, TP53 mutation, complex karyotype, monosomy 5 and 7) achieved PR; Patients 5 and 6 (both 21.3 mg/m², second-line, TP53 mutations) achieved stable disease.
Mechanistic Rationale
AB8939 employs a dual mechanism of action: it destabilizes microtubules to block leukemia cell proliferation while simultaneously targeting cancer stem cells through inhibition of ALDH1A1 (search) and ALDH2 (search). Critically, AB8939 is not subject to multi-drug resistance as it does not bind to PgP and is not degraded by myeloperoxidase.
The combination with venetoclax is supported by complementary mechanisms. Venetoclax inhibits the BCL2 (search) pathway, preventing apoptosis evasion in cancer cells, while AB8939's pro-apoptotic microtubule disruption benefits from BCL2 inhibition to optimize programmed cell death. Additionally, AB8939's ALDH inhibition specifically targets leukemia cancer stem cells, potentially reducing relapse risk.
Preclinical data showed AB8939 activity in cytarabine-resistant patient cell lines with adverse genetic features including MECOM and TP53 mutations. In vivo, AB8939 demonstrated additive effects with both venetoclax and azacitidine in MECOM-grafted PDX mouse models, and eradicated leukemia cancer stem cells in a human PDX AML model.
Expert Commentary
"This new data is very encouraging, particularly considering the very adverse risk profile of this patient's leukemia," said Nicholas J. Short, MD, Associate Professor and Co-Lead of the Section of Developmental Therapeutics, Department of Leukemia at MD Anderson Cancer Center. "These early efficacy and safety data suggest that AB8939 can be combined with venetoclax and could have significant activity in the highest-risk subtypes of AML. There is a strong interest in continuing the development of this combination in patients whose AML has high-risk features that are expected to lead to resistance to venetoclax + azacitidine."
Professor Olivier Hermine, MD, President of the Scientific Committee of AB Science (search) and member of the Académie des Sciences in France, added: "There is a strong rationale to combine AB8939 and venetoclax as both molecules have low hematologic toxicity and complementary mode of actions. These first results are supportive of this rationale."
Regulatory Strategy and Next Steps
With Step 3 completed, AB Science (search) will initiate Step 4, evaluating the triple combination of AB8939 plus venetoclax plus azacitidine. The company also plans to launch an expansion study in approximately 15 AML patients eligible for the AB8939-venetoclax doublet at the appropriate dose.
AB Science (search) has begun discussions with both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) regarding three potential registration pathways: AB8939 plus venetoclax as first-line treatment in aged patients or those with adverse genetics; the same combination as second- or third-line therapy; and AB8939 as a single agent in MECOM-rearranged AML in the second- or third-line setting.
AB8939 has received orphan drug designation for AML from both the EMA and FDA, conferring 10 and 7 years of marketing exclusivity in Europe and the US, respectively. Intellectual property is secured through a composition-of-matter patent until 2036, with potential extensions to 2041, and two additional second medical use patent applications could extend protection to 2044 and 2046 for specific AML subpopulations.
The global market for relapsed or refractory AML treatments is estimated at greater than €2 billion per annum, underscoring the commercial significance of addressing this area of high unmet medical need where approximately 70% of AML patients still relapse and die despite currently available therapies.