On July 30, 2025 AB Science SA (Euronext – FR0010557264 – AB) reported the approval of the third of four stages of the Phase I/II study (AB18001) with the compound AB8939 in adult patients with relapsed/refractory acute myeloid leukemia (AML) (Press release, AB Science, JUL 30, 2025, View Source [SID1234654633]).

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The third stage has been approved in France, Germany, Spain and Greece. The objective of the Phase 1 study is to determine the maximum tolerated dose (MTD) for different treatment stages of AB8939.

-Stage 1: Determination of the MTD after 3 consecutive days of treatment with AB8939 alone.
-Stage 2: Determination of the MTD after 14 consecutive days of treatment with AB8939 alone.
-Step 3: Determination of the MTD after 14 consecutive days of treatment with AB8939 in combination with venetoclax.
-Stage 4: Determination of MTD after 14 consecutive days of treatment with AB8939 in combination with venetoclax and azacitidine.

The first two stages of Phase 1 were completed with 28 and 13 patients enrolled, respectively, and determined the MTD of AB8939 after 3 consecutive days of treatment (21.3 mg/m2 ) and after 14 consecutive days of treatment (21.3 mg/m2 ).

The third stage now consists of evaluating the MTD after 14 consecutive days of treatment with AB8939 in combination with venetoclax, a standard treatment for AML.

Professor Olivier Hermine, MD, President of the Scientific Committee of AB Science and member of the Académie des Sciences in France said, "The approval of this third stage is a key milestone for the Phase I/II study with AB8939 in AML. The combination of AB8939 and venetoclax has the potential to change the standard of care in the treatment of relapsed/refractory AML".

▪Rationale for the AB8939 + venetoclax combination

The combination of AB8939 + venetoclax has several potential benefits:

1 – Both molecules have low hematologic toxicity. This combination could therefore be less toxic than azacitidine + venetoclax as first-line treatment for AML.

2 – These two molecules act on different and complementary targets in cancer cells, which could have an additive or even synergistic effect in terms of efficacy.

-AB8939 has two modes of action:

oMicrotubule destabilization: Microtubules are cellular structures essential for cell division (mitosis). By destabilizing them, AB8939 prevents cancer cells from dividing properly, leading to their death. The advantage is that this type of chemotherapy is independent of the TP53 mutation that creates the most resistance to standard chemotherapies.

oInhibition of ALDH (aldehyde dehydrogenase): ALDH is an enzyme found in cancer stem cells, a subtype of cells in AML that are particularly resistant to treatment and responsible for relapses, as they can survive conventional chemotherapy. By inhibiting ALDH, AB8939 specifically targets these stem cells, reducing resistance to treatment and limiting the risk ofrelapse.

-Mechanism of action of venetoclax: Inhibition of BCL2

oBCL2 is a protein that prevents apoptosis (programmed cell death) in cancer cells.

oBCL2 is another factor in AML resistance, as it allows cancer cells to survive despite treatment.

oBy blocking BCL2, venetoclax promotes apoptosis, making cancer cells more vulnerable.

-There is an additive, even synergistic, potential for the combination By simultaneously targeting these mechanisms, the combination could reduce the chances of cancer cells escaping treatment (resistance). This potential synergistic effect arises from the fact that inhibiting ALDH and BCL2 could weaken the resistance mechanisms of cancer stem cells, while destabilizing microtubules prevents cell proliferation. Together, these actions are more powerful than if each molecule were used alone.

3 – Finally, AML is difficult to treat due to its heterogeneity and resistance mechanisms. AB8939 is effective in vitro and in vivo in animals and generates responses in human patients with the poorest prognostic factors when treated with standard of care chemotherapies, namely TP53 mutation, MECOM and complex karyotype.

▪Non-clinical pharmacology data Animal studies have demonstrated the following properties of AB8939 that are relevant for the treatment of AML: -AB8939 is active ex vivo against AML cancer cells from chemotherapy-naive or chemotherapy-refractory/relapsed patients, particularly those with TP53 mutations or complex karyotypes.

-AB8939 eradicates blasts in the blood and bone marrow in PDX models resistant to 5-AraC (cytarabine), particularly those with MECOM rearrangements. -AB8939 increases survival and has an additive effect in combination with the standard treatments azacitidine and venetoclax. -ALDH expression is a characteristic of cancer stem cells (CSCs), and AB8939 is an ALDH1/2 inhibitor. Therefore, AB8939 is a targeted therapy for leukemic cancer stem cells.

-AB8939 eradicates leukemia cancer stem cells in a human PDX model of AML.

▪Potential market for AB8939 in AML

Treatments for AML represent an estimated market potential of more than €2 billion per year.

AB8939 was entirely discovered by AB Science, which retains full ownership of the intellectual property rights, reflecting AB Science’s priority to develop innovative drugs aimed at improving patients’ lives.

The composition of AB8939, including its use in the treatment of AML, is covered until 2026 by a patent granted in all geographical areas where AB8939 could be marketed, including Europe (patent EP 3253749), the United States (US 10,570,122), Canada (CA 2975644), China (CN 107531685), South Korea (KR 10-2544132), Japan (JP 6713000), Hong Kong (HK 1243700), Israel (IL 253779), Australia (AU 2016214283), Russia (RU 2758259), Brazil (BR 112017016883-9), Mexico (MX 377742), India (IN 480996) and South Africa (ZA 2017/05537). An extension of this protection for 5 years is possible in certain countries.

A second patent application for medical use has been filed to protect the use of AB8939 in the treatment of AML with certain chromosomal abnormalities. If this application is accepted, protection for AB8939 will be extended until 2044 for these subpopulations of AML patients. In addition to patent protection, AB8939 is also eligible for regulatory data protection in numerous countries, preventing generic competition for a period of up to 8 years from product registration.

AB8939 has also received orphan drug designation for AML from both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). This orphan drug designation confers 10 and 7 years of marketing exclusivity in Europe and the US, respectively, from the date of product registration.