On December 17, 2024 AB Science SA (Euronext – FR0010557264 – AB) reported an update on its AB8939 program in acute myeloid leukemia (AML) (Press release, AB Science, DEC 17, 2024, View Source [SID1234649151]).

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AB8939 target product profile

AB8939 is a next generation synthetic microtubule destabilizer and stem cell targeted ALDH1/2 inhibitor with key differentiating factors for treatment of refractory/relapsing acute myeloid leukemia (AML).

▪AB8939 blocks proliferating leukemia cells through microtubules AB8939 destabilizes microtubule, is not subjected to multidrug resistance as it does not bind to PgP, responsible of efflux outside the cells and AB8939 is not degraded by the enzyme myeloperoxidase.

▪AB8939 targets leukemia cancer stem cells though inhibition of ALDH AB8939 inhibits ALDH1/2 and favors the bone marrow repopulation of normal progenitors. ▪AB8939 is well suited for the treatment of relapsed or refractory AML AB8939 has activity seen across refractory AML cell lines, has an additive effect with referenced first line treatment for AML, namely cytarabine, azacitidine and venetoclax.

▪AB8939 has a potential use in AML with MECOM AB8939 has shown a signal of efficacy in AML with MECOM gene rearrangement, a subset of patients that show extreme resistance to chemotherapies and exhibit the worst survival prognosis

▪AB8939 shows absence of hematological toxicity based on clinical data

Addressable market with AB8939 in relapsed/refractory AML

Treatments in relapsed or refractory AML represent an estimated market size potential above EUR 2 billion per annum.

Non clinical pharmacology

Animal experiments have shown the following properties for AB8939 relevant for the treatment of AML: ▪AB8939 is active against chemotherapy naive or chemotherapy refractory/relapsing patient’s AML cancers cells ex vivo ▪AB8939 eradicates blasts in Blood and Bone Marrow in 5-AraC-resistant (Cytarabine) PDX

▪AB8939 increases survival and has an additive effect in combination with reference treatment Azacitidine and Venetoclax

▪ALDHs expression is a hallmark of cancer stem cells (CSCs) and AB8939 is an inhibitor of ALDH1/2. Therefore, AB8939 is a targeted therapy for leukemia cancer stem cells

▪AB8939 eradicates Leukemia Cancer Stem Cells in a human PDX AML model

Phase 1 preliminary safety

The objective of the phase 1 is to determine the maximum tolerated dose (MTD) for three different cycles of AB8939. The first step of the phase 1 has been completed with 28 patients enrolled, evaluating the maximum tolerated dose after 3 consecutive days of AB8939 treatment. The second step of the phase 1 is close to completion and enrolled 10 patients, evaluating the maximum tolerated dose after 10 consecutive days of AB8939 treatment. The next step is to evaluate the maximum tolerated dose after 14 consecutive days of AB8939 treatment in combination with venetoclax or azacitidine and in combination with venetoclax plus azacitidine, both drugs being widely used on AML and for which AB8939 has shown an additive effect.

Preliminary activity in MECOM

MECOM is associated with a dismal outcome, with almost all patients dying within 12 months after relapse. AB8939 is a stem cell ALDH targeted therapy with potential use in AML with MECOM.

▪ALDH gene expression is a marker of survival prognosis in AML. The higher the expression, the worse the prognosis

▪MECOM is associated with the worst prognosis in AML

▪MECOM is a rearrangement or a mutation of the chromosome 3 locus Q26 that codes for the transcription factor gene EVI1 (Ecotropic virus integration site-1)

▪The expression of ALDH1A1 is regulated by EVI1 and has an outstanding role in the formation and transformation of hematopoietic cells and in particular leukemia stem cells

▪The hypothesis is that in MECOM, the rearrangement of chromosome 3 Q26 leads to EVI1 over-expressing ALDH1A and induces high resistance of leukemia stem cells, and AB8939 should have an impact on leukaemia stem cells by inhibiting ALDH1 AB8939 has shown activity on MECOM rearrangement, based on non-clinical data and early clinical data in relapsing/refractory line of treatment, with 50% response rate observed. Planned phases 2 The next steps in the clinical development will be discussed with FDA and EMA. The first intended step is to develop AB8939 in patients with MECOM AML, through a single arm study with less than 60 patients supporting an accelerated approval based on response rate.

The second objective is to position AB8939 in broader forms of AML and position AB8939 in relapsed or refractory AML. The third objective is to capture the full market potential of AB8939 and position AB8939 in first line in combination with standard of care.

Intellectual property

AB8939 intellectual property rights in AML are secured until 2036 through a ‘composition of matter’ patent and potentially until 2044 in AML with chromosome abnormality, including MECOM, through a ‘second medical use’ patent. AB Science is the sole proprietary holder of AB8939 and its family of compounds.