On October 18, 2021 B Science SA(Euronext -FR0010557264 -AB) reported that it has been authorized by theFrench Medicine Agency, ANSM, to initiate aPhase I/II study(AB18001)evaluating AB8939 in patients with refractory and relapsed AML and refractory myelodysplastic syndrome(MDS) (Press release, AB Science, OCT 18, 2021, View Source [SID1234591449]).This approval comes just a few weeks after receiving similar authorization from the Canadian Health Authority [1].

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ProfessorNobert Vey, MD, principal investigator of the study and Director of Clinical Research at Institut Paoli-Calmettescommented,"We are very excitedto start the clinical developmentofAB8939. This drugis based on a well-known therapeutic class of compounds which are useful for the treatment of various cancers, however,AB8939 has a superior potential becauseit was designedto overcome common mechanisms of drug resistance.Numerous non-clinical data generated at Institut Paoli-Calmettes are already available suggesting that AB8939 is particularly well-suited for treatment of relapsed/refractory AML".As previously communicated [1], AB8939 is a new generationsyntheticmicrotubule destabilizer with the ability to overcome multidrug resistance and the potential for broad applicability as a potent anticancer drug.

Microtubules play a crucial role in multiple cellular functionswhich makes theman important target for cancer therapy. Indeed, chemotherapies that targetmicrotubules, such as taxanes and vinca alkaloids,are among the most successfulanticancer therapeutics available. Unfortunately, the development of drug resistance(for example, via Pgp efflux pumps that transport the drugs out of the cancer cells)oftenrestrict their clinical efficacy. Key characteristicsof AB8939 arethat it circumventsdifficulties associated with Pgp-dependent multidrug resistanceand is not deactivated by an enzymenamed myeloperoxidase, which is an advantage over existing chemotherapies.Another advantage and distinguishing characteristic of AB8939 is that it is a synthetic drug. The therapeutic potential of AB8939 has beendemonstrated through a series of preclinicalexperiments [2–4].

Invivodata from a highly resistant Ara-C patient derived xenograft (PDX)mouse modelshowed that AB8939,administered alone or in combination with Ara-C, increasedsurvivalrelative tosingle agent Ara-C, with an accompanying significant reduction of blasts in blood and decrease intumor growth [2].Ara-C is considered the clinically most relevant cytotoxic drugfor AML treatment.In another example, cancerous tumors from patients suffering from resistant acute megakaryoblastic leukemia (an AML subtype)were transplanted into mice. Data showed a complete response in mice treated with AB8939, as compared with rapid disease progression in controlanimals [3]. No apparent toxicity was observed during the time course of the treatment.Based on these results, AB8939 was granted orphan drug designation for AML from the U.S. Food and Drug Administration (FDA)[5].

Page 2/3The first indication AB8939 is being developedfor is acute myeloid leukemia (AML),a rapid proliferating hematological cancerthat originates in the bone marrow and quickly moves into the blood.Cytarabine (Ara-C) isthe current standard chemotherapy for AML treatment, however, drug resistance is a major limitation to successful therapy.

AB8939 therefore has strong potential as asecond or third-line treatment in AML patients who are unfit to receive intensive chemotherapy.The advantageous mechanistic characteristics of AB8939 mean that it is potentially applicable to a large number of other oncology indications currently treated by microtubule-inhibitor drugs (such astaxanes and vinca alkaloids)and in particular hematological cancers. The envisioned strategy is to position AB8939 in patients with abnormal cytogenetics that make these patients unresponsive to first-line therapy.AB8939 was entirely discovered by the laboratories of AB Science, which retains full ownership of intellectual rights, and is anexample of AB Science’s focus on innovative drug development focused on improving patients’ lives. About Study AB18001Study AB18001, titled‘A Phase 1/2 Study to Assess the Safety, Pharmacokinetics, and Efficacy of Daily Intravenous of AB8939 in patients with Relapsed/Refractory Acute Myeloid Leukemia’, has a multi-stage design.

Thefirst part is a dose escalation study thataims to determine the safety and tolerability of intravenous AB8939 in patients with refractory or relapsed AML or patients with refractory MDS,and to determine the recommended dose for the second-stage dose expansion study. This dose expansion study aims to determine the schedule for aPhase 2 trial in patients with relapsed/refractory AML and to also provide an early efficacy (response rate) assessment of AB8939.

About acute myeloid leukemia (AML)
Acute myeloid leukemia (AML) is a serious, life-threating condition and the most common cause of leukemia-related mortality, with a majority of patients facing a highly unsatisfactory prognosis. As such, AML represents an unmet medical need, with limited therapeutic options for patients who are refractory or too frail to benefit from potentially curative but highly toxic treatment, or for those patients that have relapsedfollowing a first complete response. The prevalence of AML in western countries is around 1 per 5,000 persons [6], corresponding to around 100,000 cases in Europe and 60,000 in the USA. Among AML patients, it is estimated that approximately 50% of the patients will not have stem cell transplantation and will relapse. Therefore, the estimated targeted population of AB8938 in AML is around 80,000 people in Europe and the US.

References
[1] Press release dated September 22, 2021
[2] Goubard A, Humbert M, Mansfield C, Hermine O, Dubreuil P, et al. In Vivo Assessment of the Next Generation Microtubule-Destabilizing Agent AB8939 in Patient-derived Xenograft Models of Acute Myeloid Leukemia.Blood (2019) 134 (Supplement_1): 5142.doi.org/10.1182/blood-2019-127143[3]Goubard A, Humbert M, Mansfield C, Hermine O, Dubreuil P, et al. AB8939, a Microtubule-DestabilizingAgent with Potential to Overcome Multidrug Resistance, is Active Across the Range (M0–M7) of Acute Myeloid Leukemia Subtypes. Blood (2019) 134 (Supplement_1): 5154.doi.org/10.1182/blood-2019-127021[4]Humbert M, Goubard A, Mansfield C, Hermine O, Dubreuil P, et al. Anticancer Activity of a Highly Potent Small Molecule Tubulin Polymerization Inhibitor, AB8939. Blood (2019) 134 (Supplement_1): 2075. doi.org/10.1182/blood-2019-122540[5] Press release dated November 7, 2019
Page 3/3[6] National Cancer Institute (View Source)