PRESS RELEASE
AB SCIENCE PROVIDES AN UPDATE ON THE
MICROTUBULE PROGRAM AB8939 AND IN PARTICULAR THE ABILITY OF AB8939
TO GENERATE RESPONSE ON MECOM REARRANGEMENT
Paris, 26 September 2024, 8.30am CET
AB Science SA (Euronext -
FR0010557264 - AB) today provides an update on the microtubule
program AB8939 and in particular the ability of AB8939 to generate
response on MECOM rearrangement.
AB8939 is a novel microtubule destabilizer
currently evaluated in phase 1 clinical trial (study AB18001,
NCT05211570) in patients with refractory and relapsed acute myeloid
leukemia (AML).
The phase 1 clinical trial of AB8939 completed
its first step, consisting in determining the maximum tolerated
dose following 3 consecutive days of AB8939 treatment, and was
authorized to proceed with the next step, consisting in determining
the maximum tolerated dose following 14 consecutive days of AB8939
treatment.
The phase 1 clinical trial continues to
determine MTD and the study is now at the last cycle of the 14 days
evaluation.
The next step will be to determine the MTD in
the combination of AB8939 with Vidaza® (azacitidine).
AB Science previously reported [1] a case of
complete bone marrow response in an AML patient in failure to prior
treatment with azacitidine and presenting with a MECOM gene
rearrangement, which consists of chromosomic aberrations of EVI1
oncogene, leading to one of the worst prognostics in AML and is
associated with lack of response and resistance to conventional
chemotherapy.
New data confirm that there is a signal of
activity against MECOM, with AB8939 generating a complete response
in combination with Vidaza, as evidenced by a synergistic effect in
a patient-derived xenograft (PDX) mouse model bearing the MECOM
rearrangement. PDX are cell lines coming from patients that are
grafted to immune deficient mice to mimic as closely as possible
the human disease.
-
AB8939 was able to generate 50% response when used as a single
agent on MECOM cell lines ex vivo in a non-clinical setting.
-
In the phase 1 trial, 4 patients bore the MECOM rearrangement and
50% responded to AB8939 when used as a single agent.
-
In phase 1, so far, AB8939 does not appear to be toxic to bone
marrow, avoiding severe neutropenia and suggesting the possibility
to use the drug for long-term treatment.
These data taken together confirm the
opportunity to develop AB8939 in phase 2 clinical trial in MECOM as
a single agent or in combination with Vidaza.
The advantage is that a small study
could be sufficient to comply with FDA guideline on accelerated
approval.
Professor Olivier Hermine, President of the AB
Science Scientific Committee and member of the French Academy of
Sciences and Head of haematology Department at Necker Hospital
commented: “AB8939 can be developed in the other patients suffering
from AML, but MECOM represents a real opportunity to use the
accelerated approval pathway, since it lacks treatment, patients
are unresponsive to existing therapy and survival is usually
inferior to 6 months. A phase 2 with a limited sample size,
non-controlled, and showing a 30% response rate at month 3, with a
survival potential at 6 months would probably be convincing enough
for an accelerated approval. This will be discussed with
FDA in future regulatory milestone. This study could be implemented
in 2025. Moreover, MECOM extends beyond AML and are present in
high-risk myelodysplasia (MDS) and ovarian cancer.”
Two patents have been filed protecting AB8939 in
AML, one global composition of matter (granted) and a second one
protecting the use of AB8939 in cancers displaying MECOM
rearrangement (pending), with protection until 2036 and 2044
respectively.
About MECOM
AML represents a heterogeneous group of diseases
with different responses to treatment, which can be separated by
genetic abnormalities. Overexpression of MECOM occurs in
approximately 10% of AML patients and is associated with a poor
prognosis, in part due to its important role in the maintenance of
leukemic stem cells (LSCs) [2]. Because of their quiescent
(inactive) state, LSCs are not targeted by any antimitotic
chemotherapy and can therefore re-establish the disease after
therapy.
About AB8939
AB8939 is a new synthetic
microtubule-destabilizing drug. Preclinical data show that AB8939
has broad anticancer activity [3-5], with a notable advantage over
standard chemotherapies that target microtubules of being able to
overcome P-glycoprotein (Pgp) and myeloperoxidase (MPO) mediated
drug resistance. Development of drug resistance often restricts the
clinical efficacy of microtubule-targeting chemotherapy drugs (for
example, taxanes and vinca alkaloids); thus, AB8939 has strong
potential to be developed in numerous oncology indications.
AB8939 was granted orphan drug designation for
AML from the U.S. Food and Drug Administration (FDA).
AB8939 was entirely discovered by the
laboratories of AB Science, which retains full ownership of
intellectual rights, and is an example of AB Science’s focus on
innovative drug development focused on improving patients’
lives.
The first indication AB8939 is being developed
for is acute myeloid leukemia (AML). Cytarabine (Ara-C) and
azacytidine are standard chemotherapies for AML treatment, however,
drug resistance is a major limitation to successful therapy. In
vivo data from a highly resistant Ara-C patient derived xenograft
(PDX) mouse model showed that AB8939, administered alone or in
combination with Ara-C, increased survival relative to single agent
Ara-C, with an accompanying significant reduction of blasts in
blood and decrease in tumor growth. Further evidence of therapeutic
potential was demonstrated using an azacytidine resistant PDX model
with AB8939, administered alone or in combination with azacytidine,
showing a significant reduction of blasts relative to single agent
azacytidine. Moreover, while azacytidine was associated with strong
treatment related hematotoxicity, AB8939 did not induce
hematotoxicity throughout its 4-week treatment period.
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 relapsed
following a first complete response. The prevalence of AML in
western countries is around 1 per 5,000 persons, 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] AB Science press release dated 13 March
2023
[2] Paubelle E, Plesa A, Hayette S, et al.
Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid
Leukemia with Overexpression of EVI1. Oncol Ther.
2019;7(2):121-130. Doi:10.1007/s40487-019-0095-9
[3] 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
[4] Goubard A, Humbert M, Mansfield C, Hermine
O, Dubreuil P, et al. AB8939, a Microtubule-Destabilizing Agent
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
[5] 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
About AB ScienceFounded in
2001, AB Science is a pharmaceutical company specializing in the
research, development and commercialization of protein kinase
inhibitors (PKIs), a class of targeted proteins whose action are
key in signaling pathways within cells. Our programs target only
diseases with high unmet medical needs, often lethal with short
term survival or rare or refractory to previous line of treatment.
AB Science has developed a proprietary portfolio of molecules and
the Company’s lead compound, masitinib, has already been registered
for veterinary medicine and is developed in human medicine in
oncology, neurological diseases, inflammatory diseases and viral
diseases. The company is headquartered in Paris, France, and listed
on Euronext Paris (ticker: AB).
Further information is available on AB Science’s
website: www.ab-science.com.
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generally, any factors that may affect marketing capacity of the
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identified in the public documents published by AB Science. AB
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