AB Science Narrows to Two Unproven Programs as EMA Rejection History Shadows Strategic Pivot

AB Science Prioritizes AML and ALS Programs, Halts Others

AB Science announced a strategic update to its clinical development program, discontinuing three non-priority masitinib studies in mast cell activation syndrome, mastocytosis, and progressive multiple sclerosis. This decision, unrelated to safety, aims to reallocate resources to two core programs: AB8939 for acute myeloid leukemia (AML) and masitinib for amyotrophic lateral sclerosis (ALS). The AB8939 program has completed Phase 1, Step 3, evaluating its combination with venetoclax, and plans to seek authorization for Phase 4 to test a triple combination. The masitinib ALS Phase 3 program, approved in 2025 but not yet started, will undergo protocol updates before seeking authorization to resume.

• AB Science is strategically discontinuing three masitinib clinical studies (AB20006 for mast cell activation syndrome, AB15003 for mastocytosis, and AB20009 for progressive multiple sclerosis) that were considered non-priority and had suspended patient enrollment. This decision is not driven by safety concerns but reflects a commitment to regulatory compliance and a focused allocation of resources towards key development programs.
• The AB8939 program for acute myeloid leukemia has successfully completed Phase 1, Step 3, which assessed the combination of AB8939 with venetoclax. Following a preliminary favorable opinion from the Independent Data Monitoring Committee (IDMC), AB Science plans to seek authorization from health authorities to advance to Phase 4, which will evaluate a triple combination therapy including AB8939, venetoclax, and azacitidine.
• The Phase 3 program for masitinib in amyotrophic lateral sclerosis, which received approval in 2025 but has not yet commenced, is undergoing a comprehensive protocol update and implementation procedure review. AB Science intends to submit a substantial amendment to health authorities and subsequently seek authorization to resume this pivotal study, underscoring its continued commitment to this therapeutic area.

Addressing Unmet Needs in Acute Myeloid Leukemia Treatment

Despite meaningful advances in molecularly targeted therapies and hematopoietic stem cell transplantation, the majority of AML patients ultimately experience relapse and succumb to their disease. The clinical landscape remains constrained by the profound biological heterogeneity of AML, the persistence of leukemic stem cells, and the absence of truly effective standards of care in the relapsed/refractory setting.

• High relapse rates and poor prognosis: More than half of AML patients develop resistance and relapse following chemotherapy, and relapsed or refractory AML carries a poor prognosis due to the lack of novel salvage therapies with durable efficacy.

• Resistance mechanisms rooted in leukemic stemness: Drug resistance and recurrence are closely linked to leukemic stem cells (LSCs) — a quiescent, self-renewing population sustained by both intrinsic properties and extrinsic cues from the tumor microenvironment. Key resistance mechanisms include acquired mutations altering drug targets, activation of bypass signaling pathways, co-occurring genetic and epigenetic alterations, and metabolic reprogramming.

• Microenvironmental feedback driving therapeutic escape: Arteriolar endothelial cells produce miR-126, which is transferred to LSCs to promote quiescence, treatment resistance, and niche retention. Following TKI administration, blast reduction lowers TNF-α levels, restoring endothelial cell miR-126 production and enabling LSCs to re-enter quiescence — thereby escaping therapy and facilitating relapse. For FLT3-ITD–mutated patients, relapse and resistance to TKIs remain common.

• Significant treatment toxicity limiting patient eligibility: Potentially curative regimens are associated with substantial toxicity, restricting treatment options for older patients or those with comorbidities — populations in whom clinical outcomes are disproportionately poor.

• Challenges in the elderly population: The clinical outcome of older AML patients remains poor, particularly for those unfit for intensive therapy. Hypomethylating agents offer an important therapeutic opportunity but yield largely unsatisfactory long-term results, representing a critical area of unmet need.

• Absence of standardized treatment protocols: For BCR-ABL(+) AML — a rare subtype with short median survival — no unified standard treatment regimen exists, complicating clinical diagnosis, drug selection, and management. For high-dose cytarabine (HDAC), the optimal dose, schedule, and benefit of additional chemotherapy agents remain controversial.

• Limitations of emerging therapeutic modalities: CAR-T cell therapy has yet to identify an effective and specific target in AML analogous to CD19 in lymphoid malignancies, and the efficacy of CD64 CAR-T cells has been limited in AML mouse models. Novel targeted agents frequently demonstrate lower single-agent toxicity but do not reliably produce durable treatment responses.

• Persistent disparities and systemic inequities: Despite overall survival improvements over two decades, substantial disparities persist. Age ≥65 years remains the strongest adverse prognostic factor, and Black race is independently associated with worse overall survival even after adjustment. Access to treatment and social determinants of health continue to play a critical role, underscoring that therapeutic advances alone are insufficient to ensure equitable outcomes.

• Rising economic burden: Major cost drivers — including hospitalization, stem cell transplantation, and escalating medication costs associated with branded targeted agents — are expected to increase as more patients become eligible for novel therapies across induction, maintenance, and relapsed/refractory disease phases, posing significant challenges for payers and healthcare systems.

Exploring Combination Strategies in Acute Myeloid Leukemia

Combination therapy development in AML has accelerated substantially, with recent trials exploring synergistic regimens across molecularly defined subgroups. Strategies range from triplet oral regimens incorporating menin and BCL-2 inhibition to CAR-T/NK platforms and epigenetic combinations, reflecting the field's shift toward biomarker-driven, mechanism-informed treatment design.

• Menin Inhibitor Triplet (Ziftomenib + Venetoclax/Azacitidine): The KOMET-007 phase 1 trial evaluated ziftomenib at 200–600 mg once daily with standard venetoclax/azacitidine in 67 relapsed/refractory NPM1-mutated AML patients (median age 66 years). At the 600 mg dose, composite complete remission (CRc) was achieved in 46% of patients overall; venetoclax-naïve patients reached a CRc of 70% with 75% MRD negativity. Median duration of response was 8.6 months. Grade ≥3 events included leukopenia (34%), thrombocytopenia (28%), and febrile neutropenia (25%); differentiation syndrome occurred in 2 patients (grade 3) and was successfully managed.

• All-Oral Menin + HMA + BCL-2 Triplet (Revumenib + Decitabine/Cedazuridine + Venetoclax): In 42 patients with relapsed/refractory AML (40% KMT2Ar, 38% NPM1-mutated, 21% NUP98r; 52% with prior venetoclax), the recommended phase 2 dose of revumenib was 160 mg twice daily with a strong CYP3A4 inhibitor. The composite complete remission rate was 71%; CR/CRh was 60%, with 80% MRD negativity by flow cytometry among CR/CRh patients. Median CR/CRh duration was not reached in KMT2Ar patients, 10.7 months in NPM1-mutated, and 5.9 months in NUP98r. Menin-binding site resistance mutations emerged in 13% of patients.

• Chidamide-Based Regimen (CACAG-VEN) for R/R AML: A phase 1 study of chidamide combined with venetoclax, azacitidine, aclarubicin, cytarabine, and G-CSF enrolled 34 patients (17 refractory, 17 relapsed) with a median follow-up of 461 days. ORR was 76.5% with a complete response rate of 73.5%; 44% of composite CR patients achieved MRD negativity. One-year OS and PFS rates were 82.3% and 79.8%, respectively. Single-cell RNA sequencing revealed post-treatment downregulation of MCL1, HIF1A, and ABCC1, with response associated with suppression of mitochondrial activity and activation of p53 signaling.

• FLT3 Inhibitor Combinations: In a real-world multicenter Turkish study, midostaurin combined with standard 3+7 induction in newly diagnosed FLT3-mutated AML yielded an ORR of 87.7%, CR rate of 84.2%, and median OS of 21.4 months; 52.6% of patients proceeded to allogeneic SCT in first remission. Separately, sitravatinib plus venetoclax demonstrated strong synergistic cytotoxicity in FLT3-ITD AML cell lines and patient bone marrow cells, suppressing AKT/ERK phosphorylation and downregulating MCL-1 and BCL-xL, with superior efficacy in patient-derived xenografts versus either monotherapy. Quizartinib plus 7+3 induction, evaluated in the QuANTUM-First phase 3 trial (n=539), demonstrated a survival advantage with maintenance quizartinib for up to 36 cycles without adverse impact on patient-reported outcomes.

• DOT1L + BCL-2 Dual Inhibition for MLL-Rearranged AML: Combined EPZ004777 (DOT1L inhibitor) and ABT-737 (BCL-2 inhibitor) produced potent synergistic cytotoxicity in THP-1 cells, reducing H3K79 di- and tri-methylation, downregulating HOXA10 and MLLT10, and blocking PI3K/AKT phosphorylation. In vivo, combination therapy in C-NKG xenograft mice prolonged survival, restored bone marrow function, and alleviated organ infiltration compared to single-agent arms.

• Omacetaxine + Venetoclax for RUNX1-Mutated MDS/AML: In 24 patients (22 AML, 2 MDS with excess blasts), the recommended phase 2 dose was venetoclax 400 mg daily (days 1–14) plus omacetaxine 1.25 mg/m² twice daily (days 2–4). No dose-limiting toxicities or tumor lysis syndrome were observed. Responses were absent in the heavily pretreated AML cohort, whereas both MDS patients achieved composite CR and bridged to allogeneic SCT. Responders showed downregulation of β-catenin and hedgehog signaling pathway genes alongside a shift toward proapoptotic protein expression.

• Hypomethylating Agent-Based and XPO1 Inhibitor Combinations: Azacitidine/venetoclax demonstrates particular activity in NPM1-mutated AML, with MRD-driven maintenance or preemptive strategies under active clinical investigation. XPO1 inhibitors (selinexor, eltanexor) show preferential activity in NPM1-mutated, DEK::NUP214-positive, and SF3B1-mutated myeloid neoplasms; combinations with HMAs and BCL-2 inhibitors enhance response depth and durability, though toxicity remains a limiting factor.

• CAR-T/NK Cell and CD123-Targeted Approaches: CAR-T constructs targeting CD123 and CD33 have demonstrated early clinical success with composite remission rates up to 66% in relapsed/refractory AML. CD123-directed agents under investigation include tagraxofusp, pivekimab sunirine, flotetuzumab, vibecotamab, and investigational CAR-T platforms (MB-102, UCART123v1.2). Emerging strategies incorporate checkpoint inhibitors, metabolic modulators, dual-targeting CAR designs, and CRISPR-edited universal cell products, with AI-driven antigen selection under exploration to optimize specificity and reduce on-target off-tumor toxicity.

• ATRA-Based and Epigenetic Combination Approaches: ATRA combined with arsenic trioxide or epigenetic modulators achieves high remission rates in APL and selected AML subtypes. Preclinical data support synergistic differentiation when ATRA is paired with CDK inhibitors, nucleotide synthesis inhibitors, BCL-2/MDM2 inhibitors, proteasome inhibitors, and antibiotic-derived compounds, operating through modulation of MAPK, AKT, and JAK/STAT pathways, RARα stabilization, chromatin remodeling, and nucleotide metabolism perturbation.

Strategic Pivot: Sharpening the Focus on ALS and AML

The recent strategic update from AB Science signals a decisive shift in its clinical development strategy, moving away from several masitinib programs to sharpen its focus on two key assets: masitinib for amyotrophic lateral sclerosis (ALS) and AB8939 for acute myeloid leukemia (AML). This move, while not related to safety concerns in the discontinued programs, reflects a common industry practice of resource optimization, concentrating efforts on areas with the most promising clinical data and highest potential impact.

For masitinib, this means a dedicated path forward in ALS, a devastating neurodegenerative disease with limited treatment options. Previous Phase 3 data for masitinib in ALS showed a significant slowing of functional decline and a notable long-term survival benefit in specific patient populations, particularly 'Normal Progressors' and those treated prior to severe functional impairment. This evidence provides a strong foundation for the planned confirmatory Phase 3 study, though the need for protocol updates suggests an ongoing effort to refine patient selection and trial design. However, it is important to acknowledge that studies of masitinib in other neurodegenerative diseases have highlighted a higher incidence of adverse events compared to placebo, a factor that will require careful management and monitoring in the ALS population.

Simultaneously, the advancement of AB8939 in AML, particularly with its planned triple combination therapy including venetoclax, positions it in a highly competitive and rapidly evolving therapeutic landscape. AML is characterized by significant molecular heterogeneity and challenges with drug resistance, making novel agents and combination strategies critical. The success of AB8939 will hinge on its ability to demonstrate superior efficacy or a distinct safety profile within these complex multi-drug regimens, especially for patients who may be resistant to existing therapies. This strategic pivot underscores a focused approach to address high unmet medical needs, but also highlights the inherent complexities and risks associated with developing therapies in challenging disease areas.