AMX-883 / Amphista Therap - LARVOL DELTA

Amx-883, a potent and selective degrader of BRD9 drives differentiation in acute myeloid leukaemia and shows synergistic efficacy in combination with venetoclax In Vivo and prevents the emergence of resistance to venetoclax in vitro. (ASH 2025) - "AMX-883 co-dosed with venetoclax and azacitidine resulted in synergy with significant cell death attherapeutically relevant concentrations. AMX-883 is a novel, orally bioavailable potent and selective degrader of BRD9with exquisite selectivity over all other bromodomain containing proteins, and proteome wide. AMX-883time dependently increases the expression of key proteins associated with myeloid differentiation inMV4-11 cells. As described in our recent paper (doi.org/10.1101/2024.12.31.630899) Amphista degradersdo not employ the commonly used E3 ligases (cereblon, VHL) but instead drives degradation via DCAF16as a targeted glue.Picomolar potency degradation of BRD9 was observed across a panel of AML cell lines with an associatedreduction in cell viability regardless of the mutational status of the cell lines, with minimal viability effectsobserved in normal peripheral blood mononuclear cells."

Combination therapy • IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Targeted Protein Degradation • BCL2 • CD14 • CD86 • CRBN • FLT3 • ITGAM • MCL1

Amphista Therapeutics presents new preclinical data showing the potential of its BRD9 Targeted Glue, AMX-883, to transform the treatment paradigm for acute myeloid leukaemia (GlobeNewswire) - "AMX-883-induced BRD9 degradation is sufficient to block patient-derived tumour growth in vivo as a monotherapy, with superiority to venetoclax. AMX-883-induced BRD9 degradation synergises with venetoclax to block tumour growth in vivo. AMX-883-induced degradation of BRD9 prevents emergence of resistance to venetoclax in vitro. Data supports progression of AMX-883 into clinical development with the first trial planned in AML for H2 2026."

New trial • Preclinical • Acute Myelogenous Leukemia

Amphista Therapeutics unveils new differentiated mechanism of action for BRD9 degradation at 2024 Protein Degradation in Focus Symposium (GlobeNewswire) - "Amphista Therapeutics...announces the unveiling of a new mechanism of action for the degradation of BRD9, an emerging target in oncology, that is differentiated from cereblon- or VHL-based PROTACs, during an oral presentation at the 2024 Protein Degradation in Focus Symposium held in Dundee, UK...At today’s presentation...Dr Andrea...showed data from proteomic and genetic validation studies which demonstrate that Amphista’s bifunctional degraders induced degradation of BRD9 by target-assisted E3 ligase recruitment...Induction of this complex leads to deep and rapid degradation of BRD9 in vivo....In the results presented, Amphista’s sub-nanomolar BRD9 degraders showed activity in both solid and liquid cancer cell lines and demonstrated a high degree of selectivity over 8,000 proteins quantified by proteomics, including the closely related proteins BRD7 and BRD4."

Preclinical • Hematological Malignancies • Oncology • Solid Tumor