Amphista Therapeutics has reported preclinical leukemia data on its protein degrader, positioning the Big Pharma-partnered biotech to target a 2026 start date for a phase 1 clinical trial.
The data, which Amphista shared at the American Society of Hematology (ASH) annual meeting, cover the company’s BRD9 degrader as a monotherapy and with AbbVie and Genentech’s Venclexta. BRD9 is an epigenetic factor involved in conditions including acute myeloid leukemia (AML), but problems including limited selectivity have hindered efforts to drug BRD9, leading scientists to explore protein degradation.
In rodents, Amphista linked its BRD9 degrader AMX-883 to a significant improvement in survival and reduction in disease burden compared to Venclexta. Combining AMX-883 with Venclexta and azacitidine resulted in synergy with significant cell death in in vitro tests.
Amphista also showed the potential for AMX-883 to prevent the emergence of resistance to Venclexta. Over three months, the biotech cultured cells with increasing concentrations of Venclexta. Some cells were also exposed to a fixed concentration of AMX-883. While resistance emerged in cells that were only exposed to Venclexta, cells treated with AMX-883 remained vulnerable to the BCL-2 inhibitor.
“The important preclinical data presented for the first time show that our Targeted Glue AMX-883, a selective degrader of BRD9, extends the durability and efficacy of combination therapy with venetoclax and prevents AML cancer cells from becoming resistant to venetoclax,” Martin Pass, Ph.D., chief development officer at Amphista, said in a statement.
Amphista plans to start testing AMX-883 in AML patients in the second half of next year. The study will mark at least the third attempt to validate a BRD9 degrader in humans. Foghorn Therapeutics and C4 Therapeutics began studying BRD9 degraders in synovial sarcoma in 2021 and 2022, respectively.
Both companies terminated the trials. Foghorn opted against further development after the FDA put a partial hold on its candidate in April 2023. C4, meanwhile, called time on its program later in 2023, citing the failure of high levels of BRD9 degradation to translate into sufficient efficacy to explain its decision to prioritize other assets.
The Foghorn and C4 candidates were CRBN-based PROTAC degraders of BRD9. Amphista is taking a different approach to BRD9 degradation. AMX-883 is a type of molecular glue degrader. Amphista’s idea is to design molecules that create an altered protein-ligand interface that is recognized by a ligase. Interaction between the target and the E3 ligase leads to protein degradation.
Amphista’s approach has caught the eye of large pharma companies. Bristol Myers Squibb and Merck KGaA inked deals with the biotech in 2022. Amphista disclosed the deals the year after securing series B funding from backers including Novartis Venture Fund and Eli Lilly.