PMD-026

P1/2, N=61, Recruiting, Phoenix Molecular Designs | Trial completion date: Mar 2026 --> Oct 2026 | Trial primary completion date: Dec 2025 --> Sep 2026

Treatment with PMD-026 suppressed disease burden across seven syngeneic and patient-derived xenograft leukemia mouse models spanning the spectrum of driver and disease-modifying mutations. These findings uncover a therapeutic avenue for a conserved dependency across MPN and sAML.

However, there is a paucity of the literature addressing RSK function in inflammation, which is critical to know as the pan RSK inhibitor, PMD-026, is entering phase II clinical trials for metastatic breast cancer. A RSK inhibitor has the potential to be used in numerous diverse diseases and disorders.

Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.

P1/2, N=61, Recruiting, Phoenix Molecular Designs | Active, not recruiting --> Recruiting

P1/2, N=61, Active, not recruiting, Phoenix Molecular Designs | Phase classification: P1 --> P1/2 | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

In this Phase 1/1b study, PMD-026 was evaluated in an ethnically diverse population of women across all breast cancer subtypes. Patients had a median of 5 prior lines of therapy and PMD-026 achieved stable disease in 44% (11/25) of the subjects. Consistent with the MOA, PMD-026 inhibited pCDK2Y15 in PBMCs from patients at C1D15.

P1, N=50, Active, not recruiting, Phoenix Molecular Designs | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

These findings demonstrate that in patients treated with PMD-026 who had received < 5 prior treatment regimens, had de novo TNBC or CDK4/6 refractory HR+ disease and had high RSK2 scores had longer PFS. Overall, PMD-026 is a well-tolerated, orally available RSK2 inhibitor that will be evaluated further for efficacy in TNBC and CDK4/6i refractory HR+ mBC, in a trial that will prospectively enroll patients based on RSK2 activation as defined by the RSK2 IHC H-scores. Clinical trial information: NCT04115306.