Plexium has dosed the first subjects in a Phase 1 clinical study of PLX-4545, an orally administered molecular glue degrader targeting IKZF2, marking a significant milestone as the company transitions to clinical-stage operations. The investigational therapy represents a novel approach to cancer immunotherapy by selectively degrading a transcription factor that maintains immune suppression within tumor environments.
Novel Mechanism Targets Regulatory T Cell Suppression
PLX-4545 is designed as a potent and selective degrader of IKZF2, also known as Helios, a transcription factor that has been classically considered undruggable. According to Simon Bailey, Ph.D., Executive Vice President of Drug Discovery at Plexium, "The immune transcription factor IKZF2 is a marker of highly suppressive regulatory T cells, and we have shown that potent and selective degradation of IKZF2 results in the conversion of Tregs into effector-like T cells."
The therapeutic strategy addresses a key limitation of current checkpoint inhibitor therapies. While these treatments have demonstrated broad clinical activity across multiple tumor types, many cancer patients remain unresponsive due to immune suppression within the tumor stroma. By targeting IKZF2, PLX-4545 aims to destabilize highly suppressive regulatory T cells (Tregs) that contribute to this immune evasion.
Promising Preclinical Efficacy Data
In preclinical studies, PLX-4545 demonstrated compelling anti-tumor activity both as a single agent and in combination therapy. The compound achieved single agent anti-tumor activity in vivo comparable to pembrolizumab, a widely used checkpoint inhibitor. More notably, the efficacy was enhanced when PLX-4545 was co-administered with a checkpoint inhibitor, suggesting potential synergistic effects.
The molecular glue degrader delivers rapid, deep and selective degradation of IKZF2, resulting in destabilization of Tregs both in vitro and in vivo. This mechanism of action represents a differentiated approach within the targeted protein degradation field, utilizing the cell's own protein disposal machinery to eliminate the target protein.
Phase 1 Study Design and Objectives
The ongoing Phase 1 clinical study follows a randomized, double-blind, placebo-controlled design with single- and multiple-ascending dose cohorts. The primary objectives include assessing the safety and tolerability profile of orally administered PLX-4545, while also measuring pharmacokinetics and pharmacodynamics to identify a pharmacologically effective dose.
"Data from this initial study will provide a strong foundation for subsequent clinical studies to evaluate PLX-4545 in cancer patients with tumors that are refractory to checkpoint inhibitors, both as a single agent and in combination with a checkpoint inhibitor, an area of high unmet need," Bailey stated.
The trial is registered under ACTRN12623001265662 in the Australian Clinical Trials Registry, and Plexium expects to announce results from the Phase 1 study in the second half of 2024.
Platform Expansion and Pipeline Development
The advancement of PLX-4545 represents the first clinical validation of Plexium's proprietary drug discovery platform, which is designed to identify novel small molecules that induce selective degradation of pathogenic proteins through E3 ligase-mediated proteasomal degradation. Mike Grey, Executive Chairman of Plexium, noted that "PLX-4545 is our first small molecule degrader program stemming from our proprietary drug discovery platform to enter human studies."
Beyond PLX-4545, Plexium continues to develop additional protein degraders targeting important cancer-related proteins, including SMARCA2, CDK2, and CRaf. The company plans to advance one or more of these programs into development in 2024, potentially expanding its clinical pipeline.
The company has also established a strategic collaboration with AbbVie to explore the application of targeted protein degradation technology in neurodegenerative diseases, demonstrating the broader therapeutic potential of the platform beyond oncology applications.
