WaveBreak Reveals Preclinical Data on WTX-245's Efficacy in ALS and FTD

WaveBreak has revealed groundbreaking preclinical data showcasing the effectiveness of WTX-245, a novel small molecule developed to target TDP-43 aggregation for ALS treatment. This promising data was unveiled through a poster presentation at the 35th International Symposium on ALS/MND in Montreal.

The primary focus of the study was TDP-43, a protein whose aggregation and subsequent nuclear depletion is a major pathological marker of ALS, leading to severe transcriptional dysregulation, neuronal dysfunction, and death. Despite its crucial role in ALS pathology, few methods have been successful in inhibiting TDP-43 misbehavior and correcting mRNA mis-splicing. Co-investigator Edward B. Lee, MD, PhD, from the University of Pennsylvania, emphasized the importance of the study, noting its dual significance: replicating ALS-like TDP-43 aggregation in a neuronal cell model and demonstrating that WTX-245 can inhibit this aggregation and swiftly restore normal transcription for multiple mRNAs.

TDP-43 is essential for motor neuron function, being involved in regulating mRNA processes such as transcription, RNA splicing, and trafficking within the cell nucleus. Its aggregation results in the loss of healthy TDP-43 function, causing widespread transcriptional dysregulation and a catastrophic loss of motor neurons typical of ALS and FTD. Patient brain data underline that neuronal dysfunction and death correlate with TDP-43 aggregation, which advances rapidly. WaveBreak’s program aims to develop small molecules that inhibit TDP-43 aggregation mechanisms, potentially protecting and restoring motor neuron function in TDP-43-related diseases.

Bart Henderson, CEO of WaveBreak, highlighted the rapid growth of scientific evidence linking TDP-43 aggregation to ALS progression. However, he pointed out the scarcity of drug discovery programs targeting TDP-43 directly and the limited preclinical models available to test potential drugs. Henderson expressed excitement about the preclinical data, which suggests that their approach could protect and restore TDP-43 function by preventing its aggregation, ultimately leading to motor neuron protection in ALS and FTD. This progress stems from WaveBreak’s advances in protein biochemistry, enabling the development of proprietary neuronal cell models of TDP-43 aggregation and the discovery of small-molecule therapeutics.

Key highlights of the presentation include:
1. WaveBreak’s proprietary neuronal cell assay for TDP-43 aggregation: Developed to support the creation of new TDP-43 therapeutics, this unique assay replicates TDP-43 pathology using tag-free TDP-43 amyloid fibrils to seed aggregation in neuroblastoma cells, reproducing ALS patient brain tissue characteristics such as cytoplasmic TDP-43 aggregation, loss of nuclear TDP-43, mRNA transcription disruption, and rapid mitochondrial function decline.
2. Preclinical results of WTX-245: The small molecule WTX-245 was designed to inhibit disease-specific nucleation mechanisms of TDP-43 aggregation. In the neuronal cell assay, WTX-245 significantly reduced cytoplasmic TDP-43 aggregation and restored normal transcription in a dose-dependent manner. It also reduced mis-spliced UNC13A and STMN2 and showed trends of rescuing healthy mRNA transcripts for these genes.

In addition to the TDP-43 program, WaveBreak has developed WTX-607, a small-molecule inhibitor targeting α-synuclein aggregation, which is Phase 1-ready for treating Parkinson’s disease and Lewy body dementia. Preclinical studies of WTX-607 demonstrate consistent reductions of pS129 aggregates and PLA oligomers, with supporting pharmacokinetics for oral dosing and good safety margins.

WaveBreak continues to advance drug discovery for neurodegenerative diseases that traditional approaches have failed to address, focusing on small molecules that inhibit disease-specific protein aggregations. This innovative approach aims to meet the significant unmet medical needs in Parkinson’s disease, Lewy body dementia, ALS, and Alzheimer’s disease.