WaveBreak Presents First Preclinical Data Demonstrating Efficacy of Small Molecule WTX-245 Inhibiting Source Mechanisms of TDP-43 Pathology, with Disease-Modifying Potential in ALS and FTD

—WTX-245 targets the source mechanisms of TDP-43 aggregation and restores healthy transcription for multiple mRNAs that are critical to motor neuron function and survival—

—WaveBreak's proprietary neuronal cell model replicates TDP-43 aggregation pathology
and disease biology—

BOSTON, Dec. 6, 2024 /PRNewswire/ -- WaveBreak announced today the presentation of pioneering preclinical data demonstrating that WTX-245, a first-in-class small molecule WaveBreak discovered that targets TDP-43 aggregation for the treatment of ALS, restores normal splicing for multiple mRNAs that are critical to motor neuron function and survival. The WaveBreak data are featured in a poster presentation at the 35th International Symposium on ALS/MND taking place from December 6–8, 2024 in Montreal.

"The cytoplasmic aggregation and nuclear depletion of TDP-43 is a pathological hallmark of ALS, resulting in global transcriptional dysregulation and, ultimately, neuronal dysfunction and death. Despite the central importance of TDP-43 aggregation to ALS pathogenesis, there are very limited approaches that successfully inhibit this protein's misbehavior and subsequently correct mRNA mis-splicing broadly," said co-investigator Edward B. Lee, MD, PhD, Associate Professor of Pathology and Laboratory Medicine at the Perelman School of Medicine and co-Director of the Institute on Aging, both at the University of Pennsylvania. "The significance of the data presented in this poster is important on two levels: It is the first demonstration that TDP-43 aggregation resembling patients' brain pathology in a neuronal cell model rapidly undermines transcription for multiple mRNAs, recreating the disease biology we see in ALS; and second, these data demonstrate that a small molecule can both inhibit this aggregation and rapidly restore normal transcription for multiple mRNAs."

TDP-43 safeguards more than 30% of the global transcriptome for motor neurons and is involved in regulating mRNA processing within the cell nucleus, including transcription, RNA splicing, and trafficking. The accumulation of TDP-43 aggregates leads to loss of healthy TDP-43 and its normal function in the nucleus, causing broad transcriptional dysregulation and a precipitous and catastrophic loss of motor neurons in ALS and FTD. Patient brain data demonstrate that neuronal dysfunction and cell death correlate with TDP-43 aggregation and progress rapidly. WaveBreak's TDP-43 program is developing small molecules that inhibit the disease-specific source mechanisms of TDP-43 aggregation, with the potential to both protect and restore motor neuron function in TDP-43 proteinopathies.

"The scientific evidence implicating TDP-43 aggregation that is at the core of ALS disease progression has expanded rapidly, yet there remain few drug discovery programs directly targeting TDP-43 dysfunction and limited preclinical models available to test drug candidates for preventing TDP-43 aggregation pathology," said Bart Henderson, CEO of WaveBreak. "We are excited about the promising preclinical data demonstrating the potential for our approach to protect and restore TDP-43 function by inhibiting the aggregation that ultimately leads to motor neuron dysfunction and death in these diseases. This progress is the result of WaveBreak advances in protein biochemistry to enable proprietary neuronal cell models of TDP-43 aggregation and in physical chemistry to discover small-molecule therapeutics that interrupt disease-causing aggregation of TDP-43 for ALS and FTD."

Highlights of the presentation follow, and the poster is available on WaveBreak's website:
https://wavebreaktx.com/our-science/publications

"Small molecule TDP-43 oligomer/aggregation inhibitor, WTX-245, corrects transcriptional dysfunction across multiple mRNAs in a neuronal cell model for ALS"
Presenter: Bochong Li
Poster Session B: 5:30-7:00 p.m. ET, Saturday, December 7

Summary and key findings:

1.   WaveBreak's proprietary neuronal cell assay for TDP-43 aggregation:

To support the development of a new class of TDP-43 therapeutics, WaveBreak developed a unique seeded neuronal cell assay that recapitulates TDP-43 pathology and disease biology. The neuronal model uses proprietary, tag-free TDP-43 amyloid fibrils to seed aggregation in neuroblastoma cells. Key disease-related features include:

• Cytoplasmic TDP-43 aggregation reproducing the full range of morphology observed in ALS patient brain tissue
• Loss of nuclear TDP-43
• Disruption of mRNA transcription correlating with onset of TDP-43 aggregation
• Rapid deterioration of mitochondrial function

2.   Preclinical small molecule WTX-245 inhibits TDP-43 aggregation, restores healthy mRNA transcription, and reduces mis-splicing:

WTX-245 was designed to directly inhibit disease-specific nucleation mechanisms at the source of TDP-43 aggregation and was tested in the seeded neuronal cell assay with the following results:

• WTX-245 significantly reduced cytoplasmic TDP-43 aggregation (p < 0.01) and restored normal transcriptional regulation (p < 0.05), both in a dose-dependent manner
• WTX-245 significantly reduced mis-spliced UNC13A and STMN2, coincident with a significant reduction of TDP-43 aggregates
• In addition, there was a dose-dependent trend for rescuing healthy mRNA transcripts for UNC13A, STMN2, and RAPGEF6

WaveBreak Pipeline
In addition to the TDP-43 program, WaveBreak has applied its biophysics-based technology platform to develop WTX-607, a first-in-class, small-molecule inhibitor of the α-synuclein aggregation pathway that is Phase 1-ready for the potential treatment of Parkinson's disease and Lewy body dementia (neuronal synuclein disease). The WTX-607 preclinical studies demonstrate consistent and deep reductions of pS129 aggregates and PLA oligomers. This effect is achieved with PK supporting oral QD dosing and toxicology studies that demonstrate good safety, with wide therapeutic margins for the projected human dose.

About WaveBreak
WaveBreak is a biopharmaceutical company transforming drug discovery for neurodegenerative diseases that are beyond the reach of conventional drug discovery approaches. We are advancing small molecules that inhibit the disease-specific aggregation source mechanisms of neurodegenerative proteinopathies to address some of the greatest unmet medical needs of our time: Parkinson's disease, Lewy body dementia, ALS, and Alzheimer's disease. For more information, please visit: www.WaveBreakTx.com.

Contact:
Mary Moynihan
M2Friend Biocommunications
+1 (802) 951-9600
[email protected]

SOURCE WaveBreak