—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, Mass., December 6, 2024— 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
mary@m2friend.com

BOSTON, Mass., March 8, 2024— WaveBreak announced today the presentation of new preclinical data for WTX-607, the company’s first-in-class small-molecule inhibitor of α-synuclein oligomer generation, demonstrating efficacy for targeting and inhibiting the source mechanisms underlying the formation of α-synuclein oligomers and aggregates with high precision and specificity in cell and mouse models of Parkinson’s disease (PD) and Lewy body dementia (LBD). Oligomeric forms of the protein, α-synuclein, form aggregates known as Lewy bodies that underlie the onset and progression of synucleinopathy diseases such as PD and LBD. WaveBreak’s clinical candidate, WTX-607, disrupts these mechanisms with precision and is a potential disease-modifying therapeutic. The data will be presented in a poster presentation on March 8 and 9 at the International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD 2024) taking place from March 5–9 in Lisbon, Portugal.

“More than 1 million people in the U.S. are living with Parkinson’s disease, and 1.4 million people are affected by Lewy Body Dementia, and there are no approved drugs to slow or stop the progression of these devastating neurodegenerative diseases,” said Bart Henderson, CEO of WaveBreak. “We are excited about the promising preclinical data for WTX-607 demonstrating inhibition of α-synuclein oligomer generation and aggregation that is at the core of both these diseases. We have recently completed pre-IND development for WTX-607, and we are now preparing to initiate a biomarker-driven Phase 1 clinical development program.”

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

Poster #0528 (Shift 2, March 8–9): “Small molecule inhibitors for precise inhibition of α-synuclein oligomer generation in Parkinson’s disease”
Presenter: Kelvin Luk

Summary and key findings:
WTX-607, WaveBreak’s lead small-molecule clinical candidate for the treatment of Parkinson’s disease (PD) and Lewy body dementia (LBD), inhibits the source of α-synuclein oligomer and aggregate generation in mouse models of synucleinopathies, including PD and LBD, demonstrating the potential for clinical development as a disease-modifying therapeutic for these indications. Specifically, WTX-607:

• Exhibits dual pharmacology and excellent PK properties, precisely inhibiting the molecular mechanisms at the source of α-synuclein oligomer formation—WTX-607 inhibited the primary nucleation process by 93% and the secondary nucleation process by 95%, with high specificity for α-synuclein, and showing no inhibition in tau and Aβ42 amyloid aggregation assays.
• Delivers efficacy in the gold-standard M83 transgenic mouse model (which expresses aggregation-prone human A53T mutant, seeded with human fibrils), significantly reducing α-synuclein oligomers by at least 35%.
• Significantly reduces pS129 α-synuclein aggregate levels in the line 61 transgenic mouse model, which overexpresses human α-synuclein, by 50%-75% in the cortex and hippocampus, respectively.

WaveBreak Technology Platform
The relatively recent understanding that oligomers resulting from errant protein folding are the toxic entities directly responsible for neurotoxicity in Parkinson’s disease, Alzheimer’s disease, and ALS has defined a new approach to treating a central molecular cause of neurodegeneration. Yet characterizing and suppressing these fleeting protein intermediates is one of the most challenging problems in drug discovery for scientists working with protein assembly reactions: Because these protein forms are highly transient, they cannot simply be put in a bottle and analyzed in isolation, which makes them difficult to target using conventional single-target drug discovery approaches. Targeting the complex, highly interconnected network of interactions that lead to oligomer formation in neurodegenerative diseases requires a fundamentally different approach to measure, assay, and analyze the proteins during their evolving assembly and disassembly process, from their formation to their disappearance. WaveBreak’s technology platform enables analysis of the inhibition of the source mechanisms that produce oligomer intermediates in complex disease processes. We are leveraging this approach to discover and develop small-molecule therapeutics that inhibit oligomer generation at the source of these protein aggregation assembly pathways with specificity and precision.

About Parkinson’s Disease
One million people in the U.S. and up to 10 million people worldwide are living with Parkinson’s disease (PD). With nearly 90,000 people in the U.S. diagnosed each year, PD is the fastest-growing neurologic disease in the U.S. and is expected to affect 1.2 million people by 2030. The accumulation of aggregated α-synuclein protein in neurons is a hallmark of the disease, with progressive development of both motor and non-motor symptoms. The therapeutics available today treat a subset of PD symptoms, and there are currently no treatments available that are disease-modifying and slow the progression of PD.

About Lewy Body Dementia
Lewy body dementia (LBD) is the second-most-common neurodegenerative dementia in the U.S. and affects an estimated 1.4 million people. Clinical care in individuals with LBD is challenging due to complex motor, cognitive, behavioral, and autonomic symptoms. LBD is associated with higher healthcare costs, lower quality of life, and greater caregiver distress than Alzheimer’s disease. The pathologic hallmark in LBD is the presence of α-synuclein–positive Lewy bodies and neurites in cortical, limbic, and brainstem regions. Lewy body formation and propagation is accompanied by progressive neurodegeneration, particularly affecting the dopaminergic and cholinergic neurons, leading to both motor and cognitive impairments. The therapeutics available today treat a subset of LBD symptoms, often with severe side effects, and there are currently no treatments available that are disease-modifying and slow the progression of LBD.

About WaveBreak
WaveBreak is a biopharmaceutical company transforming drug discovery for neurodegenerative diseases, targeting the fleeting protein intermediates central to many disease pathways that are beyond the reach of conventional drug discovery approaches. We have built a unique drug discovery platform to target the transient protein intermediates—the oligomers—in these disease pathways, to interrupt the molecular mechanisms that are the source of oligomer generation with small-molecule therapeutics. We are focusing this platform first on some of the greatest unmet medical needs of our time: Parkinson’s disease, Lewy body dementia, Alzheimer’s disease, and ALS. For more information, please visit: www.WaveBreakTx.com.

Contact:
Mary Moynihan
M2Friend Biocommunications
+1 (802) 951-9600
mary@m2friend.com