Wren Presents Preclinical Data at AD/PD 2023 Demonstrating Potential of its First-in-Class, Small-Molecule Inhibitors of α-Synuclein Toxic Oligomers for the Treatment of Parkinson's Disease

BOSTON, March 29, 2023 /PRNewswire/ -- Wren announced today the presentation of preclinical data for its first-in-class, oral inhibitors of α-synuclein oligomer generation demonstrating potent inhibition of both oligomer production and aggregate formation in cell and mouse models used for studying Parkinson's disease progression. The data were presented in poster and oral presentations today at the International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders (AD/PD 2023) taking place from March 28–April 1 in Gothenburg, Sweden.

"α-Synuclein oligomers are fleeting protein intermediates implicated in the molecular damage and cellular destruction that decimate dopaminergic neurons in Parkinson's disease and other α-synucleinopathies. Unfortunately, their elusive, ephemeral physical nature makes them difficult to target using conventional drug discovery approaches, as well as to develop biomarkers to support clinical development," said Bart Henderson, CEO of Wren. "We are taking a different approach to drug discovery, using biophysics to design landmark therapeutics that can address the urgent need for effective drugs for this rapidly expanding neurodegenerative disease. In parallel, we are advancing the latest biomarker technologies to guide preclinical and clinical development to increase the probability of clinical success. We are excited about our progress and the promising initial data we presented today for several oral, small-molecule oligomer inhibitors and for the biomarker technologies we are deploying to measure on-target efficacy in both preclinical and clinical studies."

The relatively recent understanding that α-synuclein oligomers resulting from errant protein folding are the toxic entities directly responsible for neurotoxicity in PD has defined a new approach to treating a central molecular cause of neurodegeneration in Parkinson's disease. Yet characterizing and suppressing transient 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 and cannot simply be put in a bottle and analyzed in isolation. Targeting the complex, highly interconnected process of α-synuclein formation in Parkinson's disease requires a different approach to measure, assay, and analyze the proteins during their evolving assembly and disassembly, from their formation to their disappearance. This requires targeting a network of interactions that is a fundamentally different approach from conventional single-target drug discovery.

Wren's technology platform enables the analysis of the inhibition of the source mechanisms that produce oligomer intermediates in complex disease processes. It is a network-centric approach to enable the discovery of small molecules that can block their generation with specificity and precision. Today's presentations are the first data Wren has presented publicly that demonstrate the therapeutic potential of a new class of oral, small-molecule therapeutics developed using this technology platform for targeting the fleeting intermediates at the core of neurodegeneration.

Highlights of the presentations follow, and the posters are available on Wren's website: https://www.wrentherapeutics.com/our-science/publications

Poster #825 / On-Demand Oral Presentation OD188: "The selective detection of alpha-synuclein oligomers to analyze small molecule inhibitors of their formation for the treatment of Parkinson's disease"*
Presenter: Samata Pandey
Poster #729: "Reducing toxic alpha-synuclein oligomers in PD through precise targeting of the molecular mechanisms of oligomer formation with small molecule inhibitors"*
Presenter: Sarah Ball

*Special thanks to Eisai, which collaborated with Wren in conducting some of these studies

Summary and key findings:
Wren has developed oral small molecules that target the molecular mechanisms at the source of oligomer generation: Primary nucleation, which is catalyzed by lipid membranes; and secondary nucleation, which is catalyzed by α-synuclein aggregates. In addition, Wren is developing biomarker assays for the selective detection of α-synuclein toxic oligomers that will enable biomarker-driven clinical development for these small-molecule therapeutics. In these studies, several oral, small-molecule inhibitors of α-synuclein oligomer generation demonstrated potent reduction of both oligomers and aggregates in vitro, and in both cellular and in vivo models. Specifically:

• The researchers used proprietary in vitro biochemical assays designed to measure kinetic rates of oligomer generation with high precision to optimize small-molecule oligomer inhibitors for enhanced potency and oral pharmacokinetics, with good brain penetration.
• These small-molecule compounds inhibited both molecular mechanisms of α-synuclein oligomer formation in these assays at low drug concentrations, with high specificity, without inhibiting either amyloid beta or Tau aggregation.
• The researchers also presented data for two different biomarker detection assays that use homotypic antibodies with high affinity and high specificity for α-synuclein oligomers—in a Sandwich ELISA assay and with a Proximity Ligation Assay (PLA).
• The small-molecule inhibitors significantly reduced both α-synuclein oligomer levels and α-synuclein aggregates in a dose-dependent manner in iPSC dopaminergic cells (measured with both ELISA and PLA) and in the Line 61 transgenic mouse models (ELISA and pS129).

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 Wren Therapeutics
Wren 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 assay and 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, Alzheimer's disease, and ALS. For more information, please visit: www.wrentherapeutics.com.

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

SOURCE Wren Therapeutics

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