Neurology | Biosplice

Biosplice’s neurodegeneration program is focused on a class of neurodegenerative conditions known as tauopathies. Tauopathies involve the abnormal aggregation of the protein tau, into neurotoxic, non-soluble aggregates and neurofibrillary tangles. Pathologic accumulation of tau is observed in neurodegenerative diseases such as Alzheimer’s disease, frontotemporal lobar degeneration with tau inclusions (FTLD-tau), and progressive supranuclear palsy, and Pick's disease, among others. Each of these diseases are characterized by high unmet need, with no approved treatments that slow or halt the progression of the disease.

Alzheimer’s disease, the most common cause of dementia and the most common tauopathy, is a chronic neurodegenerative disease affecting an estimated 5.8 million adults aged 65 and older in the U.S.¹ and an estimated 50 million people worldwide.²

Currently approved therapies help manage some symptoms but do not address the underlying causes or the progression of the disease, which is ultimately fatal.¹
With the world’s aging population, Alzheimer’s disease is quickly becoming a global epidemic, and a socioeconomic burden impacting families, social services, and healthcare delivery systems.¹

Symptoms of Alzheimer’s disease generally appear in patients in their mid-60s, though symptoms may occur earlier in patients with familial forms of Alzheimer’s disease stemming from a genetic predisposition. The disease is initially characterized by progressive memory loss followed by slow progression to severe difficulty in accessing basic brain functions and subsequent mental disorders.

References

Alzheimer’s Association. 2020 Alzheimer’s Disease Facts and Figures. Alzheimers Dement 2020;16(3):391+.
Dementia statistics. www.alz.co.uk/research/statistics. Accessed 03/31/2020.

Preclinical

Overview Mechanism of Action

Overview

In a P301S transgenic animal model of tauopathies, SM15685, a second-generation Biosplice Therapeutics compound, demonstrated reductions in the formation of hyperphosphorylated tau, insoluble tau and neurofibrillary-like tangles compared to vehicle .

Biosplice’s selective and specific DYRK1A inhibitors have demonstrated attractive drug-like properties, including blood-brain barrier penetration in multiple species. Lead candidate selection for future clinical trials is ongoing.

Mechanism of Action

Tau pathology is considered a key driver for a broad spectrum of neurodegenerative diseases, collectively known as tauopathies (Iqbal, Liu, & Gong, 2015). These include primary tau diseases such as frontotemporal lobar degeneration with tau inclusions (FTLD‐tau), progressive supranuclear palsy (PSP), and Pick's disease, as well as multimodal diseases such as Alzheimer's disease (AD).

Tau is a multifunctional protein, which may become neurotoxic as a result of post-translational modifications including a high degree of phosphorylation that leads to its oligomerization, sequestration, and aggregation (Spillantini & Goedert, 2013). Biosplice’s therapeutic approach is to disrupt the pathologic phosphorylation of tau, preventing its subsequent aggregation.

Dual-specificity tyrosine phosphorylation-regulated kinase-1A (DYRK1A) is known to phosphorylate the microtubule-associated tau protein. Overexpression of DYRK1A is correlated with tau hyperphosphorylation and the development of neurofibrillary tangles. Biosplice Therapeutics has identified a suite of brain-penetrant small-molecule inhibitors of DYRK1A. While a variety of therapeutics have recently been tested in clinical trials to prevent tau aggregation and spreading, the exact form(s) of tau responsible for its toxicity and spreading remain to be identified (Khanna, Kovalevich, Lee, Trojanowski, & Brunden, 2016). Therefore, regulating the tau cascade upstream at the phosphorylation level is an appealing strategy to address conditions involving the aggregation of pathologic tau.

Publications

Discovery and Preclinical Development of SM15685, a Novel Highly Selective Oral DYRK1A/B Inhibitor as a Potential Therapeutic for Alzheimer’s Disease

Alzheimer's Association International Conference (AAIC) | July 27 - 31, 2024

SM07883, a Novel, Potent, and Selective Oral DYRK1A Inhibitor, Reduces Neuroinflammatory Responses in Mouse Models

Advances in Alzheimer’s and Parkinson’s Disease Therapies (AD/PD) Focus Meeting 2020 | April 02 - 05, 2020

SM07883, a Novel, Oral DYRK1A Kinase Inhibitor, Reduced Tau Pathology and Associated Behavioral Deficits in Preclinical Models

Tau2020 Global Conference | February 12 - 13, 2020

Anti-inflammatory Effects of SM07883, a Novel, Potent, and Selective Oral DYRK1A Inhibitor in Neurodegenerative Mouse Models

Alzheimer's Association International Conference (AAIC) | July 14 - 18, 2019

Aging Cell | July 03, 2019

Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease

Aging Cell. doi: 10.1111/acel.13000

Benoît Melchior, Gopi Kumar Mittapalli, Carolyn Lai, Karen Duong‐Polk, Joshua Stewart, Bora Güner, Brian Hofilena, Amanda Tjitro, Scott D. Anderson, David S. Herman, Luis Dellamary, Christopher J. Swearingen, K.C. Sunil, Yusuf Yazici

Article

Tau Pathology Reduction with SM07883, a Novel, Potent, and Selective Oral DYRK1A Inhibitor - a Potential Therapeutic for Alzheimer’s Disease

Alzheimer’s Association International Conference (AAIC) | July 22 - 26, 2018