M102 is a proprietary disease-modifying drug therapeutic based on recently understood disease pathways in neurodegenerative diseases, particularly in ALS. M102 was identified as a lead therapeutic candidate by the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield, UK, in an effort to identify central nervous system (CNS) penetrant activators of the NRF2-ARE pathway. M102 is an orally administered, once daily, small molecule drug and a new chemical entity (NCE).
M102, a potential best-in-class drug, takes a much broader mechanistic approach to treat ALS, in that M102 has effects on nine of the eleven ALS disease pathomechanisms.
M102 is a dual activator of the NRF2 and HSF1 pathways which are disease-modifying pathways that are downregulated in ALS.
Through NRF2 and HSF1 activation, M102 reduces oxidative stress and inflammation, enhances mitochondrial biogenesis and initiates autophagy. In addition, M102 refolds misfolded proteins, disaggregates aggregated proteins, and clears misfolded and aggregated proteins.
NRF2-Antioxidant Response Element (NRF2-ARE) activation is a powerful new therapeutic strategy for ALS. NRF2 is a transcription factor regulated by the Kelch-like ECH-associated protein 1 (Keap1). The Keap1-NRF2 complex constitutes a cytoplasmic sensor of redox imbalance and electrophilic agents, and it is activated when cellular redox status shifts to an oxidative state. NRF2 pathway activation can also be mediated by small molecule electrophiles which react with Keap1. NRF2 activation manifests pleiotropic downstream effects due to transcriptional activation of genes promoting cytoprotective effects, with the potential to positively impact neuronal survival. These pleiotropic effects of NRF2 activation lead to significant neuroprotective effects and loss of NRF2 enhances neuronal sensitivity to a range of neurotoxic challenges. Attenuation of the NRF2 response has been observed in ALS, Alzheimer’s disease and in aging. In human biosamples, biochemical evidence also indicates that reduced NRF2 activity is observed in ALS. Critical to the approach we are taking here is the fact that this attenuated NRF2 response can be overcome using known small molecule inducers of this biological pathway.
HSF1-HSE activation is another powerful new therapeutic strategy in ALS. HSF1 is a transcription factor regulated by heat shock protein 90 (Hsp90), Hsp70, Hsp40, Hsf1, and/or TRiC complex in the cytoplasm. Under stress, HSF1 is derepressed, and then trimerizes and translocates to the nucleus, where it binds to HSE to promote the transcription and translation of downstream genes that enhance neuronal survival and function. The HSF1 signaling pathway can be directly activated by cellular stressors or by electrophilic drugs.
M102 has multiple in vivo and in vitro datasets that indicate strong efficacy in both familial and sporadic ALS. In the TDP-43 mouse model, M102 stopped disease progression and reverted disease animals back towards the healthy state. TDP-43 proteins exist in 97% of all ALS patients.
Aclipse has developed a comprehensive set of potential biomarkers to confirm target and pathway engagement, optimize clinical dose regimen, and enable a precision medicine approach for the treatment of ALS. More specifically, our technology allows the identification of likely M102 drug responders, which constitute 60% of all ALS patients. Industry data show that the application of a precision medicine approach increases the probability of clinical success by 2- to 3-fold.
M102 is a new chemical entity (NCE) with composition-of-matter patent protection and multiple pending patent families protecting use, biology, pharmacokinetics, formulation, and precision medicine with patent life to 2044.
M102 has received orphan drug designation from both FDA and the European Medicines Agency (EMA), which add meaningful protections for our product. M102 is also eligible for additional FDA regulatory exclusivities and/or programs, including Fast Track, Breakthrough Therapy, Priority Review and NCE exclusivities at the appropriate times of drug development.
M102 also has significant upside uses in other neurodegenerative diseases. Neurodegenerative diseases represent a range of medical conditions which primarily affect the neurons in the human brain. Neurons are the building blocks of the nervous system which includes the brain and spinal cord. Normally, neurons do not reproduce or replace themselves, so when they become damaged or dead, they cannot be replaced by the body. Neurodegeneration is the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases occur as a result of neurodegenerative processes. Such diseases are incurable, resulting in progressive degeneration and/or death of neuron cells. As research progresses, many similarities appear that relate these diseases to one another on a sub-cellular level. There are many parallels between different neurodegenerative disorders, including atypical protein assemblies and induced cell death. Neurodegeneration can be found in many different levels of neuronal circuitry, ranging from molecular to systemic. Potential additional applications of M102 includes Parkinson’s Disease, Huntington’s Disease, and Friedreich’s Ataxia.
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