MICA: M102, A Combined NRF2 and HSF1 Activator for the Treatment of Motor Neuron Disease

Lead Research Organisation: University of Sheffield
Department Name: Neurosciences


The aim of this project is to complete the key stages of drug development needed to enable a clinical trial for a promising new treatment for motor neuron disease (MND), a rapidly progressive, fatal neurodegenerative disorder.

At the University of Sheffield we have identified a candidate drug called M102, which can get into the brain and spinal cord and activate a number of biological pathways which switch on the expression of a range of genes. These genes have a number of effects in cells which improve their ability to survive various stress factors which are known to play a role in the death of neurons. These stress factors include free radicals, inflammation and protein clumps or aggregates.

We hope that by targeting multiple different causes of neuronal stress and death we will increase the probability that this drug will work in a wide range of patients and at all stages of the disease process. We have already shown in various animal models and in brain cells from patients with MND (derived from their skin cells) that we can slow down the disease process and protect neurons from death.

The next stage is to manufacture the drug to accepted regulatory standards and test it for possible side effects in animals- a requirement before conducting studies in humans. These studies will be carried out by expert companies who specialise in this work. Another strand of work will be conducted at Sheffield to allow us to be able to identify using biological signals called biomarkers the MND patients who are most likely to benefit from taking the drug. These biomarkers increase the chance of the drug showing effects in large clinical studies.

We have already done some preliminary studies to show that our plan is likely to be successful but we will conduct the work in stages to reduce the risks associated with problems arising.

As a University it is unlikely that we would take the drug through all the stages of clinical testing and so we have an Industrial partner, Aclipse One, who will share the costs and the risks of the project but will then be able to take the drug through the clinical stages of development.

Technical Summary

The overarching aim of this project is to complete the CMC (chemistry, manufacturing and control), preclinical toxicology package and develop clinical response biomarkers for a promising new treatment, M102 , for motor neuron disease (MND), a rapidly progressive, fatal neurodegenerative disorder.

We have identified M102, a CNS penetrant small molecule dual activator of the NFE2-related factor 2 antioxidant response element (NRF2-ARE) and heat shock factor 1-heat shock element (HSF1-HSE) transcription factor pathways. M102 targets multiple genetically validated pathogenic mechanisms in MND including redox imbalance, inflammation, mitochondrial dysfunction and altered proteostasis. By targeting multiple pathways we expect to significantly increase the probability of clinical success. This is demonstrated by a preclinical efficacy package which includes neuroprotective effects in two MND-related animal models (SOD1G93A and TDP43Q331K transgenic mice) as well as in patient-derived astrocyte/motor neuron toxicity assays from SOD1, C9orf72 and sporadic MND patients.

We have conducted a series of non-GLP pharmacokinetic and toxicological studies which indicate that M102 is likely to have sufficient safety margins in clinical studies following completion of GLP toxicological studies. We will also develop the response biomarkers for M102 to support its clinical development in MND patients.

Completion of the proposed study will allow the initiation of phase 1 studies in healthy volunteers to evaluate the safety and pharmacokinetics of M102, and subsequent Phase 1b studies in MND patients to evaluate biomarker responses and early efficacy. These will be funded through further public or private funding. Ultimately, the data generated will be used to leverage further investment by our Industrial Partner, Aclipse One, to progress through to large efficacy studies and approval for MND.


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