Inflammation is a process that is vital for defending the body against harm from things like infections, injuries, and toxins. When something damages our cells, they release tiny messenger proteins to alert the immune system that something is wrong.

Inflammation happens all over the body wherever a threat is detected and in the brain, the cells that respond to inflammation are called microglia.

Microglia make up 10–15% of all cells found within the brain and are its main line of defence. Under normal conditions, microglia sit around monitoring the environment for signs of trouble. There is evidence that early in neurodegenerative diseases these microglia can get stuck in an activated mode and that consequent neuroinflammation is a common feature and driver of diseases like Parkinson’s, Lewy body dementia, Alzheimer’s and Huntington’s.

Parkinson’s disease

The potential role of neuroinflammation as a driver for the neurodegenerative processes underpinning the effects of Parkinson’s disease (PD) has become a hot topic over the past 15 years. Prodromal symptoms, such as isolating REM sleep behaviour disorder (iRBD), proceed the onset of motor cognitive dysfunction by 10-20 years and are thought to be caused by neuroinflammation.

8% of people aged 70 – 89 years  have iRBD and 70 % of iRBD patients go on to develop Parkinson’s disease and the related disorders, dementia with Lewy bodies and multiple system atrophy. Identifying a treatment that can successfully reduce neuroinflammation in people with iRBD may therefore provide a mechanism for delaying the onset and/or slowing the progression of PD.

More than 50% of dopaminergic neurons in the substantia nigra are lost at the onset of motor symptoms in Parkinson’s disease.

How does PXS-4728 work in neuro inflammation?

SNT-4728 is a very potent compound that inhibits two key enzymes associated with neuroinflammation:

  • Semicarbazide-Sensitive Amine Oxidase (SSAO)
    SSAO produces reactive oxygen species (hydrogen peroxide and aldehydes) in the vasculature and an adhesion protein attracting leukocytes (white blood cells) all of which promote inflammation
  • Monoamine Oxidase-B (MAO-B) MAO-B is an amine oxidase producing reactive oxygen species (hydrogen peroxide and aldehydes) in mitochondria of many cells including microglia and neurons present in the brain.

SNT-4728 has already been the subject of an extensive development program, conducted following a 2015 deal with Boehringer Ingelheim (BI). The asset was shown to be efficacious in pre-clinical work in Nonalcoholic Steatohepatitis (NASH) and subsequently for diabetic retinopathy (DR). However, the program was discontinued by BI in September 2020 primarily because of an off-target effect on an additional inflammatory enzyme in the brain, MAO-B (monoamine oxidase B).

It was identification of this effect, and the significant body of research work underpinning SNT-4728, which has sparked the quest to explore its potential in brain diseases.

Our clinical trials

Syntara is exploring the potential of SNT-4728 in diseases where neuro inflammation plays a role and in September 2022 secured £2.9m (~A$5m) in funding from Parkinson’s UK to conduct a phase 2 clinical trial of SNT-4728 in Parkinson’s disease. The study is being carried out by Syntara in collaboration with researchers at the Universities of Oxford and Sydney.

You can read about the project from Parkinson’s UK perspective here:

The study is recruiting patients with isolated Rapid Eye Movement Sleep Behaviour Disorder (iRBD), a strong predictor of Parkinson’s, to evaluate whether SNT‐4728 can reduce neuroinflammation with results measured by nuclear imaging of the brain. The trial is a phase 2A, multi centre, double-blind, randomised, placebo-controlled, parallel-group study to assess the effect of 12 weeks treatment with SNT-4728A on neuroinflammation in patients with iRBD.

You can find details of the trial here: