Our Science:

Approach & Innovation

Therapeutic Approach

Neuropath’s approach selectively activates TRH receptors in brain to evoke TRH’s multiple neurotherapeutic actions – which impact key drivers of ND biology to counteract failing neuronal networks and reduce cognitive and motor impairment.

Although each ND has its own signature characteristics, a number of pathophysiological processes are common to many NDs.  Monotherapy with a single multifactorial drug may, therefore, have medical application across a range of conditions.

TRH-Based Approach:

Features and Advantages

  1. “Switches on” naturally occurring neurotherapeutic system in brain that modulates multiple pathogenic processes in NDs.

  2. Multi-indication therapeutic opportunity, including AD, ALS/MND and TBI, based on target biology.

  3. Potential to deliver both symptomatic relief and disease modification in NDs.

  4. Strong biological rationale leverages extensive academic and pharma knowledge base for TRH.

Our TRH-based strategy holds many parallels with that of the currently much-publicized class of drugs targeting receptors of the neuropeptide GLP-1.  The remarkable success of GLP-1-based drugs is not only revolutionizing the treatment of obesity and potentially other therapeutic indications, but also heightening appreciation of the broad clinical potential of neuropeptide signalling systems generally. 

Neuropeptides, such as TRH and GLP-1, are recognized for their pleiotropic and neuromodulatory effects, and are well placed to deliver clinically relevant homeostatic and neuroprotective actions to attenuate the progressive loss of neurons intrinsic to NDs.

A neuropeptide-based approach is distinct from others currently prominent in the ND drug development arena (for example, those targeting risk genes and misfolded proteins) and it aligns with increasing calls in the field for multifactorial drugs to address the multiplicity of pathological mechanisms underlying NDs.

The TRH signalling system in brain is inherently neurotherapeutic – through enhancing neuronal survival and modulating stress responses, activation of this system offers a promising therapeutic strategy to promote brain network resilience and combat NDs.

Innovation

The innovative design and mechanism of action of Neuropath’s TRH-based compounds is founded on breakthrough neuroscience that selectively harnesses TRH’s recognized central neurotherapeutic effects – a target with substantial history of pharma and academic interest and R&D. 

Discovered by Dr Julie A. Kelly, Neuropath’s Founder and CEO, through her Wellcome Trust-funded academic research at TCD, these compounds overcome pharmacological constraints – namely, enzymic degradation by TRH-degrading ectoenzyme (TRH-DE) and endocrine side effects – that have limited the clinical use of TRH.

As shown below, our TRH-based compounds are uniquely dual acting – they deliver potent inhibition of TRH-DE in combination with selective high affinity for TRH receptors in the brain.  Moreover, these compounds do not bind to pituitary TRH receptors that mediate TRH’s endocrine effects.

Neuropath’s TRH-based compounds provide an attractive opportunity to deliver the neurotherapeutic effects of central TRH activation without inducing endocrine side effects. 

The lead compound is demonstrated in preclinical proof-of-concept studies to counteract glutamate-induced excitotoxicity and excessive reactive oxygen species (ROS; oxidative stress), both key drivers of neurodegeneration, as well as to reduce neuronal cell death and mitigate cognitive and motor impairment.