CHISHIKI

Drug Discovery

New small molecule HTL0014242 shows early promise for slowing neurodegeneration

By Kirstie Bennett | Dec 9, 2018

Conference

"29th International Symposium on ALS / MND"

December 7-9, 2018

Glasgow, UK

MND Association

Conference website

 

Summary

Researchers from the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield, UK working with scientists at Sosei Heptares have presented findings from preclinical studies investigating a new small molecule HTL0014242 in preclinical models of the neurodegenerative condition motor neurone disease (MND).

Dr Heledd Brown-Wright from SITraN gave a talk about how HTL0014242, a novel mGlu5 negative allosteric modulator (antagonist) designed by Sosei Heptares, slowed the  decline in motor function in late stages of disease progression in a mouse MND model. The results demonstrated that HTL0014242 reduced neuroinflammation (glial activation) and exerted a neuroprotective effect as evidenced by a reduction in motor neuron loss compared to control mice.

View Presentation

 

Abstract

HTL0014242 a novel metabotropic glutamate receptor type 5 (mGlu5) negative allosteric modulator limits glial activation and slows late stage disease progression in the SOD1G93A mouse model of MND.

Heledd Brown-Wright1, Kirstie Bennett2, Pamela Shaw1, Alastair Brown2, Matt Barnes2, Richard Mead1

1 SITraN
2 Heptares Therapeutics Ltd

Background

Glutamatergic excitotoxicity is a recognised mechanism of neuronal injury and genetic and pharmacological evidence points to a role for mGlu5 in driving disease progression in the SOD1G93A mouse. Existing mGlu5 antagonists, are hampered by poor pharmacology, limiting their potential for clinical translation. Heptares Therapeutics’ mGlu5 NAM, HTL0014242, was designed using their proprietary STAR technology (1,2).

Objective

We set out to determine the pharmacology and therapeutic potential of HTL0014242 in SOD1G93A mice.

Methods

We conducted pharmacokinetic (PK) and receptor occupancy (RO) studies of HTL0014242 directly in SOD1G93A mice to enable dose selection. HTL0014242 was dosed orally, once daily, from 25 to 90 days of age at 3, 10 and 30 mg/kg to investigate effects on early disease progression in SOD1G93A transgenic mice. A second study was conducted dosing at 30mg/kg from 25 or 75 days of age through to end-stage disease. Motor neuron counts (Nissl) and measurement of microglial (IBA1) and astrocyte (GFAP) reactivity was determined in lumbar spinal cord sections.

Results

HTL0014242 (10mg/kg,po) showed good exposure in plasma and spinal cord (spinal cord/plasma ratio=5.4). Treatment from 25 days of age at 3, 10 and 30mg/kg showed marginal effects on motor function up to 90 days. However, quantification of GFAP staining in lumbar ventral horn, indicated a profound dose dependent reduction in astrocyte activation (54%, 71% and 88% at 3, 10 and 30mg/kg (p=0.0039, one-way ANOVA). IBA1 staining showed a similar trend (45%, 39% and 64% reduction at 3, 10 and 30mg/kg). This reduction correlated very well with the degree of receptor occupancy of mGlu5 by HTL0014242 in the same mice. In the second study, the reduction in astrocyte activation was confirmed when mice were dosed from 25 (p<0.0001) or 75 days of age (p<0.0001) at 30mg/kg, and the reduction in microglial IBA-1 staining was also recapitulated (25 days, p=0.0005, 75 days p=0.002). However, a delay in onset of visible signs slowing of late stage disease progression and reduction in motor neuron loss only occurred in the group dosed from 75 days of age. These mice showed a three-week extension in the time taken to fail on the rotarod test (p<0.0001). 

Discussion and Conclusion

These data suggest a key role for mGlu5 in driving glial, particularly astrocyte, activation. The therapeutic benefit from dosing at an intermediate stage of disease (75 days) versus an early stage (25 days of age) ties with substantial evidence in the literature that glial activation is a driver of late stage disease and also suggest that the point of intervention is crucial with early intervention potentially of less therapeutic benefit.

References

1.     Dore, A. S, et al. (2014). Nature 511(7511):557-562.

2.     Christopher, J. A et al. (2015). J Med Chem 58(16):6653-6664.