Sosei Group announces that the first healthy subject has been dosed with a novel small molecule HTL0014242 in a Phase I clinical study, marking the start of a new in-house clinical program targeting psychiatric and neurological disorders.

HTL0014242 is a potent, orally available, selective Metabotropic Glutamate Receptor 5 (mGlu5) negative allosteric modulator (NAM), precision-designed by the Company using its GPCR Structure-Based Drug Design (SBDD) platform.

Glutamate is one of the most abundant excitatory neurotransmitters in the human nervous system and alterations in glutamate signalling, and mGlu5, are associated with a range of neuropsychiatric and neurodegenerative disorders. HTL0014242 is one of a series of mGlu5 NAMs designed to selectively and potently reduce excessive glutamate signaling providing opportunities for new therapies in areas of high unmet medical need.

The new clinical study with HTL0014242 is a first-in-human double-blind, randomized, oral single ascending dose study in healthy male and female adult subjects. This study is being conducted in the UK and will assess safety, tolerability and pharmacokinetics of HTL0014242 in up to 48 subjects. Preliminary results are expected in the second half of 2019.

"The start of this new clinical program is a result of dedicated research that leveraged all aspects of our unique SBDD approach and our development capabilities," Dr. Malcolm Weir, Executive VP and Chief R&D Officer, said. "HTL0014242 has been designed to be a highly selective and potent blocker of mGlu5 activity and has been optimized to overcome the potential limitations seen with other small molecules targeting this important GPCR. We see great potential with this candidate in a range of indications driven by altered glutamate signaling and intend to take decisions about the ultimate Phase II development pathway following the evaluation of results from this Phase I study."

Metabotropic glutamate receptors are Class C GPCRs, which respond to the neurotransmitter glutamate and receptor subtype 5 (mGlu5) is of considerable interest as a drug target. The Company previously reported the crystal structure of the transmembrane domain of mGlu5 in complex with the NAM, mavoglurant (Dore? et al, Nature 2014). The structure provided detailed insight into the architecture of the transmembrane domain of mGlu5 including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches that regulate receptor signaling. The company used these findings to identify novel mGlu5 NAM drug candidates with high potency and selectivity, including HTL0014242.

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