Heptares Therapeutics, the leading GPCR structure-guided drug discovery and development company, has initiated a phase I clinical study of HTL9936, the first fully selective muscarinic M1 receptor agonist to enter clinical development. HTL9936 is an orally available, small molecule drug candidate discovered using the Heptares GPCR structure-based drug design (SBDD) platform.

Heptares also plans to develop HTL9936 as a novel treatment for improving cognitive function (memory and thinking abilities) in patients with Alzheimer’s disease and other diseases associated with dementia and cognitive impairment.

“We are excited to initiate clinical development of HTL9936, a first-in-class agent with the potential to become an important new medicine for improving cognitive function in patients with Alzheimer’s disease and other potential indications including schizophrenia and Lewy body dementia,” said Malcolm Weir, CEO of Heptares. “In addition, the initiation of this clinical trial with HTL9936 marks an important milestone for Heptares, as we evolve into a clinical-stage business with a rich portfolio of novel GPCR-targeted agents advancing through phase I and IIa clinical trials in the near-term.”

M1 receptor agonism is a well-validated mechanism of action for treating cognitive impairment and a valuable pharmacological profile that the pharmaceutical industry has endeavored to create for decades. The principal challenge has been to engineer selective compounds that activate the M1 receptor subtype without also activating the M2 or M3 receptors, which are associated with undesirable side effects. All previous compounds have been discontinued due to inadequate selectivity. Using a new structure-guided approach, Heptares scientists determined the x-ray crystal structure of the M1 receptor for the first time and leveraged unique insights into the receptor to identify new chemistries with fully selective M1 agonist profiles.

The phase I study will evaluate the safety, tolerability and pharmacokinetics of HTL9936. In addition, the clinical pharmacodynamics of the drug will be investigated in a series of studies over the next year. This study aims to recruit more than 100 healthy volunteers including elderly people at a single clinical centre in the UK. Initial results are expected in mid-2014

Today there is significant unmet medical need and heavy economic burden across multiple diseases characterised by cognitive impairment and dementia. In Alzheimer’s disease, currently available drugs provide limited and transient effects on cognition. Healthcare costs associated with the epidemic of AD, including nursing home care, continue to grow dramatically and new therapies with better and more durable efficacy are urgently needed. In addition, an estimated 80 per cent of schizophrenics suffer from cognitive impairment and 1.3 million patients in the US suffer from Lewy body dementia. Currently there are no approved therapies for treating cognitive impairment in schizophrenia or for treating Lewy body dementia.