Heptares announced the first healthy subject has been dosed with the first-in-class, selective muscarinic M4 receptor agonist HTL0016878 in a Phase 1 clinical study. The Phase 1 study dosing triggers a US$15 million milestone payment by Allergan to Heptares under a global R&D and commercialization partnership announced in April 2016.

Heptares and Allergan are developing HTL0016878, an orally available, small molecule drug candidate with potential to treat certain neurobehavioural symptoms of Alzheimer's disease. The compound stimulates M4 receptor activity in the brain with high selectivity, and offers the possibility for an improved safety profile over previous muscarinic receptor agonists, which have been associated with adverse effects elsewhere in the body leading to safety and tolerability issues.

HTL0016878 was designed by Heptares using its proprietary structure-based drug design platform and is the first compound, selected from a series of selective M4 agonists, to progress into clinical studies. The double-blind, randomized first-in-human study is being conducted in the UK by Heptares and will assess safety, tolerability and pharmacokinetics of single and multiple oral doses of HTL0016878 in up to 106 healthy subjects. Preliminary results are expected in the first half of 2018.

"The start of this new clinical trial marks the progression of the fourth compound designed by Heptares into clinical studies and follows the advancing clinical studies with selective M1 agonists under our partnership with Allergan," Tim Tasker, Heptares' Chief Medical Officer, said. "The target selectivity we can build into molecules increasingly highlights the potential of our approach to create new medicines with significantly improved clinical profiles for addressing a range of diseases. In creating the first selective M4 agonist to enter human studies, we are a step closer to our goal of developing a new therapeutic approach to ease the considerable burden and distress caused by diseases such as Alzheimer's."

Under the terms of the 2016 global R&D and commercialization partnership, Allergan licensed exclusive global rights to Heptares' broad portfolio of novel subtype-selective muscarinic receptor agonists (M1, M4 and dual M1/M4 agonists) for the treatment of major neurological disorders, including Alzheimer's disease. In addition to the new clinical program with HTL0016878, a selective M4 agonist, announced today, the companies are advancing a program evaluating selective M1 agonists through clinical studies as a potential treatment for symptomatic cognitive deficits inAlzheimer's patients; and are assessing the potential of dual M1/M4 agonists with potential to treat both cognitive and neurobehavioural symptoms through preclinical studies.

Muscarinic receptors are G protein-coupled receptors (GPCRs) found in multiple tissues. Until now, attempts to develop medicines that target M1 and M4 receptors have been unsuccessful because of side effects caused by the activation of M2 and M3 receptors. Selective M1 or M4 agonists that do not activate M2 or M3 therefore are highly sought after, and expected to address blockbuster markets.

There is significant unmet medical need and heavy economic burden across multiple diseases characterized by dementia. In Alzheimer's disease (AD), currently available drugs provide limited and transient effects. Healthcare costs associated with AD and dementia (estimated at over $640 billion for North America, Western Europe and Asia-Pacific) including nursing home care, continue to grow dramatically and new therapies with better and more durable efficacy are urgently needed. It is estimated that over 45 million people worldwide have dementia (4.8 million in North America, 7.5 million in Western Europe, 3.6 million in Asia-Pacific) and this is expected to increase to over 130 million in 2050. Alzheimer's disease is the most common cause of dementia and may contribute to 60-70% of cases.

Although AD is usually considered a cognitive disorder, almost all AD patients develop neurobehavioural symptoms at some stage during disease progression, ranging from mild to severe. These symptoms are associated with patient and caregiver distress, increased rates of institutionalization, and increased mortality.