Clinical Trials

Date: 2016-02-10

Type of information: Results

phase: 1b

Announcement: results

Company: Heptares Therapeutics (UK), a wholly-owned subsidiary of Sosei Group (Japan)

Product: HTL9936

Action mechanism:

muscarinic M1 receptor agonist. HTL9936  is a fully selective muscarinic M1 receptor agonist. This orally available, small molecule drug candidate has been discovered using the Heptares GPCR structure-based drug design (SBDD) platform (Heptares StaR® technology). 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.

Disease: Alzheimer’s disease and other diseases associated with dementia and cognitive impairment

Therapeutic area: Neurodegenerative diseases

Country: UK

Trial details:

The Phase 1a study assessed the safety, tolerability and pharmacokinetics of HTL9936 in relation to dose in 84 healthy volunteers, while also evaluating preliminary signs of efficacy (increase in brain activity). (NCT02291783)

Latest news:

* On February 10, 2016, Heptares Therapeutics announced positive findings from its Phase 1b clinical study with HTL9936. These positive results provide strong evidence of a therapeutic window for the selective M1 agonist mechanism in general, and for progression of HTL9936 and similar molecules as medicines to treat cognitive disorders. The Phase 1b precision medicine study involved 28 healthy elderly subjects who received different doses of HTL9936 and was designed to test the effect of drug on measures of brain activity while simultaneously monitoring side effects.
In the study, HTL9936 exhibited robust and statistically significant changes in brain electrical activity measured using multiple electroencephalography (EEG) biomarkers relevant to cognition, including effects on the P300 evoked response potential (p=0.0052). These pro-cognitive effects were seen at low doses and low blood concentrations that were safe and well tolerated.
M1 receptor selectivity was also confirmed across the dose range studied through the absence of gastrointestinal side-effects (such as diarrhoea and vomiting) typically attributed to the stimulation of M2 and M3 receptors. Such side effects are dose-limiting in standard-of-care acetylcholinesterase inhibitors, which likely work through non-selective muscarinic receptor stimulation.
Heptares is also developing a second patentably distinct M1 agonist, HTL18318, which is in Phase 1 and for which results are expected later this year. Phase 2 studies in dementia and schizophrenia patients are expected to commence in late 2016.

* On June 17, 2015, Sosei Group announced that its wholly-owned subsidiary Heptares Therapeutics has reported the positive outcome of its Phase 1a study with HTL9936, the first-ever fully selective muscarinic M1 receptor agonist to enter clinical development. Key findings were:

- Early evidence of increased brain activity, as measured by electroencephalography (EEG), was seen after dosing and gave signals similar to those seen with other cognitive enhancing agents1.

- HTL9936 was well tolerated at drug levels that result in the increased brain activity observed without side effects.

- HTL9936 demonstrates good penetration into the brain, as indicated by levels found in cerebrospinal fluid.

- M1 selectivity was demonstrated with, unlike earlier muscarinic agonists3, no adverse effects seen from stimulation of other muscarinic receptors.
These preliminary data suggest that the selective M1 agonist product profile of HTL9936 predicted from preclinical studies translates to humans. Heptares is now putting in place a series of further clinical studies with the objective of demonstrating clinical proof of concept in patients, and moreover is advancing its diverse portfolio of follow-on selective muscarinic agonists that target M1, M4, and both M1/M4 to the clinic. Heptares now looks forward to advancing HTL9936 and the M1 agonist programme into further clinical studies.

* On December 9, 2013, Heptares Therapeutics has announced that it has initiated a Phase 1 clinical study of HTL9936, a fully selective muscarinic M1 receptor agonist to enter clinical development. Heptares 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.

The Phase 1 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.

Is general: Yes