Background

ORM-12741 is an orally available α 2c adrenergic receptor antagonist being developed for Alzheimer's disease by the Finnish company Orion. The role of the α 2c adrenergic receptor in Alzheimer's disease is poorly understood. Its role in the cognitive deficits of schizophrenia is better-studied (Kalkman and Loetscher, 2003). ORM-12741 was originally found as part of a schizophrenia drug discovery program, but after some early clinical studies in Europe is not currently being developed for this indication.  The α 2c adrenergic receptor modulates numerous brain systems, including brain activity during stress. No peer-reviewed studies about ORM-1274 have been published, but according to Orion, the compound improved memory function in rodent studies (Orion media release).

Findings

From 2008 to 2010, Orion Pharma had conducted seven Phase 1 trials for ORM-12741 in a total of more than 200 healthy volunteers in Finland, France, and the Netherlands. These studies evaluated absorption, distribution, metabolism, and excretion (ADME) of ¹⁴C-labelled ORM-12741, indicating that a PET tracer is available to accompany clinical development of this drug and evaluate blood-brain barrier penetration and receptor occupancy, for example. Other Phase 1 trials examined safety, pharmacokinetics, food effects, and other parameters of single and multiple ascending doses.

From April 2011 to October 2012, a three-month Phase 2a trial in Finland and Spain compared flexible doses of 30 to 60 or 100 to 200 mg of ORM-12741 to placebo in 100 patients with moderate Alzheimer's disease who were already taking cholinesterase inhibitors or memantine. The trial assessed safety via adverse events, vital signs, laboratory values and ECG, and well as efficacy via computerized cognitive tests of various memory domains. Data were presented at the 65th Annual Meeting of the American Academy of Neurology held March 2013 in San Diego, and again at the World Congress of Neurology in September 2013 in Vienna. ORM-12741 was reported to have been generally well-tolerated and to have shown small but statistically significant benefits on working memory, episodic memory, and caregiver distress (for details, see AAN poster; company press release).

In June 2015, Orion started a Phase 2 study, called Nebula, to evaluate the efficacy of ORM-12741 for calming agitation and aggression in Alzheimer's disease. The study compares a 12-week course of either a low dose or high dose twice daily to placebo. It enrolls 300 people with probable Alzheimer's disease of moderate severity, and clinically significant agitation and aggression for change on the NPI clinician rating scale plus a range of secondary outcomes. This trial takes place in Germany, the Czech Republic, Poland, Finland, Bulgaria, and Croatia, and is set to run until summer 2017.

Previous Phase 2 clinical development of this drug for Raynaud's phenomenon, a condition marked by cold-induced vasospasms, was terminated in January 2013 following a recommendation by the trial's Data and Safety Monitoring Committee (see NCT01315899). For all clinical trials of this drug listed in the United States see clinicaltrial.gov and EU Clinical Trials Register.

Clinical Trial Timeline