Novel Add-on Drug Shows Promise in Alzheimer's Disease

Megan Brooks

March 12, 2013

Adding the selective α-2C adrenoceptor antagonist ORM-12741 to a cholinesterase inhibitor yielded "significant positive" effects on episodic memory in patients with Alzheimer's disease in a phase 2a randomized, double-blind, placebo-controlled study.

"ORM-12741 is a first-in-class compound with a mode of action that is completely different from currently marketed Alzheimer's disease drugs," Juha Rouru, MD, from Orion Pharma, told Medscape Medical News. Orion Pharma is developing the drug and supported the study.

Dr. Rouru said ORM-12741 "acts through specific subtype of brain receptors (α-2C) that are believed to modulate memory and behavior. Therefore it can be used on top of existing Alzheimer medications and this way it is giving marked additional benefit to the patients."

The study results were released March 11, ahead of their presentation at the American Academy of Neurology (AAN) 65th Annual Meeting, to be held March 16 to 23 in San Diego, California.


ORM-12741 has demonstrated good tolerability across 7 phase 1 studies in healthy persons and efficacy in rodent models suggesting beneficial effects on cognition and behavioral symptoms in Alzheimer's disease, Dr. Rouru said. This phase 2a study is the first report of a selective α-2C AR antagonist in patients with Alzheimer's disease.

The study enrolled 100 patients with moderate Alzheimer's disease (Mini-Mental State Examination scores, 12 to 21) with behavioral symptoms (Neuropsychiatric Inventory [NPI] score, 15 or higher).

They were randomly allocated to 2 flexible dose levels of 30 to 60 mg or 100 to 200 mg of ORM-12741 or matching placebo twice daily for 12 weeks as add-on to their stable cholinesterase inhibitor therapy (with or without memantine).

Overall, memory scores at 12 weeks had improved by 4% in those taking ORM-12741 and worsened by 33% in those taking placebo, according to a statement from AAN.

"The results of the study were clearly positive," Dr. Rouru said. "The beneficial effects were seen particularly on episodic memory, which is one of the most important functions affected by Alzheimer's disease. In addition, caregiver distress was significantly relieved."

In a meeting abstract, the investigators say they saw significant positive treatment effects for ORM-12741 on the Quality of Episodic Memory (P = .03) and the Quality of Memory (P = .0127) compared with placebo during the 12-week treatment period, with no clear difference in efficacy between the 2 active dose groups.

There was also a positive trend for Quality of Working Memory and NPI total score primarily for the low-dose group. ORM-12741 was generally well tolerated, the investigators say.

"Obviously the results encourage us to continue the development of this compound. At the moment, we are planning a larger phase 2 dose-finding study," Dr. Rouru told Medscape Medical News.

New Therapeutic Target

Reached for comment on these results, Maria Carrillo, PhD, vice president of medical and scientific relations for the Alzheimer's Association, told Medscape Medical News that people with Alzheimer's disease and their families "desperately need better treatments and prevention strategies.

"This is a small study conducted over a short period of time, and it is early in the drug development process, but the results are promising and welcome — particularly because this drug attacks a new therapeutic target," Dr. Carrillo said. "These results need to be replicated in a larger study, with a more diverse population, over a longer period of time."

American Academy of Neurology (AAN) 65th Annual Meeting. Abstract 002. March 16-23, 2013.