The $20 billion global antidepressant market includes many different products, yet only about one-third of patients with mood disorders currently achieve good antidepressant efficacy from their therapy. The CeNeRx RIMA program aims to change this dismal statistic by harnessing the powerful triple mechanism of the monoamine oxidase (MAO) inhibitor class to achieve superior antidepressant efficacy, while capitalizing on the unique selectivity and reversibility of its third-generation RIMA series of MAO inhibitors to avoid the potential for dietary restrictions and life-threatening side effects that have limited the use of this important class of drugs.
CeNeRx’s RIMA (Reversible Inhibitors of Monoamine oxidase-A) series represents a powerful new approach to the treatment of depression that addresses a root cause of the condition. Depression and other mood disorders are associated with decreased brain levels of the monoamine neurotransmitters serotonin, norepinephrine and dopamine. These neurotransmitters are needed to maintain normal mood, and when they are decreased, patients become depressed. Monoamine oxidase (MAO), an enzyme that breaks down these neurotransmitters, has been shown to be elevated in the brains of patients with major depression. A recent study further confirmed the link between elevated MAO-A and major depression, concluding that the elevated levels of the enzyme were a primary cause of the drop in neurotransmitter levels underlying the disease.
Antidepressant drugs that treat depression by blocking the activity of the MAO enzyme, known as MAO inhibitors, were first developed several decades ago. MAO inhibitor drugs work by shutting down monoamine oxidase, thereby preventing the degradation of the three key monoamine neurotransmitters in the brain. As a result, MAO inhibitor drugs employ a triple mechanism of action, which may provide efficacy advantages for patients who have not responded or have only partially responded to conventional antidepressants, which affect just one or two neurotransmitters.
However, the antidepressant efficacy of older MAO inhibitors comes at a price that has greatly limited their use—patients are required to observe strict dietary limitations to avoid potentially serious cardiovascular side effects that can be triggered by eating tyramine-rich foods – typically fermented foods such as aged meats and cheeses, red wine and malt beverages. Older MAO inhibitors blocked both MAO-A and MAO-B, both of which metabolize tyramine and ensure that it is maintained at a safe level in the body. The new RIMA inhibitors are highly selective for MAO-A, which leaves MAO-B unaffected and available to metabolize excessive levels of tyramine, thus avoiding the serious cardiovascular risks of the older MAO inhibitors. In addition to being selective for MAO-A, TriRima™ is also reversible, which allows MAO-A to be freed up to metabolize tyramine should levels become too high. Older MAO inhibitors are irreversible and they can bind MAO-A and MAO-B for up to two weeks. The selective and reversible properties of TriRima provide an important advance that may allow patients to realize the efficacy benefits of a triple action antidepressant mechanism without restrictive diets or fear of tyramine reactions.
Earlier-generation RIMA antidepressants have been available in select European and other international territories, but the technical and commercial limitations of those particular drugs kept this novel class from reaching the U.S. market. CeNeRx obtained exclusive rights to its unique third-generation RIMA series from Burroughs-Wellcome (now GlaxoSmithKline) and Krenitsky Pharmaceuticals Inc.
The RIMA series also includes earlier-stage compounds that may have differentiating qualities from TriRima, such as CX 2614 and CX 009, which are in the later stages of preclinical development.
TriRima™ (CX 157), the most advanced of the RIMA series, is CeNeRx’s lead RIMA candidate for the treatment of depression and anxiety.
TriRima is currently being studied in Phase II clinical trials following a successful Phase I program.
In a PET imaging study published in the December 2009 issue of Neuropsychopharmacology, researchers from Brookhaven National Laboratory confirmed that TriRima is both a potent and reversible inhibitor of MAO-A. They reported that TriRima produced a robust dose-related inhibition of brain MAO-A in human subjects at two hours post-dosing and that brain MAO-A had recovered completely by 24 hours post-dosing, confirming TriRima’s excellent reversibility. They also found that the plasma concentration of TriRima was highly correlated with the degree of inhibition of brain MAO-A, leading the authors to conclude that the study validates the use of plasma TriRima concentrations as a surrogate marker for brain MAO-A inhibition and supports its use for modeling therapeutic dosing regimens of TriRima.
These PET study results are important for several reasons. First, they independently confirm that TriRima potently inhibits human brain MAO-A, the enzyme shown in studies by Meyers (see above) and others to be a primary cause of the drop in neurotransmitter levels underlying major depression. They also definitively show that TriRima is reversible, a unique feature that helps TriRima to avoid the risk of food-associated cardiovascular effects observed with conventional, irreversible MAO-A inhibitors. This study accordingly provides further evidence that TriRima and the RIMA class may represent a potential new therapeutic option for the large segment of patients not adequately treated by current antidepressants, for whom the triple-action potential of a safe and effective MAO-A inhibitor might help relieve the disabling symptoms of depressive disease.
In addition, preclinical toxicology studies at doses many-fold higher than the target therapeutic doses have demonstrated safety, favorable tolerability and a wide therapeutic window.
TriRima, the most advanced of the CeNeRx RIMA series, is in Phase II clinical development.
TriRima has strong intellectual property protection with opportunity for market exclusivity beyond 2028.