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August 01, 2009 (Vol. 29, No. 14)

Novel Alzheimer’s Therapies Gaining Ground

Mithridion’s Compounds Aim to Selectively Activate M1 Receptors to Reduce Side Effects

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    Mithridion’s MCD-386 activated alpha-secretase in cultured cells in preclinical laboratory models, thus potentially reducing the production of neurotoxic A-beta and preventing neuron death in Alzheimer’s disease.

    The pipeline at Mithridion in Madison, WI, consists of treatments for Alzheimer’s disease and other central nervous system disorders. Company scientists are focused on improving first-generation drugs that target muscarinic receptors. Although none of the first-generation drugs ever made it to market due to unacceptable side effects that became apparent in clinical trials, those early trials confirmed that the M1 muscarinic receptor, in particular, was the best target.

    “M1 agonists have the potential to not only treat symptoms of Alzheimer’s, but also to get at the underlying disease process,” says CEO Trevor Twose, Ph.D. Dr. Twose helped to found Mithridion in 2006 to advance second-generation muscarinic agonists.

    The starting compounds were created in the laboratory of William Messer, Ph.D., Mithridion’s CSO and a pharmacology professor at the University of Toledo. In June 2008, Mithridion merged with Cognitive Pharmaceuticals, Dr. Messer’s virtual company. “The marriage was a good one,” says Dr. Twose, because it wedded Mithridion’s drug discovery expertise, management skills, and investor base with Dr. Messer’s pharmacology knowledge.

    Certain neurons in the brain, known as cholinergic neurons, communicate through the neurotransmitter acetylcholine to control memory and cognition. In Alzheimer’s disease, cholinergic neuron function is deficient due to the death of neurons caused by the neurotoxic peptide A-beta. One kind of cholinergic receptor important for memory and cognition is muscarinic receptors, especially the M1 subtype. Other muscarinic receptor subtypes include M2, which slows the heart rate, and M3, which causes sweating, salivation, and gastrointestinal problems.

    The first-generation muscarinic agonists activated several muscarinic receptor subtypes, resulting in unpleasant side effects. In contrast, Mithridion’s second-generation drugs replace the lost cholinergic function by selectively activating only M1 receptors to improve memory and cognition. This approach selectively minimizes the risk of fainting, sweating, excessive salivation, and diarrhea, common side effects that led to the demise of the first-generation drugs.

    Among the first-generation drugs, Eli Lilly’s xanomeline was regarded as the best candidate, and it showed beneficial effects on symptoms in Alzheimer’s disease and schizophrenia. Now, Frank Bymaster, one of the inventors of xanomeline, is advising Mithridion about how to design better second-generation compounds.

    Extensive scientific literature provides evidence that M1 agonists interact with several key pathways that contribute to the pathology of Alzheimer’s. These include a reduction in the production of neurotoxic A-beta; an increase in another peptide that protects against A-beta damage; a decrease in cell death; and a decrease in phosphorylation of tau protein.

    “We don’t have proof that our compounds will modify Alzheimer’s in people, but the results from animal models are highly encouraging that our drugs interact with these pathways and should modify disease activity,” says Dr. Twose. Mithridion’s compounds appear to boost memory and cognition by targeting underlying disease processes that slow neuronal death “and that’s the ultimate goal,” he adds.

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