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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

  • Better than First-Generation Drugs

    All the compounds in the pipeline at Mithridion are small molecule oral-acting drugs. The lead candidate, MCD-386, is a selective M1 muscarinic agonist that potently activates M1 receptors, yet has weaker or negligible action on other muscarinic receptors.

    In three animal models, MCD-386 improved cognitive memory functions with reduced side effects, compared to first-generation compounds. An unexpected finding was that MCD-386 also activated the enzyme alpha-secretase in laboratory models, indicating a potential reduction in the production of neurotoxic A-beta and the possible prevention of neuron death. The results suggest that MCD-386 may not only treat symptoms of Alzheimer’s disease, but also slow disease progression.

    Mithridion recently presented the results of a Phase I study of 18 volunteers. In the study, MCD-386 was rapidly absorbed and reached maximum serum levels in 1 to 1.5 hours, and serum levels were linearly related to dose. No participants reported any severe side effects, but mild sweating, salivation, and flushing occurred in some participants at the highest dose.

    Based on these encouraging results, Mithridion is working on a controlled- release formulation with the dual goal of extending the duration of action and avoiding elevated peak concentrations that contribute to side effects. Further Phase I trials are planned for later in 2009.

    Another state-of-the-art tool, triple quadrupole mass spectrometry, gives scientists at Mithridion an advantage for working in the Alzheimer’s drug arena. Triple quadrupole mass spectrometry measures accurately and quantitatively small amounts of drugs in an extract of blood or brain tissue during preclinical studies. In Alzheimer’s disease research, it’s critical to confirm that new drug candidates are capable of crossing the blood-brain barrier to work in the brain. “The blood-brain barrier is quite an obstacle, and many drugs fail to get through,” Dr. Twose notes.

    Not only does triple quadrupole mass spectrometry confirm that compounds enter the brain, but the technology also defines chemical structures required for this to happen. “We know many of the rules, so we can carry out an in silico process before we synthesize compounds,” continues Dr. Twose. Mithridion’s semi-rational approach to drug design provides a good estimate of whether compounds will pass into the brain, and triple quadrupole mass spectrometry verifies that this occurs.

    Mithridion views its forte as lead optimization, and preclinical and early clinical development of small molecule drugs. As drug candidates prove themselves, the company will seek partners to collaborate on Phase III development, regulatory approval, and marketing.

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