August 1, 2009 (Vol. 29, No. 14)

Carol Potera

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

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.

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.

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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