In the quest for a disease-modifying Alzheimer's drug, Mithridion Inc. is blazing a new trail.

While many of the disease-modifying agents in development seek to block or otherwise decrease levels of the peptide amyloid beta, Mithridion "accepts that amyloid beta is being produced" and seeks to "toughen up" the neurons so they aren't killed by it, said Trevor Twose, Mithridion's CEO.

Amyloid beta forms the plaques thought to be responsible for Alzheimer's disease, which affects more than 26 million people worldwide, according to the Alzheimer's Association. Currently available drugs - Aricept (donepezil, Pfizer Inc.), Exelon (rivastigmine, Novartis AG), Cognex (tacrine, First Horizon Pharmaceutical Corp.), Reminyl (galantamine, Shire Pharmaceuticals Group plc) and Namenda (memantine, Forest Laboratories Inc.) - boost memory and cognition but cannot slow the course of the disease.

Several companies seeking the disease-modifying Holy Grail have drugs in late-stage development. Flurizan (tarenflurbil, Myriad Genetics Inc.), which selectively lowers levels of amyloid beta 42, is in Phase III trials. The much-anticipated bapineuzumab (Elan Corp. plc and Wyeth), a monoclonal antibody that may be able to clear amyloid beta from the brain, is poised to enter Phase III. (See BioWorld Today, Jan. 13, 2005, and May 22, 2007.)

Last month, the small-molecule amyloid beta antagonist Alzhemed (tramiprosate, Neurochem Inc.) failed in a Phase III clinical trial, but Twose said he doesn't think the failure "disproved the idea" that interfering with amyloid beta is beneficial. Even so, amyloid beta isn't the only potential target for disease-modifying Alzheimer's drugs. Ketasyn (AC-1202, Accera Inc.) targets defects in glucose utilization and lipid metabolism, and many companies are working on gamma secretase inhibitors. (See BioWorld Today, Aug. 28, 2007.)

Mithridion's approach may "from a theoretical perspective" complement some of those already in development, Twose said. The company is developing small molecules that activate a pathway shown to protect neurons from amyloid beta. Initial data proved the mechanism in in vitro hippocampal samples, and Mithridion is testing the hypothesis that the neuronal protection may block the progression of Alzheimer's.

Mithridion licensed its technology from the Wisconsin Alumni Research Foundation (WARF), the technology transfer arm of the University of Wisconsin. Twose, who spent 30 years at various big pharma and small biotech companies, founded Madison, Wis.-based Mithridion along with Jeffrey Johnson and Thor Stein, both of the university.

The company kicked off operations in early 2006, supported by seed funding from Biopons Inc. and about $500,000 in grants and state loans.

In April 2007, Mithridion closed a $2.2 million Series A financing. Venture Investors led the round, with participation from WARF, Rosetta Partners and Wisconsin Investment Partners. Twose said the money should carry the 12-person company through mid-2008, but they likely will raise a Series B round in early 2008.

For now, Mithridion is focused on optimizing its selected drug lead. Twose said the company is using a Liquid Chromatograph/Mass Spectrometer to speed its optimization process by evaluating neuroprotective activity, pharmacokinetics and metabolism in parallel. He said the company has identified candidates that can cross the blood-brain barrier and anticipates beginning preclinical safety studies next year.

If all goes well, an investigational new drug application would follow in 2009. Twose plans to use a contract research organization for pre-IND and clinical trials and potentially seek a pharmaceutical partner for later trials.