New York-based biotech start-up Oligomerix Inc. is pressing a multipronged attack against tau protein, an alternate Alzheimer's disease target, using a combination of small-molecule and antibody therapeutics coupled with biomarker strategies.

Formed in 2006, Oligomerix adopted the tau protein theory of Alzheimer's disease origin over the more popular beta amyloid theory.

Specifically, it is focusing on small, cellular oligomers of tau. "A lot of evidence in the literature suggested these were the more neurotoxic entities relative to other types of aggregated species," Jack Pasini, chief commercial officer for Oligomerix, told BioWorld Today.

The company's core technological competencies include purification and characterization of soluble protein aggregates, and antibody and small-molecule development.

Oligomerix was able to secure Small Business Innovation Research (SBIR) grants to screen inhibitors of tau oligomer formation, and to develop antibodies to specific species of tau oligomer that it purified.

"Looking at these species, we realized that some of them have an intrinsic proteolytic activity," Pasini said. Within the past year, Oligomerix has prioritized the effort to understand that activity. "We've demonstrated that it's not only responsible for tau cleavage, but it can also cut other proteins that may be important to Alzheimer's disease."

Examples of those other proteins include tubulin and some peptide neurotransmitters.

When Oligomerix researchers, working in collaboration with Ottavio Arancio, at Columbia University Medical Center, introduced tau oligomers into mouse brain via cannula, there was impairment of learning and memory in the mice, localized to the oligomeric tau in the hippocampus. Monomeric tau showed no effect.

The company also is targeting tau protease activity, which causes a self-cleavage of tau. The fragments produced by tau protease represent important biomarkers for Alzheimer's disease.

Oligomerix has developed a screening assay for tau protease, and it has found a number of inhibitors that are active against it. "We're just at the point of undergoing small-molecule discovery efforts with that approach," Pasini said.

One difference between Oligomerix and other companies attacking tau is that Oligomerix is focusing more on extracellular tau as a target for therapeutic intervention. The company contended that much of tau's pathology is actually extracellular and concentrations of tau outside the neuron are much lower than inside.

"I think that we have the most unique approach in tau pathology," Pasini said. According to him, most other companies in the field are targeting tau aggregation alone.

Tau protein has inspired a flurry of dealmaking activity within recent months. Bristol-Myers Squibb Co. is funding the Gladstone Institute's efforts to identify Alzheimer's disease targets that affect tau dysfunction, with the goal of finding new disease-modifying therapies for Alzheimer's.

ADx NeuroSciences Inc. signed an agreement with K. U. Leuven in November 2011 to develop and commercialize antibodies that selectively bind phosphorylated Tau aggregates. That same month, Signum Biosciences Inc. signed a deal with GlaxoSmithKline (China) R&D Co. Ltd. to screen for drugs that target phosophoprotein phosphatase 2A (PP2A), with the intention of bridging the link between PP2A methylation and tau hyperphosphorylation.

Many of those deals may represent disillusionment with Alzheimer's strategies based on amyloid beta. A number of anti-amyloid drugs have failed in late stage trials, including Alzhemed (Neurochem Inc.), and Flurizan (Myriad Genetics Inc.).

Oligomerix currently is looking for a partner to work with to accelerate its preclinical programs. Pasini said it has "very good traction" with large pharma, and the firm is talking with multiple companies.

It has used a combination of grants and equity investment – a total of $4.7 million – to fund the company thus far.

Its most recent grant award, disclosed in November 2011, was for $1.6 million from the National Institute on Aging to discover small molecules and antibodies targeting tau protein oligomers. The grant supports screening of compound libraries at the Michigan High Throughput Screening Center.

"We've kept the company small purposely, so as not to grow too quickly," Pasini said.

Oligomerix is putting together a financing round from an equity investor, and is considering writing an application for an extension of its second phase SBIR grant. That extension grant would be worth $3 million over three years.