Solidus Biosciences Inc.

Why are fewer drugs obtaining market approval in recent years? The answer is likely complex, but toxicology issues may be part of the problem. Solidus Biosciences aims to provide pharmaceutical companies with the tools it needs for early stage tox screening. Its MetaChip, short for Metabolizing Enzyme Toxicology Assay chip, is a high through-put biochip capable of screening compounds for their toxicological and metabolic properties in a single test run.

High-throughput in vitro toxicology chips

1223 Peoples Avenue

Troy, NY 12180

Phone: [phone]

Fax: [phone]

E-Mail: [email protected]

Contact: Jonathan S. Dordick, PhD, President

Industry Segment: Biotechnology

Business: Chip-based toxicology assays

Founded: August 2002

Founders: Jonathan S. Dordick (Rensselaer Polytechnic Institute); Douglas S. Clark, PhD (University of California, Berkeley)

Employees: 2

Financing to Date: $2.3 million government grants

Investors: None

Board of Directors: Jonathan Dordick; Douglas Clark

To be approved as a drug, a new chemical entity must be effective against a particular disease or ailment, and it must also be safe and well-tolerated by humans. Despite many recent technological advances in drug discovery, fewer drugs are obtaining market approval in recent years. What's causing the pharmaceutical industry's woes? The answer is likely complex, but toxicology issues may be part of the problem.

According to Jonathan Dordick, PhD, co-founder and president of biotech start-up Solidus Biosciences Inc. , pharmaceutical companies do a great job of identifying highly active molecules, but they are not as good at predicting adverse drug reactions. One issue, claims Dordick, is pharma's limited ability to conduct high-throughput toxicology analyses in the earliest stages of drug discovery. Although large pharmas typically perform in vitro toxicology assays on about 1000 compounds a year, Dordick notes that companies invest significant time and money into those compounds before their full toxicology profiles become available. And because many different groups within a pharmaceutical company assess a drug's toxicity and metabolism, no one entity is aware of all the data associated with a particular molecule at any one time, compounding the problem.

Dordick believes pharmaceutical companies should begin toxicity screening earlier in the drug discovery process in order to identify the molecules with the highest biological activity and lowest toxicity. It's these molecules "that should enter the initial optimization process," he says. This "fail fast, fail cheap" philosophy means toxic molecules are eliminated sooner rather than later, so less money is wasted pursuing inherently flawed molecules. As clinical success rates go up, the price tag per approved molecule should go down.

Solidus Biosciences aims to provide pharmaceutical companies with the tools it needs for such early-stage tox screening. Its MetaChip, short for Metabolizing Enzyme Toxicology Assay chip, is a high-throughput biochip capable of screening compounds for their toxicological and metabolic properties in a single test run.

Dordick and his co-founder Douglas Clark, PhD, are world-class chemists with an intimate understanding of both drug toxicity and the engineering required to fashion workable assays. Though they are on opposite sides of the country—Dordick is a faculty member at Rensselaer Polytechnic Institute in New York State (RPI), while Clark holds joint appointments at the University of California, Berkeley (UCB) and Lawrence Berkeley National Laboratory --the two formed a lasting friendship back in 1989 when they met at an academic conference.

That friendship quickly turned into something more entrepreneurial. In 1994, the two men formed EnzyMed Inc., a start-up that used high-throughput combinatorial biocatalysis to generate libraries of chemically related molecules to optimize drug candidates. In 1999, the company was acquired by Albany Molecular Research Inc. in a stock swap worth roughly $21 million. [See Deal] Both Dordick and Clark feel they have mastered the learning curve associated with biotech start-ups. Missing the heady environment of EnzyMed, they were eager to pursue another business venture together. "The excitement's still there, and so are the nerves," says Dordick.

It turns out that drug companies are particularly interested in the effects novel molecules have on the cytochrome P450 enzymes, a specific class of membrane-associated proteins found in the human liver that break down drugs and other toxins. There are about 15 classes of P450 enzymes in the human body, 8 of which are involved in the metabolism of most drugs. In creating their MetaChip, Clark and Dordick therefore decided to create a biochip that mimics normal liver metabolism on a nano-level scale.

The MetaChip has two main components. The first contains multiple human P450 enzymes embedded in a silicone gel matrix array. The second is designed to be a separate, enclosed compartment containing a single layer of human cells. To test potentially toxic compounds is relatively simple: molecules are applied directly to the array and processed by the P450 enzymes to produce drug metabolites. The microarray and cell monolayer are then "stamped" together to bring the drug and its metabolites into contact with the cells. Fluorescence-based methods are used to determine whether the drug or its metabolites cause cytotoxicity or inhibition of cell growth.

Because it is easy to vary the P450 enzymes and the cell types being tested, Durdick claims the biochip has considerable experimental flexibility. To date the company has successfully incorporated three different cytochromes—CYP2B6, CYP3A4, and CYP1A2--into its microarray, work that was published in a January 2005 paper in the Proceedings of the National Academy of Sciences. In that particular study, the researchers demonstrated it was possible to detect toxic metabolites of cyclophosphamide (Cytoxan) at nanoliter quantities in a breast cancer cell line. The company is currently working on embedding five additional P450 enzymes, all of which are commercially available, into the MetaChip format.

Durdick and Clark made sure to lock down the intellectual property contained in their biochip back in 2002. The issued patent "covers the ability to have biocatalytic arrays in various matrices on a glass slide, coupled to a cell-based screening assay," says Clark. In 2003, Solidus licensed worldwide exclusive rights to the MetaChip patent, as well as additional technology developed in the Dordick and Clark laboratories, from RPI. Both UC Berkeley and RPI currently hold stock in the company. And an inter-institutional agreement gives UC Berkeley undisclosed additional rights. "Essentially, that means the universities have become partners," says Dordick.

Currently, the MetaChip array has four main uses. It can assess the toxicity of both drug candidates and their P450-generated drug metabolites. In addition, it can be used to determine if drugs interfere with the function of one or more P450s, a relatively common pharmacological side-effect that can affect normal processing of the molecule and result in drug-drug interactions. Finally, the MetaChip can measure the pharmacokinetics of potential drugs, giving chemists an understanding of how fast particular compounds are actually broken down by P450 enzymes. That's important because drugs that are metabolized very rapidly may not be efficacious. Alternatively, if they persist in the body too long, there may be unwanted side effects.

Intriguingly, Dordick and Clark hope their biochip will one day be used as a pharmacogenomic tool. Though the enzymatic reactions of metabolism are conserved from person to person, there is great variation in the process—how fast the individual reactions occur, for instance. That's a by-product of the natural variation seen in the P450 proteins from person to person. In addition, a person's metabolic profile can change as they age or as a result of illness. "Metabolism is not one-size-fits-all, it's something that's very dynamic," notes Dordick. He says Solidus's long-term goal is to use the MetaChip to stratify patients into responders and non-responders based on metabolic profiles.

So far, Solidus's financing has come solely through the National Institutes of Health (NIH)-sponsored Small Business Technology Transfer (STTR) program. The company received a Phase I grant of $500,000 in August 2003, enabling proof-of-concept studies, and a Phase II grant of $1.8M in September 2005 to support commercial development of the MetaChip. Because STTR funds can be used to finance both academic investigators as well as sub-contractors, Solidus has used the money to lease equipment and office and laboratory space from RPI. In addition to funding the work of two research chemists, the grant provides additional nominal support to the Dordick and Clark laboratories.

Dordick says the company made a conscious decision to eschew private equity in favor of government grants until it demonstrated proof-of-concept with its MetaChip. But he says it's "the right time now" to seek support from the venture community. He and Clark plan to raise a Series A "no later than early fall."

In addition to getting their name out to VCs, the company plans to launch proof-of-concept studies with two or three pharmaceutical companies this summer in order to begin generating service revenues by 2007. That's a stepping stone designed to put some much needed cash in the company's coffers. Longer term, Dordick expects the company to move away from a fee-for-service model.

Instead, the company plans to develop benchtop MetaReaders for its MetaChips, enabling customers to conduct their own toxicology testing in-house. The reader will spot plate libraries onto the microarrays, perform the assays, and output results using proprietary software. "We're not going to be able to sell a lot of the chips without a device, because pharma wants to have something that's easy to use and ready to go," admits Dordick. The company hopes to achieve its first chip/reader based revenues in 2008 and estimates potential revenues of $150 million by 2012, five years after market launch.

But meeting those numbers may not be so easy. While few companies are developing high-throughput platforms based on metabolite generation, contract research organizations like NovaScreen Biosciences Corp. , a wholly owned subsidiary of Caliper Life Sciences Inc. , could be considered competitors, says Dordick. Other potential competitors include Thermo Electron Corp. and Hurel Corp. Last year, Thermo introduced its LeadStream ADME/Tox platform, an integrated system that appears best suited for later-stage, lower-throughput analysis. Likewise, Hurel's microfluidic technology can't handle massively parallel samples in the same way as Solidus's MetaChip.

And convincing pharmaceutical companies to sign on won't be a slam dunk either. Pharmas are notoriously slow to adopt new technologies—even if it's apparent that there is a real need. To ease adoption, Dordick says Solidus has designed the MetaChip so that it's easy for companies to integrate into their early-stage bioactivity screens.

"The technology has a lot of components to it, and all of them have to come together for this to work. We've shown that the technology works on the laboratory scale, but when you're trying to develop something that's going to be used by others…we have to make it foolproof. That's what we're doing now," says Dordick.—Carolyn Riley Chapman