HemoShear LLC
This article was originally published in Start Up
Executive Summary
Only 10% of compounds that enter Phase I trials survive to FDA approval, and that has a lot to do with the inadequacy of early-stage research in cell lines. They are poor predictors of what will happen in animal models, much less in patients. The problem stems in part from the fact that cells, once removed from an organism and maintained artificially in a laboratory environment, change their behavior and phenotype in equally artificial ways, which in turn warp their response to drug candidates. HemoShear LLC's technology simulates a cell's natural environment by introducing hemodynamic blood flow and the accompanying shear stresses. Its first system focuses on blood vessels.
Predictive hemodynamic cell models
1115 5th Street SW
Charlottesville, VA 22902
Phone: (434) 872-0196
Web Site: www.hemoshear.com
Contact: James Powers, Chairman & CEO
Industry Segment: Biotechnology
Business: Predictive models for drug discovery
Founded: January 2008
Founders: Brett Blackman, PhD, CSO; Brian Wamhoff, PhD, VP, R&D
Employees: 14
Financing to Date: $5 million
Investors: Private angel investors
Board of Managers: James C. Powers; Brian M. Campbell, PhD, CFO; W. McIlwaine Thompson, Jr. (Woods Rogers PLC); Brett R. Blackman; John L. Brooks, III (Joslin Diabetes Center); Jonathan M. Sackier; Brian R. Wamhoff; Reginald F. Woods
Scientific Advisory Board: Szilard Voros, MD (Piedmont Heart Institute); Kenneth Batchelor, PhD (retired from GlaxoSmithKline); George A. Beller, MD (University of Virginia Health System); Timothy L. Pruett, MD (University of Minnesota School of Medicine); Robert Ruffolo, PhD (retired from Wyeth); Ed LeCluyse, PhD (The Hamner Institutes for Health Sciences); Douglas W. Mendenhall, PhD (retired from Merck)
Drugs fail at a dizzying rate. Only 10% of compounds that enter Phase I trials survive to FDA approval, and that has a lot to do with the inadequacy of early-stage research in cell lines.
Such experiments can identify compounds that inhibit a particular target, or even selectively kill tumor cells, but they are poor predictors of what will happen in animal models, much less in patients. The problem stems in part from the fact that cells, once removed from an organism and maintained artificially in a laboratory environment, change their behavior and phenotype in equally artificial ways, which in turn warp their response to drug candidates.
HemoShear LLC's technology simulates a cell's natural environment by introducing hemodynamic blood flow and the accompanying shear stresses. Its first system focuses on blood vessels, which comprise an endothelial cell layer and smooth muscle cell layer. Endothelial cells constantly experience changes in blood flow and shear stress as a result of the heart's pumping. "If you put them in a dish, they no longer make the same proteins that define them as endothelial cells," says Brian Wamhoff, who is HemoShear's vice president of research and development, and an associate professor of medicine at the University of Virginia.
The technology was developed at the University of Virginia by Wamhoff and Brett Blackman, an associate professor of biomedical engineering at the university. They introduced flow over the cells, but realized that they needed to simulate the ebb and flow that occurs in a natural blood vessel. "It's not like a faucet. The hemodynamic patterns we put on the cells were derived from human magnetic resonance imaging [MRI], using a process called three-dimensional velocity mapping," says Wamhoff.
The system is even more complex, because cells in different environments – for example in the aorta, a vein, or a coronary artery – experience different shear forces, and the specific forces are vital to preserving their regional biochemical characteristics. Shear forces, in part, "determine the phenotype of the cell in vivo. We can recreate any of these cell types if we impose the correct hemodynamic wave form," says Wamhoff.
That's critical in testing drugs for a variety of diseases, because different conditions originate in different cell types. To test a drug designed to counter hypertension in arteries, it's essential that the system's cells have the characteristics of arterial endothelial cells, as opposed to, say, endothelial cells in veins.
The method also incorporates smooth muscle cells, whose phenotypes are also affected by blood flow as a result of signaling from endothelial cells. A third cell type, monocytes, are also found in these systems, particularly in inflammation. HemoShear's system allows the researcher to separate the cell types at the end of the experiment so that they can be individually analyzed. "That's what separates us from everyone else in this field. There are a lot of 3D systems out there that can incorporate multiple cell types and generate a response, but they can't separate the cells at the end of the experiment. [To understand the mechanism], you need to know which cells are involved," says Wamhoff.
As evidence of the system's power, Wamhoff points to a client who asked HemoShear to create a hypertension assay. When that was completed, the client asked them to validate it by examining four blinded compounds currently approved for use in humans. Two of the compounds lowered blood pressure and two did not. "They asked us to tell them which was which, and the system was able to correctly identify the anti-hypertensive compounds," says Wamhoff. The company has also investigated a number of currently approved drugs and demonstrated that the technology can identify off-target positive and negative effects on the vasculature. The list includes Lipitor (atorvastatin), Vioxx (rofecoxib), Actos (pioglitazone), amlodipine, and others.
HemoShear enters multi-year strategic collaborations with drug companies to assist them with drug discovery and development. Current collaborations include efforts to understand the biology of atherosclerosis, hypertension, and complications of diabetes. In other cases, companies may encounter cardiovascular side effects that the system can help to explore. CEO James Powers points to the cardiovascular side effects of Avandia (rosiglitazone) and Vioxx. "Those are the kinds of things our technology could have explored much earlier in the drug discovery process."
HemoShear says it is currently working with several large pharmaceutical companies. The relationships are expanding beyond initial proof-of-concept studies, "and we're anticipating longer-term drug discovery collaborations. We expect to be rewarded in the form of milestones, and perhaps royalties," says Powers.
There are no companies that have a similar vascular system, according to Powers. There are some companies with advanced models of the liver and the blood-brain barrier. "But none of them do it quite the way we do. They can't separate the cells and analyze the individual signals," says Powers, who declines to name specific companies.
HemoShear also emphasizes its expertise in working with primary cells and vascular biology. "We find it challenging to determine how to measure what our customers ask us to measure, like protein expression on the surfaces of endothelial cells, which is not trivial. Our expertise is just as important as the technology itself," says Powers.
The company has also developed expertise in working with primary (freshly isolated) cells, which are used to construct the systems. "Very few pharmaceutical companies know how to do that. The system is not turn-key. We work very closely with the client's scientists. Sometimes we're on the phone two or three times a week. It's a true partnership," says Wamhoff.
HemoShear is currently generating revenue from its vascular system, but the technology isn't limited to the circulatory system. By changing cell types and tweaking the shear forces, "we hope to create systems that mimic other organ systems, such as the liver, the blood-brain barrier, or the kidney. Within each organ system, we can create simulated disease conditions," says Powers. The company can then tease out the genes or proteins that play a role in those diseases, and test the abilities of compounds to restore normal function. In 2009, the company began work on its human liver system.
The first liver system should be complete in 2011, according to Powers. He expects several pharmaceutical companies to participate in proof-of-concept studies using a number of known drugs.
HemoShear has raised about $5 million from angel investors. Powers won't project revenue growth, but "we expect to quickly get past the break-even point. We're well capitalized," he says.
Powers believes that HemoShear's technology can help pharmaceutical companies streamline the development process and reduce the number of drug candidates that fail in clinical trials: "Our business rationale is all about improving the predictive power of methods in the lab." – Jim Kling