Fallout from the catastrophic phase I clinical trial of TeGenero’s monoclonal antibody TGN1412 in March 2006,¹ in which 6 volunteers suffered life-threatening "cytokine storms," includes newly tightened regulations in the United Kingdom and renewed concern worldwide about first-in-human trials, particularly for compounds with novel targets or mechanisms of action. Safety issues of this magnitude have shaken the public’s confidence in the clinical trial process, as have high attrition rates during drug development and other economic and productivity issues that plague the pharmaceutical and biotechnology industries. One key to overcoming these issues, and thereby revitalizing the drug discovery process, will be early, decisive selection among drug candidates to identify those with the best potential for tolerability, efficacy, and appropriate pharmacokinetics in humans.

An innovative concept for gaining a stronger and earlier grasp on prospective pharmaceuticals has been developed by Bowman Research and is currently offered as a service to the industry. Using Bowman’s Ex Vivo Metrics™ technology, it is feasible, for the first time, to conduct ex vivo tests of drug candidates and other compounds in human whole organs. This system generates human-relevant pharmacokinetic, metabolic, safety, and efficacy data without the safety risks of human exposure or the extrapolations needed for animal or in vitro studies. By virtue of its human-relevant features, Ex Vivo Metrics is expected to improve and accelerate drug candidate selection and to complement clinical research by providing additional information about a compound and its effects.

Multiple Obstacles Overcome

Unlike the relatively straightforward development of animal perfusion systems, the development of human whole organ perfusion systems has required researchers to overcome many obstacles, such as reliable, rapid, and ethical organ procurement, transportation, and reanimation. Bowman Research was uniquely qualified to solve these problems for several reasons. First, the company has many years of experience in the perfusion of all major organs. Second, Bowman can build on the expertise of its sister company, Organ Recovery Systems (ORS), which transports organs for actual transplantation using proprietary products. These products include LifePort technology, which allows more organs to be used effectively in transplant surgery, thereby reducing waste and honoring more donors’ intentions. (This technology has won numerous awards, including being listed in 2006 by Business Week as 1 of the Ten Devices Changing Medicine.²) With proper consent from family members, ethically donated organs that are deemed inappropriate for transplantation can be used for research purposes. The same technology that ORS uses for transporting, preserving, and reanimating organs for transplantation can be applied to these organs so that whole organ perfusion studies can be conducted.

To perform these studies, oxygenated whole blood is perfused through the appropriate vessels to attain near-normal physiologic conditions. Fine control is used to attain appropriate, organ-specific pressure, temperature, pH, flow rate, filtration, oxygenation, and biochemical composition (Figure 1). Organs typically perfused using Ex Vivo Metrics include the liver, intestine, and lung. The average perfusion time for a single organ is 8 to 10 hours.

To simulate in vivo drug delivery during drug studies, the compound can be delivered in the perfusate or through other, organ-specific means (for example, into the gut lumen or via lung airways). Perfusate or tissue samples can be collected after application or over time to measure absorption (gut and lung); metabolism (liver, gut, and lung); accumulation, tissue residence time, and clearance (liver, gut, and lung); or toxicity (lung and liver). The potential for drug-drug interactions can be explored by concomitant administration of compounds. Data analysis is automated and uses liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) for metabolite profiling and pharmacokinetic evaluation. Cassette dosing is used to enhance throughput.

Results Highly Relevant to Humans

The importance of Ex Vivo Metrics as a preclinical test system lies in its relevance to humans: The human organ source is more applicable than animal models. Furthermore, unlike simpler cell-based or tissue-based systems, Ex Vivo Metrics allows researchers to study the integrated functionality of the whole organ. Ex vivo human whole organ studies also complement early clinical studies by permitting greater control over experimental parameters and data collection. For example, drug concentration and the contributions of diet or age can be systematically evaluated. Use of whole perfused organs provides much more information on the potential clinical effect of a drug besides gross efficacy and toxicity outcomes. Whole perfused organs can be closely monitored to observe the immediate impact of drug application on the organ-specific level (for example, the first-pass effect or the release of biochemical mediators) and to evaluate the effect over time by recirculating the effluate and obtaining a series of tissue or effluate samples. This finer control could improve our ability to predict how a drug is likely to behave in clinical trials or to explain why a drug candidate that showed promise in early studies failed in subsequent clinical trials.

At present, proof-of-concept studies of Ex Vivo Metrics have been satisfactorily completed for the profiling of the toxicity and pharmacokinetic features of compounds, including absorption, clearance, metabolism, and accumulation and retention. A growing body of data continues to provide convincing evidence of the system’s reliability, reproducibility, and predictability. Areas that remain to be studied include the use of Ex Vivo Metrics in diseased organs, such as those with tumors, diabetes, inflammation, or infections. This intriguing use holds much promise for predicting the fate and therapeutic effect of a drug candidate under diseased conditions.

We expect that Ex Vivo Metrics will become an important tool in drug discovery and development by focusing the drug candidate selection and profiling process on compounds with optimal safety and efficacy in humans.

Dr. Curtis is the Chief Scientific Officer of Bowman Research, Inc.
2570 East Devon Ave, Des Plaines, IL 60018.
Telephone: +1-847-544-7400
E-mail: info@bowman-research.com

References

1. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 2006, 355: 1018-1028

2. Kurt Stoller. Ten devices changing medicine. Business Week. August 16, 2007. http://www.businessweek.com/innovate/content/aug2006/id20060816_049941.htm. Accessed August 1, 2007

Organ perfusion setup for Ex Vivo Metrics

8-8-07 - Biomarker Breakthroughs