From Phenotype to Genotype: Amersham Health Paves the Way - Pharmaceutical Executive


From Phenotype to Genotype: Amersham Health Paves the Way

Pharmaceutical Executive

Georgeann McGuinness, MD, submitted a proposal to the National Institutes of Health to image the lungs of New York City firefighters who were at Ground Zero on September 11, using Amersham Health's helispin agent, which is still under development.
Tomorrow's Solutions for Today's Problems: Amersham Health works with a New York physician to extend a helping hand. With a unique approach to imaging, Amersham Health's investigational diagnostic agent, which it gained with the acquisition of Magnetic Imaging Technologies, has the potential to revolutionize treatment of chronic obstructive pulmonary disease and other respiratory disorders. By using hyperpolarized helium instead of oxygen, MRI images depict the exact pathways of gas in the lungs, which was previously impossible. Currently in Phase II trials, the technology improves the ratio of imaged helium in the lungs from one in 3,000 to 1,500 in 3,000.

Georgeann McGuinness, MD, New York University School of Medicine associate professor of radiology, saw the immediate application of helispin in diagnosing inhalation injury in many of the rescue workers who were at the site of the World Trade Center on September 11. She recently submitted a proposal to the National Institutes of Health to conduct a five-year study of 200 New York City firefighters. The study, if approved, will attempt to gauge the impact of that day on their health.

McGuinness: We have been performing computed tomography scans on a large number of World Trade Center-exposed firefighters, through a medical monitoring program jointly supported by the Fire Department of New York, the Bureau of Health Services, and the Centers for Disease Control, among others. The CT scans can give us structural information about lung injury, but this data does not provide us with functional or physiologic information, including evidence of reactive airway disease. Because the site of injury is deep in the lungs where the particle matter was inhaled, the airways involved are peripheral (small), beyond the capabilities of even high resolution CT, and correspond to a region in which lung injury is usually not detected by routine pulmonary function tests.

The New York firefighters are an interesting study cohort: They all had a unique, severe inhalational exposure on September 11. Because of mandatory medical monitoring within the fire department we have access to data, including pulmonary function tests, on the patients before 9/11.

And finally, there is the "healthy worker effect," which eliminates the confounding problems of preexisting diseases, because firefighters must be healthy to be on active duty. It is a perfect project to apply the new imaging technique to, and we may have the opportunity to provide valuable clinical insights into the lung injuries sustained by those firefighters during that tragic event.

In the past, MRI could not be utilized for lung imaging. Now, using a gas other than oxygen in the lungs allows us to gain valuable insight into lung morphology and function. Helispin can show how well the gas is delivered to specific areas of the lungs, the diffusion coefficient indicates whether air spaces and airways are altered in their dimensions; and we can visualize dynamic patterns of gas flow within the airways. We intend to compare this data with CT images and pulmonary function tests, but we already recognize that those tests are not terribly sensitive to the type of small airway disease that we suspect the firefighters have.

The subjects, many of whom are currently symptomatic, are potentially at risk for developing chronic lung diseases, and the available tests are insensitive to this type of lung injury. Even those firefighters without significant symptoms now are at risk for developing disease in the future. We wonder, when we look at the data over the five year duration of the project, if we'll pick up markers that indicate a predisposition for the development of chronic disease."

The long-term effects of breathing the air rising from the debris of the World Trade Center are still under debate, with medical experts disagreeing on its seriousness. The so-called ``World Trade Center cough'' developed by rescue workers and others at the site is characterized by various symptoms including shortness of breath and wheezing.

However, medical experts are still questioning the long-term side effects of that day. McGuninness' efforts, among others, aim to help bridge today's problems with tomorrow's solutions by using advanced imaging diagnostics.

William Clarke, MD, MSc
Questioning the Gold Standard William Clarke, MD, MSc, executive vice-president of research and development for Amersham and a practicing physician for more than 20 years, thinks it's critically important for regulators to reexamine some of the old gold standards and see if they are still applicable in light of new products, with completely novel mechanisms of action. Clarke, whose senior R&D staff will be speaking at the Parkinson's Action Network's upcoming meeting, believes that patients shouldn't have to wait for new diagnostics while investigators and companies perform longitudinal studies on chronic diseases.

Clarke: The era of molecular imaging and in vivo in-patient diagnostics is ready to happen. The question is, how will we work together to make it happen as soon as possible?

Molecular imaging and molecular in vivo diagnostics are beginning to present the regulators with products that are so much better than the existing gold standards, and they are really struggling with it. Currently, regulators reference information for a new diagnostic against clinical gold standard diagnostics. In the days of registering new x-ray and MRI products, that was quite straightforward. Now, molecular diagnostics can diagnose disease at an extremely early stage in a way that cannot be determined by any other process.

The only way to determine the sensitivity and specificity of the diagnostic is to confirm the diagnosis by following patients around for years. As an example, molecular diagnosis of early stage Alzheimer's disease appears to be on the horizon. But since the confirmation of a diagnosis of Alzheimer's disease is at autopsy, current clinical trials may take as long as a decade to prove the efficacy of the new diagnostics. That is and should be unacceptable to patients, families, regulators, and the diagnostic industry. Together, we must all work to find a new and better way to determine the clinical utility of diagnostics so that patients and physicians can access those exciting and potentially valuable new tools in a matter of a few years versus decades. However, that problem is neither new nor insurmountable.

The industry faced a similar issue in the mid 1980s when presented with the new antiretrovirals for HIV/AIDS. Initially, the regulators told the companies to conduct two- to three-year trials and look for clinical outcomes such as progression of AIDS or even death. But physicians and AIDS activists rightly said that wasn't acceptable. Working together, physicians, AIDS activists, the regulators-and the FDA was notable for its forward-looking approach-and pharmaceutical companies were able to design new and highly accurate ways to predict the safety and efficacy of new AIDS drugs. The result of that joint effort was a revolution in AIDS therapy development and in patient care. There must be a way that a similar group can come together to bring a revolution in molecular diagnostics.

Regulators, medical professionals, and patient communities need to have a joint debate about the risk/benefit ratio in diagnosing diseases earlier. Isn't it better to diagnose thousands and thousands of patients with the disease, and start them on treatment, than to wait ten years and find out that DaTSCAN is 94 percent rather than 97 percent sensitive? The same problem is happening with Alzheimer's disease. There are ways to diagnose the disease early, but we can't conduct a 12-year clinical trial. And the Alzheimer's Association (AA) doesn't want that either because it's not much use to patients or to the pharma industry to design clinical trials that will take 10-12 years, at which time patients may be dead.

What we hope to do with AA and others is to help them understand the problem: Most people focus on therapeutics, but diagnostics are important in finding patients and getting them on the right medicine. Yet information about diagnostics is not available. But not because regulators don't care about patients. They do. It is just a new era, and we need to find a better way to diagnose patients. Consider what it means to misdiagnose only one person out of 100 with a molecular diagnostic agent, when right now we know we misdiagnose one out of four with standard tests.


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