Company nears market with Definity contrast agentDu Pont Pharmaceuticals is moving into new territory with the imminent commercialization of its first ultrasound contrast agent, Definity. But the North Billerica, MA, company should not be treated
Company nears market with Definity contrast agent
Du Pont Pharmaceuticals is moving into new territory with the imminent commercialization of its first ultrasound contrast agent, Definity. But the North Billerica, MA, company should not be treated as a newcomer to the market. Du Pont has for decades been the dominant firm in the cardiac radiopharmaceutical market, and hopes to take advantage of that experience as it moves Definity into the echocardiography segment.
Du Pont submitted Definity for Food and Drug Administration review on Dec. 9, seeking approval for the use of the agent to assist in left ventricular opacification and endocardial border delineation. Company executives believe the product is still at least nine months from approval. On the horizon are radiology applications for Definity, as well as myocardial perfusion, the Holy Grail of ultrasound contrast.
Traditionally, Du Pont has been a provider of imaging agents for nuclear medicine. Its two key products are radiopharmaceuticals for cardiac assessment: thallium, which has been on the market for 20 years, and Cardiolite, which is composed of technetium-99m sestamibi. Du Pont also markets I.V. Persantine, a vasodilator product used to mimic stress in heart function testing without requiring physical activity by the patient.
Viewed from a different perspective, however, Du Pont is remaining close to its core expertise, as the primary uses of Definity will be in cardiology. The company's established distribution channels and proven ability to sell products in the cardiology community could be the edge it needs to succeed with ultrasound contrast.
"We know what is necessary to develop markets in cardiac imaging," said Susan Nemetz, vice president of contrast imaging. "We expect to be a leader in ultrasound contrast. We know we can put the right things together."
Ultrasound contrast agents have yet to achieve the commercial success predicted by many industry observers. Optison, the most recent agent to hit the market, has not been adopted as quickly by U.S. customers as its developer, San Diego-based Molecular Biosystems, had hoped. Optison sales by MBI's marketing partner, Mallinckrodt of St. Louis, have fallen short of expectations, causing MBI to cut back on staff and attempt to cut expenses by outsourcing manufacture of the agent (SCAN 11/25/98).
Nonetheless, Du Pont executives are optimistic that Definity will avoid a similar fate, due to what the company believes are inherent advantages of the agent. Definity differs from competing products in that it is composed of neither human nor animal materials; rather, the shells that form its microbubbles are composed of lipids.
"Some people believe that our shell will be responsive in a unique way to ultrasound equipment, so that it will have a positive effect on image quality," Nemetz said. "Also, the way the bubbles are made up perhaps will allow infusion of the agent."
Most published work with contrast agents has involved boluses or mini-boluses, Nemetz said. These injections have the disadvantage of providing only a short window for imaging, which is preceded by attenuation due to a high concentration of bubbles. The imaging window is then followed by fall-off in image quality resulting from dissipation of the bubbles. Infusion promises to avoid these problems by providing a steady flow of bubbles. The effect would be to expand the window during which contrast-enhanced imaging is possible. That could prove especially helpful in myocardial perfusion imaging, a still-evolving capability, Nemetz said.
Definity was originally developed by ImaRx Pharmaceuticals, the Tucson, AZ, company that also developed SonoRx, an ultrasound agent approved by the FDA last November. SonoRx is now being marketed by Bracco Diagnostics of Princeton, NJ, for use in upper abdominal sonography (SCAN 11/11/98). In 1995, Du Pont bought from ImaRx the rights to manufacture, market, and sell Definity in North America, Latin America, and Europe (SCAN 12/13/95).
Radiology applications are also being sought for the product, specifically for abdominal imaging. As a result, if the submission passes FDA review for all indications, Definity will be the first ultrasound contrast agent approved for cardiology and radiology applications, giving Du Pont an advantage over its competitors.
Winning acceptance. Nemetz believes that Definity will gain FDA approval without experiencing the problems encountered by Sonus Pharmaceuticals of Bothell, WA. Sonus' application to the FDA for its EchoGen contrast agent has languished for over a year because of lingering questions about the technology and collection of clinical data. Responses from the FDA regarding Definity indicate that the agency is moving forward quickly with the review, she said.
But even if Du Pont gains the FDA's go-ahead, a formidable challenge remains: winning acceptance for Definity by mainstream ultrasound practitioners. That is where the second part of the Du Pont equation comes in, at least in cardiology, where the company has a long history. It plans to position Definity as an enabling technology for echocardiography, spearheading the invasion of clinical turf now held by nuclear medicine.
But rather than battling nuclear medicine head on, Du Pont has the opportunity to address the strengths of the two modalities as they develop, in terms of both technical capability and reimbursement, possibly forging a complementary fit for the two imaging modalities.
Phase III clinical data from more than 200 patients support the effectiveness of Definity for its initial applications in left ventricular opacification and endocardial border delineation. But the true potential of the agent will not be realized until myocardial perfusion is proven, Nemetz said. Early results presented this month at the annual meeting of the American College of Cardiology indicate that Definity may eventually support this examination. In a phase II trial with 17 patients, investigators found that Definity enabled assessment of myocardial blood flow at rest, when using gated power harmonic Doppler.
Definity will have competition in the echocardiography arena. Optison addresses left ventricular opacification, as well as endocardial border delineation, and EchoGen will eventually reach the market, in spite of its recent problems. Optison and other agents might also eventually support myocardial perfusion. In the end, the winner will be the company that can effectively convince physicians to choose ultrasound over competing modalities. Du Pont hopes to win the trust of physicians by offering choices that will be best for the patient.
"Rather than focusing on getting a better picture, we believe it's very important to focus on enhancing patient management," Nemetz said. "Our approach on the nuclear cardiology side and now on the ultrasound side is to understand how pictures change the way a patient will be managed."