Industry shake-up shuffles leaders in ultrasound contrast media

The industry surrounding ultrasound contrast media has changed radically in the last few years. One-time leaders have vanished. Molecular Biosystems (MB), the maker of Optison, was acquired by Alliance Pharmaceutical. MB’s marketing partner, Mallinckrodt, sold Nycomed Amersham Imaging its marketing rights to Optison. Sonus Pharmaceuticals, which led a legal fight to enjoin the FDA from clearing Optison ahead of other products (including Sonus’ own EchoGen), has turned away from contrast media and is developing therapeutic oxygen and drug delivery systems.

Gone are the bluster and hype, the unbridled fervor, and the heady expectations that only a short time ago surrounded this marketplace, which many believed could generate tens of millions of dollars in revenue per year. In their place is an uneasy quiet, broken mostly by announcements of companies getting out or selling off once-prized holdings. The string of unhappy tidings was broken earlier this month, however, when DuPont Pharmaceuticals announced the FDA approval of its ultrasound contrast medium Definity for use in left ventricular opacification and endocardial border delineation.

With agency approval, DuPont is clear to begin marketing the product. This process will begin in the fourth quarter of this year. Pricing and other details of the commercialization have not yet been determined.

“We’re finalizing our plans and putting together the right teams of people,” said Dr. Peter Gardiner, vice president of medical affairs for DuPont’s cardiovascular and imaging products. “These are the types of things that you can’t do until you finally have approval.”

The product is not FDA approved for myocardial perfusion, which some industry observers believe is necessary for widespread adoption of ultrasound contrast media. The company might yet go for such labeling. In the meantime, executives have set their sights on territory within the reach but apparently not the grasp of its competitors.

The company noted-as have other vendors-the 17 million cardiac ultrasound tests performed annually in the U.S. and the 20% from which a definitive diagnosis cannot be made. These would be the most likely to benefit from Definity, which achieved a diagnostic echocardiogram in up to 91% of such cases in clinical trials prior to its FDA clearance.

At present, most of these patients go on to another modality, often nuclear cardiology. Other vendors have identified the echocardiography failures as a prime patient population for their product but for the most part have failed to convert. DuPont might be in a better position to succeed for several reasons.

First, Definity may be injected, like other ultrasound contrast media, or it may be infused intravenously, allowing the physician to titrate the dose until optimal results are achieved. There is a limit to how much can be infused. The FDA has set 1.3 mL added to 50 mL of preservative-free saline infused at a maximum rate of 10 mL per minute. The infusion time extends the imaging window beyond the standard seven-minute persistence of the product, after which the microbubbles dissipate and the imaging enhancement effect is lost, Gardiner said.

Second, the microbubble shells that constitute Definity are composed of lipids rather than the human or animal materials that make up the microbubbles of competing products. This virtually eliminates the risk of allergic reactions in patients, according to Gardiner.

Third, and perhaps most important, the company is established within the cardiology community as a premier vendor of cardiovascular imaging agents. Thallium has been a key heart-imaging radiopharmaceutical for 20 years. Cardiolite, composed of technetium-99m sestamibi, is widely used in nuclear cardiology. DuPont also markets IV Persantine, a vasodilator product used to mimic stress in heart function testing without requiring physical activity by the patient. From its position as a major provider of nuclear cardiology agents, DuPont might be able to forge a partnership between nuclear medicine and echocardiography based on technical capability and cost savings.

“We know that having a good product just isn’t enough,” Gardiner said. “We’re putting together a comprehensive approach to the contrast ultrasound market with what will be an unprecedented investment in education, technical support, and clinical research.”

While DuPont’s strategy of building on its expertise has remained unchanged since its development several years ago (SCAN 3/31/99), the character of the company has changed substantially-some would say for the better. Two years ago, DuPont was among the most contentious vendors in the industry, suing Molecular Biosystems for patent infringement and joining Sonus and others in suing the FDA to change the way it was reviewing Optison. (MB had filed a premarket approval application calling Optison microbubbles devices. The FDA eventually redirected the filing to its drug review branch.)

Today DuPont is anything but combative. Gardiner sidestepped questions about competitors, refusing to compare the attributes of Definity to competing agents. This change reflects an industry-wide evolution-the consequence of consolidation, maturation, and diminished expectations.

The race to be first to market was won in 1998 by Molecular Biosystems. But MB and partner Mallinckrodt failed to win commercial acceptance for Optison. Years of lackluster sales undercut the enthusiasm of would-be marketers of ultrasound contrast agents, some of which restructured or withdrew from licensing agreements with the developers of these agents.

DuPont is not one of these. The company has followed through on a long-standing commitment to ultrasound contrast, specifically Definity. DuPont in 1995 bought from Definity’s developer, ImaRx Pharmaceuticals, the rights to manufacture, market, and sell the product in North America, Latin America, and Europe (SCAN 12/13/95). Four years later the company bought the outstanding shares of ImaRx, bringing all activity associated with Definity under DuPont’s control (SCAN 10/27/99).

Since then Nycomed Amersham Imaging has emerged as the company to beat in ultrasound contrast. To settle a patent dispute with Mallinckrodt, Nycomed obtained in 2000 comarketing rights to Optison. On Aug. 6, Nycomed and Mallinckrodt agreed to terminate the comarketing agreement effective Dec. 31, clearing the way for Nycomed to assume worldwide marketing control of the product except in the Pacific Rim.

To effect its exit from the industry, Mallinckrodt paid $5 million to MB, a subsidiary of Alliance Pharmaceutical since December 2000. Mallinckrodt also agreed to pay royalties for a two-year period, according to a Form 8-K filed Aug. 8 with the Securities Exchange Commission. Details regarding the royalties were not released publicly. Originally, Mallinckrodt was to pay a royalty of 5% of net Optison sales in the U.S. and Europe.

Nycomed reduced its royalty obligations Aug. 6 by purchasing the ultrasound contrast media assets of Sonus Pharmaceuticals for $6.5 million. Nycomed had been saddled with those obligations in 1999 as part of a patent dispute settlement with Sonus. The company also obtained from Sonus a patent license agreement providing royalties from the sale of Optison by Chugai Pharmaceuticals in Japan, Taiwan, and South Korea. Sonus decided to leave the ultrasound contrast industry after losing its struggle to gain approval for its contrast agent, EchoGen, when the agency raised concerns in October about the product’s safety.

Both Nycomed and Alliance may be using Optison to establish and hold positions in the ultrasound marketplace until products in their own pipelines are ready for launch. Nycomed is developing a next-generation product called Sonazoid. Alliance is developing Imavist in conjunction with German company Schering, which is also believed to be developing its own advanced ultrasound media.

Ironically, just as many of the players in this theater have changed roles, so might DuPont Pharmaceuticals. In a $7.8 billion deal announced in June, DuPont agreed to sell its pharmaceuticals division to Bristol-Myers Squibb. The deal could close before the end of this year. The change in ownership, according to Gardiner, will probably not affect how Definity is marketed.

“Inasmuch as we have been allowed to share information at this stage prior to the deal closing, the people at Bristol-Myers Squibb have indicated their wish for us to move forward with the marketing of Definity,” he said. “It seems clear to us that they really value not only the people but the products that we bring to the table.”