Diagnosis of cardiovascular disease could become less costly and invasive if the alternatives to nuclear imaging and X-ray angiography that dominate the late-stage imaging agent pipeline live up to their promise (¹ see chart).

Two agents are vying to become the first ultrasound contrast agent approved for myocardial perfusion imaging: Acusphere's AI-700, with a projected 2006 NDA filing, and Point Biomedical's CardioSphere , with an NDA filing expected in the fourth quarter of 2005.

Contrast-enhanced ultrasound could expand access to routine myocardial perfusion screening for coronary heart disease. Ultrasound equipment is commonly available in hospitals and physicians' offices; nuclear stress perfusion, the standard for routine screening, is subject to high capital costs and extensive regulatory requirements attending use of radionuclides.

The definitive technology for detection of CHD, coronary angiography, is impractical for routine screening due to its cost and invasiveness.

Contrast-Enhanced Myocardial Perfusion Imaging

Acusphere's Phase III trials are designed to demonstrate non-inferiority to nuclear stress testing for stress echocardiography enhanced by the synthetic perfluorocarbon gas-filled microparticle imaging agent AI-700. The company expects to complete Phase III enrollment in early 2006.

Acusphere estimates that contrast-enhanced ultrasound would cost $200 per procedure, compared with approximately $770 for a nuclear stress test, and would take half an hour instead of around five hours.

Point Biomedical's Phase III trials for the nitrogen-containing ultrasound contrast agent CardioSphere showed statistical non-inferiority to nuclear imaging: sensitivity ranged from 63% to 75% for Cardiosphere-enhanced ultrasound and 64% to 76% for nuclear stress testing, with specificity of 48%-60% for CardioSphere and 53%-78% for nuclear stress testing.

Ultrasound contrast agents have yet to prove commercially significant. Acusphere maintains that approved agents have "limited clinical utility" because they are indicated for image enhancement in resting echocardiograms. "Less than 20% of all resting echocardiograms require a contrast agent for resting wall motion assessment," according to Acusphere.

Myocardial perfusion imaging using pharmacologic stress agents with nuclear imaging is more established. Astellas, which sells the current market leader Adenoscan (adenosine), has teamed with CV Therapeutics on the more specific A2A adenosine receptor agonist regadenoson; an NDA is planned for 2006 (² Pharmaceutical Approvals Monthly May 2005, p. 12).

King/Aderis' binodenoson (in Phase III) and Bristol-Myers Squibb/Adenosine Therapeutics' BMS-068645 (in Phase II) also act on the A2A receptor.

Magnetic Resonance Angiography

Magnetic resonance angiography is emerging as a less-invasive alternative to X-ray angiography. While existing gadolinium-based imaging agents are used off-label for MRA, new blood pool contrast agents offer a longer resonance window.

The first NDA seeking an MRA indication - Schering AG/Epix' gadolinium-based MS-325 (gadofosveset) - has a user fee deadline in November for diagnosis of peripheral vascular disease (³ Pharmaceutical Approvals Monthly June 2005, p. 5).

Schering AG also is conducting Phase III trials of its iron-based MRA contrast agent SHU-555C (ferucarbotran). Advanced Magnetics' iron-based blood pool agent ferumoxytol is in Phase II for MRA.

Meanwhile, Guerbet is preparing for a U.S. submission of its flagship European MRI contrast agent Dotarem (gadoterate); the firm projects a 2007 U.S. launch. Dotarem, a non-specific gadolinium-based agent, is well-suited to MRA, according to the company.

Guerbet had been developing a novel agent, Vistarem (gadomeritol), for MRA, but suspended the program in favor of Dotarem because Dotarem's market experience could shorten the timeline for MRA approval, the company said.

Rocky Regulatory Road For Molecular Imaging?

Four new molecular entities or novel biologics have been approved as contrast agents since 2000, with an average review time of 40.8 months.

Both of the novel ultrasound contrast agents to debut since the turn of the millennium took over two years to clear FDA - ImCor's no-longer-marketed Imagent in 2002 after 31.6 months and Bristol's Definity after 31.7 months in 2001. Bracco's central nervous system MRI contrast agent Multihance was approved in 2004 after 43.8 months.

FDA review of the molecular imaging agent NeutroSpec took 56 months. The Palatin/Mallinckrodt radiolabelled anti-CD25 monoclonal antibody, which binds to neutrophils, was approved in 2004 for diagnosis of equivocal appendicitis with scintigraphic imaging.

Molecular imaging, or the use of new molecular agents with traditional imaging tools to picture specific molecular pathways in the body, has been enthusiastically promoted as the next step beyond anatomical and functional imaging, but the NeutroSpec experience illustrates the challenges of being an early entrant into an emerging field.

Cytogen submitted an NDA for its pending molecular imaging agent for MRI, Combidex, in December 1999. If approved for differentiation of cancerous and non-cancerous lymph nodes in cancer patients at risk for lymph node metastases on its upcoming user fee deadline in November, the almost six-year review would surpass NeutroSpec's in duration.

Combidex has been "approvable" twice and was not recommended by an FDA advisory committee concerned about the generalizability of data across tumor types (⁴ Pharmaceutical Approvals Monthly April 2005, p. 11).

Boston Life Sciences is trying to reduce the regulatory risk for its molecular imaging agent Altropane by obtaining a special protocol assessment from FDA (for more coverage of the SPA process, see related story p. 3). Altropane is a radiolabelled agent that binds to dopamine transporter protein and is used with SPECT imaging to aid in differentiation of Parkinsonian Syndrome from non-Parkinsonian tremor.

In August, the company revised the Altropane SPA, replacing one large trial with two smaller Phase III trials and reducing the statistical endpoint threshold from p<0.02 to=""><0.05. the="" original="" spa="" was="" reached="" in="" spring="" 2004="" after="" eight="" months="" of="" negotiations="" with="" fda="" to="" refine="" the="" trial="" design="">⁵ Pharmaceutical Approvals Monthly April 2004, In Brief).

The high profile of molecular imaging is likely to propel development of regulatory standards.

FDA's critical path initiative is looking at molecular imaging as an important drug development tool, and NIH began seriously funding research in the 1990's. The National Cancer Institute's Cancer Imaging Program (established in 1996 as the Diagnostic Imaging Program) has a branch devoted to molecular imaging.

Industry is betting on the commercial viability of molecular imaging, and investment by major imaging device players is bringing added resources.

GE Healthcare explained its $9.5 bil. acquisition of Amersham in 2003 as an opportunity to accelerate development of molecular imaging. Siemens purchased CTI Molecular Imaging in March for $1 bil. and has combined CTI with its nuclear medicine business to create a molecular imaging division.

Earlier this year, GE also paired with Stanford to develop new molecular imaging technology and Philips entered a collaboration with Kereos and Washington University to develop molecular imaging agents for oncology and cardiovascular disease. Kereos' early-stage molecular imaging agent for cardiovascular MRI is licensed to Bristol-Myers Squibb.

Advanced Contrast Agents Aim To Improve Cost, Convenience Of Cardiac Imaging

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