Multinational vendors invest in molecular imaging

March 14, 2004

A new die has been cast in the development of molecular imaging. Historically, discoveries leading to new modalities such as PET and MR were made in university laboratories endowed by private donations and government grants. They were guided toward clinical readiness by entrepreneurial start-up firms, sometimes associated with the technology's inventors, and often financed with venture capital. Mainstream medical device companies got involved only when it became clear that commercially bankable products were sure to emerge.

Although these mechanisms can be seen fostering molecular imaging's development, GE Medical Systems, Philips Medical Systems, and Siemens Medical Solutions have made commitments to MI at an early stage in its development. They are developing internal MI research-and-development capabilities, collaborating with academic and private laboratories, allying with large pharmaceutical companies in drug development projects, and supporting educational efforts to teach radiologists about MI.

"The promise of molecular medicine is undeniable," said Joseph M. Hogan, president and CEO of GE Medical. "In the years to come, we envision a healthcare system that uses molecular medicine to diagnose and treat patients before symptoms appear and treatments that are tailored to an individual based on his or her genetic makeup."

GE established a molecular imaging division in 2000 and included its former nuclear medicine group under that umbrella. By mid-2003, the internal biotechnology research program had become the largest single research effort at GE's global research center in Schenectady, NY, according to Steven R. Bolze, vice president, Amersham integration. The laboratory employs dozens of scientists, including engineers, physicists, computer scientists, biochemists, molecular biologists, and synthetic chemists. In addition to cross-sectional imaging research, the group is investigating optical imaging technologies and biochemical probes. As of November 2003, the laboratory had applied for more than 30 patents.

"They are focused mainly on discovery of novel biomarkers covering the biggest clinical unmet needs in cardiovascular disease, cancer, and neodegenerative diseases such as Alzheimer's disease," Bolze said.

In 2002, GE began working with Amersham Health, a prominent commercial force in the radiopharmaceutical industry, to develop automated radiopharmaceutical synthesizers. As partners, the two firms produced a new cartridge-based approach that combines radioisotopes refined in a GE cyclotron and targeting agents provided by Amersham. The effort led to synthesis boxes that manufacture fluorine-18 FDG and an L-dopa SPECT agent approved in Europe and Asia for monitoring Parkinson's disease.

AMERSHAM BUYOUT

The partnership preceded GE's $9.5 billion acquisition of Amersham in October 2003. GE CEO Jeffrey Immelt attributed the buyout directly to GE's molecular imaging strategy. It reflects the company's vision of earlier disease detection and treatment fostered by the combination of imaging devices and pharmaceuticals geared to specific molecular pathways.

With annual sales of $1.7 billion, Amersham controls 35% of the global imaging contrast agent market. Its biosciences division produces cell analyzers, gene separators, and other products that could help GE sell imaging equipment to pharmaceutical manufacturers as they rely more on preclinical, small-animal imaging for investigational drug testing, Bolze said.

"To improve our understanding of diseases and their relationship with genetic pathways, we need a wealth of chemistry and biology knowledge and some of the core technologies that can be found in Amersham's biosciences business," he said.

GE's joint research agreement with GlaxoSmithKline illustrates how such collaborations can work. The partnership, formed in 2001, aims at developing imaging strategies for staging chronic obstructive pulmonary disease (COPD) and techniques to measure patients' response to COPD therapies. Among the latter are GSK's Advair Diskus, an agent approved in the U.S. and many European and Asian countries for treatment of asthma and chronic bronchitis. Investigational CT protocols developed by GE potentially allow physicians to evaluate the state of COPD and measure its progression, said Michael T. Klimas, Ph.D., manager of GE pharmaceutical programs.

SMALL-ANIMAL IMAGING

GE's involvement in preclinical small-animal imaging and optical imaging has enhanced its role in drug development, said J. Eric Stahre, general manager, genomics and molecular imaging. In November 2002, GE acquired Enhanced Vision Systems, a micro-CT scanner company in Ontario, Canada. A year later, it secured exclusive distribution rights for a small-animal PET scanner built by Suinsa in Madrid, Spain. It also established a strategic alliance with Advanced Research Technologies for its SoftScan optical breast imaging systems.

In developments associated with human trials, GE announced in November 2003 that it had accepted an invitation to participate with the National Cancer Institute in a multicenter trial of F-18 fluorodeoxythymidine (FLT), a PET radiopharmaceutical agent that measures cell proliferation. GE will supply five sites with synthesis equipment to produce FLT for the trial and with data processing assistance to track results.

GE's academic collaborators in molecular imaging include Albany (NY) Medical Center, Dana-Farber Cancer Institute, Fox Chase Cancer Center, Johns Hopkins Medical Institution, M.D. Anderson Cancer Center, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and the University of California, Los Angeles Crump Institute for Molecular Imaging.

GE has worked with the Crump Institute on molecular imaging educational programs for community-based radiologists since March 2002. Fourteen lectures on MI-related topics are available via streaming video on the Crump Institute Web site (www.crump.ucla.edu).

PHILIPS EMPHASIZES HOT PROJECTS

Philips has concentrated on hot investigational technologies that are on the fast track to clinical implementation. Whenever possible, Philips associates these innovations with SPECT products, which are among its strengths. The ratio of five SPECT systems to every PET system in the field encourages Philips to support molecular imaging projects that deliver the greatest good to the most patients.

Philips places the advancement of its clinical platforms first among its priorities in molecular imaging, said Peter Luyten, director of molecular imaging. The Skylight SPECT system equipped with Jet Stream acquisition software has been repositioned as a good MI platform because of its ability to acquire 16 data sets simultaneously. Astonish software provides advanced attenuation and scatter correction and the ability to fuse SPECT and CT images acquired on separate scanners.

Philips supports two preclinical imaging initiatives. It introduced small-animal CT and PET systems and is working on a small-animal SPECT platform. In addition to emphasizing SPECT-related projects, it supports MI research performed on its dedicated PET/CT and investigational x-ray/PET systems.

The company has established research partnerships with three technology incubator firms. Under a three-year NCI contract, Philips is working with Kereos, a small R&D company with ties to the molecular imaging research program at Washington University in St. Louis, and with Dow Chemical to develop target-specific nanoparticle radiopharmaceuticals and contrast agents. Washington University and Kereos researchers developed variations of their nanoparticle model loaded with gadolinium for MR imaging and either indium-111 or technetium-99m for SPECT imaging. Because nanoparticles are inherently echogenic they can also be used as an ultrasound contrast medium.

Dow Chemical was recruited in April 2003 to formulate a more stable version of the Tc-labeled agent, said Dr. David Rollo, Philips' medical director. Nanoparticles have shown promise for imaging fibrin in atherosclerotic thrombi and plaques.

With help from University of Colorado researchers, Philips has concentrated on developing pinhole collimation and reconstruction algorithms to eliminate scatter associated with Kereos's nanoparticles.

"It is one thing to create a targeted molecular agent," Rollo said. "It is quite another to produce a picture with it. That's why collaborations between device companies and pharmaceutical companies become so critical."

CELLPOINT COLLABORATION

With start-up firm Cellpoint in Houston, Philips is helping develop a SPECT agent based on ethylenedicysteine (EC) drug conjugate technology. EC is a universal linker that can bind Tc-99m to deoxyglucose, producing a SPECT variant of FDG-PET.

Philips is working with Cellpoint on a new radioimmunotherapy strategy that potentially could compete with Zevalin and Bexxar, the two FDA-approved radioimmunotherapies for patients with relapsed or low-grade B-cell recurrent non-Hodgkin's lymphoma. Cellpoint researchers propose using a combination of Tc-99m-EC-deoxyglucose to test the agent's localization properties in individual cases and rhenium-188, a beta emitter, for actual treatment. In preclinical development, the new combination could gain popularity because technetium and rhenium are inexpensive and can be generated wherever they are administered, Rollo said.

Philips is also working with Theseus, a Boston-based developer of Tc-99m-hynic-annexin-V (Apomate), a promising molecular agent that identifies concentrated sites of apoptosis associated with cancer therapy, myocardial infarction, and atherosclerotic plaques.

And Philips has supported educational initiatives to help radiologists understand molecular imaging. It sponsored two Internet-based teleconferences last year, one designed for a North American audience and the other for Europeans. The company is involved in academic collaborations with Cornell University, the University of California, San Francisco, the University of Iowa, the University of Pennsylvania, Washington University, and Memorial Sloan-Kettering.

SIEMENS GAINS FOOTHOLD

Siemens has been less visible than GE or Philips in educating its customer base about molecular imaging or in publicizing its progress toward establishing a research and development foothold in this field. The multinational company in Erlangen, Germany, however, sees huge potential in molecular imaging to increase healthcare quality and reduce healthcare costs, said Dr. Mohammed Naraghi, senior vice president of global business development.

Siemens Medical Solutions has positioned itself as an integrated healthcare solutions provider. It is pursuing opportunities to apply lessons from the genomic revolution to every aspect of healthcare, including disease prevention, diagnosis, and treatment, Naraghi said.

"There is a huge potential to identify and diagnose diseases earlier by leveraging the level of specificity possible with molecular imaging," he said.

Siemens created a molecular imaging unit in 2003. The firm's global business development group, led by Naraghi, is coordinating the effort.

Internally, Naraghi established an interdivision organizational matrix involving business unit heads from nuclear medicine and MR and from strategic business development groups to devise a molecular imaging strategy. Externally, Siemens has concentrated on collaborations with academic research sites and start-up companies to advance its cause.

Even before the MI unit coalesced, the company scored a major success last June by forming a long-term R&D relationship with Dr. Ralph Weissleder's Center for Molecular Imaging Research at Massachusetts General Hospital. The collaboration will involve applications in oncology and inflammatory disease processes, Naraghi said.

Siemens will supply the CMIR with a new high-field MR system, a PET/CT scanner, and optical imaging capabilities. Advanced informatics technology designed by Siemens to quantify, process, and display molecular and proteomic imaging data is an important component of the mix. Cash payments and access to onsite Siemens scientists and engineers were also part of the deal, he said.

Several developments followed the CMIR announcement. In July, Siemens attained exclusive U.S. marketing rights to X-SPECT, a small-animal SPECT system built by Gamma Medica in Northridge, CA. On Aug. 7, Siemens secured an equity position in Visen Medical. The small company is developing smart contrast agents for optical imaging for human and animal models. And later in August, it introduced the Bonsai, a fluorescence optical scanner developed by Siemens engineers in Erlangen.

Collaborations are central to Siemens' MI strategy, according to Naraghi.

"We at Siemens strongly think in terms of partnerships. We don't want to do everything ourselves, and we don't think that it makes sense to do everything ourselves," he said.

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