To shadow an unsuspecting drug dealer, wire his car with anelectronic beeper. But if the quarry is cholesterol, capture itwith radioactive lipoprotein peptides at the scene ofatherosclerotic plaque.
So says Diatech Inc. of Londonderry, N.H., which will announcetoday Phase I clinical trials of its plaque-tracking, isotope-imaging synthetic oligopeptide, P215.
This seeing-eye-dog molecule is a modified 17-amino-acidsegment that guides low-density lipoproteins (LDLs) and theircargo of plaque-building cholesterol to disease sites on thewalls of arteries. Instead, P215 delivers scannable radiation.
Robert S. Lees, a co-founder of Diatech, developed theprocedure for sequencing and synthesizing P215, and linking itto 99meta-Technetium (99mTc), a radioisotope much used innuclear medicine imaging. New England Deaconess Hospital inBoston licensed the technology to Diatech.
In animal studies leading up to the impending trials, thepeptide radiopharmaceutical accumulated at the healing edgesof regenerating endothelial cells on the inner walls of rabbitaorta that had been scraped clean by balloon-catheterization.
Patient recruitment has already begun at Mt. Sinai MedicalCenter in New York, one of the three tertiary hospitals planningthe Phase I clinical trials of 99mT-P215. New York Hospital-Cornell Medical Center and Boston's Massachusetts GeneralHospital, are expected to join in the next few weeks, Richard T.Dean, Diatech's president and chief executive officer, toldBioWorld.
"Although technically Phase I trials, to gauge safety and dosagelevels," Dean explained, "these are also in effect Phase II, aspatients suffering from atherosclerosis will get whole-bodyimaging for plaque by injection of the lesion-seeking P215peptide linked to the imaging 99mTc isotope."
Each participating center will enroll six subjects, most withsevere carotid-artery disease, a major cause of cerebral stroke,when fragments of plaque break off and block blood flow tothe brain.
Cardiologist Jeffrey S. Borer, who will conduct the trials atCornell Medical Center, told BioWorld that test patientsscheduled for carotid endarterectomy will be imaged with the99mTc-P215 package before and after surgeons slit open theirclogged arteries and remove the plaque. "That way," heexplained, "we can compare the images directly with theexcised lesion and see exactly where the peptide is taken up.Our purpose," he added, "is not merely to identify the targettissue, but to interpret the results for clinical managementdecisions."
Borer noted that there is no existing method for imagingatherosclerosis.
Asked about Cytogen Corp.'s OncoScint, the monoclonal-antibody-based imaging agent, which won FDA approval latelast December for visualizing colorectal and ovarian tumors,Borer cited "inherent problems with antibodies." Because oftheir large molecular size, he pointed out, they would have todeliver an excessive amount of radioactivity.
"That's the beauty of using a small peptide such as P215, whichis a molecule only one-fiftieth or one-hundredth the size of amonoclonal, so it delivers correspondingly less radiation. Andat 2,000 kilodaltons of molecular mass, it clears the bodyreadily.
"Another nice thing: The peptide is easily manufactured bychemical synthesis."
But Borer emphasized that "how effectively P215 will imageplaque in practice can be determined only by clinical trials." Heconcluded, "Its efficacy remains to be seen -- literally."
Dean cited "emerging medical opinion that atheroscleroticplaques alone are not the culprit in cardiovascular disease. Anunstable plaque can rupture and induce a thrombus, or clot,which grows to occlude the artery. That is why tissue clot-busting plasminogen activator and streptokinase work, whythrombus-preventing aspirin is so useful. P215 imaging tellsthe difference between stable and unstable plaques."
Cost factors, too, are "highly favorable," Diatech's CEO declared."Our peptide costs less than half of a monoclonal antibody.OncoScint, for example, is priced at $700 to $800 per dose,compared with P215 at $200."
As its first product enters the clinic, Diatech is going back to themoney market, said its vice-president and chief operatingofficer, Hersch Petrocelly. "We're in the dog-and-pony-showphase," he told BioWorld, looking for $10 million in pre-IPOmezzanine financing." With only $1 million in the bank --residue of two earlier funding rounds that brought in $7.2million in 1990 and 91 -- Diatech needs the new funding to getits first product into Phase III clinical trials.
"We hope to close this round in mid-March," Petrocelly said.
Other peptides on the company's drawing board will imagethrombi, tumors and infections. For the first of these, Diatechhas concluded a deal with Genentech Corp. to screen the lattercompany's anti-thrombus agents.
Another alliance, with Biomeasure Inc. of Hopkinton, Mass., willgive Diatech access to their peptide library and animal modelsfor tumor imaging. Biomeasure is the U.S. subsidiary of a largeFrench company, Ipsen-Beaufour of Paris, which has a $600million turnover in therapeutic drugs "If we select theirpeptide," said Dean, "by the mid-1990s, we can look forward toproduct copromotion by both our sales forces of theirtherapeutic and our imaging agent."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.