Angiogene has sparked concerns about the safety of its human testing of a method to keep coronary arteries clear. Was the exposure too large?
DON MACDONALD THE GAZETTE [ 15 Feb. 2003, BUSINESS SECTION ]
A Montreal biotech company that has attracted the support of some of Canada biggest investors has raised concern among medical experts over the safety of a radioactive therapy it used in experiments on human subjects.
Angiogene Inc.'s longest- standing research effort has been aimed at developing thera- pies to prevent the reblockage of coronary arteries once they have been cleared by means of a common medical procedure known as balloon angioplasty.
This research involves the use of a radioactive compound, which the firm has patented under the striking trade name Oliglow.
Investors certainly seem to like what they've seen of the company's track record - not only in its research into combating the reblockage of arteries but al- so in separate programs aimed at developing treatments for cerebral aneurysms and conges- tive heart failure.
Angiogene has so far attracted $18.5 million Rom such investors as a Royal Bank of Canada venture-capital fund, the Caisse de depot et placement du Quebec and the Quebec Federation of Labour's Solidarity Fund.
The company says it will be looking for more private financing this year and eventually would like to issue shares in an initial public offering.
But medical experts inter- viewed by The Gazette raised doubts about the market potential of Angiogene's approach for treating coronary arteries and about the long-term health effects of a procedure the company tested in 2001-02 on human subjects.
These experts questioned Angiogene's use of a radioactive compound, given the existence of other therapies for reblockage of arteries that do not involve the release of a radioactive substance into the body.
Angiogene's research holds out the prospect of not only helping patients with a life-threatening condition but also tapping into one of the hottest markets in medicine today. By some estimates, it will be worth more than $5.5 billion U.S. annually by mid-decade.
Angioplasty, a procedure in which a balloon is inflated in an artery to dear a blockage, is successful in 90 per cent of cases in restoring blood flow to the heart.
But in30 to 40 percent of those cases, the artery renarrows because of tissue growth - a condition known as restinosis. In previous research, radiation has been shown to be an effective tool in combating restinosis because it prevents the growth of cells.
In November 2001, Angiogene announced it was going ahead with trials on humans of a restinosis-fighting procedure that involved the injection of the Oliglow compound directly into the wall of patients' comnary arteries with a device called an infiltrating catheter.
The experiments received the blessing of Health Canada, the firm's own scientific-advisory board and the ethics committee at the Centre hospitalier de 1'Universite de Montreal, where Angiogene maintains its laboratories. The trials were given the green light by the authorities on the basis of extensive preclinical experiments that Angiogene had carried out on several species of animals over three and a half years, the firm says.
In all, six patients were treated to prevent restinosis before Angiogene discontinued its infiltrator-based program last June.
The man who founded Angiogene in 1997, Dr. Guy Leclerc, said the experiments were halted for reasons that had nothing to do with safety. Indeed, he maintained the results obtained from the six patients were excellent from a safety point of view. They have been submitted to Health Canada and are to be scientifically published, probably this year.
But a medical physicist at the McGill University Health Centre, Dr. Christian Janicki, has publicly raised questions about the amount of radiation released into patients in the infiltrator trials on human subjects.
In a paper delivered to an academic conference last summer and at a recent talk at the Montreal General Hospital, Janicki said he calculated that Angiogene's experiments on human subjects would have resulted in an important dose of radiation to vital organs.
Other experts in nuclear medicine told The Gazette that doses of the size calculated by Janicki wouldn't damage the organs but could be of concern because of an increase in the long-term disk of developing cancer.
In his talks at the Montreal General Hospital last month, Janicki said he had calculated a dose of radiation in the range of 1 Grey would have been delivered to the spleen and about half that much to the kidneys of the people treated by Angiogene.
A leading expert in nuclear medicine describes 1 Grey as "a big dose" equivalent to about 50 CT scans.
Such a dose would increase the probability of radiation-induced cancer 10 to 25 years later, said Dr. Fred Mettler, former chairman of the radiology department at the University of New Mexico Health Sciences Centre and author of several books on nuclear medicine.
Mettler told The Gazette in an interview that the age of the patients, the fact they are suffering from a serious heart condition and the potential efficacy of the treatment would be important factors in determining whether the risk of cancer was acceptable.
But Mettler said: "I would want to make sure that the therapy was going to be a lot better than anything else available, given the size of the radiation dose."
Leclerc, for his part, disagreed with Janicki's conclusions about the size of the dose to patients' organs. But he said he could not divulge data from the study in advance of scientific publication.
Leclerc, 43, insisted Angiogene had done its homework before the human trials by carrying out extensive research on animals to ensure that the radiation dose was safe and this data had been reviewed by the authorities.
"The very first goal of (the human trials) was to study security, toxicity - safety outcomes," said Lederc, who besides being Angiogene's chief scientific officer is an interventional cardiologist at Notre Dame Hospital. "I can tell you we were extremely satisfied with the outcome."
Leclerc acknowledged there could be a "minimal" increase in the long-term risk of cancer to patients from the procedure, but compared this risk to the one associated with routinely administered nuclear diagnostic tests.
But a leading U.S. medical physicist interviewed by The Gazette questioned the radiation dose, given his basic doubts about the usefulness of Angiogene's experiments with the infiltrator device.
Dr. Howard Amols said in an interview that research had previously demonstrated that it's extremely difficult to measure the radioactive dose administered with an infiltrating catheter. "There have been other attempts to use radioactive liquid infusion, and as far as I know, it's virtually impossible to predict or even determine after the fact where the liquid went and what the dose to the tissue really is," said Amols, head of clinical physics at the Memorial Sloan-Kettering Cancer Centre in New York. "The chances of it being absorbed uniformly within the tissues you want to treat, I think, are extremely remote."
Leclerc said Angiogene discontinued its trials with the infiltrating catheter to concentrate on its program to deliver the Oliglow by way of a stent, a device now used in more than 80 per cent of all angioplasty procedures. A stent is wire-mesh scaffolding that is inserted into the artery after balloon angioplasty to prop it open.
Angiogene is now experimenting with a stent that is coated with Oliglow. The radioactive preparation is released over time or "eluted," into damaged arteries. Currently, the company is testing its product in animals and is looking for a partner to finance human trials.
But here again, several experts expressed skepticism about Angiogene's research on the grounds that stents that release non-radioactive drugs have shown spectacular results in clinical trials and are nearing approval by the U.S. Food and Drug Administration. One such stent has already been approved for use in Canada.
The availability of effective non-radioactive therapies makes it unlikely that Angiogene's product would gain acceptance by cardiologists, said Dr. Mark Eisenberg, an interventional cardiologist at the Jewish General Hospital.
"Nobody likes to have radiation. We don't know what the long-term implications of having radiation are. Not in the coronary arteries, we don't know," Eisenberg said. "We can't do our procedures without radiation. But we don't want to have additional radiation." Eisenberg said recent results for conventional drug-eluting stents have been extremely positive. Researchers have found they can reduce restinosis rates to less than 10 per cent.
Angiogene executives respond that they believe their stent - which would deliver a much smaller dose of radiation to the organs than the infiltrating-catheter technique - might be able to produce better results than conventional drug-coated stents in one particular
niche - hard-to-treat cases of restinosis where, for example, the damaged area of the artery is heavily calcified. Limited clinical trial results have shown lower effectiveness for drug-eluting stents in these types of situations.
Still, experts interviewed for this story said it's unclear to them how an Oliglow-coated stent would be any more effective than a drug-eluting stent on hard-to-treat arteries. Angiogene CEO François Bergeron said in an interview the firm's restinosis research is far from its only pursuit. He said the company has produced excellent results in animal tests for a therapy for treating cerebral aneurysms using a radioactive device and is putting increasing emphasis on this program. A third research program aims to use a combined gene and cell therapy to improve the cardiac function of patients suffering from congestive heart failure as a result of a heart attack.