TUESDAY, Oct. 5, 2004 (HealthDayNews) -- A trial for what appeared to be a promising new therapy for Parkinson's disease has been halted, although researchers haven't given up hope that the drug will one day prove useful.
The announcement, made Oct. 5 at the American Neurological Association annual meeting in Toronto, included details of the failure of biotechnology company Amgen's first trial of GDNF (glial-derived neurotrophic factor).
At the very least, the fate of the drug shows just how difficult and involved the search for new therapies can be, experts said.
"This kind of work is very hard. No matter how much promise we have in the laboratory, it's never a guarantee of success in patients," said Dr. Michael Kaplitt, director of stereotactic and functional neurosurgery at Weill Cornell Medical College in New York City. He was not involved with the trial.
At the same time, Kaplitt and others don't believe this is the end for GDNF.
"We don't know what this means," said Dr. Anthony Lang, head of the writing committee for the study and director of the movement disorders center at Toronto Western Hospital in Canada. "There was a great deal of hope for GDNF and there still is a great deal of interest" in finding different ways to provide it to the brain.
Parkinson's disease results when brain nerve cells that produce the neurotransmitter dopamine die or somehow stop functioning fully. Dopamine is involved in the functioning of the body's muscles. When the brain no longer produces enough dopamine, Parkinson's symptoms appear, including tremors and balance and speech problems.
Scientists felt that GDNF might be able to prevent the cells from dying. "It was considered a very promising area of neurorestoration therapy," said Amy Comstock, executive director of the Parkinson's Action Network in Washington, D.C.
A preliminary study seemed to bear out these hopes. A small group of patients in Bristol, England, who were given a synthetic version of GDNF did experience improvements in their symptoms. The study was an "open-label" one, meaning the patients knew if they were taking GDNF or a placebo. As a result, the trial did not carry as much weight as a double-blind, placebo-controlled study. Researchers could not rule out the possibility that the "placebo effect" had been responsible for some of the improvement.
Indeed, the next study, a double-blind, placebo-controlled trial of 34 Parkinson's patients, indicated GDNF was no better than a placebo. There was one small ray of hope, however.
"The only positive that came out of that was that PET [brain imaging] scans did show an improvement at the site where the infusion was being made in a very similar fashion than that had had been described in patients in England," Lang said.
But other problems with GDNF soon appeared. Toxicology reports from two monkeys that had received higher doses of the drug showed abnormalities in the cerebellum region of the brain. That prompted the company to halt another open-label trial.
In addition, four patients in the double-blind study developed antibodies to GDNF.
"The concern now is that we have patients who have an immunologic response to a normal protein that would be in their brain and we don't know what the consequences might be," Lang said. "It might be nothing. On the other hand, it might be that in the long term it might result in quite a serious consequence."
While frustrating, these events do not seem to spell doom for GDNF. It may be that another delivery system or another dose is required. Or it may be that a particular group of Parkinson's patients may benefit, researchers said.
"Maybe we need to change how we're doing things or how long we're doing things or the dosing," Kaplitt said. "My suspicion is that there are patients who could or maybe have legitimately benefited from this, but we still don't understand enough about who are the most optimal patients for this kind of thing."
Patient advocates, for one, aren't giving up. "Something just doesn't feel right. The investigators we've talked to seem to have a lot of questions about the halting of the trial," Comstock said. "There seems to be a disconnect in the analysis so we are continuing to try and understand and make sure this gets resolved."
Kaplitt added: "This area of work is without question continuing and moving forward. It's just that this particular trial will not move forward now and that means it will take a little more time for this kind of thing to come to clinical benefit for patients but I think it will get there."
More information
Visit the National Parkinson Foundation for more on the disease.
