WASHINGTON -- Azilect (rasagiline), which is already approved to treat symptoms of Parkinson's disease, does not appear effective at slowing progression of the neurodegenerative disease, according to an FDA review.
Rasagiline was approved in 2006 to treat the signs and symptoms of Parkinson's disease -- such as tremors, difficulty walking, slowness of movement, and decreased facial expressions -- either when used by itself or with levodopa.
Teva, which makes rasagiline, would like the drug's indication expanded to include slowing disease progression.
The review document was released Thursday in advance of a Monday advisory panel meeting to discuss the issue.
If rasagiline were to be approved to slow development of Parkinson's -- which affects an estimated one million people in the U.S. -- it would be a major advance in the field of brain and central nervous systems disorders, and a practice-changer for doctors who treat patients with Parkinson's disease.
The FDA has never approved a treatment to slow progression of a neurodegenerative disease, Russell Katz, MD, director of the FDA's division of neurology products, wrote in a memo to the advisory panel.
And if the negative FDA review released Thursday is any indication, it likely won't any time soon.
Teva's original TEMPO trial -- on which approval of rasagiline was based -- suggested that the drug might slow progression. To test whether rasagiline could actually alter the course of the disease, Teva performed the ADAGIO trial, in which more than 1,000 patients with untreated, early-stage Parkinson's disease were randomized to receive either 1 mg/day or 2 mg/day of rasagiline for 72 weeks, or placebo for 36 weeks and then rasagiline either 1 mg/day or 2 mg/day for 36 weeks, dubbed the "delayed start group."
Patients in the all-rasagiline 1 mg/day group showed a 2.82-point worsening of symptoms compared with a 4.52-point worsening among patients in the "delayed start" group who received the 1-mg dose (P=0.02).
But that difference didn't hold true for the arms of the study that received 2 mg/day dosages. And in some instances -- such as at the 72-week mark -- the "delayed start" group was actually showing fewer signs of Parkinson's than the group that started medication earlier.
"There is no obvious biological or mechanistic reason why the 2-mg dose should not be disease-modifying, if the 1-mg dose is," Katz said, adding that the lack of congruity raises questions about the reliability of the 1-mg findings.
"There is no demonstrated benefit of rasagiline for slowing the rate of progression of Parkinson's Disease," another reviewer wrote.
Katz also called into question the theory behind the delayed start study method, which is that if patients who start the drug later catch up to the patients in whom treatment was initiated earlier, then the benefit in the earlier-treatment group likely didn't alter the course of the disease.
"The design is complicated, and presupposes that the course of the disease is fairly well understood," Katz wrote.
Indeed, the underlying causes and the progression of Parkinson's are far from well-understood.
In the company's briefing documents, Teva said that the difference seen in the 1 mg/day group is a real benefit that "cannot be explained by symptomatic effect only." Patients in the lower-dose group for patients who took rasagiline from the beginning of the study had a 38% reduction in clinical progression compared with the delayed start group, and the benefit might be even greater over the long run, the company said.
The FDA's Peripheral and Central Nervous System Advisory Committee will meet Monday and vote on whether Teva has shown that rasagiline slows the progression of Parkinson's. The FDA does not have to follow the advice of its advisory committees, but it often does.