FDA Committee Rejects Expanded Indication for Rasagiline

Allison Gandey

October 17, 2011

October 17, 2011 — A US Food and Drug Administration (FDA) advisory committee has voted unanimously against an expanded indication for rasagiline (Azilect, Teva).

The company is making the case that rasagiline mesylate not only treats symptoms but is disease modifying. However, in 3 separate unanimous votes, the Peripheral and Central Nervous System Drugs Advisory Committee rejected the new indication, arguing the evidence isn't robust.

The group, led by Nathan Fountain, MD, from the University of Virginia in Charlottesville, said, "the bar must be set appropriately high to establish a disease-modifying effect."

Many committee members said they will continue to prescribe rasagiline. "I consider this to be a safe and effective drug," Samuel Frank, MD, from Boston University in Massachusetts, said at the meeting.

But when asked whether the company had provided compelling evidence the drug met the protocol-specified criteria for success, the committee voted no.

Warren Olanow, MD, from the Mount Sinai School of Medicine in New York City, presented results from the TEMPO and ADAGIO trials.

TEMPO, ADAGIO

TEMPO, or Rasagiline in Early Monotherapy for Parkinson's Disease Outpatients, included 404 patients. The primary prespecified measure of efficacy was the change in the total Unified Parkinson's Disease Rating Scale between baseline and 26 weeks of treatment. Investigators compared active treatment with 1 mg or 2 mg of rasagiline with placebo.

Researchers found that rasagiline is effective as monotherapy for patients with early Parkinson's disease. The 1-mg and 2-mg doses in this trial were both beneficial.

This contrasted with the results from the ADAGIO (Attenuation of Disease Progression with Azilect Given Once-Daily) trial.

As previously reported by Medscape Medical News, ADAGIO showed opposite outcomes for the 2 doses of rasagiline.

Findings from the double-blind study suggest the 1-mg dose may afford a disease-modifying effect in early Parkinson's, whereas the 2-mg dose does not. It is a contradiction the researchers were unable to explain. The puzzling results were published in the New England Journal of Medicine in September 2009.

Dr. Olanow was lead investigator and acknowledged at the meeting that "uncertainty remains about why the higher dose failed to meet prespecified endpoints."

FDA statisticians reviewing the trials criticized them. One reviewer wrote, "The slopes for baseline treatment were not statistically significantly different from zero in both ADAGIO and TEMPO studies." The reviewer said an additional sequence of hypothesis testing is required to confirm a disease-modifying effect. "The sponsor submitted sensitivity analyses and secondary analyses for dealing with the missing data in the 2 studies. The sensitivity analyses do not support the presence of any disease-modifying benefit."

Dr. Olanow says he respects the FDA's concerns. "The problem is this may be the best study we can do. This is the most rigorous work in Parkinson's that I'm aware of."

ADAGIO has also been criticized for its delayed-start study design. Some consider such trials overly complex and question their ability to answer the study question. Delayed-start trial designs have regulatory support but are rarely used.

Delayed-Start Study Design

With the conflicting findings, the FDA brought this question to its advisory committee. There was some skepticism on the panel; however, the general consensus seemed to be that the trial design was appropriate.

I take no pleasure in voting no on this very important topic.

In an accompanying editorial when ADAGIO was first published, Ralph D'Agostino, PhD, from the Mathematics and Statistics Department at Boston University, came to a similar conclusion. He suggested that the design affords great promise when used appropriately, and suggested the ADAGIO investigators used the design with "some success."

"I take no pleasure in voting no on this very important topic," panel member Eric Ahlskog, MD, from the Mayo Clinic in Rochester, Minnesota, said.

"They came close, but not close enough," Robert Clancy, MD, from the Children's Hospital of Philadelphia in Pennsylvania added. "We have to set the standard for neuroprotection very high."

In a joint statement by 6 Parkinson's disease organizations, the groups agreed it would be premature to approve rasagiline as disease modifying.

"While we are encouraged by the evidence presented to date, it appears to our community that the data surrounding rasagiline as a therapy that slows clinical progression of Parkinson's are not yet definitive, and that additional information is required to completely determine the impact of rasagiline on clinical disease progression," noted the American Parkinson Disease Association, the Michael J Fox Foundation for Parkinson's Research, the National Parkinson Foundation, the Parkinson's Action Network, the Parkinson Alliance, and the Parkinson's Disease Foundation.

"As a community, when it comes to finding new ways of confronting Parkinson's disease, we are fiercely pro-investment, pro-progress and pro-development. Each one of us has welcomed the achievement of each milestone in the development of new therapies, from levodopa in the 1960s, to dopamine agonists and improved surgical approaches in the 1990s, and to monoamine oxidase-B inhibitors, such as rasagiline, in the 2000s."

The organizations said, "There is as yet no disease-modifying therapy available — nothing that slows, reverses, or prevents the progression of the disease. And the treatments that we do have merely ease or mask the motor symptoms of Parkinson's disease for a limited period of time." They emphasize, "We believe that the distinction between a treatment that slows the clinical progression of the disease and a true disease-modifying treatment requires elucidation, as the subtle yet significant difference between the 2 is likely to cause confusion and artificially raise expectations of general practitioners and people with Parkinson's disease."

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