Original article by Donna Young, Associated Press

While Teva was praised by members of a US FDA advisory panel and regulators on 17 October for conducting a complex clinical trial aimed at demonstrating that its Parkinson's disease drug Azilect (rasagiline) may slow the progression of the disease, the committee unanimously said the study ultimately failed in providing substantial evidence to back up that claim.

"The data are promising, but just not compelling," said panellist Dr Pooja Khatri, an associate professor of neurology at the University of Cincinnati in Ohio.

"I think we have to be very solid in this and set a very high standard," said panellist Dr Robert Clancy, a professor of neurology at the Children's Hospital of Philadelphia. "If we are wishy-washy with this, the next thing that comes around is going to be expecting that being close is good enough. This is close, but it is not good enough."

The FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted 17-0 that Teva's 1,176-patient, randomized, multicentre, double-blind study, known as ADAGIO, failed to provide compelling evidence that the 1mg dose of Azilect met the protocol specified criteria for success.

The panel also voted 17-0 that the Israeli drug maker failed to provide substantial evidence of the effectiveness of Azilect as a treatment to delay clinical disease progression in patients with Parkinson's disease.

Azilect already is approved in the US as a treatment for the signs and symptoms of idiopathic Parkinson's disease – both as monotherapy and as adjunctive therapy to levodopa – gaining the FDA's blessing for that indication in 2006. But Teva is seeking to expand the drug's use for slowing clinical progression of the disease.

Dr Russell Katz, director of the FDA's Division of Neurology Products, noted that US regulators have never approved a treatment for disease modification in any neurodegenerative conditions.
"The effect of disease progression is something that is tremendously important, both from a clinical point of view for patients, but also from a regulatory point of view," he said. "If you tell people in labelling that a drug has an effect on disease progression, you really want to be sure it has an effect on disease progression."

If a drug is found to have an effect on disease progression, Dr Katz said it would "change dramatically" not only clinical practice, but controlled trials in the future.

"You could argue that everybody would have to be on that treatment, because to deny patients a drug that initially changes the course of the disease I think would be highly problematic," he said.

Although Teva's proposed indication for Azilect is for use to slow clinical progression, "from our point of view, there's little to no difference between a claim for clinical progression and a claim for disease modification," Dr Katz pointed out.

"We take those things to be the same thing," he explained. "Once you say to people in the labelling 'progression,' no matter what word you append before it, it has a strong implication that the drug has an effect on progression of the underlying disease."

Much of the daylong advisory committee meeting was focused on whether Teva's use of a delayed-start design was an appropriate type of trial to study disease progression for Parkinson's disease.
The purpose of the delayed treatment arm is to allow separation of symptomatic effects from the beneficial effect of slowing disease progression. Teva expected that if Azilect only has a symptomatic effect, patients that have a delay in treatment should simply "catch up" to those that are treated earlier – differing only in when they achieve the symptomatic effect.

But if the delayed treatment group does not catch up to the early treatment group, then the progression of disease was slowed by earlier treatment.

Dr Warren Olanow, a professor of neuroscience at Mount Sinai School of Medicine and the principal investigator for ADAGIO, noted that the study was the first to test a delayed-start design in Parkinson's patients.

"It was one of the most rigorous and challenging studies that has been performed," he said, pointing out that accruing 1,176 untreated patients and following them for 18 months with no additional treatments beyond Azilect or placebo was no easy task.
"Carrying out ADAGIO was an extraordinary effort that involved more than 100 Parkinson's disease centres around the world and literally hundreds of Parkinson's disease investigators specifically trained for their role in this study," he said.

Dr Olanow noted ADAGIO had three primary endpoints. "To my knowledge, no other study in Parkinson's disease has ever had to meet these requirements," he said.

ADAGIO consisted of a 36-week, placebo-controlled period followed by a double-blind, 36-week extension of all active treatment.

Patients initially started on Azilect were the early-start group, while those randomized to placebo and then Azilect in the second phase were the delayed-start group. There were 288 patients who entered into 1mg early-start treatment group, while 293 patients entered the 2mg early-start treatment group. In the delayed-start group, there were 298 patients given the 1mg dose, while 295 received the 2mg.

There were two additional patients originally randomized to the 1mg delayed-start group, but they withdrew their consent prior to receiving any study drug.

"Despite the complexity and duration of this study, we still managed to have 85% of patient data evaluable, with only 19% drop out," Dr Olanow said. "This is better than I would have expected. The ADAGIO study was a formidable achievement."

But while the 1mg dose appeared to have met the protocol-specified rule for success in ADAGIO, the 2mg dose failed to show that it delayed Parkinson's, which has "led to uncertainty to what it means," Dr Olanow acknowledged.

At the 17 October meeting, a group of six Parkinson's disease advocacy groups said that although they were encouraged, the data surrounding Azilect as a therapy to slow clinical progression of the disease "are not yet definitive". They said more data are needed beyond ADAGIO.

While the delayed-start trial design is "really good at helping you to tease out the slowing of clinical progression, it doesn't really tell you that the underlying disease process has been altered," Dr Brian Fiske, director of research programmes at the Michael J Fox Foundation for Parkinson's Research, told Scrip.

He noted that his organization, which has provided more than $265 million in research funding, is pushing towards finding a disease-modifying therapy.

Dr Fiske said the foundation has launched a $45 million partnership effort to try to find a biological progression marker for Parkinson's disease, with industry helping to cover much of those funds.

Industry partners in the project, known as the Parkinson's Progression Markers Initiative, include Abbott, Biogen Idec, Covance, GE Healthcare, Genentech, GlaxoSmithKline, Merck, Pfizer and Roche, Dr Fiske said.

At the centre of the project is a large five-year prospective study following 400 patients newly diagnosed with Parkinson's disease, plus healthy subjects in the control group, he explained.

The study, whose enrolment is expected to be completed by fall 2012, is set up as a precompetitive endeavour, in which the data are being made freely available to industry and academic researchers, Dr Fiske said.

Finding biological biomarkers for disease progression is "most critical if you are truly going to find a disease-modifying drug," he declared.