Panel Says No to Progression Claim for Rasagiline

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously agreed that there was not enough evidence to support approval of rasagiline for slowing the clinical progression of Parkinson's disease, although they believed the data were promising.

The FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted 17-0 that the manufacturer of rasagiline had not provided substantial evidence that the drug was effective in delaying clinical progression of the disease in patients. Rasagiline was approved in 2006 in the United States for treating the signs and symptoms of Parkinson's disease, as initial monotherapy and as adjunct therapy to levodopa; it is marketed as Azilect by Teva Pharmaceuticals.

“The data are promising, they are just not compelling…it's crucial that there be compelling data for us to really move forward,” said Dr. Pooja Katri, one of the panelists and a neurologist at the University of Cincinnati.

Currently, no treatment is approved for slowing the clinical progression of Parkinson's disease.

Teva based its request for adding an indication for slowing clinical progression to the 1-mg dose of the monoamine oxidase B inhibitor on the results of two “delayed start” studies of patients with early Parkinson's: the ADAGIO (Attenuation of Disease Progression with Agilect/Azilect Once Daily) study, and the TEMPO (TVP-1012 in Early Monotherapy for PD Outpatient) study, which was part of the original approval application for rasagiline.

The ADAGIO study evaluated the drug's effects on clinical progression in about 1,100 patients with early, mild Parkinson's, who were not on other medications for the disease (N. Engl. J. Med. 2009;361:1268-78). The patients (mean age 62 years) were enrolled a mean of 138 days after diagnosis and were treated with 1 mg or 2 mg of rasagiline per day or placebo for 36 weeks, at which point those on placebo were switched to 1-mg or 2-mg doses. Progression of disease was measured with the Unified Parkinson's Disease Rating Scale (UPDRS).

At 72 weeks, the increase in mean UPDRS scores from baseline was smaller among patients who had been treated with the 1-mg dose from the start of the study than it was in those who had started the 1-mg dose at 36 weeks, indicating less disease progression in the former. The difference was statistically significant.

However, there was no difference in the UPDRS scores from baseline to the end of the study among those who had started the 2-mg dose at the start of the study and those who started the 2-mg dose at 36 weeks.

“This is the closest we have come to showing a drug slows clinical progression,” said Dr. C. Warren Olanow, the director of the Robert and John N. Bendheim Parkinson and Movement Disorder Center, Mount Sinai School of Medicine, New York. He spoke on behalf of Teva at the meeting.

In the TEMPO study, about 400 patients (mean age 61 years) in the United States and Canada, who had had PD for a mean of 12 years, were randomized to 1 mg, 2 mg, or placebo for 26 weeks, at which time those on placebo were switched to the 2-mg dose (the delayed start group). Clinical outcomes, as measured by the impact on UPDRS scale changes, was better among those who started treatment early: the difference was 1.8 among those on 1 mg (P value of 0.05) and with 2 mg, the difference was 2.3 (P value of 0.01). At 52 weeks, those on 2 mg from the beginning of the study showed less deterioration, based on UPDRS scores, than did those whose treatment was delayed.

Dr. Olanow, the lead investigator of ADAGIO, said that patients in TEMPO had higher baseline UPDRS scores than those in ADAGIO, and that a post hoc analysis of ADAGIO data found that the 2-mg dose was associated with benefits among the patients with the highest baseline UPDRS scores. “We speculate that the UPDRS floor effect might have masked our ability to detect a difference between early and delayed start groups with this higher dose in such a mild population of patients,” he added, noting that the concept of a floor effect is “well-known” in Parkinson's disease and has been observed in previous trials where more prominent treatment effects have been observed in patients with higher UPDRS scores at baseline.

The failure of the 2-mg dose in the ADAGIO study was “the most troubling issue” with the data and there was “no robust finding for either dose,” said Tristan Massie, Ph.D., an FDA statistician who presented the agency's statistical analysis of the data at the meeting. The absence of an effect in the 2-mg group “raised questions about the biological plausibility of the 1 mg,” he added.

The panel agreed, cited other issues with the data, and voted unanimously that the study did not provide compelling evidence that the 1-mg, once-daily dose was effective. While they agreed that there was an unmet need for a treatment that slowed progression and that the data were promising and showed a signal for a disease-modifying effect, they said the evidence did not meet the high bar that should be set for proving such an effect, considering the enormous public health implications of a neuroprotection claim for a Parkinson's disease treatment.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

In addition to Teva, the companies on Dr. Olanow's conflict of interest disclosure statement included Ceregene, Novartis, Lundbeck, and Merck Serono.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously agreed that there was not enough evidence to support approval of rasagiline for slowing the clinical progression of Parkinson's disease, although they believed the data were promising.

The FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted 17-0 that the manufacturer of rasagiline had not provided substantial evidence that the drug was effective in delaying clinical progression of the disease in patients. Rasagiline was approved in 2006 in the United States for treating the signs and symptoms of Parkinson's disease, as initial monotherapy and as adjunct therapy to levodopa; it is marketed as Azilect by Teva Pharmaceuticals.

“The data are promising, they are just not compelling…it's crucial that there be compelling data for us to really move forward,” said Dr. Pooja Katri, one of the panelists and a neurologist at the University of Cincinnati.

Currently, no treatment is approved for slowing the clinical progression of Parkinson's disease.

Teva based its request for adding an indication for slowing clinical progression to the 1-mg dose of the monoamine oxidase B inhibitor on the results of two “delayed start” studies of patients with early Parkinson's: the ADAGIO (Attenuation of Disease Progression with Agilect/Azilect Once Daily) study, and the TEMPO (TVP-1012 in Early Monotherapy for PD Outpatient) study, which was part of the original approval application for rasagiline.

The ADAGIO study evaluated the drug's effects on clinical progression in about 1,100 patients with early, mild Parkinson's, who were not on other medications for the disease (N. Engl. J. Med. 2009;361:1268-78). The patients (mean age 62 years) were enrolled a mean of 138 days after diagnosis and were treated with 1 mg or 2 mg of rasagiline per day or placebo for 36 weeks, at which point those on placebo were switched to 1-mg or 2-mg doses. Progression of disease was measured with the Unified Parkinson's Disease Rating Scale (UPDRS).

At 72 weeks, the increase in mean UPDRS scores from baseline was smaller among patients who had been treated with the 1-mg dose from the start of the study than it was in those who had started the 1-mg dose at 36 weeks, indicating less disease progression in the former. The difference was statistically significant.

However, there was no difference in the UPDRS scores from baseline to the end of the study among those who had started the 2-mg dose at the start of the study and those who started the 2-mg dose at 36 weeks.

“This is the closest we have come to showing a drug slows clinical progression,” said Dr. C. Warren Olanow, the director of the Robert and John N. Bendheim Parkinson and Movement Disorder Center, Mount Sinai School of Medicine, New York. He spoke on behalf of Teva at the meeting.

In the TEMPO study, about 400 patients (mean age 61 years) in the United States and Canada, who had had PD for a mean of 12 years, were randomized to 1 mg, 2 mg, or placebo for 26 weeks, at which time those on placebo were switched to the 2-mg dose (the delayed start group). Clinical outcomes, as measured by the impact on UPDRS scale changes, was better among those who started treatment early: the difference was 1.8 among those on 1 mg (P value of 0.05) and with 2 mg, the difference was 2.3 (P value of 0.01). At 52 weeks, those on 2 mg from the beginning of the study showed less deterioration, based on UPDRS scores, than did those whose treatment was delayed.

Dr. Olanow, the lead investigator of ADAGIO, said that patients in TEMPO had higher baseline UPDRS scores than those in ADAGIO, and that a post hoc analysis of ADAGIO data found that the 2-mg dose was associated with benefits among the patients with the highest baseline UPDRS scores. “We speculate that the UPDRS floor effect might have masked our ability to detect a difference between early and delayed start groups with this higher dose in such a mild population of patients,” he added, noting that the concept of a floor effect is “well-known” in Parkinson's disease and has been observed in previous trials where more prominent treatment effects have been observed in patients with higher UPDRS scores at baseline.

The failure of the 2-mg dose in the ADAGIO study was “the most troubling issue” with the data and there was “no robust finding for either dose,” said Tristan Massie, Ph.D., an FDA statistician who presented the agency's statistical analysis of the data at the meeting. The absence of an effect in the 2-mg group “raised questions about the biological plausibility of the 1 mg,” he added.

The panel agreed, cited other issues with the data, and voted unanimously that the study did not provide compelling evidence that the 1-mg, once-daily dose was effective. While they agreed that there was an unmet need for a treatment that slowed progression and that the data were promising and showed a signal for a disease-modifying effect, they said the evidence did not meet the high bar that should be set for proving such an effect, considering the enormous public health implications of a neuroprotection claim for a Parkinson's disease treatment.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

In addition to Teva, the companies on Dr. Olanow's conflict of interest disclosure statement included Ceregene, Novartis, Lundbeck, and Merck Serono.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel unanimously agreed that there was not enough evidence to support approval of rasagiline for slowing the clinical progression of Parkinson's disease, although they believed the data were promising.

The FDA's Peripheral and Central Nervous System Drugs Advisory Committee voted 17-0 that the manufacturer of rasagiline had not provided substantial evidence that the drug was effective in delaying clinical progression of the disease in patients. Rasagiline was approved in 2006 in the United States for treating the signs and symptoms of Parkinson's disease, as initial monotherapy and as adjunct therapy to levodopa; it is marketed as Azilect by Teva Pharmaceuticals.

“The data are promising, they are just not compelling…it's crucial that there be compelling data for us to really move forward,” said Dr. Pooja Katri, one of the panelists and a neurologist at the University of Cincinnati.

Currently, no treatment is approved for slowing the clinical progression of Parkinson's disease.

Teva based its request for adding an indication for slowing clinical progression to the 1-mg dose of the monoamine oxidase B inhibitor on the results of two “delayed start” studies of patients with early Parkinson's: the ADAGIO (Attenuation of Disease Progression with Agilect/Azilect Once Daily) study, and the TEMPO (TVP-1012 in Early Monotherapy for PD Outpatient) study, which was part of the original approval application for rasagiline.

The ADAGIO study evaluated the drug's effects on clinical progression in about 1,100 patients with early, mild Parkinson's, who were not on other medications for the disease (N. Engl. J. Med. 2009;361:1268-78). The patients (mean age 62 years) were enrolled a mean of 138 days after diagnosis and were treated with 1 mg or 2 mg of rasagiline per day or placebo for 36 weeks, at which point those on placebo were switched to 1-mg or 2-mg doses. Progression of disease was measured with the Unified Parkinson's Disease Rating Scale (UPDRS).

At 72 weeks, the increase in mean UPDRS scores from baseline was smaller among patients who had been treated with the 1-mg dose from the start of the study than it was in those who had started the 1-mg dose at 36 weeks, indicating less disease progression in the former. The difference was statistically significant.

However, there was no difference in the UPDRS scores from baseline to the end of the study among those who had started the 2-mg dose at the start of the study and those who started the 2-mg dose at 36 weeks.

“This is the closest we have come to showing a drug slows clinical progression,” said Dr. C. Warren Olanow, the director of the Robert and John N. Bendheim Parkinson and Movement Disorder Center, Mount Sinai School of Medicine, New York. He spoke on behalf of Teva at the meeting.

In the TEMPO study, about 400 patients (mean age 61 years) in the United States and Canada, who had had PD for a mean of 12 years, were randomized to 1 mg, 2 mg, or placebo for 26 weeks, at which time those on placebo were switched to the 2-mg dose (the delayed start group). Clinical outcomes, as measured by the impact on UPDRS scale changes, was better among those who started treatment early: the difference was 1.8 among those on 1 mg (P value of 0.05) and with 2 mg, the difference was 2.3 (P value of 0.01). At 52 weeks, those on 2 mg from the beginning of the study showed less deterioration, based on UPDRS scores, than did those whose treatment was delayed.

Dr. Olanow, the lead investigator of ADAGIO, said that patients in TEMPO had higher baseline UPDRS scores than those in ADAGIO, and that a post hoc analysis of ADAGIO data found that the 2-mg dose was associated with benefits among the patients with the highest baseline UPDRS scores. “We speculate that the UPDRS floor effect might have masked our ability to detect a difference between early and delayed start groups with this higher dose in such a mild population of patients,” he added, noting that the concept of a floor effect is “well-known” in Parkinson's disease and has been observed in previous trials where more prominent treatment effects have been observed in patients with higher UPDRS scores at baseline.

The failure of the 2-mg dose in the ADAGIO study was “the most troubling issue” with the data and there was “no robust finding for either dose,” said Tristan Massie, Ph.D., an FDA statistician who presented the agency's statistical analysis of the data at the meeting. The absence of an effect in the 2-mg group “raised questions about the biological plausibility of the 1 mg,” he added.

The panel agreed, cited other issues with the data, and voted unanimously that the study did not provide compelling evidence that the 1-mg, once-daily dose was effective. While they agreed that there was an unmet need for a treatment that slowed progression and that the data were promising and showed a signal for a disease-modifying effect, they said the evidence did not meet the high bar that should be set for proving such an effect, considering the enormous public health implications of a neuroprotection claim for a Parkinson's disease treatment.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

In addition to Teva, the companies on Dr. Olanow's conflict of interest disclosure statement included Ceregene, Novartis, Lundbeck, and Merck Serono.