Parkinson's symptoms improved in new drug trials

Parkinson’s disease symptoms that affect the quality of life of patients with the condition improved in studies of drugs that are under investigational status or have already been approved, according to new research coming from the annual meeting of the American Academy of Neurology.*

The reports include phase II studies evaluating a novel, nondopaminergic adjunctive treatment with levodopa and an oral precursor to norepinephrine to treat neurogenic orthostatic hypotension, as well as a phase IV study testing an already approved therapy as an add-on treatment to patients not well controlled on a dopamine agonist.

"All of these treatments are promising news for people with Parkinson’s disease," said Dr. Robert Hauser, in a statement issued by the AAN. He is an author in all three studies and is a neurologist at the University of South Florida, Tampa.

In the first of the phase II studies, patients with PD treated with tozadenant as an adjunct to levodopa experienced significant reductions in off-time without worsening dyskinesia, compared with those on placebo. Tozadenant is an oral, selective adenosine 2-alpha receptor antagonist.

The international, 12-week, double-blind study enrolled patients who had had PD for about 9 years, were on stable doses of levodopa, and had at least 2.5 hours of off-time per day. A total of 337 patients (mean age, 63 years) completed treatment. Comparisons against placebo for four different doses of the drug taken twice daily showed that those on the 120-mg and 180-mg twice-daily doses had a mean 1.1-1.2 hours’ reduction in off-time over placebo.

Scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale also improved significantly among those on these two doses, with a mean reduction of 2.2 and 2.5 among people on the 120-mg and 180-mg twice-daily doses, respectively, compared with placebo. The Patient Global Impression of Improvement (PGI-I) scores also significantly improved among those on 120 mg twice daily.

Dyskinesia, nausea, dizziness, constipation, and worsening of PD were the most common adverse events among all the patients on tozadenant.

"With our most effective doses, we were able to show significant reductions in off-time in comparison with placebo, but importantly, we were able to do that without seeing a worsening of dyskinesia," said the lead author, Dr. C. Warren Olanow. There were also some improvements in motor skills, he added in an interview.

While it is too early to make a statement on how tozadenant compares with other drugs, "the fact that it is nondopaminergic and well tolerated is very promising," said Dr. Olanow, the Henry P. and Georgette Goldschmidt professor of neurology and professor of neuroscience at Mount Sinai School of Medicine, New York.

"Now that we have shown benefit and identified what we think are the good doses," the next step is to conduct phase III confirmatory studies, which will evaluate the two doses that were effective in the phase II study, he said.

In another phase II randomized, double-blind study, 225 people with PD received droxidopa, an oral precursor of norepinephrine, or placebo to treat symptomatic neurogenic orthostatic hypotension. The 10-week study evaluated changes in the OHQ (Orthostatic Hypotension Questionnaire), dizziness/light-headedness (based on the Orthostatic Hypotension Symptom Assessment Item 1), standing systolic blood pressure, and frequency of falls.

The dosing regimen for droxidopa was titrated to 100-600 mg three times a day over a 2-week period. After 1 week on the drug, those on droxidopa had significant improvements in dizziness and light-headedness, compared with those on placebo. At 8 weeks, there was a trend toward improvement over placebo, but the difference was no longer significant, according to the investigators. Significant improvement in standing systolic blood pressure at 1 week (a 6.8 mm Hg difference over placebo) also did not hold up at 8 weeks (a 2.2 mm Hg improvement over placebo).

In the treated patients, there was also a drop in the number of falls per patient per week (0.38 fewer among those on placebo vs. 1.73 fewer among those on droxidopa), which was not statistically significant. Headache, dizziness, hypertension, nausea, and fatigue were each reported in more than 5% of patients taking droxidopa and in more than 5% of untreated patients.

A third study, called ANDANTE, evaluated rasagiline as add-on therapy to a dopamine agonist in 321 patients with early PD whose symptoms were not well controlled on the dopamine agonist. The patients were on stable doses of a dopamine agonist and were randomized to receive 1 mg of rasagiline per day or placebo, while remaining on stable doses of the dopamine agonist (ropinirole or pramipexole).

Approved in 2006, rasagiline (Azilect), a selective irreversible MAO-B inhibitor, is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease as initial monotherapy and as adjunct therapy to levodopa.

Over the first 18 weeks of the postmarketing, randomized, double-blind study, those treated with rasagiline had a significantly greater change from the baseline in the total UPDRS score (a mean reduction of 2.4 vs. placebo), the primary endpoint. There were also significant improvements in UPDRS motor scores among those on rasagiline, but no significant differences between the two groups in UPDRS activities of daily living scores. The rates of adverse events and serious adverse events were similar between the two groups: Among those on rasagiline, the overall rate of adverse events was 64% (5% were serious), compared with 61% (3% serious) for the placebo group.

Dr. Olanow disclosed that he is a consultant for almost all manufacturers of drugs for PD, including Biotie Therapies, the manufacturer of tozadenant, which also supported the study. The droxidopa study was supported by Chelsea Therapeutics, the drug’s manufacturer. The ANDANTE study was supported by Teva Pharmaceuticals, the manufacturer of rasagiline.

* This article was revised on 3/15/13.

[email protected]

Parkinson’s disease symptoms that affect the quality of life of patients with the condition improved in studies of drugs that are under investigational status or have already been approved, according to new research coming from the annual meeting of the American Academy of Neurology.*

The reports include phase II studies evaluating a novel, nondopaminergic adjunctive treatment with levodopa and an oral precursor to norepinephrine to treat neurogenic orthostatic hypotension, as well as a phase IV study testing an already approved therapy as an add-on treatment to patients not well controlled on a dopamine agonist.

"All of these treatments are promising news for people with Parkinson’s disease," said Dr. Robert Hauser, in a statement issued by the AAN. He is an author in all three studies and is a neurologist at the University of South Florida, Tampa.

In the first of the phase II studies, patients with PD treated with tozadenant as an adjunct to levodopa experienced significant reductions in off-time without worsening dyskinesia, compared with those on placebo. Tozadenant is an oral, selective adenosine 2-alpha receptor antagonist.

The international, 12-week, double-blind study enrolled patients who had had PD for about 9 years, were on stable doses of levodopa, and had at least 2.5 hours of off-time per day. A total of 337 patients (mean age, 63 years) completed treatment. Comparisons against placebo for four different doses of the drug taken twice daily showed that those on the 120-mg and 180-mg twice-daily doses had a mean 1.1-1.2 hours’ reduction in off-time over placebo.

Scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale also improved significantly among those on these two doses, with a mean reduction of 2.2 and 2.5 among people on the 120-mg and 180-mg twice-daily doses, respectively, compared with placebo. The Patient Global Impression of Improvement (PGI-I) scores also significantly improved among those on 120 mg twice daily.

Dyskinesia, nausea, dizziness, constipation, and worsening of PD were the most common adverse events among all the patients on tozadenant.

"With our most effective doses, we were able to show significant reductions in off-time in comparison with placebo, but importantly, we were able to do that without seeing a worsening of dyskinesia," said the lead author, Dr. C. Warren Olanow. There were also some improvements in motor skills, he added in an interview.

While it is too early to make a statement on how tozadenant compares with other drugs, "the fact that it is nondopaminergic and well tolerated is very promising," said Dr. Olanow, the Henry P. and Georgette Goldschmidt professor of neurology and professor of neuroscience at Mount Sinai School of Medicine, New York.

"Now that we have shown benefit and identified what we think are the good doses," the next step is to conduct phase III confirmatory studies, which will evaluate the two doses that were effective in the phase II study, he said.

In another phase II randomized, double-blind study, 225 people with PD received droxidopa, an oral precursor of norepinephrine, or placebo to treat symptomatic neurogenic orthostatic hypotension. The 10-week study evaluated changes in the OHQ (Orthostatic Hypotension Questionnaire), dizziness/light-headedness (based on the Orthostatic Hypotension Symptom Assessment Item 1), standing systolic blood pressure, and frequency of falls.

The dosing regimen for droxidopa was titrated to 100-600 mg three times a day over a 2-week period. After 1 week on the drug, those on droxidopa had significant improvements in dizziness and light-headedness, compared with those on placebo. At 8 weeks, there was a trend toward improvement over placebo, but the difference was no longer significant, according to the investigators. Significant improvement in standing systolic blood pressure at 1 week (a 6.8 mm Hg difference over placebo) also did not hold up at 8 weeks (a 2.2 mm Hg improvement over placebo).

In the treated patients, there was also a drop in the number of falls per patient per week (0.38 fewer among those on placebo vs. 1.73 fewer among those on droxidopa), which was not statistically significant. Headache, dizziness, hypertension, nausea, and fatigue were each reported in more than 5% of patients taking droxidopa and in more than 5% of untreated patients.

A third study, called ANDANTE, evaluated rasagiline as add-on therapy to a dopamine agonist in 321 patients with early PD whose symptoms were not well controlled on the dopamine agonist. The patients were on stable doses of a dopamine agonist and were randomized to receive 1 mg of rasagiline per day or placebo, while remaining on stable doses of the dopamine agonist (ropinirole or pramipexole).

Approved in 2006, rasagiline (Azilect), a selective irreversible MAO-B inhibitor, is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease as initial monotherapy and as adjunct therapy to levodopa.

Over the first 18 weeks of the postmarketing, randomized, double-blind study, those treated with rasagiline had a significantly greater change from the baseline in the total UPDRS score (a mean reduction of 2.4 vs. placebo), the primary endpoint. There were also significant improvements in UPDRS motor scores among those on rasagiline, but no significant differences between the two groups in UPDRS activities of daily living scores. The rates of adverse events and serious adverse events were similar between the two groups: Among those on rasagiline, the overall rate of adverse events was 64% (5% were serious), compared with 61% (3% serious) for the placebo group.

Dr. Olanow disclosed that he is a consultant for almost all manufacturers of drugs for PD, including Biotie Therapies, the manufacturer of tozadenant, which also supported the study. The droxidopa study was supported by Chelsea Therapeutics, the drug’s manufacturer. The ANDANTE study was supported by Teva Pharmaceuticals, the manufacturer of rasagiline.

* This article was revised on 3/15/13.

[email protected]

Parkinson’s disease symptoms that affect the quality of life of patients with the condition improved in studies of drugs that are under investigational status or have already been approved, according to new research coming from the annual meeting of the American Academy of Neurology.*

The reports include phase II studies evaluating a novel, nondopaminergic adjunctive treatment with levodopa and an oral precursor to norepinephrine to treat neurogenic orthostatic hypotension, as well as a phase IV study testing an already approved therapy as an add-on treatment to patients not well controlled on a dopamine agonist.

"All of these treatments are promising news for people with Parkinson’s disease," said Dr. Robert Hauser, in a statement issued by the AAN. He is an author in all three studies and is a neurologist at the University of South Florida, Tampa.

In the first of the phase II studies, patients with PD treated with tozadenant as an adjunct to levodopa experienced significant reductions in off-time without worsening dyskinesia, compared with those on placebo. Tozadenant is an oral, selective adenosine 2-alpha receptor antagonist.

The international, 12-week, double-blind study enrolled patients who had had PD for about 9 years, were on stable doses of levodopa, and had at least 2.5 hours of off-time per day. A total of 337 patients (mean age, 63 years) completed treatment. Comparisons against placebo for four different doses of the drug taken twice daily showed that those on the 120-mg and 180-mg twice-daily doses had a mean 1.1-1.2 hours’ reduction in off-time over placebo.

Scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale also improved significantly among those on these two doses, with a mean reduction of 2.2 and 2.5 among people on the 120-mg and 180-mg twice-daily doses, respectively, compared with placebo. The Patient Global Impression of Improvement (PGI-I) scores also significantly improved among those on 120 mg twice daily.

Dyskinesia, nausea, dizziness, constipation, and worsening of PD were the most common adverse events among all the patients on tozadenant.

"With our most effective doses, we were able to show significant reductions in off-time in comparison with placebo, but importantly, we were able to do that without seeing a worsening of dyskinesia," said the lead author, Dr. C. Warren Olanow. There were also some improvements in motor skills, he added in an interview.

While it is too early to make a statement on how tozadenant compares with other drugs, "the fact that it is nondopaminergic and well tolerated is very promising," said Dr. Olanow, the Henry P. and Georgette Goldschmidt professor of neurology and professor of neuroscience at Mount Sinai School of Medicine, New York.

"Now that we have shown benefit and identified what we think are the good doses," the next step is to conduct phase III confirmatory studies, which will evaluate the two doses that were effective in the phase II study, he said.

In another phase II randomized, double-blind study, 225 people with PD received droxidopa, an oral precursor of norepinephrine, or placebo to treat symptomatic neurogenic orthostatic hypotension. The 10-week study evaluated changes in the OHQ (Orthostatic Hypotension Questionnaire), dizziness/light-headedness (based on the Orthostatic Hypotension Symptom Assessment Item 1), standing systolic blood pressure, and frequency of falls.

The dosing regimen for droxidopa was titrated to 100-600 mg three times a day over a 2-week period. After 1 week on the drug, those on droxidopa had significant improvements in dizziness and light-headedness, compared with those on placebo. At 8 weeks, there was a trend toward improvement over placebo, but the difference was no longer significant, according to the investigators. Significant improvement in standing systolic blood pressure at 1 week (a 6.8 mm Hg difference over placebo) also did not hold up at 8 weeks (a 2.2 mm Hg improvement over placebo).

In the treated patients, there was also a drop in the number of falls per patient per week (0.38 fewer among those on placebo vs. 1.73 fewer among those on droxidopa), which was not statistically significant. Headache, dizziness, hypertension, nausea, and fatigue were each reported in more than 5% of patients taking droxidopa and in more than 5% of untreated patients.

A third study, called ANDANTE, evaluated rasagiline as add-on therapy to a dopamine agonist in 321 patients with early PD whose symptoms were not well controlled on the dopamine agonist. The patients were on stable doses of a dopamine agonist and were randomized to receive 1 mg of rasagiline per day or placebo, while remaining on stable doses of the dopamine agonist (ropinirole or pramipexole).

Approved in 2006, rasagiline (Azilect), a selective irreversible MAO-B inhibitor, is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease as initial monotherapy and as adjunct therapy to levodopa.

Over the first 18 weeks of the postmarketing, randomized, double-blind study, those treated with rasagiline had a significantly greater change from the baseline in the total UPDRS score (a mean reduction of 2.4 vs. placebo), the primary endpoint. There were also significant improvements in UPDRS motor scores among those on rasagiline, but no significant differences between the two groups in UPDRS activities of daily living scores. The rates of adverse events and serious adverse events were similar between the two groups: Among those on rasagiline, the overall rate of adverse events was 64% (5% were serious), compared with 61% (3% serious) for the placebo group.

Dr. Olanow disclosed that he is a consultant for almost all manufacturers of drugs for PD, including Biotie Therapies, the manufacturer of tozadenant, which also supported the study. The droxidopa study was supported by Chelsea Therapeutics, the drug’s manufacturer. The ANDANTE study was supported by Teva Pharmaceuticals, the manufacturer of rasagiline.

* This article was revised on 3/15/13.

[email protected]