Pimavanserin reduced Parkinson’s psychosis without motor worsening

BOSTON – A novel 5-HT_2A receptor inverse agonist significantly improved psychotic symptoms in Parkinson’s disease patients without the worsening of motor symptoms that usually occurs with antipsychotic treatment, according to the results of a randomized, placebo-controlled phase III trial.*

In addition to benefiting patients, the drug eased caregiver burden, Dr. Clive Ballard said at the Alzheimer’s Association International Conference 2013.

"By 4 weeks into the study, the benefit for caregivers began to appear, and it continued to increase" until the study ended at 6 weeks, said Dr. Ballard, professor of age-related diseases at King’s College London.

Parkinson’s psychosis is a common manifestation of the disease, and about 50% of patients will experience it, he said. "It’s not just frequent. It’s impactful. It’s distressing for patients and for those caring for them. It’s also associated with more impairment, with mortality, and it’s the leading cause of nursing home placement."

Sadly, he noted that there are not many medical options for the problem. Most antipsychotics produce extrapyramidal symptoms, which worsen parkinsonism. Atypical antipsychotics may be well tolerated, but are not very effective against the delusions and hallucinations that can occur in Parkinson’s patients.

"The situation in Parkinson’s is even worse than it is in Alzheimer’s. At least we do have some options for Alzheimer’s psychosis, even if they’re not great," Dr. Ballard said.

The atypical antipsychotics quetiapine and clozapine are the only well-tolerated options, he said. "Quetiapine is ineffective, though, leaving only clozapine. It’s well tolerated from a motor point of view, but it has other safety and tolerability issues that limit its use in clinical practice."

As a selective 5-HT_2A inverse agonist, pimavanserin is in a unique drug class. According to Acadia Pharmaceuticals, the company developing the drug, it has the benefits of a 5HT_2A agonist but doesn’t affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems.

"Previous studies suggested that it was well tolerated and had some signal of potential benefit in psychosis," Dr. Ballard said. But those trials posted an unusually large placebo effect as well, making the results "difficult to interpret."

Investigators in the pimavanserin phase III study made a number of study design changes to compensate for the placebo response. In order to qualify for the trial, for example, patients had to have high baseline minimum scores on the Neuropsychiatric Inventory and the Scale for the Assessment of Positive Symptoms (SAPS).

They also took part in a brief psychosocial intervention before randomization. "In this intervention, the caregiver spends about 10 minutes each day with the patient, enabling the patient to do an activity they enjoy." This reduces the placebo response rate when the study medication commences, Dr. Ballard said.

The study also centralized any robust key findings, which were interpreted by independent, blinded raters.

The primary endpoint was antipsychotic efficacy as measured using the SAPS-PD, a nine-item scale adapted from the hallucinations and delusions domains of SAPS.

Secondary endpoints included the entire 20-item SAPS, the SAPS hallucinations and delusions subscores, the Clinical Global Impression (CGI) score, Unified Parkinson’s Disease Rating Scale (UPDRS) domains I and II, and a measure of caregiver burden.

The patients were randomized to 40 mg of pimavanserin daily (n = 105) or to placebo (n = 94) for 6 weeks. They were assessed at baseline and at 2, 4, and 6 weeks. After the randomization period, they could join a long-term, open-label extension study at the 40-mg/day dose. Most of the patients completed the trial protocol (87 in the placebo group and 89 in the pimavanserin group). Seven placebo patients dropped out, including two because of an adverse event. Of 15 patients in the pimavanserin group who dropped out, 10 did so because of adverse events. One patient randomized to pimavanserin did not take the medication.

At 6 weeks, patients in the active treatment group had significantly greater improvement on the SAPS-PD, the primary endpoint. By 15 days, both groups had experienced a significant improvement from baseline. Thereafter, the curves separated, with the placebo group becoming stable; Dr. Ballard said this indicated that the study design compensated for a large placebo response. The pimavanserin group, however, continued to improve. By the study’s end, there was a mean SAPS-PD decrease of 5.79 points in the active group, significantly better than the mean 2.73-point decrease in the placebo group. This translated to a 37% improvement for the study drug, compared with a 14% improvement for placebo.

The scores also translated into a meaningful clinical benefit, Dr. Ballard added. By the SAPS-PD measurement, response rates were 42% and 65%, respectively – a significant difference.

Changes on the CGI subscores were also significantly different. Patients in the placebo group experienced a mean decrease of less than half a point on the improvement subscale, compared with a decrease of about 1 point in the pimavanserin group. On the severity subscale, the placebo group stayed close to baseline, while the pimavanserin group decreased by about 1 point. About 27% of those taking placebo and 49% of those taking pimavanserin were considered responders.

Caregiver burden also significantly improved with the study drug.

In an exploratory analysis examining pimavanserin’s effect on sleep, the drug was associated with improvements in both nighttime sleep and daytime wakefulness on the Scale for Outcomes in Parkinson’s Disease sleep measure, Dr. Ballard said.

There were three deaths during the study – one in the placebo group (sudden cardiac death) and two in the active group (sepsis and septic shock). There were also four urinary tract infections – one in the placebo group and three in the active group. Other adverse events reported during the trial included peripheral edema (7% active vs. 3% placebo), falls (11% vs. 6%), confusion (6% vs. 3%), headache (1% vs. 5%), and hallucination (7% vs. 4%).

Based on the favorable results, Acadia announced that it had discontinued its work on a planned confirmatory phase III study. A New Drug Application for pimavanserin is in preparation, Dr. Ballard said.*

Acadia is also planning to study the drug’s effect in Alzheimer’s-associated psychosis in a phase II feasibility trial later this year, according to the company’s website.

"Similar to Parkinson’s disease psychosis, there is no therapy approved to treat Alzheimer’s psychosis in the U.S.," the company said in a written statement. "As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in these patients. ... Antipsychotic drugs may exacerbate the cognitive disturbances associated with Alzheimer’s disease and also have a black box warning for use in elderly patients with dementia-related psychosis due to increased risks of mortality and morbidity."

The trial was funded by Acadia. Dr. Ballard disclosed that he has received honoraria and consulting fees from the company.

msullivan@fronlinemedcom.com

On Twitter @Alz_Gal

* Correction 7/30/13: An earlier version of this article misstated pimavanserin's mechanism of action and the status of its New Drug Application.

BOSTON – A novel 5-HT_2A receptor inverse agonist significantly improved psychotic symptoms in Parkinson’s disease patients without the worsening of motor symptoms that usually occurs with antipsychotic treatment, according to the results of a randomized, placebo-controlled phase III trial.*

In addition to benefiting patients, the drug eased caregiver burden, Dr. Clive Ballard said at the Alzheimer’s Association International Conference 2013.

"By 4 weeks into the study, the benefit for caregivers began to appear, and it continued to increase" until the study ended at 6 weeks, said Dr. Ballard, professor of age-related diseases at King’s College London.

Parkinson’s psychosis is a common manifestation of the disease, and about 50% of patients will experience it, he said. "It’s not just frequent. It’s impactful. It’s distressing for patients and for those caring for them. It’s also associated with more impairment, with mortality, and it’s the leading cause of nursing home placement."

Sadly, he noted that there are not many medical options for the problem. Most antipsychotics produce extrapyramidal symptoms, which worsen parkinsonism. Atypical antipsychotics may be well tolerated, but are not very effective against the delusions and hallucinations that can occur in Parkinson’s patients.

"The situation in Parkinson’s is even worse than it is in Alzheimer’s. At least we do have some options for Alzheimer’s psychosis, even if they’re not great," Dr. Ballard said.

The atypical antipsychotics quetiapine and clozapine are the only well-tolerated options, he said. "Quetiapine is ineffective, though, leaving only clozapine. It’s well tolerated from a motor point of view, but it has other safety and tolerability issues that limit its use in clinical practice."

As a selective 5-HT_2A inverse agonist, pimavanserin is in a unique drug class. According to Acadia Pharmaceuticals, the company developing the drug, it has the benefits of a 5HT_2A agonist but doesn’t affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems.

"Previous studies suggested that it was well tolerated and had some signal of potential benefit in psychosis," Dr. Ballard said. But those trials posted an unusually large placebo effect as well, making the results "difficult to interpret."

Investigators in the pimavanserin phase III study made a number of study design changes to compensate for the placebo response. In order to qualify for the trial, for example, patients had to have high baseline minimum scores on the Neuropsychiatric Inventory and the Scale for the Assessment of Positive Symptoms (SAPS).

They also took part in a brief psychosocial intervention before randomization. "In this intervention, the caregiver spends about 10 minutes each day with the patient, enabling the patient to do an activity they enjoy." This reduces the placebo response rate when the study medication commences, Dr. Ballard said.

The study also centralized any robust key findings, which were interpreted by independent, blinded raters.

The primary endpoint was antipsychotic efficacy as measured using the SAPS-PD, a nine-item scale adapted from the hallucinations and delusions domains of SAPS.

Secondary endpoints included the entire 20-item SAPS, the SAPS hallucinations and delusions subscores, the Clinical Global Impression (CGI) score, Unified Parkinson’s Disease Rating Scale (UPDRS) domains I and II, and a measure of caregiver burden.

The patients were randomized to 40 mg of pimavanserin daily (n = 105) or to placebo (n = 94) for 6 weeks. They were assessed at baseline and at 2, 4, and 6 weeks. After the randomization period, they could join a long-term, open-label extension study at the 40-mg/day dose. Most of the patients completed the trial protocol (87 in the placebo group and 89 in the pimavanserin group). Seven placebo patients dropped out, including two because of an adverse event. Of 15 patients in the pimavanserin group who dropped out, 10 did so because of adverse events. One patient randomized to pimavanserin did not take the medication.

At 6 weeks, patients in the active treatment group had significantly greater improvement on the SAPS-PD, the primary endpoint. By 15 days, both groups had experienced a significant improvement from baseline. Thereafter, the curves separated, with the placebo group becoming stable; Dr. Ballard said this indicated that the study design compensated for a large placebo response. The pimavanserin group, however, continued to improve. By the study’s end, there was a mean SAPS-PD decrease of 5.79 points in the active group, significantly better than the mean 2.73-point decrease in the placebo group. This translated to a 37% improvement for the study drug, compared with a 14% improvement for placebo.

The scores also translated into a meaningful clinical benefit, Dr. Ballard added. By the SAPS-PD measurement, response rates were 42% and 65%, respectively – a significant difference.

Changes on the CGI subscores were also significantly different. Patients in the placebo group experienced a mean decrease of less than half a point on the improvement subscale, compared with a decrease of about 1 point in the pimavanserin group. On the severity subscale, the placebo group stayed close to baseline, while the pimavanserin group decreased by about 1 point. About 27% of those taking placebo and 49% of those taking pimavanserin were considered responders.

Caregiver burden also significantly improved with the study drug.

In an exploratory analysis examining pimavanserin’s effect on sleep, the drug was associated with improvements in both nighttime sleep and daytime wakefulness on the Scale for Outcomes in Parkinson’s Disease sleep measure, Dr. Ballard said.

There were three deaths during the study – one in the placebo group (sudden cardiac death) and two in the active group (sepsis and septic shock). There were also four urinary tract infections – one in the placebo group and three in the active group. Other adverse events reported during the trial included peripheral edema (7% active vs. 3% placebo), falls (11% vs. 6%), confusion (6% vs. 3%), headache (1% vs. 5%), and hallucination (7% vs. 4%).

Based on the favorable results, Acadia announced that it had discontinued its work on a planned confirmatory phase III study. A New Drug Application for pimavanserin is in preparation, Dr. Ballard said.*

Acadia is also planning to study the drug’s effect in Alzheimer’s-associated psychosis in a phase II feasibility trial later this year, according to the company’s website.

"Similar to Parkinson’s disease psychosis, there is no therapy approved to treat Alzheimer’s psychosis in the U.S.," the company said in a written statement. "As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in these patients. ... Antipsychotic drugs may exacerbate the cognitive disturbances associated with Alzheimer’s disease and also have a black box warning for use in elderly patients with dementia-related psychosis due to increased risks of mortality and morbidity."

The trial was funded by Acadia. Dr. Ballard disclosed that he has received honoraria and consulting fees from the company.

msullivan@fronlinemedcom.com

On Twitter @Alz_Gal

* Correction 7/30/13: An earlier version of this article misstated pimavanserin's mechanism of action and the status of its New Drug Application.

BOSTON – A novel 5-HT_2A receptor inverse agonist significantly improved psychotic symptoms in Parkinson’s disease patients without the worsening of motor symptoms that usually occurs with antipsychotic treatment, according to the results of a randomized, placebo-controlled phase III trial.*

In addition to benefiting patients, the drug eased caregiver burden, Dr. Clive Ballard said at the Alzheimer’s Association International Conference 2013.

"By 4 weeks into the study, the benefit for caregivers began to appear, and it continued to increase" until the study ended at 6 weeks, said Dr. Ballard, professor of age-related diseases at King’s College London.

Parkinson’s psychosis is a common manifestation of the disease, and about 50% of patients will experience it, he said. "It’s not just frequent. It’s impactful. It’s distressing for patients and for those caring for them. It’s also associated with more impairment, with mortality, and it’s the leading cause of nursing home placement."

Sadly, he noted that there are not many medical options for the problem. Most antipsychotics produce extrapyramidal symptoms, which worsen parkinsonism. Atypical antipsychotics may be well tolerated, but are not very effective against the delusions and hallucinations that can occur in Parkinson’s patients.

"The situation in Parkinson’s is even worse than it is in Alzheimer’s. At least we do have some options for Alzheimer’s psychosis, even if they’re not great," Dr. Ballard said.

The atypical antipsychotics quetiapine and clozapine are the only well-tolerated options, he said. "Quetiapine is ineffective, though, leaving only clozapine. It’s well tolerated from a motor point of view, but it has other safety and tolerability issues that limit its use in clinical practice."

As a selective 5-HT_2A inverse agonist, pimavanserin is in a unique drug class. According to Acadia Pharmaceuticals, the company developing the drug, it has the benefits of a 5HT_2A agonist but doesn’t affect the dopaminergic, histaminergic, adrenergic, or muscarinic systems.

"Previous studies suggested that it was well tolerated and had some signal of potential benefit in psychosis," Dr. Ballard said. But those trials posted an unusually large placebo effect as well, making the results "difficult to interpret."

Investigators in the pimavanserin phase III study made a number of study design changes to compensate for the placebo response. In order to qualify for the trial, for example, patients had to have high baseline minimum scores on the Neuropsychiatric Inventory and the Scale for the Assessment of Positive Symptoms (SAPS).

They also took part in a brief psychosocial intervention before randomization. "In this intervention, the caregiver spends about 10 minutes each day with the patient, enabling the patient to do an activity they enjoy." This reduces the placebo response rate when the study medication commences, Dr. Ballard said.

The study also centralized any robust key findings, which were interpreted by independent, blinded raters.

The primary endpoint was antipsychotic efficacy as measured using the SAPS-PD, a nine-item scale adapted from the hallucinations and delusions domains of SAPS.

Secondary endpoints included the entire 20-item SAPS, the SAPS hallucinations and delusions subscores, the Clinical Global Impression (CGI) score, Unified Parkinson’s Disease Rating Scale (UPDRS) domains I and II, and a measure of caregiver burden.

The patients were randomized to 40 mg of pimavanserin daily (n = 105) or to placebo (n = 94) for 6 weeks. They were assessed at baseline and at 2, 4, and 6 weeks. After the randomization period, they could join a long-term, open-label extension study at the 40-mg/day dose. Most of the patients completed the trial protocol (87 in the placebo group and 89 in the pimavanserin group). Seven placebo patients dropped out, including two because of an adverse event. Of 15 patients in the pimavanserin group who dropped out, 10 did so because of adverse events. One patient randomized to pimavanserin did not take the medication.

At 6 weeks, patients in the active treatment group had significantly greater improvement on the SAPS-PD, the primary endpoint. By 15 days, both groups had experienced a significant improvement from baseline. Thereafter, the curves separated, with the placebo group becoming stable; Dr. Ballard said this indicated that the study design compensated for a large placebo response. The pimavanserin group, however, continued to improve. By the study’s end, there was a mean SAPS-PD decrease of 5.79 points in the active group, significantly better than the mean 2.73-point decrease in the placebo group. This translated to a 37% improvement for the study drug, compared with a 14% improvement for placebo.

The scores also translated into a meaningful clinical benefit, Dr. Ballard added. By the SAPS-PD measurement, response rates were 42% and 65%, respectively – a significant difference.

Changes on the CGI subscores were also significantly different. Patients in the placebo group experienced a mean decrease of less than half a point on the improvement subscale, compared with a decrease of about 1 point in the pimavanserin group. On the severity subscale, the placebo group stayed close to baseline, while the pimavanserin group decreased by about 1 point. About 27% of those taking placebo and 49% of those taking pimavanserin were considered responders.

Caregiver burden also significantly improved with the study drug.

In an exploratory analysis examining pimavanserin’s effect on sleep, the drug was associated with improvements in both nighttime sleep and daytime wakefulness on the Scale for Outcomes in Parkinson’s Disease sleep measure, Dr. Ballard said.

There were three deaths during the study – one in the placebo group (sudden cardiac death) and two in the active group (sepsis and septic shock). There were also four urinary tract infections – one in the placebo group and three in the active group. Other adverse events reported during the trial included peripheral edema (7% active vs. 3% placebo), falls (11% vs. 6%), confusion (6% vs. 3%), headache (1% vs. 5%), and hallucination (7% vs. 4%).

Based on the favorable results, Acadia announced that it had discontinued its work on a planned confirmatory phase III study. A New Drug Application for pimavanserin is in preparation, Dr. Ballard said.*

Acadia is also planning to study the drug’s effect in Alzheimer’s-associated psychosis in a phase II feasibility trial later this year, according to the company’s website.

"Similar to Parkinson’s disease psychosis, there is no therapy approved to treat Alzheimer’s psychosis in the U.S.," the company said in a written statement. "As symptoms progress and become more severe, physicians often resort to off-label use of antipsychotic medications in these patients. ... Antipsychotic drugs may exacerbate the cognitive disturbances associated with Alzheimer’s disease and also have a black box warning for use in elderly patients with dementia-related psychosis due to increased risks of mortality and morbidity."

The trial was funded by Acadia. Dr. Ballard disclosed that he has received honoraria and consulting fees from the company.

msullivan@fronlinemedcom.com

On Twitter @Alz_Gal

* Correction 7/30/13: An earlier version of this article misstated pimavanserin's mechanism of action and the status of its New Drug Application.