CTAD

PHILADELPHIA – Leuprolide acetate, in combination with an acetylcholinesterase inhibitor, helped to preserve cognitive function in Alzheimer’s disease patients in an exploratory study.

The study is small and the results are modest. But they do warrant further investigation in a larger group, Dr. Richard L. Bowen said at the Clinical Trials Conference on Alzheimer’s Disease.

Leuprolide acetate is an agonist of gonadotropin-releasing hormone (GnRH). Dr. Bowen, a family physician in Charleston, S.C., has long postulated that luteinizing hormone, which is highly present in Alzheimer’s brains – especially in the hippocampus – predisposes to cognitive decline. Some preclinical evidence exists to support the idea that luteinizing hormone may modulate amyloid precursor processing predisposing to amyloid plaque formation. Leuprolide’s effect of indirectly down-regulating the secretion of luteinizing hormone by desensitizing GnRH receptors improved cognition in a mouse model of Alzheimer’s, Dr. Bowen noted.

But it was actually a conversation about an Alzheimer’s patent with prostate cancer that sparked his 10-year work on leuprolide. “As a family practice physician, I was doing an annual exam on a postmenopausal woman, talking about the risks and benefits of hormone replacement therapy. She mentioned that her husband, who had Alzheimer’s, had been getting ‘some kind of hormone therapy’ for his prostate cancer. And she said very specifically that since he’d been on it he had not gotten any worse, and in fact, had improved a little,” he said in an interview.

This started Dr. Bowen to thinking about the relationship between gonadotropin suppression and its possible link to neurons and cognition. “Gonadotropins are very important in cell division and very high in fetal life – obviously important for fetal development, when you do want lots of cell division.”

Estrogen and testosterone eventually take center stage in human life, effectively shutting down gonadotropin production – for a while, at least. But when estrogen levels fall at menopause, gonadotropins rise again. “This could predispose terminally differentiated neurons – which aren’t supposed to divide – to cell division, thus, death.”

His theory holds that such a process could also increase amyloid burden. “This does seem to pan out in cellular and animal models, where the expression of gonadotropins in the brain perfectly correlates with amyloid deposition. It’s a coherent model of this disease that speaks to why and when we develop it.”

In 2004, Dr. Bowen and his colleagues published a paperdemonstrating that neuroblastoma cells exposed to luteinizing hormone showed a significant increase in amyloid precursor protein and a resultant increase in amyloidogenic processing.

That same paper found that leuprolide treatment in an ovariectomized Alzheimer’s mouse model decreased amyloid expression, suggesting that luteinizing hormone, not estrogen, drove the change.

At the meeting, he reported a 48-week, dose-ranging study of 109 women with mild to moderate Alzheimer’s. They received either placebo or leuprolide acetate injections with a low dose (11.25 mg) or high dose (22.5 mg), which were carried out over 12 weeks, with cognitive assessments conducted at regular intervals during the remainder of the study.

The primary endpoints were scores on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included the Neuropsychiatric Inventory, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Burden Interview, and ADCS-CGI Severity Rating.

There were no significant between-group differences in the ADAS-cog or the ADCS-CGIC scores in the entire group. But a preplanned subgroup analysis turned up an intriguing finding in the 78 patients who were also taking an acetylcholinesterase inhibitor (AChEI).

Although they didn’t improve cognitively, patients taking the combination of an AChEI and leuprolide held their scores at baseline level in the ADAS-cog and ADCS-CGIC throughout the 36-week follow-up period. At 48 weeks, mean ADAS-cog score declined by 3.3 in the placebo group, 4.1 in the low-dose combination group, and 0.18 in the high-dose combination group.

Results were similarly significant on the ADCS-CGIC measure, with mean declines of 63% and 82% in the placebo and low-dose groups, respectively, compared with a 38% decline in the high-dose group.

The subgroup analysis found no differences on the other measures.

Dr. Bowen said the results of his study are even more intriguing when viewed in light of a studypublished by investigators at the Dana Farber Cancer Institute that showed a 50% reduction in Alzheimer’s incidence in men who had received leuprolide for prostate cancer.

“This was remarkably similar to what we saw in our own 12-year Medicare database review,” which examined incident Alzheimer’s after prostate cancer, gallbladder surgery, hernia repair, and enlarged prostate. “Again, the decrease in the risk of developing Alzheimer’s associated with prostate cancer was about 50%.”

Dr. Bowen noted that his data are about 10 years old now. He holds a soon-to-expire patent on the use of leuprolide for Alzheimer’s and was pursuing that with a corporation. However, the company fell apart and he said he has become free to share the information only now.

But the data are enough for him to be using the treatment on at least a few patients. “I have about five or six people, both men and women, who are taking it in combination with an AChEI. The families are very happy with what they see, and I’m hoping we can get the word out so we can accumulate more data on it.”

[email protected]

On Twitter @alz_gal

PHILADELPHIA – Leuprolide acetate, in combination with an acetylcholinesterase inhibitor, helped to preserve cognitive function in Alzheimer’s disease patients in an exploratory study.

The study is small and the results are modest. But they do warrant further investigation in a larger group, Dr. Richard L. Bowen said at the Clinical Trials Conference on Alzheimer’s Disease.

Leuprolide acetate is an agonist of gonadotropin-releasing hormone (GnRH). Dr. Bowen, a family physician in Charleston, S.C., has long postulated that luteinizing hormone, which is highly present in Alzheimer’s brains – especially in the hippocampus – predisposes to cognitive decline. Some preclinical evidence exists to support the idea that luteinizing hormone may modulate amyloid precursor processing predisposing to amyloid plaque formation. Leuprolide’s effect of indirectly down-regulating the secretion of luteinizing hormone by desensitizing GnRH receptors improved cognition in a mouse model of Alzheimer’s, Dr. Bowen noted.

But it was actually a conversation about an Alzheimer’s patent with prostate cancer that sparked his 10-year work on leuprolide. “As a family practice physician, I was doing an annual exam on a postmenopausal woman, talking about the risks and benefits of hormone replacement therapy. She mentioned that her husband, who had Alzheimer’s, had been getting ‘some kind of hormone therapy’ for his prostate cancer. And she said very specifically that since he’d been on it he had not gotten any worse, and in fact, had improved a little,” he said in an interview.

This started Dr. Bowen to thinking about the relationship between gonadotropin suppression and its possible link to neurons and cognition. “Gonadotropins are very important in cell division and very high in fetal life – obviously important for fetal development, when you do want lots of cell division.”

Estrogen and testosterone eventually take center stage in human life, effectively shutting down gonadotropin production – for a while, at least. But when estrogen levels fall at menopause, gonadotropins rise again. “This could predispose terminally differentiated neurons – which aren’t supposed to divide – to cell division, thus, death.”

His theory holds that such a process could also increase amyloid burden. “This does seem to pan out in cellular and animal models, where the expression of gonadotropins in the brain perfectly correlates with amyloid deposition. It’s a coherent model of this disease that speaks to why and when we develop it.”

In 2004, Dr. Bowen and his colleagues published a paperdemonstrating that neuroblastoma cells exposed to luteinizing hormone showed a significant increase in amyloid precursor protein and a resultant increase in amyloidogenic processing.

That same paper found that leuprolide treatment in an ovariectomized Alzheimer’s mouse model decreased amyloid expression, suggesting that luteinizing hormone, not estrogen, drove the change.

At the meeting, he reported a 48-week, dose-ranging study of 109 women with mild to moderate Alzheimer’s. They received either placebo or leuprolide acetate injections with a low dose (11.25 mg) or high dose (22.5 mg), which were carried out over 12 weeks, with cognitive assessments conducted at regular intervals during the remainder of the study.

The primary endpoints were scores on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included the Neuropsychiatric Inventory, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Burden Interview, and ADCS-CGI Severity Rating.

There were no significant between-group differences in the ADAS-cog or the ADCS-CGIC scores in the entire group. But a preplanned subgroup analysis turned up an intriguing finding in the 78 patients who were also taking an acetylcholinesterase inhibitor (AChEI).

Although they didn’t improve cognitively, patients taking the combination of an AChEI and leuprolide held their scores at baseline level in the ADAS-cog and ADCS-CGIC throughout the 36-week follow-up period. At 48 weeks, mean ADAS-cog score declined by 3.3 in the placebo group, 4.1 in the low-dose combination group, and 0.18 in the high-dose combination group.

Results were similarly significant on the ADCS-CGIC measure, with mean declines of 63% and 82% in the placebo and low-dose groups, respectively, compared with a 38% decline in the high-dose group.

The subgroup analysis found no differences on the other measures.

Dr. Bowen said the results of his study are even more intriguing when viewed in light of a studypublished by investigators at the Dana Farber Cancer Institute that showed a 50% reduction in Alzheimer’s incidence in men who had received leuprolide for prostate cancer.

“This was remarkably similar to what we saw in our own 12-year Medicare database review,” which examined incident Alzheimer’s after prostate cancer, gallbladder surgery, hernia repair, and enlarged prostate. “Again, the decrease in the risk of developing Alzheimer’s associated with prostate cancer was about 50%.”

Dr. Bowen noted that his data are about 10 years old now. He holds a soon-to-expire patent on the use of leuprolide for Alzheimer’s and was pursuing that with a corporation. However, the company fell apart and he said he has become free to share the information only now.

But the data are enough for him to be using the treatment on at least a few patients. “I have about five or six people, both men and women, who are taking it in combination with an AChEI. The families are very happy with what they see, and I’m hoping we can get the word out so we can accumulate more data on it.”

[email protected]

On Twitter @alz_gal

PHILADELPHIA – Leuprolide acetate, in combination with an acetylcholinesterase inhibitor, helped to preserve cognitive function in Alzheimer’s disease patients in an exploratory study.

The study is small and the results are modest. But they do warrant further investigation in a larger group, Dr. Richard L. Bowen said at the Clinical Trials Conference on Alzheimer’s Disease.

Leuprolide acetate is an agonist of gonadotropin-releasing hormone (GnRH). Dr. Bowen, a family physician in Charleston, S.C., has long postulated that luteinizing hormone, which is highly present in Alzheimer’s brains – especially in the hippocampus – predisposes to cognitive decline. Some preclinical evidence exists to support the idea that luteinizing hormone may modulate amyloid precursor processing predisposing to amyloid plaque formation. Leuprolide’s effect of indirectly down-regulating the secretion of luteinizing hormone by desensitizing GnRH receptors improved cognition in a mouse model of Alzheimer’s, Dr. Bowen noted.

But it was actually a conversation about an Alzheimer’s patent with prostate cancer that sparked his 10-year work on leuprolide. “As a family practice physician, I was doing an annual exam on a postmenopausal woman, talking about the risks and benefits of hormone replacement therapy. She mentioned that her husband, who had Alzheimer’s, had been getting ‘some kind of hormone therapy’ for his prostate cancer. And she said very specifically that since he’d been on it he had not gotten any worse, and in fact, had improved a little,” he said in an interview.

This started Dr. Bowen to thinking about the relationship between gonadotropin suppression and its possible link to neurons and cognition. “Gonadotropins are very important in cell division and very high in fetal life – obviously important for fetal development, when you do want lots of cell division.”

Estrogen and testosterone eventually take center stage in human life, effectively shutting down gonadotropin production – for a while, at least. But when estrogen levels fall at menopause, gonadotropins rise again. “This could predispose terminally differentiated neurons – which aren’t supposed to divide – to cell division, thus, death.”

His theory holds that such a process could also increase amyloid burden. “This does seem to pan out in cellular and animal models, where the expression of gonadotropins in the brain perfectly correlates with amyloid deposition. It’s a coherent model of this disease that speaks to why and when we develop it.”

In 2004, Dr. Bowen and his colleagues published a paperdemonstrating that neuroblastoma cells exposed to luteinizing hormone showed a significant increase in amyloid precursor protein and a resultant increase in amyloidogenic processing.

That same paper found that leuprolide treatment in an ovariectomized Alzheimer’s mouse model decreased amyloid expression, suggesting that luteinizing hormone, not estrogen, drove the change.

At the meeting, he reported a 48-week, dose-ranging study of 109 women with mild to moderate Alzheimer’s. They received either placebo or leuprolide acetate injections with a low dose (11.25 mg) or high dose (22.5 mg), which were carried out over 12 weeks, with cognitive assessments conducted at regular intervals during the remainder of the study.

The primary endpoints were scores on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included the Neuropsychiatric Inventory, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), Burden Interview, and ADCS-CGI Severity Rating.

There were no significant between-group differences in the ADAS-cog or the ADCS-CGIC scores in the entire group. But a preplanned subgroup analysis turned up an intriguing finding in the 78 patients who were also taking an acetylcholinesterase inhibitor (AChEI).

Although they didn’t improve cognitively, patients taking the combination of an AChEI and leuprolide held their scores at baseline level in the ADAS-cog and ADCS-CGIC throughout the 36-week follow-up period. At 48 weeks, mean ADAS-cog score declined by 3.3 in the placebo group, 4.1 in the low-dose combination group, and 0.18 in the high-dose combination group.

Results were similarly significant on the ADCS-CGIC measure, with mean declines of 63% and 82% in the placebo and low-dose groups, respectively, compared with a 38% decline in the high-dose group.

The subgroup analysis found no differences on the other measures.

Dr. Bowen said the results of his study are even more intriguing when viewed in light of a studypublished by investigators at the Dana Farber Cancer Institute that showed a 50% reduction in Alzheimer’s incidence in men who had received leuprolide for prostate cancer.

“This was remarkably similar to what we saw in our own 12-year Medicare database review,” which examined incident Alzheimer’s after prostate cancer, gallbladder surgery, hernia repair, and enlarged prostate. “Again, the decrease in the risk of developing Alzheimer’s associated with prostate cancer was about 50%.”

Dr. Bowen noted that his data are about 10 years old now. He holds a soon-to-expire patent on the use of leuprolide for Alzheimer’s and was pursuing that with a corporation. However, the company fell apart and he said he has become free to share the information only now.

But the data are enough for him to be using the treatment on at least a few patients. “I have about five or six people, both men and women, who are taking it in combination with an AChEI. The families are very happy with what they see, and I’m hoping we can get the word out so we can accumulate more data on it.”

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An amyloid PET scan with florbetapir detected which patients with mild cognitive impairment had a high risk for further cognitive decline to Alzheimer’s disease in a large analysis of patients in the Alzheimer’s Disease Neuroimaging Initiative.

Participants who tested positive for amyloid on florbetapir (Amyvid) PET scan at baseline were five times more likely to convert to Alzheimer’s dementia within 3 years than were amyloid-negative subjects, according to data from the large, multisite imaging registry.

The finding suggests that amyloid imaging could help rule out Alzheimer’s as the underlying cause of cognitive problems, allowing physicians to focus more closely on other potential diagnoses, said Mr. Ming Lu, lead statistician at Avid Radiopharmaceuticals, a subsidiary of Eli Lilly,which markets florbetapir and sponsored the study.

“This study supports the hypothesis that amyloid PET scans are able to detect those levels of AD pathology that are associated with risk of cognitive decline, even in subjects that are not showing evidence of dementia,” Mr. Lu said in an interview at the Clinical Trials Conference on Alzheimer’s Disease, where he presented the study. “It also underscores the potential importance of diagnosing the cause of someone’s cognitive decline earlier rather than later, as this may provide useful information for physician’s management/treatment plan on these patients.”

Similar findings have been previously noted in smaller studies; this one, comprising 478 subjects, is the largest prospective study to date to look at the issue.

On PET imaging, florbetapir binds to amyloid plaques, a pathophysiologic hallmark of Alzheimer’s. So far, the agent is used only in studies of patients with diagnosed mild cognitive impairment (MCI) or Alzheimer’s disease, and patients are limited to one scan. It is not covered by Medicare in clinical use.

The patients had a mean age of 72 years, but ranged from 48 to 91 years. All had undergone at least one florbetapir scan as well as extensive cognitive testing with a variety of instruments, including the widely used Mini-Mental State Examination (MMSE), the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), and the Clinical Dementia Rating-Sum of Boxes (CDR-SB).

On imaging, 212 were amyloid negative and 266 were amyloid positive. Over a 3-year follow-up period, amyloid-positive patients declined a mean of 4.03 points on the ADAS-cog, compared with 0.26 points for amyloid-negative patients. Amyloid-positive patients declined 2.61 points on the MMSE, compared with 0.40 in the negative patients, and on the CDR-SB, the change was 1.53 vs. –0.11 points. All of these changes were statistically significant, Mr. Lu said.

Declines of this magnitude would correlate with significant clinical changes, Mr. Lu noted. Compared with the amyloid-negative patients, the amyloid-positive patients had a twofold higher risk to progress to a clinically significant change (ADAS-cog score decline of 4 points or more), and nearly a fivefold higher risk of conversion to Alzheimer’s.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An amyloid PET scan with florbetapir detected which patients with mild cognitive impairment had a high risk for further cognitive decline to Alzheimer’s disease in a large analysis of patients in the Alzheimer’s Disease Neuroimaging Initiative.

Participants who tested positive for amyloid on florbetapir (Amyvid) PET scan at baseline were five times more likely to convert to Alzheimer’s dementia within 3 years than were amyloid-negative subjects, according to data from the large, multisite imaging registry.

The finding suggests that amyloid imaging could help rule out Alzheimer’s as the underlying cause of cognitive problems, allowing physicians to focus more closely on other potential diagnoses, said Mr. Ming Lu, lead statistician at Avid Radiopharmaceuticals, a subsidiary of Eli Lilly,which markets florbetapir and sponsored the study.

“This study supports the hypothesis that amyloid PET scans are able to detect those levels of AD pathology that are associated with risk of cognitive decline, even in subjects that are not showing evidence of dementia,” Mr. Lu said in an interview at the Clinical Trials Conference on Alzheimer’s Disease, where he presented the study. “It also underscores the potential importance of diagnosing the cause of someone’s cognitive decline earlier rather than later, as this may provide useful information for physician’s management/treatment plan on these patients.”

Similar findings have been previously noted in smaller studies; this one, comprising 478 subjects, is the largest prospective study to date to look at the issue.

On PET imaging, florbetapir binds to amyloid plaques, a pathophysiologic hallmark of Alzheimer’s. So far, the agent is used only in studies of patients with diagnosed mild cognitive impairment (MCI) or Alzheimer’s disease, and patients are limited to one scan. It is not covered by Medicare in clinical use.

The patients had a mean age of 72 years, but ranged from 48 to 91 years. All had undergone at least one florbetapir scan as well as extensive cognitive testing with a variety of instruments, including the widely used Mini-Mental State Examination (MMSE), the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), and the Clinical Dementia Rating-Sum of Boxes (CDR-SB).

On imaging, 212 were amyloid negative and 266 were amyloid positive. Over a 3-year follow-up period, amyloid-positive patients declined a mean of 4.03 points on the ADAS-cog, compared with 0.26 points for amyloid-negative patients. Amyloid-positive patients declined 2.61 points on the MMSE, compared with 0.40 in the negative patients, and on the CDR-SB, the change was 1.53 vs. –0.11 points. All of these changes were statistically significant, Mr. Lu said.

Declines of this magnitude would correlate with significant clinical changes, Mr. Lu noted. Compared with the amyloid-negative patients, the amyloid-positive patients had a twofold higher risk to progress to a clinically significant change (ADAS-cog score decline of 4 points or more), and nearly a fivefold higher risk of conversion to Alzheimer’s.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An amyloid PET scan with florbetapir detected which patients with mild cognitive impairment had a high risk for further cognitive decline to Alzheimer’s disease in a large analysis of patients in the Alzheimer’s Disease Neuroimaging Initiative.

Participants who tested positive for amyloid on florbetapir (Amyvid) PET scan at baseline were five times more likely to convert to Alzheimer’s dementia within 3 years than were amyloid-negative subjects, according to data from the large, multisite imaging registry.

The finding suggests that amyloid imaging could help rule out Alzheimer’s as the underlying cause of cognitive problems, allowing physicians to focus more closely on other potential diagnoses, said Mr. Ming Lu, lead statistician at Avid Radiopharmaceuticals, a subsidiary of Eli Lilly,which markets florbetapir and sponsored the study.

“This study supports the hypothesis that amyloid PET scans are able to detect those levels of AD pathology that are associated with risk of cognitive decline, even in subjects that are not showing evidence of dementia,” Mr. Lu said in an interview at the Clinical Trials Conference on Alzheimer’s Disease, where he presented the study. “It also underscores the potential importance of diagnosing the cause of someone’s cognitive decline earlier rather than later, as this may provide useful information for physician’s management/treatment plan on these patients.”

Similar findings have been previously noted in smaller studies; this one, comprising 478 subjects, is the largest prospective study to date to look at the issue.

On PET imaging, florbetapir binds to amyloid plaques, a pathophysiologic hallmark of Alzheimer’s. So far, the agent is used only in studies of patients with diagnosed mild cognitive impairment (MCI) or Alzheimer’s disease, and patients are limited to one scan. It is not covered by Medicare in clinical use.

The patients had a mean age of 72 years, but ranged from 48 to 91 years. All had undergone at least one florbetapir scan as well as extensive cognitive testing with a variety of instruments, including the widely used Mini-Mental State Examination (MMSE), the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), and the Clinical Dementia Rating-Sum of Boxes (CDR-SB).

On imaging, 212 were amyloid negative and 266 were amyloid positive. Over a 3-year follow-up period, amyloid-positive patients declined a mean of 4.03 points on the ADAS-cog, compared with 0.26 points for amyloid-negative patients. Amyloid-positive patients declined 2.61 points on the MMSE, compared with 0.40 in the negative patients, and on the CDR-SB, the change was 1.53 vs. –0.11 points. All of these changes were statistically significant, Mr. Lu said.

Declines of this magnitude would correlate with significant clinical changes, Mr. Lu noted. Compared with the amyloid-negative patients, the amyloid-positive patients had a twofold higher risk to progress to a clinically significant change (ADAS-cog score decline of 4 points or more), and nearly a fivefold higher risk of conversion to Alzheimer’s.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

Continued on next page >>

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

Continued on next page >>

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

Continued on next page >>

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – A combination drug of dextromethorphan and quinidine significantly reduced aggression and agitation in patients with Alzheimer’s disease.

Associated with those improvements were significant reductions in measures of caregiver strain and distress, Dr. Erik Pioro said at the Clinical Trials Conference on Alzheimer’s Disease.

“These were very clear, stable, and statistically and clinically meaningful differences,” when compared with patients who received placebo, said Dr. Pioro, director of the Section of Amyotrophic Lateral Sclerosis and Related Disorders at the Cleveland Clinic.

The drug, Nuedexta, is already approved for pseudobulbar affect and is being investigated as AVP-923 for several other indications, including depression, migraine, neuropathic pain, autism, and Parkinson’s disease dyskinesia.

This phase II trial comprised 220 patients with moderate Alzheimer’s who displayed clinically significant agitation or aggression as measured by the Neuropsychiatric Inventory (NPI) and the Clinical Global Impressions Scale.

Most (87%) were living at home, about 5% were in nursing homes, and the remainder were in assisted living facilities. At baseline, 74% were taking cholinesterase inhibitors; 50%, memantine; 56%, an antidepressant (including trazodone); 21%, an antipsychotic; and 8%, a benzodiazepine.

As measured by scores on the NPI, 92% displayed clinically significant aggression; 70%, irritability/lability; 52%, apathy/indifference; and 47%, anxiety and aberrant motor behaviors. About a third of the group had nighttime behavioral disorders, depression, dysphoria, delusions, disinhibition, elation, and hallucinations.

“These symptoms had to be severe enough that their physician would normally consider pharmacological treatment for them even if they were not enrolled in this trial,” Dr. Pioro said.

They were randomized to dextromethorphan hydrobromide and quinidine sulfate (20 mg/10 mg) or placebo for 10 weeks. Patients in the active group stayed on the study drug for the entire time. Those in the placebo group were assessed for response; 30 of these had improved on placebo. These were rerandomized to active and placebo groups. Placebo nonresponders were also rerandomized to the drug or placebo.

This allowed not only for a comparison of groups who had taken the drug or placebo for the full study, but also for the investigators to accurately tease out any placebo effects.

By the end of the first 5-week phase, patients in the active group experienced a mean improvement of 3.3 points on the NPI aggression subscale, which was significantly better than the 1.7-point improvement seen among those taking placebo.

After the placebo nonresponders had been rerandomized and treated for another 5 weeks, those taking the study drug had a mean 2-point improvement, compared with a 0.8-point improvement among those taking placebo.

In the group that been on their originally assigned treatment for the entire 10 weeks, those taking the study drug again fared significantly better (a mean improvement of about 4.5 points vs. 1.5 points with placebo).

In all randomization schemes, the clinical and physicians’ global impression improved significantly more in the active group than in the placebo group.

The total NPI score improved significantly more in the active group (13.5 vs. 8.5 points for those who had been on the same treatments for 10 weeks). NPI symptom clusters showed the same pattern of improvement favoring the study drug.

Measurements of caregiver response based on the Caregivers Strain Index and the NPI Caregiver Distress Score both significantly improved more for caregivers of patients taking the study drug for 10 weeks, compared to those taking placebo.

Treatment-emergent adverse events were significantly more common among the patients who took the study drug (61% vs. 43%). The most common were falls (9% vs. 4%), diarrhea (6% vs. 3%), urinary tract infection (5% vs. 4%), and dizziness (5% vs. 2.5%). These caused 5% of patients taking the drug and 3% taking placebo to discontinue treatment.

Dr. Pioro is a consultant for Avanir, which manufactures Nuedexta.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An investigational 5-HT6 inhibitor in combination with donepezil significantly boosted cognition in patients with moderate Alzheimer’s disease and has advanced into three placebo-controlled phase III trials.

The investigational drug, idalopirdine, is a potent antagonist of the 5-HT6 receptor, which plays a key part in neurotransmission in the cerebral cortex and hippocampus. When activated, it inhibits glutamatergic, noradrenergic, and dopaminergic transmission, and it inhibits cholinergic function when blocked. The drug seems to enhance acetylcholine and glutamate signaling by blocking this system, Dr. Alireza Atri said at the Clinical Trials Conference on Alzheimer’s Disease.

Rat studies showed that combining idalopirdine with the acetylcholinesterase inhibitor improved cognition. The effect seen only when the two drugs were combined, said Dr. Atri of Massachusetts General Hospital, Boston. “Vehicle/vehicle and vehicle/ idalopirdine effected no change at all. But the combination gave us a nice augmentation of potentiation that lasted quite a long time.”

However, idalopirdine’s lack of an effect when not used in combination with donepezil may signal that it’s inhibitory effect on CYP206 just serves to increase the bioavailability of donepezil, which is metabolized by CYP206, according to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center, Los Angeles.

The preclinical experiments with idalopirdine were sufficient to launch the phase II trial, Dr. Atri said. It comprised 278 patients with moderate Alzheimer’s; all were already taking donepezil 10 mg. They were randomized to placebo plus their donepezil or to idalopirdine 90 mg/day plus donepezil. Treatment lasted 24 weeks, which included a 2-week donepezil run-in and a 2-week washout. The trial was published in the November issue of Lancet Neurology (2014;13:1092-9).

The primary endpoints were cognitive change as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and safety and tolerability. Secondary endpoints were the clinical outcomes on the Alzheimer’s Disease Cooperative Study measures, including clinical global impression (ADCS-CGI), activities of daily living (ADCS-ADL), and behavioral symptoms.

Mean age of the patients was 74.5 years, and about 70% were women. They had been diagnosed about 2 years prior to the start of the study and had used donepezil for about 1.5 years. Their mean Mini Mental State Exam score was 17, and their mean ADAS-Cog score was 28.

At week 24, scores in the placebo group worsened by about 1.4 points from baseline (indicating cognitive decline) while those in the idalopirdine group had improved by about 1 point from baseline. The 24-week score spread was slightly more than 2 points, which is a statistically and clinically significant difference, Dr. Atri said. None of the changes on the secondary endpoints were significant.

Adverse events caused 25 patients to discontinue treatment (18 taking the study drug and 7 taking placebo). The most common were increased liver enzymes, which were transient and discovered incidentally during routine blood work (10% with idalopirdine vs. 2% with placebo); diarrhea (4% vs. 7%); urinary tract infection (2% vs. 7%); falls (2% vs. 6%); and benign prostatic hyperplasia (5% vs. 0%). One death occurred in each treatment group; neither was regarded as being related to treatment.

The analysis included 12 measures of behavior. “On eight of these, there was not even a whiff of a signal,” Dr. Atri said. “On two – depression and dysphoria/appetite – there was maybe a hint of an effect, at least enough to keep and eye on.” The other measures showed nonsignificant differences.

The codevelopers of idalopirdine, Lundbeck and Otsuka, will continue to study the drug in three phase III trials, he said.

STARSHINE will randomize an estimated 930 patients to 30 mg or 60 mg idalopirdine plus donepezil or placebo for 20 weeks followed by a 4-week donepezil washout.

STARBEAM will randomize 840 patients to donepezil plus 10 mg or 30 mg idalopirdine for 20 weeks, followed by a 4-week donepezil washout.

STARBRIGHT will randomize 720 patients to any acetylcholinesterase inhibitor plus 60 mg idalopirdine for 20 weeks, plus a 4-week acetylcholinesterase inhibitor washout.

A 24-week open-label extension of donepezil plus 60 mg idalopirdine is also planned.

While Dr. Atri suggested that the drug exerts a direct effect on neurotransmission, Dr. Schneider suggested that it could simply be potentiating the effect of donepezil.

Idalopirdine is a potent inhibitor of CYP206 and its use will probably increase the bioavailability of the many drugs that depend on CYP206 for their clearance, including donepezil. In this trial, bioavailability of donepezil increased by 10%. A pharmacokinetic action could have been the real driver of results, Dr. Schneider said in an interview.

He questioned the wisdom of pursuing a drug that may have little inherent action.

“If as a hypothetical, the drug is inactive itself, but blocks an enzyme responsible for metabolizing donepezil, and donepezil levels rise and cause improvement, then one can’t say that the drug in question is effective. One can’t even say that the ‘combination’ is effective. Would you take a drug that may have side effects such as liver toxicity and others, just so it can block an enzyme to raise the level of another drug, and especially when several marketed drugs may do the same? What would likely happen if the drug group showed advantageous effects in these STAR trials is that sensitivity analyses would be done to help assess whether the drug also had an effect or what the contribution of donepezil levels was to the effect.”

Dr. Atri is on advisory board for several pharmaceutical companies, but has no financial ties with Lundbeck or Otsuka. Dr. Schneider has financial relationships with a number of pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An investigational 5-HT6 inhibitor in combination with donepezil significantly boosted cognition in patients with moderate Alzheimer’s disease and has advanced into three placebo-controlled phase III trials.

The investigational drug, idalopirdine, is a potent antagonist of the 5-HT6 receptor, which plays a key part in neurotransmission in the cerebral cortex and hippocampus. When activated, it inhibits glutamatergic, noradrenergic, and dopaminergic transmission, and it inhibits cholinergic function when blocked. The drug seems to enhance acetylcholine and glutamate signaling by blocking this system, Dr. Alireza Atri said at the Clinical Trials Conference on Alzheimer’s Disease.

Rat studies showed that combining idalopirdine with the acetylcholinesterase inhibitor improved cognition. The effect seen only when the two drugs were combined, said Dr. Atri of Massachusetts General Hospital, Boston. “Vehicle/vehicle and vehicle/ idalopirdine effected no change at all. But the combination gave us a nice augmentation of potentiation that lasted quite a long time.”

However, idalopirdine’s lack of an effect when not used in combination with donepezil may signal that it’s inhibitory effect on CYP206 just serves to increase the bioavailability of donepezil, which is metabolized by CYP206, according to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center, Los Angeles.

The preclinical experiments with idalopirdine were sufficient to launch the phase II trial, Dr. Atri said. It comprised 278 patients with moderate Alzheimer’s; all were already taking donepezil 10 mg. They were randomized to placebo plus their donepezil or to idalopirdine 90 mg/day plus donepezil. Treatment lasted 24 weeks, which included a 2-week donepezil run-in and a 2-week washout. The trial was published in the November issue of Lancet Neurology (2014;13:1092-9).

The primary endpoints were cognitive change as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and safety and tolerability. Secondary endpoints were the clinical outcomes on the Alzheimer’s Disease Cooperative Study measures, including clinical global impression (ADCS-CGI), activities of daily living (ADCS-ADL), and behavioral symptoms.

Mean age of the patients was 74.5 years, and about 70% were women. They had been diagnosed about 2 years prior to the start of the study and had used donepezil for about 1.5 years. Their mean Mini Mental State Exam score was 17, and their mean ADAS-Cog score was 28.

At week 24, scores in the placebo group worsened by about 1.4 points from baseline (indicating cognitive decline) while those in the idalopirdine group had improved by about 1 point from baseline. The 24-week score spread was slightly more than 2 points, which is a statistically and clinically significant difference, Dr. Atri said. None of the changes on the secondary endpoints were significant.

Adverse events caused 25 patients to discontinue treatment (18 taking the study drug and 7 taking placebo). The most common were increased liver enzymes, which were transient and discovered incidentally during routine blood work (10% with idalopirdine vs. 2% with placebo); diarrhea (4% vs. 7%); urinary tract infection (2% vs. 7%); falls (2% vs. 6%); and benign prostatic hyperplasia (5% vs. 0%). One death occurred in each treatment group; neither was regarded as being related to treatment.

The analysis included 12 measures of behavior. “On eight of these, there was not even a whiff of a signal,” Dr. Atri said. “On two – depression and dysphoria/appetite – there was maybe a hint of an effect, at least enough to keep and eye on.” The other measures showed nonsignificant differences.

The codevelopers of idalopirdine, Lundbeck and Otsuka, will continue to study the drug in three phase III trials, he said.

STARSHINE will randomize an estimated 930 patients to 30 mg or 60 mg idalopirdine plus donepezil or placebo for 20 weeks followed by a 4-week donepezil washout.

STARBEAM will randomize 840 patients to donepezil plus 10 mg or 30 mg idalopirdine for 20 weeks, followed by a 4-week donepezil washout.

STARBRIGHT will randomize 720 patients to any acetylcholinesterase inhibitor plus 60 mg idalopirdine for 20 weeks, plus a 4-week acetylcholinesterase inhibitor washout.

A 24-week open-label extension of donepezil plus 60 mg idalopirdine is also planned.

While Dr. Atri suggested that the drug exerts a direct effect on neurotransmission, Dr. Schneider suggested that it could simply be potentiating the effect of donepezil.

Idalopirdine is a potent inhibitor of CYP206 and its use will probably increase the bioavailability of the many drugs that depend on CYP206 for their clearance, including donepezil. In this trial, bioavailability of donepezil increased by 10%. A pharmacokinetic action could have been the real driver of results, Dr. Schneider said in an interview.

He questioned the wisdom of pursuing a drug that may have little inherent action.

“If as a hypothetical, the drug is inactive itself, but blocks an enzyme responsible for metabolizing donepezil, and donepezil levels rise and cause improvement, then one can’t say that the drug in question is effective. One can’t even say that the ‘combination’ is effective. Would you take a drug that may have side effects such as liver toxicity and others, just so it can block an enzyme to raise the level of another drug, and especially when several marketed drugs may do the same? What would likely happen if the drug group showed advantageous effects in these STAR trials is that sensitivity analyses would be done to help assess whether the drug also had an effect or what the contribution of donepezil levels was to the effect.”

Dr. Atri is on advisory board for several pharmaceutical companies, but has no financial ties with Lundbeck or Otsuka. Dr. Schneider has financial relationships with a number of pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – An investigational 5-HT6 inhibitor in combination with donepezil significantly boosted cognition in patients with moderate Alzheimer’s disease and has advanced into three placebo-controlled phase III trials.

The investigational drug, idalopirdine, is a potent antagonist of the 5-HT6 receptor, which plays a key part in neurotransmission in the cerebral cortex and hippocampus. When activated, it inhibits glutamatergic, noradrenergic, and dopaminergic transmission, and it inhibits cholinergic function when blocked. The drug seems to enhance acetylcholine and glutamate signaling by blocking this system, Dr. Alireza Atri said at the Clinical Trials Conference on Alzheimer’s Disease.

Rat studies showed that combining idalopirdine with the acetylcholinesterase inhibitor improved cognition. The effect seen only when the two drugs were combined, said Dr. Atri of Massachusetts General Hospital, Boston. “Vehicle/vehicle and vehicle/ idalopirdine effected no change at all. But the combination gave us a nice augmentation of potentiation that lasted quite a long time.”

However, idalopirdine’s lack of an effect when not used in combination with donepezil may signal that it’s inhibitory effect on CYP206 just serves to increase the bioavailability of donepezil, which is metabolized by CYP206, according to Dr. Lon Schneider, director of the California Alzheimer’s Disease Center, Los Angeles.

The preclinical experiments with idalopirdine were sufficient to launch the phase II trial, Dr. Atri said. It comprised 278 patients with moderate Alzheimer’s; all were already taking donepezil 10 mg. They were randomized to placebo plus their donepezil or to idalopirdine 90 mg/day plus donepezil. Treatment lasted 24 weeks, which included a 2-week donepezil run-in and a 2-week washout. The trial was published in the November issue of Lancet Neurology (2014;13:1092-9).

The primary endpoints were cognitive change as measured by the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog) and safety and tolerability. Secondary endpoints were the clinical outcomes on the Alzheimer’s Disease Cooperative Study measures, including clinical global impression (ADCS-CGI), activities of daily living (ADCS-ADL), and behavioral symptoms.

Mean age of the patients was 74.5 years, and about 70% were women. They had been diagnosed about 2 years prior to the start of the study and had used donepezil for about 1.5 years. Their mean Mini Mental State Exam score was 17, and their mean ADAS-Cog score was 28.

At week 24, scores in the placebo group worsened by about 1.4 points from baseline (indicating cognitive decline) while those in the idalopirdine group had improved by about 1 point from baseline. The 24-week score spread was slightly more than 2 points, which is a statistically and clinically significant difference, Dr. Atri said. None of the changes on the secondary endpoints were significant.

Adverse events caused 25 patients to discontinue treatment (18 taking the study drug and 7 taking placebo). The most common were increased liver enzymes, which were transient and discovered incidentally during routine blood work (10% with idalopirdine vs. 2% with placebo); diarrhea (4% vs. 7%); urinary tract infection (2% vs. 7%); falls (2% vs. 6%); and benign prostatic hyperplasia (5% vs. 0%). One death occurred in each treatment group; neither was regarded as being related to treatment.

The analysis included 12 measures of behavior. “On eight of these, there was not even a whiff of a signal,” Dr. Atri said. “On two – depression and dysphoria/appetite – there was maybe a hint of an effect, at least enough to keep and eye on.” The other measures showed nonsignificant differences.

The codevelopers of idalopirdine, Lundbeck and Otsuka, will continue to study the drug in three phase III trials, he said.

STARSHINE will randomize an estimated 930 patients to 30 mg or 60 mg idalopirdine plus donepezil or placebo for 20 weeks followed by a 4-week donepezil washout.

STARBEAM will randomize 840 patients to donepezil plus 10 mg or 30 mg idalopirdine for 20 weeks, followed by a 4-week donepezil washout.

STARBRIGHT will randomize 720 patients to any acetylcholinesterase inhibitor plus 60 mg idalopirdine for 20 weeks, plus a 4-week acetylcholinesterase inhibitor washout.

A 24-week open-label extension of donepezil plus 60 mg idalopirdine is also planned.

While Dr. Atri suggested that the drug exerts a direct effect on neurotransmission, Dr. Schneider suggested that it could simply be potentiating the effect of donepezil.

Idalopirdine is a potent inhibitor of CYP206 and its use will probably increase the bioavailability of the many drugs that depend on CYP206 for their clearance, including donepezil. In this trial, bioavailability of donepezil increased by 10%. A pharmacokinetic action could have been the real driver of results, Dr. Schneider said in an interview.

He questioned the wisdom of pursuing a drug that may have little inherent action.

“If as a hypothetical, the drug is inactive itself, but blocks an enzyme responsible for metabolizing donepezil, and donepezil levels rise and cause improvement, then one can’t say that the drug in question is effective. One can’t even say that the ‘combination’ is effective. Would you take a drug that may have side effects such as liver toxicity and others, just so it can block an enzyme to raise the level of another drug, and especially when several marketed drugs may do the same? What would likely happen if the drug group showed advantageous effects in these STAR trials is that sensitivity analyses would be done to help assess whether the drug also had an effect or what the contribution of donepezil levels was to the effect.”

Dr. Atri is on advisory board for several pharmaceutical companies, but has no financial ties with Lundbeck or Otsuka. Dr. Schneider has financial relationships with a number of pharmaceutical companies.

[email protected]

On Twitter @alz_gal

PHILADELPHIA – Despite some tantalizing hints of efficacy, the antiamyloid antibody crenezumab failed overall to post significant imaging and biomarker results in a phase II study.

The drug did not effect any statistically significant changes in amyloid plaque burden on PET imaging in the prespecified analysis, Dr. Steven Salloway said at the Clinical Trials Conference on Alzheimer’s Disease. A secondary assessment using a different technique yielded slightly better, although still nonsignificant, results.

There was a slight increase in serum amyloid beta 42 (Abeta42), but no effect at all on serum total or phosphorylated tau, said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I.

The lackluster findings, combined with crenezumab’s failure to meet cognitive and functional endpoints in this and a companion study announced last July, are prompting questions about the antibody’s future, Dr. Salloway said. “As a result of these clinical trials ... the company is in discussion with regulators about further development of crenezumab, although no decision has been made.”

These new data will not, however, endanger the landmark API (Alzheimer’s Prevention Initiative–Autosomal Dominant Alzheimer’s Disease Treatment Trial), now launching in Colombia. Crenezumab is the active treatment in this first-ever primary prevention trial.

In fact, these new imaging and biomarker data have led to a dosing protocol change for the API study. Originally, the study called for the 300-mg bimonthly subcutaneous dose; instead, it will use the IV dosing equivalent, a company spokesperson said in an interview.

“Based on the learnings from the crenezumab exploratory data, which may suggest greater benefit in [patients with mild Alzheimer’s disease] treated with the higher IV dose, Genentech is taking next steps to enable use of a higher subcutaneous dose in the API study,” said Carole Ho. She noted that the ongoing extension studies will also drop the subcutaneous dose in favor of IV dosing.

The 69-week study, dubbed BLAZE, looked at 91 patients with mild to moderate, imaging-proven Alzheimer’s disease. They were randomized to either crenezumab 300 mg subcutaneously every other week, 15 mg/kg intravenously once a month, or matching placebo in each arm.

The study group was a typical Alzheimer’s cohort, with a mean age of about 69 years. The Mini-Mental State Exam scores ranged from 18 to 26 (mean score, about 21).

At baseline, all patients had amyloid PET imaging, fluorodeoxyglucose (FDG)-PET imaging, cerebrospinal fluid (CSF) sampling, and brain MRI. Amyloid PET was repeated at week 47, and all of the tests were repeated again at study completion.

Dropout rates in each treatment group – especially the intravenous group – were rather high. In the subcutaneous group, 77% of the placebo arm and 88% of the active arm completed treatment. In the intravenous arms, 59% of the placebo group and 60% of the active group finished the study. There were two deaths, both in the active intravenous group.

The prespecified amyloid imaging used a cerebellar gray matter reference region. With this method, there were no significant differences in amyloid plaque burden by the end of the study.

Serial scans showed some odd variability that led researchers to question whether the reference region was accurately picking up any changes, Dr. Salloway said. In the subcutaneous group, the placebo group measurement stayed flat, as expected, but the active group measure took a significant dip at the interim scan, and then returned to baseline for the last scan, suggesting that amyloid dispersed and then reformed. In the IV arm, the placebo group took a significant dive from the interim scan to the final scan, suggesting that those patients were spontaneously clearing amyloid. The active IV group seemed to stay flat.

That prompted the investigators to reassess the results with a different reference region, a white matter region closer to the corpus callosum and centrum semiovale, Dr. Salloway said. This region is being used in the Alzheimer’s Disease Neuroimaging Initiative longitudinal cohort study. Data were sent to an independent investigator for a blinded reassessment.

The results obtained using this reference region were more in line with expectations, although not spectacular, Dr. Salloway said.

In the subcutaneous group, amyloid burden rose from baseline, with no difference at all between placebo and crenezumab. In the IV group, amyloid burden also rose in both arms. However, the curves showed some nonsignificant separation at the interim scan, which continued to the end of the study. The difference was still not significant at the final scan (P = .169).

When assessed by yet another white matter reference region, the results were similar, with no difference in the subcutaneous arm and a nonsignificant separation in the IV arm (P = .131).

“The suggestion of a separation with a relative reduction of amyloid in the IV group [in both of the alternate assessments] was very encouraging,” Dr. Salloway said.

In a small subset of patients with complete CSF data (30 subcutaneous and 25 IV patients), crenezumab was associated with a significant increase in Abeta₄₂, suggesting that it was interacting with amyloid brain plaques.

However, there was no movement in tau or phosphorylated tau, no changes in brain volume on MRI, and no changes in FDG-PET results.

The negative results may seem disappointing, but they don’t necessarily mean failure, Dr. Maria Carillo said in an interview.

Although disappointing in some ways, the BLAZE study did exactly what a phase II study should, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. It provided good safety data and just enough efficacy data to strengthen the phase III API trial.

“Yes, BLAZE was a negative trial, but it informed the Colombian team,” she said. “It told them that the IV dosing was better. It told them that higher doses would be better. That’s critical, regardless of this study’s negative results.”

Alzheimer’s researcher Peter Davies, Ph.D., said in an interview, “I’m disappointed. It is hard to understand how the high dose of crenezumab does not move the amyloid imaging signal – unless of course this is just too crude a measure. The CSF data did appear promising, but the lack of effect on cognitive function is what is going to decide the fate of this treatment.” Dr. Davies is the director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at Hofstra North Shore-Long Island Jewish School of Medicine.

Both BLAZE and API are sponsored by Genentech. Dr. Salloway has been a consultant for Roche, Lilly, and Genentech, and disclosed a number of other financial relationships with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

PHILADELPHIA – Despite some tantalizing hints of efficacy, the antiamyloid antibody crenezumab failed overall to post significant imaging and biomarker results in a phase II study.

The drug did not effect any statistically significant changes in amyloid plaque burden on PET imaging in the prespecified analysis, Dr. Steven Salloway said at the Clinical Trials Conference on Alzheimer’s Disease. A secondary assessment using a different technique yielded slightly better, although still nonsignificant, results.

There was a slight increase in serum amyloid beta 42 (Abeta42), but no effect at all on serum total or phosphorylated tau, said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I.

The lackluster findings, combined with crenezumab’s failure to meet cognitive and functional endpoints in this and a companion study announced last July, are prompting questions about the antibody’s future, Dr. Salloway said. “As a result of these clinical trials ... the company is in discussion with regulators about further development of crenezumab, although no decision has been made.”

These new data will not, however, endanger the landmark API (Alzheimer’s Prevention Initiative–Autosomal Dominant Alzheimer’s Disease Treatment Trial), now launching in Colombia. Crenezumab is the active treatment in this first-ever primary prevention trial.

In fact, these new imaging and biomarker data have led to a dosing protocol change for the API study. Originally, the study called for the 300-mg bimonthly subcutaneous dose; instead, it will use the IV dosing equivalent, a company spokesperson said in an interview.

“Based on the learnings from the crenezumab exploratory data, which may suggest greater benefit in [patients with mild Alzheimer’s disease] treated with the higher IV dose, Genentech is taking next steps to enable use of a higher subcutaneous dose in the API study,” said Carole Ho. She noted that the ongoing extension studies will also drop the subcutaneous dose in favor of IV dosing.

The 69-week study, dubbed BLAZE, looked at 91 patients with mild to moderate, imaging-proven Alzheimer’s disease. They were randomized to either crenezumab 300 mg subcutaneously every other week, 15 mg/kg intravenously once a month, or matching placebo in each arm.

The study group was a typical Alzheimer’s cohort, with a mean age of about 69 years. The Mini-Mental State Exam scores ranged from 18 to 26 (mean score, about 21).

At baseline, all patients had amyloid PET imaging, fluorodeoxyglucose (FDG)-PET imaging, cerebrospinal fluid (CSF) sampling, and brain MRI. Amyloid PET was repeated at week 47, and all of the tests were repeated again at study completion.

Dropout rates in each treatment group – especially the intravenous group – were rather high. In the subcutaneous group, 77% of the placebo arm and 88% of the active arm completed treatment. In the intravenous arms, 59% of the placebo group and 60% of the active group finished the study. There were two deaths, both in the active intravenous group.

The prespecified amyloid imaging used a cerebellar gray matter reference region. With this method, there were no significant differences in amyloid plaque burden by the end of the study.

Serial scans showed some odd variability that led researchers to question whether the reference region was accurately picking up any changes, Dr. Salloway said. In the subcutaneous group, the placebo group measurement stayed flat, as expected, but the active group measure took a significant dip at the interim scan, and then returned to baseline for the last scan, suggesting that amyloid dispersed and then reformed. In the IV arm, the placebo group took a significant dive from the interim scan to the final scan, suggesting that those patients were spontaneously clearing amyloid. The active IV group seemed to stay flat.

That prompted the investigators to reassess the results with a different reference region, a white matter region closer to the corpus callosum and centrum semiovale, Dr. Salloway said. This region is being used in the Alzheimer’s Disease Neuroimaging Initiative longitudinal cohort study. Data were sent to an independent investigator for a blinded reassessment.

The results obtained using this reference region were more in line with expectations, although not spectacular, Dr. Salloway said.

In the subcutaneous group, amyloid burden rose from baseline, with no difference at all between placebo and crenezumab. In the IV group, amyloid burden also rose in both arms. However, the curves showed some nonsignificant separation at the interim scan, which continued to the end of the study. The difference was still not significant at the final scan (P = .169).

When assessed by yet another white matter reference region, the results were similar, with no difference in the subcutaneous arm and a nonsignificant separation in the IV arm (P = .131).

“The suggestion of a separation with a relative reduction of amyloid in the IV group [in both of the alternate assessments] was very encouraging,” Dr. Salloway said.

In a small subset of patients with complete CSF data (30 subcutaneous and 25 IV patients), crenezumab was associated with a significant increase in Abeta₄₂, suggesting that it was interacting with amyloid brain plaques.

However, there was no movement in tau or phosphorylated tau, no changes in brain volume on MRI, and no changes in FDG-PET results.

The negative results may seem disappointing, but they don’t necessarily mean failure, Dr. Maria Carillo said in an interview.

Although disappointing in some ways, the BLAZE study did exactly what a phase II study should, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. It provided good safety data and just enough efficacy data to strengthen the phase III API trial.

“Yes, BLAZE was a negative trial, but it informed the Colombian team,” she said. “It told them that the IV dosing was better. It told them that higher doses would be better. That’s critical, regardless of this study’s negative results.”

Alzheimer’s researcher Peter Davies, Ph.D., said in an interview, “I’m disappointed. It is hard to understand how the high dose of crenezumab does not move the amyloid imaging signal – unless of course this is just too crude a measure. The CSF data did appear promising, but the lack of effect on cognitive function is what is going to decide the fate of this treatment.” Dr. Davies is the director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at Hofstra North Shore-Long Island Jewish School of Medicine.

Both BLAZE and API are sponsored by Genentech. Dr. Salloway has been a consultant for Roche, Lilly, and Genentech, and disclosed a number of other financial relationships with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal

PHILADELPHIA – Despite some tantalizing hints of efficacy, the antiamyloid antibody crenezumab failed overall to post significant imaging and biomarker results in a phase II study.

The drug did not effect any statistically significant changes in amyloid plaque burden on PET imaging in the prespecified analysis, Dr. Steven Salloway said at the Clinical Trials Conference on Alzheimer’s Disease. A secondary assessment using a different technique yielded slightly better, although still nonsignificant, results.

There was a slight increase in serum amyloid beta 42 (Abeta42), but no effect at all on serum total or phosphorylated tau, said Dr. Salloway, director of neurology and the Memory and Aging Program at Butler Hospital in Providence, R.I.

The lackluster findings, combined with crenezumab’s failure to meet cognitive and functional endpoints in this and a companion study announced last July, are prompting questions about the antibody’s future, Dr. Salloway said. “As a result of these clinical trials ... the company is in discussion with regulators about further development of crenezumab, although no decision has been made.”

These new data will not, however, endanger the landmark API (Alzheimer’s Prevention Initiative–Autosomal Dominant Alzheimer’s Disease Treatment Trial), now launching in Colombia. Crenezumab is the active treatment in this first-ever primary prevention trial.

In fact, these new imaging and biomarker data have led to a dosing protocol change for the API study. Originally, the study called for the 300-mg bimonthly subcutaneous dose; instead, it will use the IV dosing equivalent, a company spokesperson said in an interview.

“Based on the learnings from the crenezumab exploratory data, which may suggest greater benefit in [patients with mild Alzheimer’s disease] treated with the higher IV dose, Genentech is taking next steps to enable use of a higher subcutaneous dose in the API study,” said Carole Ho. She noted that the ongoing extension studies will also drop the subcutaneous dose in favor of IV dosing.

The 69-week study, dubbed BLAZE, looked at 91 patients with mild to moderate, imaging-proven Alzheimer’s disease. They were randomized to either crenezumab 300 mg subcutaneously every other week, 15 mg/kg intravenously once a month, or matching placebo in each arm.

The study group was a typical Alzheimer’s cohort, with a mean age of about 69 years. The Mini-Mental State Exam scores ranged from 18 to 26 (mean score, about 21).

At baseline, all patients had amyloid PET imaging, fluorodeoxyglucose (FDG)-PET imaging, cerebrospinal fluid (CSF) sampling, and brain MRI. Amyloid PET was repeated at week 47, and all of the tests were repeated again at study completion.

Dropout rates in each treatment group – especially the intravenous group – were rather high. In the subcutaneous group, 77% of the placebo arm and 88% of the active arm completed treatment. In the intravenous arms, 59% of the placebo group and 60% of the active group finished the study. There were two deaths, both in the active intravenous group.

The prespecified amyloid imaging used a cerebellar gray matter reference region. With this method, there were no significant differences in amyloid plaque burden by the end of the study.

Serial scans showed some odd variability that led researchers to question whether the reference region was accurately picking up any changes, Dr. Salloway said. In the subcutaneous group, the placebo group measurement stayed flat, as expected, but the active group measure took a significant dip at the interim scan, and then returned to baseline for the last scan, suggesting that amyloid dispersed and then reformed. In the IV arm, the placebo group took a significant dive from the interim scan to the final scan, suggesting that those patients were spontaneously clearing amyloid. The active IV group seemed to stay flat.

That prompted the investigators to reassess the results with a different reference region, a white matter region closer to the corpus callosum and centrum semiovale, Dr. Salloway said. This region is being used in the Alzheimer’s Disease Neuroimaging Initiative longitudinal cohort study. Data were sent to an independent investigator for a blinded reassessment.

The results obtained using this reference region were more in line with expectations, although not spectacular, Dr. Salloway said.

In the subcutaneous group, amyloid burden rose from baseline, with no difference at all between placebo and crenezumab. In the IV group, amyloid burden also rose in both arms. However, the curves showed some nonsignificant separation at the interim scan, which continued to the end of the study. The difference was still not significant at the final scan (P = .169).

When assessed by yet another white matter reference region, the results were similar, with no difference in the subcutaneous arm and a nonsignificant separation in the IV arm (P = .131).

“The suggestion of a separation with a relative reduction of amyloid in the IV group [in both of the alternate assessments] was very encouraging,” Dr. Salloway said.

In a small subset of patients with complete CSF data (30 subcutaneous and 25 IV patients), crenezumab was associated with a significant increase in Abeta₄₂, suggesting that it was interacting with amyloid brain plaques.

However, there was no movement in tau or phosphorylated tau, no changes in brain volume on MRI, and no changes in FDG-PET results.

The negative results may seem disappointing, but they don’t necessarily mean failure, Dr. Maria Carillo said in an interview.

Although disappointing in some ways, the BLAZE study did exactly what a phase II study should, said Dr. Carillo, vice president of medical and scientific relations for the Alzheimer’s Association. It provided good safety data and just enough efficacy data to strengthen the phase III API trial.

“Yes, BLAZE was a negative trial, but it informed the Colombian team,” she said. “It told them that the IV dosing was better. It told them that higher doses would be better. That’s critical, regardless of this study’s negative results.”

Alzheimer’s researcher Peter Davies, Ph.D., said in an interview, “I’m disappointed. It is hard to understand how the high dose of crenezumab does not move the amyloid imaging signal – unless of course this is just too crude a measure. The CSF data did appear promising, but the lack of effect on cognitive function is what is going to decide the fate of this treatment.” Dr. Davies is the director of the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease at Hofstra North Shore-Long Island Jewish School of Medicine.

Both BLAZE and API are sponsored by Genentech. Dr. Salloway has been a consultant for Roche, Lilly, and Genentech, and disclosed a number of other financial relationships with pharmaceutical companies.

[email protected] 


On Twitter @alz_gal