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Results from the phase 2b/3 AMBAR study showed that the treatment, which aims to remove amyloid-beta (Abeta) from plasma, was associated with a 60% decrease in functional and cognitive decline in patients with moderate Alzheimer’s disease.
The reduction in cognitive decline uncovered by the study is more striking than that reported for other investigational treatments targeting Abeta, such as monoclonal antibodies, said coinvestigator Antonio Páez, MD, medical director of the AMBAR program, Alzheimer’s Research Group, Grifols, Barcelona.
The results “open a new path for the development of plasma protein replacement therapies not only in Alzheimer’s disease but also in other degenerative diseases that we are planning to investigate,” Dr. Páez said.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were simultaneously published in Alzheimer’s and Dementia.
Removing amyloid
Plasma exchange treatments, which have been available for several decades, are used to treat a range of neurologic, immunologic, and metabolic disorders. The treatment involves plasmapheresis, whereby plasma is separated from blood cells (red blood cells, white blood cells, platelets, etc) and toxic substances are removed. The albumin in plasma, to which plasma Abeta is bound, is replaced with a fresh commercial albumin product made from plasma from healthy donors.
“Our initial hypothesis was that, by removing albumin together with Abeta and substituting it with newer albumin periodically, we may be removing Abeta from the cerebrospinal fluid and eventually from the brain,” Dr. Páez said.
The AMBAR study included 347 men and women aged 55-85 years with probable Alzheimer’s disease dementia who were enrolled at 41 sites in Spain and the United States. All were diagnosed with mild Alzheimer’s disease, as shown by a baseline Mini-Mental State Examination score of 22-26, or moderate Alzheimer’s disease, having a baseline MMSE score of 18-21.
Investigators randomly assigned the participants to four groups; one group received placebo, and each of the other three treatment arms received different doses of albumin and intravenous immunoglobulin (IVIg) replacement.
During the first 6-week study phase, patients received weekly sham or conventional plasma exchange treatments of 2.5-3 liters of plasma, which Dr. Páez referred to as the “intensive-treatment phase to remove as much Abeta as possible.”
This was followed by a 12-month maintenance phase, which involved monthly low-volume (700-800 mL) plasma exchange or sham treatments.
Although the volume of plasma removed was the same in all three active-treatment groups, the amount of albumin and IVIg that was subsequently replaced varied. In one group, the same amount of albumin and IVIg that was removed was replaced; in another, half the amount removed was replaced; and in the third, only albumin was replaced.
The researchers collected cerebrospinal fluid (CSF) samples at baseline and after each treatment period. They assessed Abeta40, Abeta42, total tau, and phosphorylated-tau biomarkers.
The two primary outcomes were change from baseline to 14 months in scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog).
Symptom reduction
Results showed a reduction in the progression of symptoms in the plasma exchange–treated patients for both primary endpoints.
The ADCS-ADL showed 52% less decline in the plasma exchange–treated group, compared with the placebo group (P = .03); the ADAS-Cog showed 66% less decline (P = 0.06). In the moderate group, both endpoints showed 61% less decline (P = .002 and .05, respectively).
There were no clear differences between the three active-treatment groups, “suggesting that any of them could be considered for further investigation,” said Dr. Páez.
Differences in baseline demographic characteristics did not appear to have an influence on the outcomes. ADAS-Cog was more than twice as effective as some candidate monoclonal antibodies targeting Abeta that are being investigated for Alzheimer’s disease, Dr. Páez noted.
Although the plasma exchange approach is relatively invasive, so too are monoclonal antibody therapies that are infused intravenously through a pump, he said. In addition, a low-volume plasma exchange maintenance treatment takes less than 2 hours, which is on a par with some monoclonal antibody treatments.
Key secondary outcomes
For both primary outcomes, changes were found in those with moderate but not mild Alzheimer’s disease, possibly because the ADAS-Cog was designed for patients with more severe symptoms and may not be sensitive enough for patients with better cognitive performance, said Dr. Páez.
However, the difference between mild and moderate Alzheimer’s disease did not hold up in post hoc analyses that included additional baseline characteristics, including amyloid and APOE e4 status.
“We observed that both mild and moderate subjects performed better than placebo even in the two coprimary endpoints,” Dr. Páez said. “It suggested that the differences between mild and moderate patients was not so apparent.”
The study’s key secondary outcomes included scores on the Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scales. Treated patients scored better than the placebo group on both the CDR-sb (71% less decline, P = .002) and the ADCS-CGIC (100% less decline, P < .0001) scales.
For disease biomarkers in the moderate Alzheimer’s disease study population, levels of CSF Abeta42 and tau protein remained stable in the treated patients. In the placebo group, Abeta42 was decreased and tau protein increased. Dr. Páez explained that, if amyloid in the brain comes from the CSF, this process may take some time.
The findings suggest that more than one mechanism may be involved in the plasma exchange approach, such as changes in oxidation status and inflammatory mediators, the investigators noted.
Safety profile
About 28% of the participants dropped out of the study, which the researchers note is a rate similar to that reported in studies of solanezumab and other treatments in patients with Alzheimer’s disease. “The high percentage (72%) of patients who completed the study further supports that this procedure is feasible in mild to moderate Alzheimer’s disease,” the investigators wrote.
Overall, adverse events were similar to the known safety profile of plasma exchange procedures for other indications. The two most common adverse events were catheter local reactions and hypotension.
Almost 90% of the apheresis procedures were “uneventful,” the researchers reported. Two patients (0.6%) died during the study, which is similar to the low mortality rates reported elsewhere.
However, the investigators stressed that, because many patients with Alzheimer’s disease are in fragile health, plasma exchange treatments should be undertaken with caution, because of its invasive nature.
Dr. Páez noted that a possible limitation of this treatment approach is the availability of plasma for manufacturing plasma products. In the future, this plasma exchange approach might be combined with current and future Alzheimer’s disease therapies.
They are currently in discussions with the American Society for Apheresis, which develops guidelines for plasma exchange. After additional research, the investigators hope to eventually receive Food and Drug Administration approval of plasma exchange with albumin replacement as a treatment for Alzheimer’s disease.
Speculative, yet reasonable approach
Commenting on the research findings, Pierre N. Tariot, MD, director of Banner Alzheimer’s Institute and research professor of psychiatry at the University of Arizona, both in Phoenix, said the study is “meaningful and large enough” to “come close” to determining whether the therapy is safe and effective. “The fundamental rationale for this experimental approach, while speculative, is reasonable and certainly seems to be worth testing,” said Dr. Tariot, who was not involved with the research.
However, “there’s a decent chance” that not all trial participants had Alzheimer’s disease. Although some CSF amyloid measures suggest levels consistent with AD, “this is not conclusive,” he said.
In addition, “there’s a slightly low rate of apolipoprotein E4 allele carriage [in the current study], compared with most Alzheimer’s disease trials,” Dr. Tariot said.
He also pointed out that the trial failed to show statistical significance on both coprimary outcomes. “It’s unclear what health authorities, if presented with these data, would decide to do with the file.”
Although it was “encouraging” that secondary endpoints were supportive, the fact that they had greater statistical significance than some of the other objective measures “raises at least the potential for partial unblinding as a result of side effects,” said Dr. Tariot. It is also unclear why changes would be more evident in the moderate subpopulation.
The study was funded by Grifols. Dr. Páez is an employee of Grifols. Dr. Tariot reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Results from the phase 2b/3 AMBAR study showed that the treatment, which aims to remove amyloid-beta (Abeta) from plasma, was associated with a 60% decrease in functional and cognitive decline in patients with moderate Alzheimer’s disease.
The reduction in cognitive decline uncovered by the study is more striking than that reported for other investigational treatments targeting Abeta, such as monoclonal antibodies, said coinvestigator Antonio Páez, MD, medical director of the AMBAR program, Alzheimer’s Research Group, Grifols, Barcelona.
The results “open a new path for the development of plasma protein replacement therapies not only in Alzheimer’s disease but also in other degenerative diseases that we are planning to investigate,” Dr. Páez said.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were simultaneously published in Alzheimer’s and Dementia.
Removing amyloid
Plasma exchange treatments, which have been available for several decades, are used to treat a range of neurologic, immunologic, and metabolic disorders. The treatment involves plasmapheresis, whereby plasma is separated from blood cells (red blood cells, white blood cells, platelets, etc) and toxic substances are removed. The albumin in plasma, to which plasma Abeta is bound, is replaced with a fresh commercial albumin product made from plasma from healthy donors.
“Our initial hypothesis was that, by removing albumin together with Abeta and substituting it with newer albumin periodically, we may be removing Abeta from the cerebrospinal fluid and eventually from the brain,” Dr. Páez said.
The AMBAR study included 347 men and women aged 55-85 years with probable Alzheimer’s disease dementia who were enrolled at 41 sites in Spain and the United States. All were diagnosed with mild Alzheimer’s disease, as shown by a baseline Mini-Mental State Examination score of 22-26, or moderate Alzheimer’s disease, having a baseline MMSE score of 18-21.
Investigators randomly assigned the participants to four groups; one group received placebo, and each of the other three treatment arms received different doses of albumin and intravenous immunoglobulin (IVIg) replacement.
During the first 6-week study phase, patients received weekly sham or conventional plasma exchange treatments of 2.5-3 liters of plasma, which Dr. Páez referred to as the “intensive-treatment phase to remove as much Abeta as possible.”
This was followed by a 12-month maintenance phase, which involved monthly low-volume (700-800 mL) plasma exchange or sham treatments.
Although the volume of plasma removed was the same in all three active-treatment groups, the amount of albumin and IVIg that was subsequently replaced varied. In one group, the same amount of albumin and IVIg that was removed was replaced; in another, half the amount removed was replaced; and in the third, only albumin was replaced.
The researchers collected cerebrospinal fluid (CSF) samples at baseline and after each treatment period. They assessed Abeta40, Abeta42, total tau, and phosphorylated-tau biomarkers.
The two primary outcomes were change from baseline to 14 months in scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog).
Symptom reduction
Results showed a reduction in the progression of symptoms in the plasma exchange–treated patients for both primary endpoints.
The ADCS-ADL showed 52% less decline in the plasma exchange–treated group, compared with the placebo group (P = .03); the ADAS-Cog showed 66% less decline (P = 0.06). In the moderate group, both endpoints showed 61% less decline (P = .002 and .05, respectively).
There were no clear differences between the three active-treatment groups, “suggesting that any of them could be considered for further investigation,” said Dr. Páez.
Differences in baseline demographic characteristics did not appear to have an influence on the outcomes. ADAS-Cog was more than twice as effective as some candidate monoclonal antibodies targeting Abeta that are being investigated for Alzheimer’s disease, Dr. Páez noted.
Although the plasma exchange approach is relatively invasive, so too are monoclonal antibody therapies that are infused intravenously through a pump, he said. In addition, a low-volume plasma exchange maintenance treatment takes less than 2 hours, which is on a par with some monoclonal antibody treatments.
Key secondary outcomes
For both primary outcomes, changes were found in those with moderate but not mild Alzheimer’s disease, possibly because the ADAS-Cog was designed for patients with more severe symptoms and may not be sensitive enough for patients with better cognitive performance, said Dr. Páez.
However, the difference between mild and moderate Alzheimer’s disease did not hold up in post hoc analyses that included additional baseline characteristics, including amyloid and APOE e4 status.
“We observed that both mild and moderate subjects performed better than placebo even in the two coprimary endpoints,” Dr. Páez said. “It suggested that the differences between mild and moderate patients was not so apparent.”
The study’s key secondary outcomes included scores on the Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scales. Treated patients scored better than the placebo group on both the CDR-sb (71% less decline, P = .002) and the ADCS-CGIC (100% less decline, P < .0001) scales.
For disease biomarkers in the moderate Alzheimer’s disease study population, levels of CSF Abeta42 and tau protein remained stable in the treated patients. In the placebo group, Abeta42 was decreased and tau protein increased. Dr. Páez explained that, if amyloid in the brain comes from the CSF, this process may take some time.
The findings suggest that more than one mechanism may be involved in the plasma exchange approach, such as changes in oxidation status and inflammatory mediators, the investigators noted.
Safety profile
About 28% of the participants dropped out of the study, which the researchers note is a rate similar to that reported in studies of solanezumab and other treatments in patients with Alzheimer’s disease. “The high percentage (72%) of patients who completed the study further supports that this procedure is feasible in mild to moderate Alzheimer’s disease,” the investigators wrote.
Overall, adverse events were similar to the known safety profile of plasma exchange procedures for other indications. The two most common adverse events were catheter local reactions and hypotension.
Almost 90% of the apheresis procedures were “uneventful,” the researchers reported. Two patients (0.6%) died during the study, which is similar to the low mortality rates reported elsewhere.
However, the investigators stressed that, because many patients with Alzheimer’s disease are in fragile health, plasma exchange treatments should be undertaken with caution, because of its invasive nature.
Dr. Páez noted that a possible limitation of this treatment approach is the availability of plasma for manufacturing plasma products. In the future, this plasma exchange approach might be combined with current and future Alzheimer’s disease therapies.
They are currently in discussions with the American Society for Apheresis, which develops guidelines for plasma exchange. After additional research, the investigators hope to eventually receive Food and Drug Administration approval of plasma exchange with albumin replacement as a treatment for Alzheimer’s disease.
Speculative, yet reasonable approach
Commenting on the research findings, Pierre N. Tariot, MD, director of Banner Alzheimer’s Institute and research professor of psychiatry at the University of Arizona, both in Phoenix, said the study is “meaningful and large enough” to “come close” to determining whether the therapy is safe and effective. “The fundamental rationale for this experimental approach, while speculative, is reasonable and certainly seems to be worth testing,” said Dr. Tariot, who was not involved with the research.
However, “there’s a decent chance” that not all trial participants had Alzheimer’s disease. Although some CSF amyloid measures suggest levels consistent with AD, “this is not conclusive,” he said.
In addition, “there’s a slightly low rate of apolipoprotein E4 allele carriage [in the current study], compared with most Alzheimer’s disease trials,” Dr. Tariot said.
He also pointed out that the trial failed to show statistical significance on both coprimary outcomes. “It’s unclear what health authorities, if presented with these data, would decide to do with the file.”
Although it was “encouraging” that secondary endpoints were supportive, the fact that they had greater statistical significance than some of the other objective measures “raises at least the potential for partial unblinding as a result of side effects,” said Dr. Tariot. It is also unclear why changes would be more evident in the moderate subpopulation.
The study was funded by Grifols. Dr. Páez is an employee of Grifols. Dr. Tariot reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Results from the phase 2b/3 AMBAR study showed that the treatment, which aims to remove amyloid-beta (Abeta) from plasma, was associated with a 60% decrease in functional and cognitive decline in patients with moderate Alzheimer’s disease.
The reduction in cognitive decline uncovered by the study is more striking than that reported for other investigational treatments targeting Abeta, such as monoclonal antibodies, said coinvestigator Antonio Páez, MD, medical director of the AMBAR program, Alzheimer’s Research Group, Grifols, Barcelona.
The results “open a new path for the development of plasma protein replacement therapies not only in Alzheimer’s disease but also in other degenerative diseases that we are planning to investigate,” Dr. Páez said.
The findings were presented at the virtual annual meeting of the Alzheimer’s Association International Conference and were simultaneously published in Alzheimer’s and Dementia.
Removing amyloid
Plasma exchange treatments, which have been available for several decades, are used to treat a range of neurologic, immunologic, and metabolic disorders. The treatment involves plasmapheresis, whereby plasma is separated from blood cells (red blood cells, white blood cells, platelets, etc) and toxic substances are removed. The albumin in plasma, to which plasma Abeta is bound, is replaced with a fresh commercial albumin product made from plasma from healthy donors.
“Our initial hypothesis was that, by removing albumin together with Abeta and substituting it with newer albumin periodically, we may be removing Abeta from the cerebrospinal fluid and eventually from the brain,” Dr. Páez said.
The AMBAR study included 347 men and women aged 55-85 years with probable Alzheimer’s disease dementia who were enrolled at 41 sites in Spain and the United States. All were diagnosed with mild Alzheimer’s disease, as shown by a baseline Mini-Mental State Examination score of 22-26, or moderate Alzheimer’s disease, having a baseline MMSE score of 18-21.
Investigators randomly assigned the participants to four groups; one group received placebo, and each of the other three treatment arms received different doses of albumin and intravenous immunoglobulin (IVIg) replacement.
During the first 6-week study phase, patients received weekly sham or conventional plasma exchange treatments of 2.5-3 liters of plasma, which Dr. Páez referred to as the “intensive-treatment phase to remove as much Abeta as possible.”
This was followed by a 12-month maintenance phase, which involved monthly low-volume (700-800 mL) plasma exchange or sham treatments.
Although the volume of plasma removed was the same in all three active-treatment groups, the amount of albumin and IVIg that was subsequently replaced varied. In one group, the same amount of albumin and IVIg that was removed was replaced; in another, half the amount removed was replaced; and in the third, only albumin was replaced.
The researchers collected cerebrospinal fluid (CSF) samples at baseline and after each treatment period. They assessed Abeta40, Abeta42, total tau, and phosphorylated-tau biomarkers.
The two primary outcomes were change from baseline to 14 months in scores on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog).
Symptom reduction
Results showed a reduction in the progression of symptoms in the plasma exchange–treated patients for both primary endpoints.
The ADCS-ADL showed 52% less decline in the plasma exchange–treated group, compared with the placebo group (P = .03); the ADAS-Cog showed 66% less decline (P = 0.06). In the moderate group, both endpoints showed 61% less decline (P = .002 and .05, respectively).
There were no clear differences between the three active-treatment groups, “suggesting that any of them could be considered for further investigation,” said Dr. Páez.
Differences in baseline demographic characteristics did not appear to have an influence on the outcomes. ADAS-Cog was more than twice as effective as some candidate monoclonal antibodies targeting Abeta that are being investigated for Alzheimer’s disease, Dr. Páez noted.
Although the plasma exchange approach is relatively invasive, so too are monoclonal antibody therapies that are infused intravenously through a pump, he said. In addition, a low-volume plasma exchange maintenance treatment takes less than 2 hours, which is on a par with some monoclonal antibody treatments.
Key secondary outcomes
For both primary outcomes, changes were found in those with moderate but not mild Alzheimer’s disease, possibly because the ADAS-Cog was designed for patients with more severe symptoms and may not be sensitive enough for patients with better cognitive performance, said Dr. Páez.
However, the difference between mild and moderate Alzheimer’s disease did not hold up in post hoc analyses that included additional baseline characteristics, including amyloid and APOE e4 status.
“We observed that both mild and moderate subjects performed better than placebo even in the two coprimary endpoints,” Dr. Páez said. “It suggested that the differences between mild and moderate patients was not so apparent.”
The study’s key secondary outcomes included scores on the Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scales. Treated patients scored better than the placebo group on both the CDR-sb (71% less decline, P = .002) and the ADCS-CGIC (100% less decline, P < .0001) scales.
For disease biomarkers in the moderate Alzheimer’s disease study population, levels of CSF Abeta42 and tau protein remained stable in the treated patients. In the placebo group, Abeta42 was decreased and tau protein increased. Dr. Páez explained that, if amyloid in the brain comes from the CSF, this process may take some time.
The findings suggest that more than one mechanism may be involved in the plasma exchange approach, such as changes in oxidation status and inflammatory mediators, the investigators noted.
Safety profile
About 28% of the participants dropped out of the study, which the researchers note is a rate similar to that reported in studies of solanezumab and other treatments in patients with Alzheimer’s disease. “The high percentage (72%) of patients who completed the study further supports that this procedure is feasible in mild to moderate Alzheimer’s disease,” the investigators wrote.
Overall, adverse events were similar to the known safety profile of plasma exchange procedures for other indications. The two most common adverse events were catheter local reactions and hypotension.
Almost 90% of the apheresis procedures were “uneventful,” the researchers reported. Two patients (0.6%) died during the study, which is similar to the low mortality rates reported elsewhere.
However, the investigators stressed that, because many patients with Alzheimer’s disease are in fragile health, plasma exchange treatments should be undertaken with caution, because of its invasive nature.
Dr. Páez noted that a possible limitation of this treatment approach is the availability of plasma for manufacturing plasma products. In the future, this plasma exchange approach might be combined with current and future Alzheimer’s disease therapies.
They are currently in discussions with the American Society for Apheresis, which develops guidelines for plasma exchange. After additional research, the investigators hope to eventually receive Food and Drug Administration approval of plasma exchange with albumin replacement as a treatment for Alzheimer’s disease.
Speculative, yet reasonable approach
Commenting on the research findings, Pierre N. Tariot, MD, director of Banner Alzheimer’s Institute and research professor of psychiatry at the University of Arizona, both in Phoenix, said the study is “meaningful and large enough” to “come close” to determining whether the therapy is safe and effective. “The fundamental rationale for this experimental approach, while speculative, is reasonable and certainly seems to be worth testing,” said Dr. Tariot, who was not involved with the research.
However, “there’s a decent chance” that not all trial participants had Alzheimer’s disease. Although some CSF amyloid measures suggest levels consistent with AD, “this is not conclusive,” he said.
In addition, “there’s a slightly low rate of apolipoprotein E4 allele carriage [in the current study], compared with most Alzheimer’s disease trials,” Dr. Tariot said.
He also pointed out that the trial failed to show statistical significance on both coprimary outcomes. “It’s unclear what health authorities, if presented with these data, would decide to do with the file.”
Although it was “encouraging” that secondary endpoints were supportive, the fact that they had greater statistical significance than some of the other objective measures “raises at least the potential for partial unblinding as a result of side effects,” said Dr. Tariot. It is also unclear why changes would be more evident in the moderate subpopulation.
The study was funded by Grifols. Dr. Páez is an employee of Grifols. Dr. Tariot reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM AAIC 2020