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The study arms did not contain comparable numbers of patients who carried APOE4.
CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.
Imbalanced Treatment Groups
The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits. 
“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”
Regulators Influenced the Trial
Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.
“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”
“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”
Treatment Reduced Amyloid Levels
In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.
—Michele G. Sullivan
The study arms did not contain comparable numbers of patients who carried APOE4.
The study arms did not contain comparable numbers of patients who carried APOE4.
CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.
Imbalanced Treatment Groups
The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.
“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”
Regulators Influenced the Trial
Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.
“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”
“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”
Treatment Reduced Amyloid Levels
In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.
—Michele G. Sullivan
CHICAGO—BAN2401, a monoclonal antibody that targets soluble amyloid-beta oligomers, slows cognitive decline by as much as 47% and clears brain amyloid in 81% of patients with mild cognitive impairment (MCI) and very mild Alzheimer’s disease, according to the results of a phase II study presented at AAIC 2018.
Imbalanced Treatment Groups
The treatment groups were not well balanced in at least one respect, however, which could influence the interpretation of the data. APOE4-positive patients were unequally distributed through the six treatment groups, which included BAN2401 (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) and placebo. This imbalance could have biased cognitive results in the antibody’s favor. APOE4 carriers represented between 70% and 80% of every unsuccessful treatment arm in the trial and approximately 29% of the arm that enjoyed significant cognitive benefits.
“This is a big confound,” said Keith Fargo, PhD, Director of Scientific Programs and Outreach at the Alzheimer’s Association. “According to the trial sponsors, … a regulatory body requested that people with the APOE4 Alzheimer’s risk gene not be included in the highest dose group for safety reasons. Because of this [request], the people in the highest-dose group are different from people in the other groups on an important dimension: they were much less likely to have the APOE4 gene, which is known to be a major risk factor for cognitive decline. So, it is plausible that the people on the highest dose declined differently due to genetic differences, rather than due to being on the highest dose. A planned subgroup analysis will shed more light on this [question] and [on] whether it reduces confidence in the overall findings.”
Regulators Influenced the Trial
Eisai, which is headquartered in Tokyo, and Biogen, which is based in Cambridge, Massachusetts, are developing the antibody. The decision to restructure the randomization was not Eisai’s, according to David Knopman, MD, a consultant in the department of neurology at Mayo Clinic in Rochester, Minnesota.
“European regulators did not allow randomization of [some] APOE4 carriers to the highest dose,” he said in an interview. “I ultimately don’t know what it would do to the results except make them even more difficult to justify as sufficient for registration. In general, in symptomatic Alzheimer’s dementia patients, APOE4 carriage has no substantial impact on rate of decline, but whether [APOE4] status interacted with the treatment is of course completely unknown. Bottom line: just another feature that makes this a phase II study that needs to be followed by a phase III study with a simple design using the high dose.”
“Regardless of who made the decision and why, the data is what it is, and the question remains,” said Michael S. Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas in Lawrence. “Given the numbers of E4-positive [patients] versus E4-negative [patients] for each treatment group, the interpretation of the results is now seriously thrown into question. The one group that showed a clear slowing of cognitive decline versus placebo—10 mg/kg biweekly—also has far fewer E4-positive [patients] versus E4-negative [patients]. This difference in proportion of E4-positive [patients] could be a major factor in the apparent reduced rate of cognitive decline and confounds the ability to tell if the 10-mg/kg biweekly dose is effective. In contrast, the 10-mg/kg monthly dose group has an E4-positive to E4-negative ratio more comparable to that of placebo, and the effect of the drug on cognitive decline under this dosing regimen is not clearly distinguishable from that seen with placebo.”
Treatment Reduced Amyloid Levels
In addition, BAN2401 failed to meet its 12-month prespecified primary cognitive end points. The investigators reached this conclusion through Bayesian analysis that strove to predict an 80% probability of achieving at least a 25% cognitive benefit. In December 2017, Eisai announced that the treatment had reached 64% probability. Because the company was optimistic about the treatment’s success, it continued with the additional six months of treatment, as the study design allowed, and reanalyzed results with a simpler and more straightforward method. This analysis concluded that the 10-mg/kg biweekly dose slowed decline on the Alzheimer’s Disease Composite Score (ADCOMS), a new tool developed and promoted by Eisai, by 30%. It also found that treatment slowed decline on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) by 47%. Treatment cleared brain amyloid in 81% of subjects and had positive effects on CSF biomarkers. CSF amyloid levels increased, and CSF total tau levels decreased, which indicated decreased neuronal injury.
—Michele G. Sullivan