Two Immunotherapies for Alzheimer’s Disease Fail to Show Benefit in Four Studies

Two investigational immunotherapies for Alzheimer’s disease failed to show any benefit in a series of phase III trials involving more than 4,000 patients, according to data published in the January 23 issue of the New England Journal of Medicine. Neither bapineuzumab, which targets soluble and aggregated amyloid-beta, nor solanezumab, which targets soluble amyloid-beta, achieved the primary end points in their overall cohorts.

No clinical gains were detected with either drug on the primary end points of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale and the Disability Assessment for Dementia. In addition, no gains were detected on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

Bapineuzumab May Reduce Amyloid Plaque Burden
The two bapineuzumab studies were 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all of the final data, including several a priori subanalyses that were designed to identify possible treatment effects. Although bapineuzumab did not show any clinical benefits, it did apparently act on its main target: brain plaques composed of aggregated amyloid-beta. In one trial involving patients who carried the high-risk APOE ε4 allele, PET brain scans with Pittsburgh compound B showed no increase in amyloid-beta plaque burden in bapineuzumab-treated patients. In contrast, participants who had placebo infusions had increases in amyloid-beta plaque burden.

APOE ε4 carriers also showed significant changes in two biomarkers of plaque dissolution. In one trial, phosphorylated tau, a marker of neuronal damage, decreased in serum and CSF among patients treated with bapineuzumab. Amyloid-beta in CSF increased among these patients, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers did not show these changes.

Amyloid-related imaging abnormalities with edema occurred in as much as 27% of APOE ε4 carriers, depending on their zygosity. It also appeared in as much as 14% of noncarriers; the relationship was dose-dependent.

Solanezumab May Benefit Patients With Mild Disease
The findings were similar in the two studies of solanezumab. EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and included approximately 2,000 patients. Results initially were reported at the 2013 Alzheimer’s Association International Conference.

More detail is available in the new study, including numerous biomarker findings. Solanezumab increased amyloid-beta in plasma and CSF, which indicates that the protein was no longer accumulating in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab did not have any significant effect on plaque burden or brain pathophysiology. Because it is designed to prevent plaques from forming, investigators did not expect that it would attack existing plaques.

In addition, the drug provided no cognitive or functional gains. In contrast with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted the launch of the EXPEDITION 3 trial. The study is now recruiting patients who have cognitive changes consistent with Alzheimer’s disease and brain plaques detected with 18F-florbetapir amyloid-beta imaging.

These more stringent entry requirements should ensure the enrollment of an appropriate cohort. Investigators who conducted previous EXPEDITION studies said that as many as 25% of patients enrolled with mild Alzheimer’s disease did not actually have Alzheimer’s disease. This factor could have diluted or negated any treatment effect, according to the investigators.

Potential Regulatory Pathways for Solanezumab
If EXPEDITION 3 can complement the potentially positive biomarker data for solanezumab with a positive clinical benefit, the drug might have a future as a preventive agent, said Samuel E. Gandy, MD, PhD, Professor of Neurology at Mount Sinai Hospital in New York City. “Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit,” he added. Dr. Gandy was not involved in the four studies.

“There are currently two pathways to FDA registration of a new Alzheimer’s drug,” he continued. The first pathway is proof of cognitive and functional benefit. “Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely.”

The second pathway is approval as a preventive agent, which means providing biomarker and neuropsychologic benefit. “This seems the more attractive pathway until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the FDA would be supportive,” concluded Dr. Gandy.

—Michele G. Sullivan

Two investigational immunotherapies for Alzheimer’s disease failed to show any benefit in a series of phase III trials involving more than 4,000 patients, according to data published in the January 23 issue of the New England Journal of Medicine. Neither bapineuzumab, which targets soluble and aggregated amyloid-beta, nor solanezumab, which targets soluble amyloid-beta, achieved the primary end points in their overall cohorts.

No clinical gains were detected with either drug on the primary end points of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale and the Disability Assessment for Dementia. In addition, no gains were detected on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

Bapineuzumab May Reduce Amyloid Plaque Burden
The two bapineuzumab studies were 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all of the final data, including several a priori subanalyses that were designed to identify possible treatment effects. Although bapineuzumab did not show any clinical benefits, it did apparently act on its main target: brain plaques composed of aggregated amyloid-beta. In one trial involving patients who carried the high-risk APOE ε4 allele, PET brain scans with Pittsburgh compound B showed no increase in amyloid-beta plaque burden in bapineuzumab-treated patients. In contrast, participants who had placebo infusions had increases in amyloid-beta plaque burden.

APOE ε4 carriers also showed significant changes in two biomarkers of plaque dissolution. In one trial, phosphorylated tau, a marker of neuronal damage, decreased in serum and CSF among patients treated with bapineuzumab. Amyloid-beta in CSF increased among these patients, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers did not show these changes.

Amyloid-related imaging abnormalities with edema occurred in as much as 27% of APOE ε4 carriers, depending on their zygosity. It also appeared in as much as 14% of noncarriers; the relationship was dose-dependent.

Solanezumab May Benefit Patients With Mild Disease
The findings were similar in the two studies of solanezumab. EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and included approximately 2,000 patients. Results initially were reported at the 2013 Alzheimer’s Association International Conference.

More detail is available in the new study, including numerous biomarker findings. Solanezumab increased amyloid-beta in plasma and CSF, which indicates that the protein was no longer accumulating in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab did not have any significant effect on plaque burden or brain pathophysiology. Because it is designed to prevent plaques from forming, investigators did not expect that it would attack existing plaques.

In addition, the drug provided no cognitive or functional gains. In contrast with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted the launch of the EXPEDITION 3 trial. The study is now recruiting patients who have cognitive changes consistent with Alzheimer’s disease and brain plaques detected with 18F-florbetapir amyloid-beta imaging.

These more stringent entry requirements should ensure the enrollment of an appropriate cohort. Investigators who conducted previous EXPEDITION studies said that as many as 25% of patients enrolled with mild Alzheimer’s disease did not actually have Alzheimer’s disease. This factor could have diluted or negated any treatment effect, according to the investigators.

Potential Regulatory Pathways for Solanezumab
If EXPEDITION 3 can complement the potentially positive biomarker data for solanezumab with a positive clinical benefit, the drug might have a future as a preventive agent, said Samuel E. Gandy, MD, PhD, Professor of Neurology at Mount Sinai Hospital in New York City. “Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit,” he added. Dr. Gandy was not involved in the four studies.

“There are currently two pathways to FDA registration of a new Alzheimer’s drug,” he continued. The first pathway is proof of cognitive and functional benefit. “Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely.”

The second pathway is approval as a preventive agent, which means providing biomarker and neuropsychologic benefit. “This seems the more attractive pathway until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the FDA would be supportive,” concluded Dr. Gandy.

—Michele G. Sullivan

Two investigational immunotherapies for Alzheimer’s disease failed to show any benefit in a series of phase III trials involving more than 4,000 patients, according to data published in the January 23 issue of the New England Journal of Medicine. Neither bapineuzumab, which targets soluble and aggregated amyloid-beta, nor solanezumab, which targets soluble amyloid-beta, achieved the primary end points in their overall cohorts.

No clinical gains were detected with either drug on the primary end points of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale and the Disability Assessment for Dementia. In addition, no gains were detected on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

Bapineuzumab May Reduce Amyloid Plaque Burden
The two bapineuzumab studies were 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all of the final data, including several a priori subanalyses that were designed to identify possible treatment effects. Although bapineuzumab did not show any clinical benefits, it did apparently act on its main target: brain plaques composed of aggregated amyloid-beta. In one trial involving patients who carried the high-risk APOE ε4 allele, PET brain scans with Pittsburgh compound B showed no increase in amyloid-beta plaque burden in bapineuzumab-treated patients. In contrast, participants who had placebo infusions had increases in amyloid-beta plaque burden.

APOE ε4 carriers also showed significant changes in two biomarkers of plaque dissolution. In one trial, phosphorylated tau, a marker of neuronal damage, decreased in serum and CSF among patients treated with bapineuzumab. Amyloid-beta in CSF increased among these patients, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers did not show these changes.

Amyloid-related imaging abnormalities with edema occurred in as much as 27% of APOE ε4 carriers, depending on their zygosity. It also appeared in as much as 14% of noncarriers; the relationship was dose-dependent.

Solanezumab May Benefit Patients With Mild Disease
The findings were similar in the two studies of solanezumab. EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and included approximately 2,000 patients. Results initially were reported at the 2013 Alzheimer’s Association International Conference.

More detail is available in the new study, including numerous biomarker findings. Solanezumab increased amyloid-beta in plasma and CSF, which indicates that the protein was no longer accumulating in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab did not have any significant effect on plaque burden or brain pathophysiology. Because it is designed to prevent plaques from forming, investigators did not expect that it would attack existing plaques.

In addition, the drug provided no cognitive or functional gains. In contrast with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted the launch of the EXPEDITION 3 trial. The study is now recruiting patients who have cognitive changes consistent with Alzheimer’s disease and brain plaques detected with 18F-florbetapir amyloid-beta imaging.

These more stringent entry requirements should ensure the enrollment of an appropriate cohort. Investigators who conducted previous EXPEDITION studies said that as many as 25% of patients enrolled with mild Alzheimer’s disease did not actually have Alzheimer’s disease. This factor could have diluted or negated any treatment effect, according to the investigators.

Potential Regulatory Pathways for Solanezumab
If EXPEDITION 3 can complement the potentially positive biomarker data for solanezumab with a positive clinical benefit, the drug might have a future as a preventive agent, said Samuel E. Gandy, MD, PhD, Professor of Neurology at Mount Sinai Hospital in New York City. “Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit,” he added. Dr. Gandy was not involved in the four studies.

“There are currently two pathways to FDA registration of a new Alzheimer’s drug,” he continued. The first pathway is proof of cognitive and functional benefit. “Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely.”

The second pathway is approval as a preventive agent, which means providing biomarker and neuropsychologic benefit. “This seems the more attractive pathway until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the FDA would be supportive,” concluded Dr. Gandy.

—Michele G. Sullivan