Alzheimer’s disease antibody crenezumab doesn’t deliver in phase II trial

COPENHAGEN – Once more, an antiamyloid antibody has failed to live up to hopes for the treatment of Alzheimer’s disease.

Roche’s contender, crenezumab, faltered on all of the primary endpoints of its phase II clinical trial, dubbed ABBY. The drug delivered no overall benefit over placebo in measures of both cognition and function, except in a small, unplanned subanalysis, Dr. Jeffrey Cummings said at the Alzheimer’s Association International Conference 2014.

The subanalysis of patients who were the least impaired – with scores of 22-26 on the Mini-Mental State Exam (MMSE) – showed a significant 35% reduction in cognitive decline (P = .036) and a nonsignificant 19.6% reduction in global functional decline (P = .42) after 68 weeks of treatment, said Dr. Cummings, a primary investigator on the study and director of Cleveland Clinic’s Lou Ruvo Center for Brain Health in Las Vegas.

The news is a blow to researchers, who hoped crenezumab might break the string of antiamyloid antibody failures that has hampered immunotherapy clinical trials in Alzheimer’s. The drug’s early promise secured Roche $100 million in federal funds to help launch the first-ever Alzheimer’s primary prevention study.

The Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease Treatment Trial is recruiting Colombian families who carry the presenilin 1 mutation – a virtual guarantee of early-onset Alzheimer’s disease. It was set to randomize cognitively healthy subjects to placebo or to 300 mg subcutaneous crenezumab – the dose that showed absolutely no efficacy signal in ABBY.

The trial’s future seems uncertain now, Dr. Cummings said at the meeting.

"These data require interpretation and then, proper ethical application in that study," he said. "Exactly what the outcome of that decision process will be, I don’t know."

ABBY enrolled 431 patients with mild to moderate Alzheimer’s disease (MMSE 18-26). They were randomized to two placebo-controlled arms: subcutaneous crenezumab 300 mg once every 2 weeks (low dose) or a matching placebo and intravenous crenezumab 15 mg/kg once every 4 weeks (high dose) or a matching placebo. The trial included a 68-week treatment period and a 4-week washout period.

The subjects had a mean age of 70 years and a mean MMSE of 21. Most of the low- and high-dose group included homozygous carriers of the apolipoprotein epsilon-4 allele (65% and 70%, respectively).

For either dosage arm, there were no significant differences in any of the co–primary endpoints, which included a reduction in cognitive decline on the Alzheimer’s Disease Assessment Scale-cognitive domain (ADAS-cog), the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), or in the secondary endpoint of change in the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scores (ADCS-ADL). In a prespecified subgroup analysis of patients with milder disease (MMSE 20-26), the high-dose intravenous arm experienced a 24% reduction in cognitive decline relative to placebo, but this was not statistically significant (P = .15).

However, the encouraging trend prompted the additional subgroup analysis of some patients with even milder disease (MMSE 22-26). Here there was a significant 35% reduction in cognitive decline (P = .036) and a nonsignificant 19.6% reduction in global functional decline (P = .42).

Crenezumab was safe and generally well tolerated. The 25% discontinuation rate was consistent in each treatment group as well as the placebo groups. There was one case of asymptomatic amyloid-related imaging abnormalities (ARIA) in a patient taking high-dose crenezumab.

There were three deaths: one from disease progression, one from respiratory failure, and one from pneumonia; none were considered related to the study drug.

Roche and its subsidiary Genentech sponsored the study. Dr. Cummings has received financial remuneration from the company.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

COPENHAGEN – Once more, an antiamyloid antibody has failed to live up to hopes for the treatment of Alzheimer’s disease.

Roche’s contender, crenezumab, faltered on all of the primary endpoints of its phase II clinical trial, dubbed ABBY. The drug delivered no overall benefit over placebo in measures of both cognition and function, except in a small, unplanned subanalysis, Dr. Jeffrey Cummings said at the Alzheimer’s Association International Conference 2014.

The subanalysis of patients who were the least impaired – with scores of 22-26 on the Mini-Mental State Exam (MMSE) – showed a significant 35% reduction in cognitive decline (P = .036) and a nonsignificant 19.6% reduction in global functional decline (P = .42) after 68 weeks of treatment, said Dr. Cummings, a primary investigator on the study and director of Cleveland Clinic’s Lou Ruvo Center for Brain Health in Las Vegas.

The news is a blow to researchers, who hoped crenezumab might break the string of antiamyloid antibody failures that has hampered immunotherapy clinical trials in Alzheimer’s. The drug’s early promise secured Roche $100 million in federal funds to help launch the first-ever Alzheimer’s primary prevention study.

The Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease Treatment Trial is recruiting Colombian families who carry the presenilin 1 mutation – a virtual guarantee of early-onset Alzheimer’s disease. It was set to randomize cognitively healthy subjects to placebo or to 300 mg subcutaneous crenezumab – the dose that showed absolutely no efficacy signal in ABBY.

The trial’s future seems uncertain now, Dr. Cummings said at the meeting.

"These data require interpretation and then, proper ethical application in that study," he said. "Exactly what the outcome of that decision process will be, I don’t know."

ABBY enrolled 431 patients with mild to moderate Alzheimer’s disease (MMSE 18-26). They were randomized to two placebo-controlled arms: subcutaneous crenezumab 300 mg once every 2 weeks (low dose) or a matching placebo and intravenous crenezumab 15 mg/kg once every 4 weeks (high dose) or a matching placebo. The trial included a 68-week treatment period and a 4-week washout period.

The subjects had a mean age of 70 years and a mean MMSE of 21. Most of the low- and high-dose group included homozygous carriers of the apolipoprotein epsilon-4 allele (65% and 70%, respectively).

For either dosage arm, there were no significant differences in any of the co–primary endpoints, which included a reduction in cognitive decline on the Alzheimer’s Disease Assessment Scale-cognitive domain (ADAS-cog), the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), or in the secondary endpoint of change in the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scores (ADCS-ADL). In a prespecified subgroup analysis of patients with milder disease (MMSE 20-26), the high-dose intravenous arm experienced a 24% reduction in cognitive decline relative to placebo, but this was not statistically significant (P = .15).

However, the encouraging trend prompted the additional subgroup analysis of some patients with even milder disease (MMSE 22-26). Here there was a significant 35% reduction in cognitive decline (P = .036) and a nonsignificant 19.6% reduction in global functional decline (P = .42).

Crenezumab was safe and generally well tolerated. The 25% discontinuation rate was consistent in each treatment group as well as the placebo groups. There was one case of asymptomatic amyloid-related imaging abnormalities (ARIA) in a patient taking high-dose crenezumab.

There were three deaths: one from disease progression, one from respiratory failure, and one from pneumonia; none were considered related to the study drug.

Roche and its subsidiary Genentech sponsored the study. Dr. Cummings has received financial remuneration from the company.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

COPENHAGEN – Once more, an antiamyloid antibody has failed to live up to hopes for the treatment of Alzheimer’s disease.

Roche’s contender, crenezumab, faltered on all of the primary endpoints of its phase II clinical trial, dubbed ABBY. The drug delivered no overall benefit over placebo in measures of both cognition and function, except in a small, unplanned subanalysis, Dr. Jeffrey Cummings said at the Alzheimer’s Association International Conference 2014.

The subanalysis of patients who were the least impaired – with scores of 22-26 on the Mini-Mental State Exam (MMSE) – showed a significant 35% reduction in cognitive decline (P = .036) and a nonsignificant 19.6% reduction in global functional decline (P = .42) after 68 weeks of treatment, said Dr. Cummings, a primary investigator on the study and director of Cleveland Clinic’s Lou Ruvo Center for Brain Health in Las Vegas.

The news is a blow to researchers, who hoped crenezumab might break the string of antiamyloid antibody failures that has hampered immunotherapy clinical trials in Alzheimer’s. The drug’s early promise secured Roche $100 million in federal funds to help launch the first-ever Alzheimer’s primary prevention study.

The Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease Treatment Trial is recruiting Colombian families who carry the presenilin 1 mutation – a virtual guarantee of early-onset Alzheimer’s disease. It was set to randomize cognitively healthy subjects to placebo or to 300 mg subcutaneous crenezumab – the dose that showed absolutely no efficacy signal in ABBY.

The trial’s future seems uncertain now, Dr. Cummings said at the meeting.

"These data require interpretation and then, proper ethical application in that study," he said. "Exactly what the outcome of that decision process will be, I don’t know."

ABBY enrolled 431 patients with mild to moderate Alzheimer’s disease (MMSE 18-26). They were randomized to two placebo-controlled arms: subcutaneous crenezumab 300 mg once every 2 weeks (low dose) or a matching placebo and intravenous crenezumab 15 mg/kg once every 4 weeks (high dose) or a matching placebo. The trial included a 68-week treatment period and a 4-week washout period.

The subjects had a mean age of 70 years and a mean MMSE of 21. Most of the low- and high-dose group included homozygous carriers of the apolipoprotein epsilon-4 allele (65% and 70%, respectively).

For either dosage arm, there were no significant differences in any of the co–primary endpoints, which included a reduction in cognitive decline on the Alzheimer’s Disease Assessment Scale-cognitive domain (ADAS-cog), the Clinical Dementia Rating Scale sum of boxes (CDR-SOB), or in the secondary endpoint of change in the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scores (ADCS-ADL). In a prespecified subgroup analysis of patients with milder disease (MMSE 20-26), the high-dose intravenous arm experienced a 24% reduction in cognitive decline relative to placebo, but this was not statistically significant (P = .15).

However, the encouraging trend prompted the additional subgroup analysis of some patients with even milder disease (MMSE 22-26). Here there was a significant 35% reduction in cognitive decline (P = .036) and a nonsignificant 19.6% reduction in global functional decline (P = .42).

Crenezumab was safe and generally well tolerated. The 25% discontinuation rate was consistent in each treatment group as well as the placebo groups. There was one case of asymptomatic amyloid-related imaging abnormalities (ARIA) in a patient taking high-dose crenezumab.

There were three deaths: one from disease progression, one from respiratory failure, and one from pneumonia; none were considered related to the study drug.

Roche and its subsidiary Genentech sponsored the study. Dr. Cummings has received financial remuneration from the company.

msullivan@frontlinemedcom.com

On Twitter @alz_gal