An experimental Alzheimer’s disease drug called BAN2401 has generated intriguing additional results in a a Phase II clinical trial. The trial sponsors, Eisai Co., Ltd. and Biogen Inc, had already announced topline results on the 18-month analysis on July 5.
Though the trial was negative on the goals set as the study’s primary endpoint, at the Alzheimer’s Association International Conference 2018 the researchers have now reported additional results on several of the trial’s secondary outcomes, including reduction of amyloid plaques and improvement of cognition and function, though the trial was not intended to demonstrate efficacy in cognitive outcomes.
BAN2401, administered intravenously, targets beta amyloid, a protein that forms plaques around neurons. It is a humanized version of a mouse monoclonal antibody that recognizes protofibrils and prevents amyloid beta deposition in animal models of Alzheimer’s disease.
Clearance Of Amyloid
This is the second Alzheimer’s clinical trial that has demonstrated both clearance of amyloid from the brain and cognitive benefits - again, the studies were not large enough to definitely demonstrate cognitive efficacy and the BAN2401 study did not meet its primary endpoint. However, these two studies indicate that amyloid remains an important therapeutic target to pursue in Alzheimer’s disease.
“It’s encouraging, but a lot more needs to be done. I would not say it’s shock and awe,”
said Julie Schneider, associate director of Rush Alzheimer’s Disease Center in Chicago, speaking to Bloomberg. Shares of Biogen fell as much as 12 percent the day the results were released.
There are many limitation to the research. It was led by company scientists, not academic researchers. It was not reviewed by outside experts. The study also was small, and the results need to be confirmed with further work, dementia experts cautioned. But they welcomed any glimmer of success after multiple prior failures of Alzheimer’s drugs.
The study is a placebo-controlled, double-blind, parallel-group, randomized Phase II clinical study in 856 patients with mild cognitive impairment (MCI) due to Alzheimer’s disease or mild Alzheimer’s dementia, with confirmed amyloid pathology in the brain. Patients were randomized to five dose regimens, 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly and 10 mg/kg biweekly, or placebo.
This study used a Bayesian Adaptive Randomization Design to automatically allocate newly enrolled patients into the study to treatment arms showing higher probability of efficacy based on the results of interim analyses.
BAN2401 demonstrated a dose-dependent reduction in amyloid plaques as measured by amyloid PET, and this reduction was statistically significant at all doses. At the highest dose of BAN2401 (10 mg/kg biweekly), an analysis of amyloid accumulated in the brain using standardized PET as measured on the Centiloid scale showed an observed mean at baseline of 74.5 and at 18 months of 5.5.
Using a Mixed-effects Model with Repeated Measures (MMRM), the mean reduction in amyloid load was 70 units, which was statistically significant (p<0.0001). In amyloid PET image visual read, BAN2401 demonstrated a dose dependent conversion from amyloid positive to negative, and at the highest dose, 81% of patients converted from amyloid positive to negative at 18 months (p<0.0001).
A dose-dependent increase in Aβ levels in cerebrospinal fluid in patients on BAN2401 (highest dose at 18 months: p<0.0001) was observed. Combined analysis of patients receiving BAN2401 at 10 mg/kg (either monthly or biweekly) demonstrated a statistically significant reduction in total tau over time compared to placebo (p<0.05).
BAN2401 demonstrated an acceptable tolerability profile through 18 months of study drug administration. The incidence rate of treatment-related adverse events was 26.5% for the placebo arm, 53.4% for the 10 mg/kg monthly treatment arm and 47.2% for the 10 mg/kg biweekly treatment arm.
The most common side events were Amyloid Related Imaging Abnormalities (ARIA) and infusion-related reactions. Incidence of ARIA-E (edema) was 9.9% at the highest treatment dose, and not more than 10% in any of the treatment arms.
Incidence of ARIA-E in APOE4 carriers was 14.6% at the highest dose. Per protocol, all patients presenting with ARIA-E on MRI were discontinued in the study. The incidence rate of serious adverse events was 17.6% for the placebo arm, 12.3% for the 10 mg/kg monthly treatment arm and 15.5% for the 10 mg/kg biweekly arm.
The Alzheimer’s Association is encouraged by the varied approaches being explored by the research field to treat and prevent Alzheimer’s disease.
The scientific community consensus is that we may need combination therapy in the future - that may include anti-amyloid approaches as well as other approaches to potential treatments that address multiple aspects of the disease, and include both drug and lifestyle interventions.
Veronika Logovinsky, Andrew Satlin, Robert Lai, Chad Swanson, June Kaplow, Gunilla Osswald, Hans Basun and Lars Lannfelt Safety and tolerability of BAN2401 - a clinical study in Alzheimer’s disease with a protofibril selective Aβ antibody Alzheimer’s Research & Therapy20168:14 https://doi.org/10.1186/s13195-016-0181-2
Image: Columbia University Medical Center