Within the defined amyloid-tau-neurodegeneration framework of Alzheimer disease, the investigational agent has displayed a hopeful effect on all 3 pieces.
Jeffrey Cummings, MD, ScD
Eisai and Biogen have announced additional topline data from Study 201, exploring the effect on patients with Alzheimer disease of their investigational agent BAN2401.1
The anti-amyloid ß protofibril antibody demonstrated a statistically significant reduction in brain amyloid measured by positron emission tomography (PET) at 18 months (P <.0001). Over 80% of subjects on the highest dose of BAN2401 converted from positive to negative on amyloid PET.
Additionally, the therapy displayed a significant slowing of clinical decline as measured by Alzheimer’s Disease Composite Score (ADCOMS), with those treated with BAN2401 seeing a 30% greater slowing compared to placebo (P = .034).
“I’m encouraged by these findings,” said Jeffrey Cummings, MD, ScD, from the Center for Neurodegeneration and Translational Neuroscience at Cleveland Clinic’s Lou Ruvo Center for Brain Health, in the presentation at the 11th Clinical Trials in Alzheimer’s Disease (CTAD) conference in Barcelona, Spain.2 “I do think they need to be confirmed by additional studies, but they’re certainly moving the direction that we have wanted, and I think provide a compelling platform for studies of [BAN]2401.”
Earlier this year, Lynn Kramer, MD, the chief clinical and medical officer in the Neurology Business Group at Eisai told NeurologyLive of the therapy: “I think it gives the entire community—after many, many years of research on the amyloid hypothesis and some negative trials which diminished people's expectations—hope.”
The data also showed a group-level correlation between the clearance of brain amyloid and slowing of clinical decline (Pearson’s coefficient, 0.838), as well as a significant difference over 18 months between placebo and the highest dose in the slope of change from baseline on the rate of disease progression (P <.001)—suggesting a disease-modifying impact.
“The bi-weekly dose was clearly effective as we see it in terms of reducing the rate of decline, reducing the amyloid burden, and affecting the biomarkers,” Cummings said in the presentation. “The worry that there was asymmetric allocation of subjects bearing the APOE4 genotype, I think, has been allayed by these analyses.”
“In terms of brain amyloid, there was a significant reduction in the total amyloid burden...It’s a striking effect. I think we couldn’t even have imagined that a few years ago,” Cummings added.
At the highest treatment dose, the therapy showed that patients who were APOE4 carriers treated with BAN2401 at the 10 mg/kg bi-weekly dose (the highest dose tested) experienced lesser decline in disease progression of 63%, while non-carriers observed a 7% less decline, compared to placebo at 18 months.
Subgroup analyses were also presented, with the highest dose also resulting in disease progression decline on ADCOMS across the clinical stages of Alzheimer. Those with mild cognitive impairment due to Alzheimer experienced a 33% decline and those with mild Alzheimer experienced a 35% decline. These results also extended to those both with and without concomitant use of Alzheimer medications, with respective declines of 23% and 41% in disease progression. Notably, statistical significance was unable to be determined by the power of the study.
“Even more interesting, from my point of view, is the CSF biomarkers demonstrated an effect consistent with ameliorating the underlying pathophysiology of Alzheimer disease,” Cummings explained. “You know that we’re working in this ATN framework now—amyloid, tau, neurodegeneration framework—with the new NIA-AA definition of Alzheimer disease. So, if you look at what this trial brought to bear, then you see that there was a reduction in amyloid, or A; there was a reduction in the downstream tau pathology of phospho-tau, T; and there was a reduced elevation of neurofilament light, which is an indicator of neurodegeneration.”
In July,3 Kramer noted that this was the first late-stage therapy of its kind to successfully achieve significance at the 18-month timepoint, “further validating the amyloid hypothesis.”
“We will discuss these very encouraging results with regulatory authorities to determine the best path forward,” he said. “We continue to work towards the goal of delivering BAN2401 to patients and healthcare professionals as early as possible.”
With regard to safety, the therapy showed an “acceptable tolerability profile,” according to the manufacturers. The most common treatment-emergent adverse events (AEs) were infusion-related reactions and amyloid-related imaging abnormalities (ARIA), both of which were determined as dose-dependent. All told, 10% of ARIA-edema cases, which were more common in APOE4 carriers, were symptomatic and included headache, visual disturbances, and confusion. Of the ARIA-edema cases, 60% occurred within the first 3 months and roughly 89% were mild to moderate in severity.
The results have lead Biogen and Eisai to announce that they are discussing next steps with regulatory authorities for the therapy. An open-label extension for Study 201 is expended to begin later this year.
1. Eisai and Biogen Announce Presentation of Additional Data From the Phase II Clinical Trial of BAN2401 in Early Alzheimer’s Disease at the 2018 Clinical Trials on Alzheimer’s Disease (CTAD) Conference [press release]. Tokyo: Eisai Co; Cambridge: Biogen. Published October 25, 2018. eisai.com/news/2018/pdf/enews201892pdf.pdf. Accessed October 25, 2018.
2. Eisai Presentation at CTAD. CTAD website. Published October 25, 2018. streamingbarcelona.com/plataforma/ctad-eisai. Accessed October 25, 2018.
3. Eisai and Biogen announce positive topline results of the final analysis for BAN2401 at 18 months [press release].Esiai Public Relations Department. Tokyo, Japan. Biogen Inc. Public Affiars. Cambridge, Massachusetts. investors.biogen.com/news-releases/news-release-details/eisai-and-biogen-announce-positive-topline-results-final. October 25, 2018.