A new drug called BAN2401 has shown promise in decreasing amyloid in early Alzheimer disease (AD), according to results from a phase II study presented on July 25 2018, at the Alzheimer’s Association International Conference (AAIC), in Chicago, Illinois.[1-3]
“BAN2401-G000-201 is the first late-stage study that provides compelling evidence for the amyloid hypothesis. Treatment with BAN2401 produced a dose dependent substantial reduction in brain amyloid plaque at the 10 mg/kg bi-weekly dose, which resulted in the majority of subjects converting to amyloid negative as determined by PET visual read,” wrote first author Chad J Swanson, PhD, of Eisai Inc, Woodcliff Lake, NJ, USA. “These results were accompanied by significant reduction in clinical decline compared to placebo as measured by the ADCOMS [a composite clinical outcome score for cognitive functioning in pro-dromal and early AD, used in clinical trials],” they added.
BAN2401 (under development by Eisai and Biogen) is a humanized monoclonal antibody directed against amyloid beta (Aβ) protofibrils thought to be important in the pathogenesis of AD.
The study also evaluated changes in biomarkers involved in AD pathology, as well as clinical endpoints using the Alzheimer’s Disease Composite Score (ADCOMS), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Sum of Boxes (CDR-SB). An interim analysis had suggested that the highest doses (10 mg/kg monthly and 10 mg/kg biweekly) had greater efficacy. Consequently, researchers assigned a greater proportion of participants to treatment arms with higher doses: placebo: 247 patients, 2.5 mg/kg biweekly: 52 patients, 5 mg/kg monthly: 51 patients, 5 mg/kg biweekly: 92 patients, 10 mg/kg monthly: 253 patients, 10 mg/kg biweekly: 161 patients. To comply with a regulatory request outside of the US, researchers also restricted the number of APOE4 carriers in the 10 mg/kg biweekly treatment arm. As a result, more patients were assigned to 10 mg/kg monthly.
More results ADCOMS: dose-dependent reduction in clinical decline vs placebo (p=0.011) •10 mg/kg biweekly: declined by 35% (p=0.027) at 12 months and 30% (p=0.034) at 18 months Acceptable tolerability profile, most common treatment emergent adverse events: •Infusion related reactions: mostly mild to moderate •Amyloid Related Imaging Abnormalities (ARIA-E, edema): no more than 10% in any treatment arm, less than 15% in APOE4 carriers at the highest dose
In a statement, the Alzheimer’s Association noted that the trial was not large enough to prove efficacy in cognitive outcomes. Also, the study did not meet its primary endpoint, which was change in ADCOMS score from baseline to 12 months. However, the study may be an important step forward because results support amyloid as a therapeutic target in AD. “On behalf of the millions living with Alzheimer’s disease and other dementias now and the millions more at risk, the Alzheimer’s Association finds these results important to report and share with the scientific community. The data is intriguing and we look forward to hearing the sponsors’ plans for moving forward,” the Alzheimer’s Association stated in a press release.
Take home points •Phase II RCT suggests BAN2401 was associated with a dose-dependent reduction in brain amyloid, especially at the highest doses •Most participants converted to amyloid negative by 18 months •Participants showed a dose-dependent reduction in clinical decline compared with placebo •Results support targeting amyloid in the development of new drugs for AD