BAN2401 produced a dose-dependent substantial reduction in brain amyloid plaque at the highest dose, resulting in subjects converting to amyloid negative.
Lynn Kramer, MD, Chief Clinical Officer and Chief Medical Officer at Eisai
Lynn Kramer, MD
BAN2401, an anti-beta protofibril antibody, significantly slowed disease progression for patients with Alzheimer disease, according to the global phase II Study 201 trial reported by Eisai and Biogen at the 2018 Alzheimer’s Association International Conference (AAIC) in Chicago, Illinois.
At 18 months, the highest tested BAN2401 treatment dose of 10 mg/kg biweekly demonstrated a significant slowing of cognitive decline of 30% versus placebo (P = .034) as measured by the Alzheimer Disease Composite Score (ADCOMS), an Eisai-devised test drawing from 3 established Alzheimer assessment scales designed to detect subtle changes in those with early-stage disease and evaluate progression. BAN2401 also reduced the formation of new beta-amyloid clusters in the brain and decreased existing clusters by 70% on average.
“The unique trial was designed using unique endpoints and traditional endpoints in an attempt to validate some new endpoints that might be better for these earlier staged patients, rather than the traditional ADAS-cog, MMSC, CDR-SOB, which were really developed for late stage, mild, moderate, severe patients,” Lynn Kramer, MD, chief clinical officer and chief medical officer at Eisai, told NeurologyLive.
In the 18-month phase II trial, 856 patients with mild cognitive impairment due to Alzheimer disease or Alzheimer dementia, with confirmed amyloid pathology in the brain, were randomized to placebo or 1 of 5 BAN2401 dosing regimens: 2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, or 10 mg/kg biweekly. Researchers relied on the Bayesian Adaptive Randomization Design to automatically allocate newly enrolled patients to treatment arms displaying a higher probability of efficacy, based on the results of interim analyses. This is the first use of Bayesian statisticians in an Alzheimer disease trial.
Changes in ADCOMS were compared from baseline and to placebo using mixed model repeated measures (MMRM). The study measured changes from baseline to 18 months in biomarkers of pathophysiology, which included amyloid accumulation in the brain measured by amyloid positron emission tomography (PET). Clinical endpoints of ADCOMS, Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), and Clinical Dementia Rating Sum of Boxes (CDR-SB) were measured from baseline to 18 months.
A dose-dependent reduction in ADCOMS was produced versus placebo (P = .011), with the top dose significantly reducing decline by 35% (P = .027) and 30% (P = .034) at 12 and 18 months, respectively. Treatment with BAN2401 demonstrated a statistically significant reduction in amyloid plaques for all doses with the top dose—10 mg/kg biweekly—achieving an adjusted mean change from baseline versus placebo of -.26 at 12 months (P <.0001) and -.30 at 18 months (P <.0001).
The amyloid PET analysis showed significant reductions of amyloid PET standardized uptake value ratio (SUVR) and amyloid PET image visual read of subjects adapting from amyloid positive to amyloid negative in 65% (P <.0001) and 81% (P <.0001) of subjects on the top dose at both 12 and 18 months, respectively.
A dose-dependent, statistically significant slower decline in clinical outcome measures of cognition and function were also observed on ADAS-cog, with a 47% less decline on the top dose, and for CDR-SB, with 26% less decline on the top dose.
The updated results contradicted initial data from the 12-month analysis announced in December 2017, which suggested that BAN2401 did not meet the primary endpoint. In order to reach significance, the model called for an 80% probability that BAN2401 could reduce the rate of cognitive decline by 25% or more compared with placebo; however, the probability was judged to be 64% at the analysis, which Kramer noted at the AAIC presentation was “relatively close.”
“The results were very consistent across imaging biomarkers, clinical endpoints, and fluid CSF biomarkers,” Kramer added. “By that I mean we did PET SUVR, conversion from positive to PET negative, we did ADCOMS our newly developed, slightly more sensitive endpoint for these patients, ADAS-cog, CDR-SOB, and then we looked at CSF Aβ42, and total tau over the treatment period showing the hope for changes.”
An acceptable tolerability profile was demonstrated through 18 months of study drug administration, with the most common treatment-emergent adverse effects reported as amyloid-related imaging abnormalities (ARIA) and infusion-related reactions.
The incidence rate of treatment-related adverse effects was 26.5% for the placebo arm, 53.4% for the BAN2401 10 mg/kg monthly treatment arm, and 47.2% for the 10 mg/kg biweekly treatment arm, while the incidence rate of serious adverse effects was 17.6% for placebo, 12.3% for the 10 mg/kg monthly treatment arm, and 15.5% for the 10 mg/kg biweekly arm. ARIA-E (edema) did not occur in >10% of any treatment arms. The incidence of ARIA-E in APOE3 carriers was 14.6% at the highest dose, and per protocol, patients presenting with ARIA-E on MRI were discontinued from the study.
The Alzheimer’s Association noted that BAN2401 is the second experimental drug to show effectiveness in reducing amyloid burden in the brain, with the first being aducanumab, also developed and tested by Eisai and Biogen in a more advanced phase III trial—results are expected in 2019 or early 2020.
“We believe the BAN2401 data provides evidence to support beta-amyloid as a therapeutic target for Alzheimer’s disease,” Samantha Budd Haeberlein, PhD, Vice President of Clinical Development at Biogen, told NeurologyLive. “We are encouraged by the results that our partner Eisai, as the lead party on the development of BAN2401, has presented. We continue to more fully evaluate the data with Eisai and look forward to gaining a deeper understanding of these results.”
Eisai and Biogen will move forward with late-stage clinical trials and are working with regulatory agencies in the United States, Japan, and Europe to discuss the results, design additional trials, and gain expedited review as a breakthrough therapy for Alzheimer disease.
The FDA said that it’s open to trials measuring effects on biomarkers like beta-amyloid rather than symptoms like memory loss so that companies are able to test treatments earlier in the disease.
Swanson C, Zhang Y, Dhadda S, et al. Treatment of Early AD Subjects With BAN2401, an Anti-Aβ Protofibril Monoclonal Antibody, Significantly Clears Amyloid Plaque and Significantly Reduces Clinical Decline. Paper presented
2018 Alzheimer’s Association International Conference; July 25, 2018; Chicago, IL. July 25, 2018.