Eisai: New Phase 3 Data Show Positive Correlation Between ADUHELM Treatment Effect on Biomarkers and Reduction in Clinical Decline in Alzheimer's Disease
- In a pre-specified analysis, ADUHELM significantly lowered plasma p-tau181, a biomarker of the hallmark tau tangles in Alzheimer's disease, in both Phase 3 trials in a dose- and time-dependent manner vs. placebo
- Change in plasma p-tau181 was significantly correlated with change in amyloid beta plaque and reduced cognitive and functional decline on all primary and secondary outcome measures
- These data provide further evidence of ADUHELM's effect on clinical decline by lowering amyloid beta plaque and tangles of tau proteins, two defining pathologies of Alzheimer's disease
TOKYO, Nov 12, 2021 - (JCN Newswire) - Biogen Inc. and Eisai Co., Ltd. (Tokyo, Japan) announced that data from approximately 7,000 plasma samples from more than 1,800 patients in the ADUHELM (aducanumab-avwa) Phase 3 clinical trials showed a statistically significant correlation between plasma p-tau reduction and less cognitive and functional decline in Alzheimer's disease. Reductions in plasma p-tau181 were also correlated with a lowering of amyloid beta plaque. The pre-specified analysis of plasma samples was conducted by an independent lab, drawing from the two pivotal ADUHELM Phase 3 EMERGE and ENGAGE trials. The findings were presented today at the Clinical Trials on Alzheimer's Disease conference (CTAD), held November 9-12 virtually and in Boston, Massachusetts.
The analysis highlighted that ADUHELM significantly reduced tau pathology, a defining feature of Alzheimer's disease, as measured by plasma p-tau181, when compared to placebo. The effect was greater with higher doses and longer duration of ADUHELM treatment. Greater reduction in plasma p-tau181 also had a statistically significant correlation with less decline in cognition and function in ADUHELM-treated patients. Furthermore, the analysis demonstrated a statistically significant correlation between change in plasma p-tau181 and lowering of amyloid beta plaque, showing the effect of ADUHELM on the two core pathological features of Alzheimer's disease.
"We now have robust and concordant data that ADUHELM has effect on two core defining pathologies of Alzheimer's disease, and substantial evidence of treatment correlation between changes in plasma p-tau181 and the slowing of disease progression," said Alfred Sandrock, Jr., M.D., Ph.D., Head of Research and Development at Biogen. "We are committed to continuing to generate data, and we believe these new findings can help inform treatment choice and advance Alzheimer's research including in diagnosis and disease monitoring."
The findings showed that ADUHELM significantly lowered plasma p-tau181 in a dose- and time-dependent manner vs. placebo in both Phase 3 trials. In the EMERGE high-dose group, p-tau decreased 13% from baseline (p<0.001), while placebo rose 8%; in the ENGAGE high-dose group, p-tau decreased 16% from baseline (p<0.001), while placebo rose 9%.
Greater reduction in plasma p-tau181 was correlated with less clinical decline in all four clinical outcome measures in the Phase 3 trials. Correlation values across these endpoints were as follows for EMERGE and ENGAGE, respectively: Clinical Dementia Rating Sum of Boxes Score (CDR-SB) R = 0.11 (p=0.0166) and R = 0.14 (p = 0.0005); Mini-Mental State Examination (MMSE) R = -0.21 (p < 0.0001) and R = -0.15 (p = 0.0002); Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) R = 0.17 (p = 0.0001) and R = 0.15 (p = 0.0002); and Alzheimer's Disease Cooperative Study/Activities of Daily Living scale adapted for MCI (ADCS-ADL-MCI) R = -0.12 (p = 0.0086) and R = -0.14 (p = 0.0010).
Changes in plasma p-tau181 was also significantly correlated with change in amyloid beta positron emission tomography (PET) standardized uptake value ratio (SUVR): EMERGE R = 0.38, p< 0.0001; ENGAGE R = 0.42, p < 0.0001.
"These data not only show an important link between the ability of ADUHELM to clear amyloid beta plaque and reduce plasma p-tau levels, but also significantly correlate those reductions with slowing cognitive decline," said Oskar Hansson, M.D., Ph.D., Professor of Neurology at Lund University and Skane University Hospital, Sweden, who led the oral late-breaker presentation at the CTAD conference. "Having research from nearly two thousand patients provides invaluable insights into the dynamics of the interconnected pathologies within this complex disease."
The two pathological hallmarks of Alzheimer's disease--amyloid beta plaque and neurofibrillary tangles (composed of abnormal p-tau)--disrupt communication between neurons, which leads to the loss of brain function, as well as neurodegeneration and clinical decline, which can begin in the early stages of Alzheimer's disease.
Biogen also presented data from the Phase 3b redosing study, EMBARK, which examined the impact of patients with Alzheimer's disease stopping ADUHELM treatment for an extended period of time (average length of 1.7 years) before re-initiating treatment. The study showed that reductions in amyloid beta plaque were maintained in the high-dose group during the treatment gap period compared to the placebo group. Although the disease continued to progress after treatment discontinuation, numerical differences in favor of ADUHELM were maintained across clinical endpoints.
The EMBARK baseline data underscore that further scientific evidence is needed to better understand the impact of discontinuation from anti-amyloid treatment and the role that other underlying pathological processes may play in disease progression.
EMBARK is not a randomized study and there may be selection bias for the enrolling patients; Interpretation of these data must weigh the potential influence of the heterogeneity of dose, duration of exposure, and treatment gap periods across individuals in the study. The analysis is from the largest clinical trial dataset available in early Alzheimer's disease, which included 1,856 screened patients from EMERGE, ENGAGE, PRIME and EVOLVE.
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