Biogen Inc. and Eisai Co., Ltd. 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 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. 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. 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 large clinical trial dataset available in early Alzheimer's disease, which included 1,856 screened patients from EMERGE, ENGAGE, PRIME and EVOLVE.

ADUHELM is indicated for the treatment of Alzheimer's disease. Treatment with ADUHELM should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied.

This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). Aducanumab-avwa is a monoclonal antibody directed against amyloid beta.

The accumulation of amyloid beta plaques in the brain is a defining pathophysiological feature of Alzheimer's disease. The accelerated approval of ADUHELM has been granted based on data from clinical trials showing the effect of ADUHELM on reducing amyloid beta plaques, a surrogate biomarker that is reasonably likely to predict clinical benefit, in this case a reduction in clinical decline. ADUHELM can cause serious side effects including: Amyloid Related Imaging Abnormalities or “ARIA”.

ARIA is a common side effect that does not usually cause any symptoms but can be serious. Although most people do not have symptoms, some people may have symptoms such as: headache, confusion, dizziness, vision changes and nausea. The patient's healthcare provider will do magnetic resonance imaging (MRI) scans before and during treatment with ADUHELM to check for ARIA.

ADUHELM can also cause serious allergic reactions. The most common side effects of ADUHELM include: swelling in areas of the brain, with or without small spots of bleeding in the brain or on the surface of the brain (ARIA); headache; and fall. Patients should call their healthcare provider for medical advice about side effects.

As of October 2017, Biogen and Eisai Co., Ltd. are collaborating on the global co-development and co-promotion of aducanumab.