The data, which suggest that a lessened decline in cognition and function was correlated with a reduction in plasma p-tau181 levels in those with Alzheimer disease treated with aducanumab (Aduhelm; Biogen), were presented at CTAD 2021.
In a newly presented data set from the phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) clinical trials of aducanumab (Aduhelm; Biogen), findings from analyses of more than 7000 plasma samples from more than 1800 individuals suggest that treatment with the amyloid-ß targeting agent results in a significant correlation between the reduction in plasma p-tau and lessened decline in cognition and function in those with Alzheimer disease.1,2
Presented at the 14th Clinical Trials on Alzheimer’s Disease Conference (CTAD), November 9-12, by Oskar Hansson, MD, PhD, professor of neurology, Lund University and Skåne University Hospital, and several colleagues in a late-breaking panel session, the high-dose group data from EMERGE (n = 514-521) showed a 13% reduction from baseline in tau pathology that was associated with aducanumab treatment in a dose- and time-dependent fashion compared with placebo, which experienced an 8% rise (P <.001). ENGAGE’s high-dose group (n = 577-581) showed a p-tau reduction of 16% in the treatment group, compared with a 9% rise for placebo (P <.001).
These changes in plasma p-tau181 were also significantly correlated with the change in amyloid-ß PET standardized uptake value ratio in both EMERGE (R = 0.38; P <.0001) and ENGAGE (R = 0.42; P <.0001). “This is consistent with the hypothesized relationship among the underlying pathologies of Alzheimer's disease,” Hansson said in the presentation.2
"These data showing that aducanumab lowers plasma p-tau and slows clinical decline in early Alzheimer disease provides exciting new evidence that targeting amyloid alters tau and that plasma biomarkers may be useful in tracking response to treatment," Stephen Salloway, MD, MS, Martin M. Zucker Professor of Psychiatry and Neurology, Warren Alpert Medical School, Brown University, who was part of the presenting panel, told NeurologyLive.
“These data not only show an important link between the ability of ADUHELM to clear amyloid-ß plaque and reduce plasma p-tau levels, but also significantly correlate those reductions with slowing cognitive decline. Having research from nearly 2000 patients provides invaluable insights into the dynamics of the interconnected pathologies within this complex disease,” Hansson added, in a statement.1
A greater reduction in plasma p-tau181 was shown to be correlated with a lessened level of clinical decline in all 4 of the trials’ outcome measures: Clinical Dementia Rating Sum of Boxes Score (CDR-SB), Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog 13), and Alzheimer’s Disease Cooperative Study/Activities of Daily Living scale adapted for MCI (ADCS-ADL-MCI). Those correlation values were as follows:
"These data confirm that in both studies the reduction in p-tau was correlated with clinical outcomes. Being correlated with clinical change is a first and important step towards a biomarker being considered as a surrogate. Although additional study is needed, these findings add to the growing evidence that biomarkers could be a reasonable indicator of clinical measures in Alzheimer disease," Ivana Rubino, PhD, Head of Medical, Global Alzheimer's, Biogen, told NeurologyLive.
Gil Rabinovici, MD, Edward Fein and Pearl Landrith Endowed Professor in Memory & Aging, University of California, San Francisco, noted during the presentation that the correlation values were promising, though modest, and added in response to a question from the crowd that additional biomarkers would be helpful in determining the effects of treatment on congition.2
“We now have robust and concordant data that ADUHELM has [an] effect on 2 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,” Alfred Sandrock Jr, MD, PhD, head, Research and Development, Biogen, said in a statement.1 “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.”
Anton Porsteinsson, MD, director, University of Rochester Alzheimer's Disease Care, Research and Education Program, and William B. and Sheila Konar Professor of Psychiatry, University of Rochester School of Medicine and Dentistry, who was an investigator in the trials, told NeurologyLive that the plasma p-tau 181 results were significant because of their association with amyloid lowering and clinical outcomes. "It is easier to make a case for a connection between lowering of p-tau and reduced decline in cognition and function. This adds confidence to the overall aducanumab results," he said.
The plasma p-tau 181 results are significant as they correlate with both the degree of amyloid lowering and clinical outcomes in both phase 3 aducanumab studies. It is easier to make a case for a connection between lowering of p-tau and reduced decline in cognition and function. This adds confidence to the overall aducanumab results.
"Plasma biomarkers are relatively easy to incorporate into clinical trials, and we do intend to include them in our clinical trials in Alzheimer disease," Rubino said.
Aducanumab was approved by the FDA for the treatment of Alzheimer disease in June 2021, after nearly 2 years of debate among members of the healthcare, research, and patient communities who grappled with the treatment's promising—but questionable—clinical trial data. The therapy was approved under the accelerated approval pathway, which will require Biogen to conduct post-approval phase 4 studies to confirm the benefit of the drug. The agency noted that in the case that the anticipated clinical benefit is not confirmed, it "has regulatory procedures in place that could lead to removing the drug from the market."3
At the 2021 Alzheimer Association International Conference (AAIC), July 26-30, a number of physicians presented appropriate use criteria for aducanumab in order to clarify some of these lingering questions, which were published in The Journal of Prevention of Alzheimer's Disease prior to the meeting. Among them was Jeffrey L. Cummings, MD, ScD, professor of brain science, and director, Chambers-Grundy Center for Transformative Neuroscience, University of Nevada–Las Vegas, who told NeurologyLive at the time that "they deal very seriously with safety, how to manage the ARIA [amyloid-related imaging abnormalities] and the safety of aducanumab, and how to choose the patient for aducanumab—because we want to keep those patients very close to the trial patients in terms of their characteristics—and then how to talk with the patients."
"This is a complicated drug. The patient has to commit themselves to monthly infusions, they have to commit themselves to frequent MRI scanning in the first year, they have to know that ARIA occurs and that it can be a symptomatic outcome of the treatment with aducanumab. The shared decision-making between the clinician and the patient is extremely important for this particular agent, and we emphasize that a lot in terms of the appropriate use recommendations," Cummings added.