Navigating the Future of Alzheimer’s Treatment

Simplifying ARIA-E Assessment with SSAE Scales

Luc Bracoud, M.Sc. – Senior Director, Medical and Scientific Affairs at Clario
Joyce Suhy, Ph.D. – EVP, Medical Imaging and Specialty Solutions at Clario

Introduction

Alzheimer’s disease (AD) is a pervasive neurodegenerative condition and the leading cause of dementia. Current research and drug development mainly target cerebral amyloid and tau pathologies as the driving forces behind AD-related neurodegeneration. Anti-Aβ monoclonal antibody therapies have seen recent successes after years of disappointing results. Some clinical efficacy was shown, in spite of associated side effects termed amyloid-related imaging abnormalities (ARIA).

This post provides a summary of a contributing research article co-written by Joyce Suhy, Ph.D., EVP, Medical Imaging and Specialty Solutions and Luc Bracoud, M.Sc., Senior Director, Medical and Scientific Affairs – both employed by Clario and published online at https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/dad2.12503. The article formally describes and validates the visual scales rating the severity of ARIA-E (edema), which were empirically developed by and applied by Clario to most amyloid-targeting treatments being explored over the past two decades.

Anti-Aβ monoclonal antibodies: A promising approach

The clearance of Aβ plaque has emerged as a promising strategy for slowing AD progression. Anti-Aβ monoclonal antibodies (mAbs) have garnered attention for their potential to reduce Aβ plaques in the brain, showing promising results in delaying cognitive and functional decline. Of these, 3 compounds have made significant strides. Aducanumab (Aduhelm) received accelerated approval from the U.S. Food and Drug Administration (FDA) in 2021 and lecanemab (Leqembi) received traditional approval in 2023.  Approval of donanemab was recently submitted to the FDA, with US traditional approval expected in Q1 2024, according to Eli Lilly’s CEO Dave Ricks.

ARIA: Unveiling a challenge in treatment

However, the development of anti-Aβ mAbs came with its own set of challenges, particularly in the form of ARIA. These were first observed during the successive phases of development of bapineuzumab between 2006 and 2013, and have gained attention since then. As first described in 2012, ARIA includes MRI signal abnormalities suggestive of vasogenic edema and sulcal effusions (ARIA-E) and hemosiderin deposits (ARIA-H). While ARIA is mostly asymptomatic, shows a dose-dependance, higher likelihood with early exposure to treatment, and increased risk in APOE4 carriers, its pathophysiological mechanism remains unclear. Due to associated blood-brain barrier alteration, it nevertheless poses a risk that, if left undetected, could lead to severe clinical consequences.

The need for accurate assessment: SSAE-3 and SSAE-5

ARIA-E tends to resolve spontaneously upon treatment interruption, while ARIA-H may at best stabilize after some time. As a means to mitigate adverse reactions to treatment while maximizing patient’s exposure and therefore ensuring optimal amyloid plaque clearance, pharmaceutical companies have designed treatment administration plans which take radiological ARIA severity into account in order to allow treatment continuation in milder ARIA-E cases, and temporary treatment suspension in more severe presentations of ARIA-E, while termination of treatment remains restricted to situations where ARIA-H development becomes a safety concern.

The article introduces the Severity Scales of ARIA-E (SSAE-3 and SSAE-5), simplified rating scales designed both for clinical trial conduct and for practical use in clinical practice. These scales provide a clear and consistent method to assess ARIA-E severity radiologically, facilitating routine MRI monitoring and accurate scoring of ARIA-E in patients undergoing anti-Aβ mAb treatment.

Validation of SSAE-3 and SSAE-5

The article describes how images should be rated, delves into the validation results of the SSAE-3 and SSAE-5 scales, demonstrating high inter- and intra-reader agreements among experienced radiologists, and provides some guidelines for administration. These rating scales offer a practical, understandable, and reliable assessment of ARIA-E severity.

Implications for future Alzheimer’s treatment

As more anti-Aβ mAbs become available, the adoption of standardized MRI protocols and reliable ARIA-E severity assessment tools becomes crucial. The SSAE-3 and SSAE-5 rating scales, with their simplicity and validity, offer a readily available solution for routine clinical practice.  The utilization of our (Clario’s) SSAE-3 scale in the commercial sector is now printed on the FDA labels of both Aduhelm and Leqembi. The article concludes by emphasizing the potential of these scales to support the expansion of anti-Aβ mAbs as a viable treatment option for individuals living with Alzheimer’s disease.

To learn more about this, the article can be found here. Additional insights into scale comparability and treatment management thresholds are presented here.

Written by

Luc Bracoud, M.Sc.

Senior Director, Medical and Scientific Affairs at Clario

Joyce Suhy, Ph.D.

EVP, Medical Imaging and Specialty Solutions at Clario