Defining Disease Modifying Therapy for Alzheimer’s Disease

Abstract

Background: Disease-modifying therapies (DMTs) are urgently needed to treat the growing number of individuals with Alzheimer’s disease (AD) or at immanent risk for AD. A definition of DMT is required to facilitate the process of DMT drug development. Process: This is a review of the state of the science with regard to definition and development of DMTs. Results: A DMT is as an intervention that produces an enduring change in the clinical progression of AD by interfering in the underlying pathophysiological mechanisms of the disease process that lead to cell death. Demonstration of DMT efficacy is garnered through clinical trial designs and biomarkers. Evidence of disease modification in the drug development process is based on trial designs such as staggered start and delayed withdrawal showing an enduring effect on disease course or on combined clinical outcomes and correlated biomarker evidence of an effect on the underlying pathophysiological processes of the disease. Analytic approaches such as showing change in slope of cognitive decline, increasing drug-placebo difference over time, and delay of disease milestones are not conclusive by themselves but support the presence of a disease modifying effect. Neuroprotection is a related concept whose demonstration depends on substantiating disease modification. No single type of evidence in itself is sufficient to prove disease modification – consistency, robustness, and variety of sources of data will all contribute to convincing stakeholders that an agent is a DMT. Conclusion: DMT is defined by its enduring effect on processes leading to cell death. A variety of types of data can be used to support the hypothesis that disease modification has occurred.

Influence of common reference regions on regional tau patterns in cross-sectional and longitudinal [18F]-AV-1451 PET data

“…These methodological decisions are particularly important for the integration of tau PET into clinical trials, which has become commonplace in multiple high profile anti-amyloid trials investigating aducanamab ( Sevigny et al, 2016 ), solanezumab ( Siemers et al, 2016 ), lecanemab ( Swanson et al, 2021 ), and donanamab ( Mintun et al, 2021 ). In the context of these clinical trials, tau PET represents a key modality that can provide insight into disease modification answering questions such as whether removal of amyloid results in downstream changes to tau PET signal ( Cummings and Fox, 2017 ). In these large-scale studies it is not possible to perform gold-standard dynamic imaging along with arterial sampling ( Barret et al, 2017 ; Wooten et al, 2017 ; Hahn et al, 2017 ) to enable true quantification of the PET signal.…”

Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer’s disease

“…Predictive benefit may be demonstrated if changes captured on a disease-relevant biomarker or on a core disease domain, such as cognition, predict longer-term clinical benefit, such as reduced clinical decline [ 8 ]. Cumulative benefits [ 9 ] reflect an accrual of effects over long-term therapy, such that the difference in outcome between those treated with placebo and those treated with drug increases over time. The recent approval of aducanumab under the accelerated pathway (i.e., that β-amyloid plaque removal is reasonably likely to predict clinical benefit) makes the concept of predictive benefit unquestionably relevant in AD drug development and clinical practice.…”

The National Institute on Aging—Alzheimer's Association Framework on Alzheimer's disease: Application to clinical trials

“…Development of DMTs depends on demonstrating target engagement in phase II trials to insure that near-and intermediate-term steps critical to disease modification are being achieved [29]. A successful DMT must exert neuroprotection, and this goal will be reflected most closely in a drug-placebo difference on N [30,31]. A and T are intermediate targets whose modification may result in neuroprotection and disease modification through linked mechanisms.…”

“…Successful DMTs will exert neuroprotection [30,31]. Neurodegeneration in the ATN Framework is assessed by MRI atrophy, CSF t-tau, for FDG PET.…”