Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer’s Disease

Ting Shen,Stuart L Graham,Veer Gupta,Morteza Abyadeh,Ghasem H Salekdeh,Nitin Chitranshi,Kunal Dhiman,Samran Sheriff,Anna Meyfour,Yunqi Wu,Ardeshir Amirkhani,Paul A Haynes,Mehdi Mirzaei,Vivek Gupta

doi:10.14336/ad.2021.0719

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia that has remained a major medical, sociocultural and economical challenge globally. Previously developed treatments like anticholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor (NMDAR) antagonists only provide short-term symptomatic improvement and do not prevent progression. Repeated setbacks and failures over the past 25 years in AD clinical trials have hindered efforts to develop effective AD treatments. Fortunately, Aducanumab, a specific anti-amyloid β antibody, has shown promising clinical results and was recently approved by the Food and Drug Administration (FDA) through an accelerated approval pathway. This has raised hopes for AD patients; however post-approval trials are necessary to estimate the true scope of its clinical benefits. We have reviewed several AD clinical studies and summarized the experience to date with Aducanumab and two other potential AD drugs including Zagotenemab (an anti-tau antibody) and Pioglitazone (nuclear Peroxisome-Proliferator Activated Receptor γ (PPARγ) agonist). These have shown mixed results so far and the next few years will be critical to elucidate and interpret their broad long-term protective effects. A concerted effort is required to understand and strengthen the translation of pre-clinical findings from these drugs to routine clinical practice.

Highlights

Alzheimer’s disease (AD) is the leading cause of dementia that has remained a major medical, sociocultural and economical challenge globally
amyloid-related imaging abnormalities (ARIA) was the common side-effect of Aducanumab which was notable in clinical results, but it was transient and manageable using a titration schedule and safety monitoring with MRI
In June 2021 Food and Drug Administration (FDA) approved Aducanumab as a drug for AD through accelerated approval pathway, which is used when drug is the first available treatment or shows advantages over existing treatments for life-threatening illness and is likely to predict clinical benefit based on a surrogate endpoint, Biogen is still required to conduct post-approval trial to verify the anticipated clinical benefit

Summary

Introduction

Alzheimer’s disease (AD) is the leading cause of dementia that has remained a major medical, sociocultural and economical challenge globally. In 2012, the phase Ib clinical trial (NCT01677572) initiated by Biogen used doses ≤ 10 mg/kg (1, 3, 6 or 10 mg kg−1) in 197 participants with prodromal or mild AD to assess the safety and tolerability of these concentrations further based on phase Ia observations; examine the efficacy of the mAb on reducing the cerebral Aβ plaque content as evaluated by florbetapir-fluorine-18 (18F-AV-45F-AV-45) Positron Emission Tomography (PET) imaging; and determine the serum concentrations of Aducanumab and serum antiAducanumab antibodies, in order to determine the optimum dose for phase II.

Results

Conclusion