Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review

Beshir, Semira Abdi; Aadithsoorya, A. M.; Parveen, Affana; Goh, Sheron Sir Loon; Hussain, Nadia; Menon, Vineetha Bharathan

doi:https://doi.org/10.1155/2022/9343514

International Journal of Alzheimer’s Disease

On this page

Abstract Introduction Materials Conclusions Conflicts of Interest Authors’ Contributions References Copyright Related Articles

Review Article | Open Access

Volume 2022 | Article ID 9343514 | https://doi.org/10.1155/2022/9343514

Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review

Semira Abdi Beshir,¹A. M. Aadithsoorya,²Affana Parveen,³Sheron Sir Loon Goh,⁴Nadia Hussain,⁵and Vineetha Bharathan Menon⁶

Academic Editor: giulia abate

Received10 Sept 2021

Accepted16 Feb 2022

Published09 Mar 2022

Abstract

Background. Aducanumab, a new monoclonal antibody that targets β-amyloid aggregates, has been granted conditional approval by the U.S. FDA for treatment of mild Alzheimer’s disease (AD). The approval of this drug without a confirmed significant clinical impact has resulted in several debates. Objective. In this narrative review, aducanumab approval-related controversy, the drug’s pharmacokinetics and pharmacodynamic characteristics, evidence from the efficacy and safety trials of aducanumab, implications of the drug approval, and the future directions in the management of patients with AD are summarized. Methods. Using relevant keywords, Google Scholar, Web of Science, and MEDLINE databases and manufacturer’s website were searched. Results. Infusion of aducanumab at a higher dose resulted in a modest slowing of cognitive decline among patients with mild cognitive impairment or early-onset AD dementia. The drug however can cause amyloid-related imaging abnormalities. Due to modest impact on cognition, the use of this drug by patients with AD will most likely be limited. The manufacturer is required to run an extended phase IIIb trial to verify the benefit of this drug. Access to therapy requires a careful selection of patients and periodic monitoring to ensure the optimal use of the drug. Conclusion. Despite the limitations, aducanumab is the first disease-modifying therapy approved for the treatment of AD. Aducanumab addresses a part of the pathogenesis of AD; therefore, drugs that can act on multiple targets are needed. In addition, the search for preventive strategies, validated plasma-based assays, and newer drugs for AD, which are effective, safe, convenient, and affordable, is vital.

1. Introduction

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases resulting in progressive cognitive decline. Over 55 million individuals worldwide are affected by this debilitating disease which has a detrimental impact on quality of life, productivity, and the economy [1]. Due to the increased aging population, the prevalence of Alzheimer’s disease is anticipated to increase [1, 2]. The causes of AD remain unclear; however, the occurrence of AD is associated with aging, environmental, genetic, and lifestyle factors. Aggregates of β-amyloid protein peptides and neurofibrillary tangles (NFT) which damage the neurons are thought to be linked with the pathogenesis of AD [3]. Neuronal loss, gliosis, genetic mutations, cerebrovascular amyloidosis, and reduced concentrations of the neurotransmitter are also cited as additional factors [3, 4].

The cure for AD remains elusive, despite the advances made in AD drug research and development. Most drugs that are developed for AD are aimed at reducing the symptoms associated with the disease rather than targeting the underlying cause of the disease [5]. The common drugs used for the symptomatic management of patients with Alzheimer’s include cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), neuroprotective N-methyl-D-aspartate (NMDA) receptor antagonist (memantine) [6, 7], or combination therapy. Aducanumab was first manufactured by Neurimmune, and later in 2007, the license was sold to Biogen [8]. On June 7, 2021, FDA granted the conditional accelerated approval for aducanumab as the first disease-modifying agent for treating AD. This monoclonal antibody targets soluble (β-amyloid oligomers) and insoluble aggregates of β-amyloid proteins (fibrils and β-amyloid plaques) as depicted in Figure 1 [9].

Despite the data from several studies indicating that β-amyloid is linked to AD, most trials of anti-amyloid drugs have failed to show a significant impact on cognition [10, 11]. Aducanumab when used at higher doses is shown to have a modest impact on the cognitive decline of patients at the early stage of Alzheimer’s dementia or mild cognitive impairment (MCI) [12–14]. However, aducanumab does not reverse prior memory loss that is associated with AD. The conditional approval was granted contingent on the conduct of further studies although the majority of U.S. FDA advisory board members voted against the drug’s approval.

Though most patient advocates are pleased with the hope of having a new drug to treat AD, the approval of aducanumab creates unnecessary uncertainties for patients, clinicians, and researchers. The drug is under review in Japan, Brazil, and Australia [15]. The European Medicines Agency has recently voted against the approval of aducanumab for use in European countries. In this review, evidence from clinical trials of aducanumab, implications of aducanumab approval, and future directions in the management of patients with Alzheimer’s disease are discussed.

2. Materials and Method

The literature search was conducted in August 2021. Relevant search terms such as aducanumab OR anti beta-amyloid therapy OR immunotherapy OR monoclonal antibody and Alzheimer’s disease OR dementia OR mild cognitive impairment were used. Google Scholar, Web of Science, and MEDLINE databases and manufacturer’s website were searched to identify clinical trials, reviews, and updates on aducanumab in patients with AD.

3. Pharmacokinetics and Pharmacodynamic Characteristics of Aducanumab

According to the “amyloid theory,” aggregates of amyloid-β oligopeptides are linked with Alzheimer’s disease [16]. Aducanumab is a fully human IgG1 monoclonal antibody with a high affinity that acts by breaking down these β-amyloid aggregates into smaller oligopeptides or amino acids [17]. Aducanumab has been shown to selectively bind to parenchymal amyloid over vascular amyloid [18, 19]. The initial package insert of aducanumab generally states that the drug is indicated to treat AD even though the drug is only tested in early-onset AD patients. Hence, the U.S. FDA has recently approved an updated indication, which indicates that aducanumab should be initiated in patients with MCI due to AD or mild Alzheimer’s dementia. After an initial titration period, aducanumab should be administered at a dose of 10 mg/kg, given as a monthly intravenous infusion. Aducanumab is absorbed and reaches a Cmax of 182.7 μg/mL, with a Tmax of 3.0 hours, and an AUCinf of [20]. The drug achieves steady-state concentrations after 16 weeks of repeated dosing and a mean volume of distribution of 9.63 L. Aducanumab is eliminated after being broken down into smaller oligopeptides and amino acids [21]. The mean clearance and the terminal half-life for the drug are 0.0159 L/h and 24.8 days, respectively. Bodyweight, age, sex, and race seem to have no clinically significant impact on the exposure to the drug. Aducanumab may cause allergic reactions and amyloid-related imaging abnormalities (ARIA). ARIA events most commonly (80%) occur without any symptoms [12]. Even if symptoms appear, they include edema or microhemorrhages of the brain, which are transient adverse effects that may be reversed upon discontinuation of the drug [20].

4. Controversy on the Approval of Aducanumab

The approval of aducanumab by the U.S. FDA has resulted in a debate. Most patient advocates, AD patients, and their caregivers are pleased with the hope of having a new drug to treat AD [22], while some experts are against the approval of the drug due to multiple reasons [23, 24]. Firstly, the dug was approved based on surrogate endpoints and the modest impact on cognition [23, 25]. Furthermore, aducanumab is only tested in selected AD patients experiencing MCI or early-onset AD dementia, limiting its broader indications for all patients with AD. The lack of a confirmed causal relationship between β-amyloid plaques and cognitive decline may explain the lack of significant clinical impact [26]. However, it is important to note that there is no consensus on the definition of the minimum clinically significant difference (MCID) in Alzheimer’s disease [27]. Inconsistent results have cast a doubt on the potential targeting of β-amyloid protein to improve cognitive and functional decline in AD patients [23, 28, 29]. Secondly, the experts argue that the risk associated with the drug may outweigh the benefit of the drug [14, 30]. According to Gleason et al., aducanumab dose-dependent transient amyloid-related imaging abnormalities (ARIA) may outweigh the slight improvement in cognitive decline attributed to the drug [31]. Thirdly, the drug is deemed to be not cost-effective with the initial annual acquisition cost of aducanumab which is $56,000 [26, 32, 33]. Recently, the manufacturer has declared an annual price cut ($28,200) for aducanumab to improve the uptake of this medication by patients with early-onset Alzheimer’s. The cost associated with the drug is further increased by the need for screening and monitoring tests (PET imaging and periodic MRI) and drug administration costs. If the drug is ineffective, it may have a detrimental impact on human and economic resources [23]. Thirdly, approval of aducanumab may divert researchers away from potentially effective preventive and therapeutic measures [28]. Moreover, approval of an ineffective drug may destroy the people’s trust in regulatory and licensing organizations [28]. A recent study by Anderson et al. assessed the representativeness of ENGAGE and EMERGE trial subjects by evaluating the proportion of Medicare patients with AD and MCI who would be excluded from these trials [34]. Based on this study, a large proportion of Medicare patients would not be eligible to receive aducanumab due to their comorbid conditions. This further raises a question regarding the broad indication of aducanumab for mild onset Alzheimer’s disease. Regardless of the above concerns, the decision not to approve aducanumab might hinder investment by manufacturers involved in AD therapeutic research [12].

5. Studies That Evaluated the Efficacy or Safety of Aducanumab

A total of 11 studies were included in this review (Table 1); six of the reviewed studies are phase I clinical trials, one study is a phase II clinical trial, three studies are phase III clinical trials, and the remaining one study is a phase IV prospective observational study (Table 1). Most of the included studies were conducted in the U.S.A. (), 1 study was conducted in Japan, and the remaining three studies were conducted in more than one country (Table 1). The number of participants in these studies ranged from 21 [35] to 6000 [36].

The pharmacokinetics, safety, or tolerability of aducanumab was demonstrated using the following phase I trials: NCT01677572 [18], NCT02782975 [37], NCT01397539 [20], and NCT02434718 [35]. The latter trial investigated the drug’s tolerability among Japanese patients [35]. Additional phase I open label trial assessing the bioavailability of aducanumab among healthy participants is currently underway (NCT04924140) and is expected to be completed on October 14, 2021 [38]. No results have been posted for this trial. In phase Ib PRIME trial [18], aducanumab was administered via monthly infusion to 165 patients with mild cognitive impairment and confirmed elevated β-amyloid plaques. This trial was conducted to check if aducanumab at different doses has an impact on clearing the β-amyloid deposition. The β-amyloid plaque was visualized using a PET scan; there was clear evidence of dose-dependent and treatment duration-dependent clearance of this plaque [39]. Patients in the higher dose group had a better clearance of β-amyloid. Amyloid-related imaging abnormalities (ARIA) such as ARIE (edema) and ARIH (hemorrhage) were observed among patients receiving higher doses of the drug, especially among patients who are APOE4 gene carriers. Moreover, a phase Ib clinical trial was conducted to assess the ability of PET scan in identifying β-amyloid plaques [40]. The study found that PET screening is a feasible and effective tool in identifying the β-amyloid plaques in AD patients [40].

The EVOLVE phase II trial (NCT03639987) [41] assessed the safety and impact of continuing aducanumab dosing in asymptomatic ARIA in participants with mild cognitive impairment (MCI) due to AD or with mild AD dementia. In addition, the study was aimed at characterizing ARIA from both the imaging and the clinical perspective and characterizing the safety, tolerability, pharmacokinetics (PK), and immunogenicity of aducanumab. The study was terminated based on the anticipated lack of impact of aducanumab in EMERGE [42] and ENGAGE [43] trials.

After the promising results from phase 1B (PRIME) trial [18], two identically designed phase III (ENGAGE [43] and EMERGE [42]) trials of 18-month duration were conducted to study if the clearance of β-amyloid plaques had an impact on delaying the progression of the cognitive impairment among patients with mild cognitive impairment (MCI) and early dementia. Both trials had patients with an average age of 70 years and included patients with APOE gene carriers and noncarriers. The trial used a clinical dementia rating scale to evaluate the impact of taking the drug in delaying the progression of the disease. The ENGAGE trial and EMERGE trials were terminated before completion due to lack of benefit based on data of the early 1748 patients in March 2019. The trials were not terminated due to safety concerns [44].

However, the reanalysis of larger data of 3285 patients showed there was a benefit with a higher dose in the EMERGE trial [45]. The patients in the EMERGE trial receiving high-dose aducanumab showed 22% improvement in adjusted mean clinical dementia rating scores [46]. Moreover, an 84% reduction of caregiver distress was also observed. Additionally, compared to the placebo group, 40% slowing of functional decline was noted through the ADCS-ADL scale and assessment by Neuropsychiatric Inventory (NPI) showed an 87% reduction in behavioral changes from baseline scores especially in the high-dose group of EMERGE. The ENGAGE trial on the contrary showed no dose-dependent benefit of drug therapy as compared to placebo [47]. The inconsistencies can be linked with fewer numbers of patients in the ENGAGE trial receiving higher doses of aducanumab. Based on this finding, the ENGAGE trial protocol was amended to allow patients with APOE4 gene carriers to receive higher doses. Subgroup analysis after protocol amendment showed similar results as the EMERGE trail [46]. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble Aβ-oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies [48]. The most common adverse events reported within these two studies were ARIA, headache, diarrhea, and fall. ARIA-E was reported in 34% and 35.5% of patients who received high-dose aducanumab in EMERGE and ENGAGE, respectively.

A study by Salloway et al. reviewed the clinical and radiographic aspects of ARIA in both EMERGE and ENGAGE trials [49]. The study found that 425 of 1029 individuals (41.3%) developed ARIA during the placebo-controlled trial period, with 14 patients developing significant events (1.4%) [49]. ARIA-E was the most prevalent adverse event (362 of 1029 (35.2%)), with 263 initial incidents (72.7%) occurring during the first 8 doses of aducanumab use. The incidence of ARIA-E was noted to be greater in aducanumab-treated APOE4 carriers than in the noncarriers. However, the majority of ARIA-E-related occurrences (479 of 488 (98.2%)) were resolved radiographically. The most prevalent kind of ARIA-H was brain microhemorrhages (6.6% in the placebo and 19.1% in the 10 mg/kg group), followed by localized superficial siderosis (2.2% in the placebo and 14.7% in the 10 mg/kg group). The incidence of ARIA has caused 64 participants (6.2%) to discontinue the study. The discontinuation was more prevalent in APOE4 gene carriers than noncarriers [49].

Currently, three clinical programs are under development to generate postapproval real-world data about aducanumab. These include ICARE AD-US [36] study, ongoing phase IIIb redosing EMBARK study [50], and planned phase 4 postmarketing trial study that is currently under development.

6. Implications of Aducanumab Approval

The approval of the first disease-targeting antiamyloid β-drug is likely to inflate the hopes of patients with Alzheimer’s disease. FDA’s decision on the approval of aducanumab is of great importance to AD patients and their families, which can increase the pressure on clinicians to prescribe this drug. Hence, it is important to identify the right patients who are more likely to benefit from this drug. To maintain optimal effectiveness and safety of the drugs, patients who are eligible to take the drug via long-term monthly infusion need to be carefully selected. Before initiating the drug, a recent MRI and a PET scan to visualize the density of β-amyloid aggregates are needed [51]. Periodic safety MRI after the seventh and twelfth infusion and anytime when ARIA is suspected is required [18]. Hence, according to available data, patients with early-onset AD and MCI with clear β-amyloid plaques who are willing and able to undergo periodic follow-up with imaging studies such as PET and safety MRI and APOE4 genotype testing are good candidates for this drug.

The pressure on physicians to select patients who are most likely to benefit from the drug with available limited evidence [27] is anticipated to accelerate the development of less cumbersome and less costly serum-based tests to assess β-amyloid plaque. In addition, better collaboration with primary care centers is needed to screen and identify individuals at the early stage of the disease to offer disease-modifying intervention.

7. Future Directions in Treatment of Alzheimer’s Disease

Future AD management is likely to focus on passive immunotherapy, vaccines, and early diagnosis based on neuroimaging, CSF, and plasma biomarkers.

AD CSF biomarkers have been the main diagnostic criteria for the disease. Recently, ultrasensitive immunoassays and novel mass spectrometry techniques have enabled the assessment of plasma biomarkers to monitor amyloid plaque formation (the Aβ42/40 or APP669-711/Aβ42 ratios) and neurodegeneration (tau and neurofilament light proteins) [52]. A similar study has also showed plasma P-tau217 has a potential to discriminate AD from other neurodegenerative diseases with comparable accuracy as key CSF- or PET-based measures. Another plasma biomarker, P-tau181, discriminated AD at MCI and dementia stages and was strongly associated with cognitive decline and gray matter loss [53]. Similarly, a study showed that U-p532D3A8+ can be used as additional plasma-based biomarker for AD [54]. These findings highlight the potential value of plasma biomarkers as a noninvasive and cost-effective screening, diagnostic, and monitoring tool. Before these assays can be used routinely, the assays need to be optimized and validated in several AD populations and its potential role in clinical care determined.

Several anti-amyloid beta and anti-tau therapies have been evaluated or are currently under evaluation. Anti-β-amyloid therapies act by reducing the pathologic β-amyloid oligomers or by inhibiting β-amyloid plaque formation or by increasing clearance of β-amyloid peptides. However, many of the trials on anti-β-amyloid therapies have failed to demonstrate clinical impact or pose safety concerns.

A few passive immunotherapies which act in a similar mode as aducanumab have been evaluated or are under evaluation. Currently, three clinical trials are assessing the efficacy and safety of lecanemab (NCT03887455, NCT04468659, and NCT01767311) in patients with AD. Another agent donanemab has demonstrated an improvement in composite cognition scores and ability to do activities of daily living (ADLs) in patients with early AD [55]. In addition, the trial that is assessing the safety and efficacy of gantenerumab among early AD patients is currently underway (NCT03443973, NCT03444870, and NCT01760005). Crenezumab’s efficacy among preclinical AD patients is being tested in two clinical trials (NCT03977584, NCT01998841).

Agents that inhibit β-site amyloid precursor protein cleaving enzyme (BACE) (lanabecestat, elenbecestat, atabecestat, and verubecestat) have also been evaluated in individuals with mild to moderate AD and prodromal AD. The trials of BACE inhibitors have also failed to show clinical significance, and a trial was stopped due to safety concerns [56].

Anti-β-amyloid aggregating agent scyllo-inositol was ineffective among patients with mild to moderate AD while ALZ-801 is under investigation (NCT04770220). Currently, a small molecule, GAL-101, which can inhibit toxic β-amyloid oligomers, is under development. If proven effective, this molecule may provide a more convenient alternative oral therapy to patients with AD with less antibody-related adverse reactions such as allergies [57].

Failure of several agents that act on β-amyloid aggregates has forced researchers to shift the focus of potential to anti-tau therapies [58]. It is hypothesized that tau tangles are more correlated than β-amyloid aggregates with Alzheimer’s disease pathogenesis [59]. Despite the hypothesis, anti-tau drugs that act through inhibition of tau formation, aggregation, and stabilizing microtubule have failed to demonstrate significant efficacy and some are associated with adverse effects [60–62]. However, it is important to note that patients who have β-amyloid aggregates are more likely to have tau tangles [63].

Vaccines against tau tangles have demonstrated modest clinical benefits [64]. This age-related diminished immune response in the elderly patients diagnosed with AD makes vaccines less effective. Therefore, vaccines for the elderly might require a potent adjuvant to enhance the immune response [65]. However, vaccines provide cheaper and affordable alternatives to drugs [65, 66].

An active vaccine (AADvac1) which acts against nonphosphorylated tau was evaluated in the phase I trial. The vaccine was found to be safe and well tolerated and triggered high levels of IgG antibody responses and significantly reduced neurofibrillary tangles. The vaccine slowed the degeneration of the brain by about 30%. It also significantly reduced 58% accumulation of neurofilament light chains in the blood [67]. However, the need for frequent booster doses is the main limitation of this vaccine. In addition, another active vaccine (ACI-35) that works on phosphorylated tau tangles is currently under investigation (NCT04445831). Additionally, the anti-amyloid E22W42-sensitized DC vaccine is also currently under development. The antigen in this vaccine will stimulate a highly specific T cell response, thereby destroying β-amyloid, while inhibiting harmful activities that may lead to autoimmunity. Along with slowing down the memory impairment of AD patients, it may help to strengthen the immune system of elderly patients [68].

In addition to active vaccines, the following passive immunization alternatives are under evaluation. These include agents such as RG7345, gosuranemab, tilavonemab, zagotenemab, semorinemab, BIIB076, JNJ-63733657, and bepranemab. The trial of RG7345 was ceased due to pharmacokinetic issues (NCT02281786). On the other hand, the phase II clinical trials in AD patients for gosuranemab (NCT03352557), for JNJ-63733657 (NCT04619420), and for semorinemab (NCT03828747) are still ongoing. Although trials of tilavonemab (ABBV-8E12) (NCT02880956, NCT03712787) were completed in 2021, no results are available. The phase II study of bepranemab (UCB 0107) involving AD patients (NCT04867616) is now recruiting.

Anti-tau compounds (epothilone, TPI287, and davunetide) which act by stabilizing tau microfilaments were also tested. The phase I trial of epothilone was discontinued. Similarly, the compound TPI287 was associated with an increased risk of hypersensitivity reaction in patients with AD [61]. On the other hand, davunetide failed to significantly improve the composite cognitive memory scores in patients with AD and this drug was associated with tauopathies [69]. Similarly, no significant benefits for patients with AD were observed after use of methylene blue [70] and curcumin (NCT01383161) which act by inhibiting tau aggregation. Moreover, trials of antitau drugs that inhibit glycogen synthase kinase (GSK 3) (lithium and tideglusib) in patients with mild AD also failed to show significant benefit [60, 62].

Since AD pathogenesis is multifactorial, drugs, which act on the combination of these targets, also need to be developed [9, 54]. In the future, there is a need for trials to demonstrate cognitive and functional benefits rather than focusing only on surrogate endpoints [28]. Neuroinflammation, metabolic disorder, infection, and genetic modifications may provide new targets for Alzheimer’s disease management [26, 71]. Multiple interventions such as risk factors or lifestyle modification such as healthy nutrition, exercise, rest, social participation, and cognitive activity are anticipated to effectively halt the progression of the disease [72].

8. Conclusions

Aducanumab at a high dose has the potential to slow down the cognitive decline linked with Alzheimer’s in patients with early-onset disease. However, aducanumab does not reverse memory loss. The approval of the drug has made patients with Alzheimer’s disease hopeful but raised lots of doubts regarding its true benefit. The manufacturer is expected to verify the clinical benefit of aducanumab therapy to delay disease progression through an extended study. Aducanumab therapy will be limited by the need for prior authorization, intravenous administration, and uncertainties regarding benefit-risk ratio and cost-effectiveness. Despite its drawbacks, aducanumab is the first disease-modifying drug approved for AD. It is important to note that this drug only partially addresses the underlying pathology of AD. Hence, future interventions for AD require incorporating multiple strategies to effectively treat the disease.

9. Limitation

This narrative review did not include studies indexed in databases other than Google Scholar, Web of Science, and MEDLINE.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

VBM and SAB conceptualized the idea included in this review; all authors were involved in reviewing the relevant articles, write up, and reviewing of the final manuscript.

References

World Health Organization, Dementia, 2021, https://www.who.int/news-room/fact-sheets/detail/dementia.
“Dementia statistics,” Alzheimer’s Disease International, 2021, https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/.
View at: Google Scholar
T. Guo, D. Zhang, Y. Zeng, T. Y. Huang, H. Xu, and Y. Zhao, “Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease,” Molecular Neurodegeneration, vol. 15, no. 1, pp. 1–37, 2020.
View at: Publisher Site | Google Scholar
Y. G. Chen, “Research progress in the pathogenesis of Alzheimer’s disease,” Chinese Medical Journal, vol. 131, no. 13, pp. 1618–1624, 2018.
View at: Publisher Site | Google Scholar
G. Plascencia-Villa and G. Perry, “Alzheimer’s disease pharmacology,” Reference Module in Biomedical Sciences, 2021.
View at: Publisher Site | Google Scholar
R. Briggs, S. P. Kennelly, and D. O’Neill, “Drug treatments in Alzheimer’s disease,” Clinical Medicine, vol. 16, no. 3, pp. 247–253, 2016.
View at: Publisher Site | Google Scholar
F. Panza, D. Seripa, V. Solfrizzi et al., “Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients,” Expert Opinion on Emerging Drugs, vol. 21, no. 4, pp. 377–391, 2016.
View at: Publisher Site | Google Scholar
Neurimmune, Discovery of aducanumab, Neurimmune, 2020, https://www.neurimmune.com/aducanumab/discovery-of-aducanumab.
A. T. H. Kwan, S. Arfaie, J. Therriault, P. Rosa-Neto, and S. Gauthier, “Lessons learnt from the second generation of anti-amyloid monoclonal antibodies clinical trials,” Dementia and Geriatric Cognitive Disorders, vol. 49, no. 4, pp. 334–348, 2021.
View at: Publisher Site | Google Scholar
S. F. Ackley, S. C. Zimmerman, W. D. Brenowitz et al., “Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis,” BMJ, vol. 372, 2021.
View at: Publisher Site | Google Scholar
K. Madrasi, R. Das, H. Mohmmadabdul et al., “Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer’s disease,” Alzheimer’s Dementia, vol. 17, no. 9, pp. 1487–1498, 2021.
View at: Publisher Site | Google Scholar
J. Cummings, P. Aisen, C. Lemere, A. Atri, M. Sabbagh, and S. Salloway, “Aducanumab produced a clinically meaningful benefit in association with amyloid lowering,” Alzheimer's Research & Therapy, vol. 13, no. 1, pp. 10–12, 2021.
View at: Publisher Site | Google Scholar
L. Schneider, “A resurrection of aducanumab for Alzheimer’s disease,” Lancet Neurology, vol. 19, no. 2, pp. 111-112, 2020.
View at: Publisher Site | Google Scholar
D. S. Knopman, D. T. Jones, and M. D. Greicius, “Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019,” Alzheimer's & Dementia, vol. 17, no. 4, pp. 696–701, 2021.
View at: Publisher Site | Google Scholar
R. Nisticò and J. J. Borg, “Aducanumab for Alzheimer's disease: a regulatory perspective,” Pharmacological Research, vol. 171, no. 5-6, pp. 23–25, 2021.
View at: Publisher Site | Google Scholar
J. A. Hardy and G. A. Higgins, “Alzheimer’s disease: the amyloid Alzheimer’s disease,” Science, vol. 256, no. 5054, pp. 184-185, 1992.
View at: Publisher Site | Google Scholar
J. W. Arndt, F. Qian, B. A. Smith et al., “Structural and kinetic basis for the selectivity of aducanumab for aggregated forms of amyloid-β,” Scientific Reports, vol. 8, no. 1, 2018.
View at: Publisher Site | Google Scholar
J. Sevigny, P. Chiao, T. Bussière et al., “The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease,” Nature, vol. 537, no. 7618, 2016.
View at: Publisher Site | Google Scholar
C. V. Frost and M. Zacharias, “From monomer to fibril: abeta-amyloid binding to aducanumab antibody studied by molecular dynamics simulation,” Proteins: Structure, Function, and Bioinformatics, vol. 88, no. 12, pp. 1592–1606, 2020.
View at: Publisher Site | Google Scholar
J. Ferrero, L. Williams, H. Stella et al., “First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab BIIB037 in mild-to-moderate Alzheimer’s disease,” Alzheimer's & Dementia: Translational Research & Clinical Interventions, vol. 2, no. 3, pp. 169–176, 2016.
View at: Publisher Site | Google Scholar
J. T. Ryman and B. Meibohm, “Pharmacokinetics of monoclonal antibodies,” CPT: Pharmacometrics & Systems Pharmacology, vol. 6, no. 9, pp. 576–588, 2017.
View at: Publisher Site | Google Scholar
Alzheimer’s Association, Peripheral and Central Nervous System Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket, 2020.
E. Mahase, “Three FDA advisory panel members resign over approval of Alzheimer’s drug,” BMJ, Michigan Ave, FL.17. Chicago, vol. 373, 2021.
View at: Publisher Site | Google Scholar
J. Talan, “FDA panel votes no to approving aducanumab for Alzheimer’s, citing inconsistent data,” Neurology Today, vol. 20, no. 23, 2020.
View at: Publisher Site | Google Scholar
K. A. A. GC and S. Emerson, “Evaluation of aducanumab for Alzheimer disease,” Journal of the American Medical Association, vol. 325, no. 17, p. 1717, 2021.
View at: Publisher Site | Google Scholar
K. Mullane and M. Williams, “Alzheimer’s disease beyond amyloid: can the repetitive failures of amyloid-targeted therapeutics inform future approaches to dementia drug discovery,” Biochemical Pharmacology, vol. 177, article 113945, 2020.
View at: Publisher Site | Google Scholar
K. Y. Liu, L. S. Schneider, and R. Howard, “The need to show minimum clinically important differences in Alzheimer’s disease trials,” The Lancet Psychiatry, vol. 8, no. 11, pp. 1013–1016, 2021.
View at: Publisher Site | Google Scholar
S. Walsh, R. Merrick, R. Milne, and C. Brayne, “Aducanumab for Alzheimer’s disease,” BMJ, vol. 374, pp. 10-11, 2021.
View at: Publisher Site | Google Scholar
A. Mullard, “Landmark Alzheimer’s drug approval confounds research community,” Nature, vol. 594, no. 7863, pp. 309-310, 2021.
View at: Publisher Site | Google Scholar
J. C. Loureiro, M. V. Pais, F. Stella et al., “Passive antiamyloid immunotherapy for Alzheimer’s disease,” Current Opinion in Psychiatry, vol. 33, no. 3, pp. 284–291, 2020.
View at: Publisher Site | Google Scholar
A. Gleason, S. Ayton, and A. I. Bush, “Unblinded by the light: amyloid-related imaging abnormalities in Alzheimer’s clinical trials,” European Journal of Neurology, vol. 28, no. 1, p. e1, 2021.
View at: Publisher Site | Google Scholar
F. Piazza and B. Winblad, “Amyloid-related imaging abnormalities (ARIA) in immunotherapy trials for Alzheimer’s disease: need for prognostic biomarkers,” Journal of Alzheimer's Disease, vol. 52, no. 2, 2016.
View at: Publisher Site | Google Scholar
P. J. Lin, J. T. Cohen, and P. J. Neumann, “Preparing the health-care system to pay for new Alzheimer’s drugs,” Alzheimer’s Dement., vol. 16, no. 11, pp. 1568–1570, 2020.
View at: Publisher Site | Google Scholar
T. S. Anderson, J. Z. Ayanian, J. Souza, and B. E. Landon, “Representativeness of participants eligible to be enrolled in clinical trials of aducanumab for Alzheimer disease compared with Medicare beneficiaries with Alzheimer disease and mild cognitive impairment,” Journal of the American Medical Association, vol. 326, no. 16, pp. 1627–1629, 2021.
View at: Publisher Site | Google Scholar
B. Inc, “Single and multiple ascending dose study of aducanumab (BIIB037) in Japanese participants with Alzheimer’s disease,” 2020, https://clinicaltrials.gov/ct2/show/results/NCT02434718.
View at: Google Scholar
L. Biogen and E. Co, “ADUHELM ICARE AD-US Study, the first real-world observational phase 4 study in Alzheimer’s disease at AAIC 2021,” Biogen, 2021, https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-announce-design-aduhelm-icare-ad-us-study-first.
View at: Google Scholar
L. Biogen Inc and E. Co, “Absolute bioavailability of a single, fixed subcutaneous dose of aducanumab in healthy participants,” 2017, https://clinicaltrials.gov/ct2/show/NCT02782975.
View at: Google Scholar
L. Biogen Inc and E. Co, “A study to assess absolute bioavailability of aducanumab in healthy volunteers,” 2021, https://clinicaltrials.gov/ct2/show/NCT04924140.
View at: Google Scholar
S. Y. Hung and W. M. Fu, “Drug candidates in clinical trials for Alzheimer’s disease,” Journal of Biomedical Science, vol. 24, no. 1, p. 47, 2017.
View at: Publisher Site | Google Scholar
J. Sevigny, J. Suhy, P. Chiao et al., “Amyloid PET screening for enrichment of early-stage Alzheimer disease clinical trials,” Alzheimer Disease and Associated Disorders, vol. 30, no. 1, pp. 1–7, 2016.
View at: Publisher Site | Google Scholar
B. Inc, “A study of aducanumab in participants with mild cognitive impairment due to Alzheimer’s disease or with mild Alzheimer’s disease dementia to evaluate the safety of continued dosing in participants with asymptomatic amyloid-related imaging abnormalities,” 2020, https://clinicaltrials.gov/ct2/show/NCT03639987.
View at: Google Scholar
B. Inc, “221AD302 phase 3 study of aducanumab BIIB037 in early Alzheimer’s disease,” 2021, https://clinicaltrials.gov/ct2/show/NCT02484547.
View at: Google Scholar
B. Inc, “221AD301 phase 3 study of aducanumab BIIB037 in early Alzheimer’s disease,” 2020, https://clinicaltrials.gov/ct2/show/NCT02477800.
View at: Google Scholar
B. Inc and L. Eisai Co, “Biogen and Eisai to discontinue phase 3 ENGAGE and EMERGE trials of aducanumab in Alzheimer’s disease,” Biogen, 2019, https://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials.
View at: Google Scholar
B. Inc, “Aducanumab update,” Investors Conference, 2019.
View at: Google Scholar
S. B. Haeberlein, C. von Hehn, Y. Tian et al., “Emerge and Engage topline results: phase 3 studies of aducanumab in early Alzheimer’s disease,” Alzheimer's & Dementia, vol. 16, no. S9, p. e047259, 2020.
View at: Publisher Site | Google Scholar
L. H. Kuller and O. L. Lopez, “ENGAGE and EMERGE: truth and consequences,” Alzheimer's & Dementia, vol. 17, no. 4, 2021.
View at: Publisher Site | Google Scholar
M. Tolar, S. Abushakra, and M. Sabbagh, “The path forward in Alzheimer’s disease therapeutics: reevaluating the amyloid cascade hypothesis,” Alzheimer’s Dementia, vol. 16, no. 11, pp. 1553–1560, 2020.
View at: Publisher Site | Google Scholar
S. Salloway, S. Chalkias, F. Barkhof et al., “Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease,” JAMA Neurology, vol. 79, no. 1, pp. 13–21, 2022.
View at: Publisher Site | Google Scholar
B. Inc, “A study to evaluate safety and tolerability of aducanumab in participants with Alzheimer’s disease who had previously participated in the aducanumab studies 221AD103, 221AD301, 221AD302 and 221AD205,” 2021, https://clinicaltrials.gov/ct2/show/NCT04241068.
View at: Google Scholar
S. Hameed, J. L. Fuh, V. Senanarong et al., “Role of fluid biomarkers and PET imaging in early diagnosis and its clinical implication in the management of Alzheimer’s disease,” Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 21–37, 2020.
View at: Publisher Site | Google Scholar
K. Blennow and H. Zetterberg, “Biomarkers for Alzheimer's disease: current status and prospects for the future,” Journal of Internal Medicine, vol. 284, no. 6, pp. 643–663, 2018.
View at: Publisher Site | Google Scholar
J. Simrén, A. Leuzy, T. K. Karikari et al., “The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer’s disease,” Alzheimer's & Dementia, vol. 17, no. 7, pp. 1145–1156, 2021.
View at: Publisher Site | Google Scholar
G. Abate, M. Vezzoli, L. Polito et al., “A conformation variant of p53 combined with machine learning identifies Alzheimer disease in preclinical and prodromal stages,” Journal of Personalized Medicine, vol. 11, no. 1, p. 14, 2021.
View at: Publisher Site | Google Scholar
M. A. Mintun, A. C. Lo, C. Duggan Evans et al., “Donanemab in early Alzheimer’s disease,” The New England Journal of Medicine, vol. 384, no. 18, pp. 1691–1704, 2021.
View at: Publisher Site | Google Scholar
B. P. Imbimbo and M. Watling, “Investigational BACE inhibitors for the treatment of Alzheimer’s disease,” Expert Opinion on Investigational Drugs, vol. 28, no. 11, pp. 967–975, 2019.
View at: Publisher Site | Google Scholar
H. Russ and A. Gebauer, “Therapeutic focus the future of treating Alzheimer’s disease: aducanumab & beyond,” Drug Development & Delivery, vol. 20, no. 6, 2020.
View at: Google Scholar
F. Kametani and M. Hasegawa, “Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease,” Frontiers in Neuroscience, vol. 12, p. 25, 2018.
View at: Publisher Site | Google Scholar
H. Braak and E. Braak, “Neuropathological stageing of Alzheimer-related changes,” Acta Neuropathologica, vol. 82, no. 4, pp. 239–259, 1991.
View at: Publisher Site | Google Scholar
S. Lovestone, M. Boada, B. Dubois et al., “A phase II trial of tideglusib in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 75–88, 2015.
View at: Publisher Site | Google Scholar
R. M. Tsai, Z. Miller, M. Koestler et al., “Reactions to multiple ascending doses of the microtubule stabilizer TPI-287 in patients with Alzheimer disease, progressive supranuclear palsy, and corticobasal syndrome,” JAMA Neurology, vol. 77, no. 2, pp. 215–224, 2020.
View at: Publisher Site | Google Scholar
S. Matsunaga, H. Fujishiro, and H. Takechi, “Efficacy and safety of glycogen synthase kinase 3 inhibitors for Alzheimer’s disease: a systematic review and meta-analysis,” Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1031–1039, 2019.
View at: Publisher Site | Google Scholar
W. Gulisano, D. Maugeri, M. A. Baltrons et al., “Role of amyloid-β and tau proteins in Alzheimer’s disease: confuting the amyloid cascade,” Journal of Alzheimer’s Disease, vol. 64, no. s1, pp. S611–S631, 2018.
View at: Publisher Site | Google Scholar
D. J. Marciani, “Promising results from Alzheimer’s disease passive immunotherapy support the development of a preventive vaccine,” Research, vol. 2019, pp. 1–14, 2019.
View at: Publisher Site | Google Scholar
D. J. Marciani, “Rejecting the Alzheimer's disease vaccine development for the wrong reasons,” Drug Discovery Today, vol. 22, no. 4, pp. 609–614, 2017.
View at: Publisher Site | Google Scholar
D. J. Selkoe and J. Hardy, “The amyloid hypothesis of Alzheimer’s disease at 25 years,” EMBO Molecular Medicine, vol. 8, no. 6, 2016.
View at: Publisher Site | Google Scholar
P. Novak, B. Kovacech, S. Katina et al., “ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer’s disease,” Nature Aging, vol. 1, no. 6, pp. 521–534, 2021.
View at: Publisher Site | Google Scholar
G. Song, H. Yang, N. Shen et al., “An immunomodulatory therapeutic vaccine targeting oligomeric amyloid-β,” Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1639–1653, 2020.
View at: Publisher Site | Google Scholar
B. H. Morimoto, D. Schmechel, J. Hirman et al., “A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment,” Dementia and Geriatric Cognitive Disorders, vol. 35, no. 5–6, pp. 325–339, 2013.
View at: Publisher Site | Google Scholar
Y. Soeda, M. Saito, S. Maeda et al., “Methylene blue inhibits formation of tau fibrils but not of granular tau oligomers: a plausible key to understanding failure of a clinical trial for Alzheimer’s disease,” Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1677–1686, 2019.
View at: Publisher Site | Google Scholar
A. O. Sasmita, “Current viral-mediated gene transfer research for treatment of Alzheimer’s disease,” Biotechnology & Genetic Engineering Reviews, vol. 35, no. 1, pp. 26–45, 2019.
View at: Publisher Site | Google Scholar
A. M. Meyer, N. Podolski, L. Pickert, and M. C. Polidori, “Strategies to prevent age-related cognitive decline,” Deutsche Medizinische Wochenschrift, vol. 145, no. 3, pp. 146–150, 2020.
View at: Publisher Site | Google Scholar
S. T. Ferreira, M. V. Lourenco, M. M. Oliveira, and F. G. De Felice, “Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease,” Frontiers in Cellular Neuroscience, vol. 9, p. 191, 2015.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Semira Abdi Beshir et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3793

Downloads

2241

Citations