Amyloid-Directed Antibodies: Past,Present,and Future

Abstract

Background:

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in patient demographics over 65 years old causing debilitating cognitive impairment. Most commonly, AD is diagnosed clinically as “probable AD”, and definitive diagnosis is confirmed through postmortem brain autopsies to detect extracellular amyloid-β (Aβ) plaques and intraneuronal hyperphosphorylated tau tangles. The exact mechanism causing AD is still unknown, but treatments for AD have been actively investigated. Currently, immunotherapies have shown substantial promise in reducing the pathologic and clinical signs of AD.

Objective:

This review aims to evaluate passive immunotherapies deemed to have promise for further development and use in the treatment of AD.

Methods:

Immunotherapies were selected via a narrative review of medications that have potential clinical effectiveness with a status of FDA accepted, FDA fast-track, FDA status pending, or emerging therapies poised to pursue FDA approval.

Results:

This review has yielded two anti-Aβ monoclonal antibodies (mAb) that are currently fully FDA approved, one mAb granted FDA fast-track status, two therapies on hold, three discontinued medications, and three promising emerging therapies.

Conclusions:

We conclude that, in the near future, passive immunotherapies will be the preferred and evidence-based method of treatment for AD with the presence of brain Aβ deposits for both symptom management and potential slowing of disease progression. Specifically, lecanemab and donanemab will require further clinical studies to optimize patient selection based on safety profiles. Despite some key limitations, these two drugs are paving the way for disease-modifying treatments in patients displaying early signs of amyloid pathology.

Keywords

Alzheimer’s disease amyloid plaques clinical trials FDA approval passive immunotherapy

INTRODUCTION

Alzheimer’s disease (AD) is the leading cause of neurodegenerative disorders in the geriatric population leading to progressive cognitive impairment [1]. With no definitive treatment and only the ability to diagnose AD as “probable”, presently, formal clinical AD diagnosis is primarily based on an exclusion process with diagnosis confirmation via postmortem brain pathology analysis. Diagnostic criteria established by the National Institute on Aging and the Alzheimer’s Association (NIA-AA) updated in 2011 for “probable AD” dementia include the presence of dementia plus symptoms consisting of: cognitive impairment in a minimum of two domains established by history-taking from the patient or a knowledgeable informant, objective bedside mental status examination or neuropsychological testing, interference with ability to function at work or at usual activities, a decline from a previous level of functioning and performing, and not explained by delirium or major psychiatric disorder [2, 3]. Postmortem neuropathology is used to confirm AD diagnosis, although biomarkers such as lower levels of amyloid-β (Aβ)₄₂ in the cerebrospinal fluid (CSF) [4] and amyloid and tau positron emission tomography (PET) imaging [5, 6] are highly correlated with the diagnosis of AD. Additionally, mixed pathologies are often identified in the brain of dementia cases. While the brain undergoes a normal decrease in weight and/or volume of approximately 5% per decade after age 40, when there is a neurodegenerative cause of dementia, including AD, the rate of brain atrophy is accelerated [7]. In AD, brain shrinkage correlates with the increased accumulation of both extracellular plaques comprising Aβ peptides and intraneuronal neurofibrillary tangles (NFT) made up of hyperphosphorylated tau proteins [8]. Remarkably, despite large efforts in AD research for more than four decades since the identification of Aβ peptides [9], the underlying cause for these proteinopathies being associated only with AD progression and symptoms is still not fully understood [10].

The pathogenesis of Aβ has been extensively investigated. Aβ is generated from the single-pass transmembrane protein amyloid-β protein precursor (AβPP) via sequential proteolysis by β-secretase and the γ-secretase quaternary complex [11]. Interestingly, AβPP is expressed in the highest quantity by neurons in the brain, though it can also be expressed by reactive astrocytes and microglia [12]. One prominent theory pertaining to AD pathogenesis is the “amyloid cascade hypothesis”, originally proposed in 1992 stating that the deposition of Aβ is the primary cause of AD with secondary pathologic features such as NFTs, cell loss, and vascular damage occurring after the initial Aβ insult [13]. A consequence of this theory is that the removal of Aβ deposits should stop the progression of AD. However, empirical evidence has shown a lack of correlation between clinical outcomes (i.e., cognitive measures) and the amount of Aβ loads in the brain, location of Aβ accumulation, and neuronal loss associated with dementia [14]. A proposed amendment to the amyloid cascade hypothesis is that Aβ is a trigger for tau bundles that then cause AD. But, Aβ acting only as a trigger for NFT is inconsistent with data showing Aβ’s active role in disease progression, such as an increased Aβ₄₂/Aβ₄₀ ratio in the CSF, which predisposes individuals to develop AD [15]. Low values of the Aβ₄₂/Aβ₄₀ ratio in the CSF are (i) associated with higher concentrations of total-tau and P-tau-181; (ii) associated with biomarkers identified with NFT pathology and neurodegeneration; and (iii) more strongly correlated with clinical progression than Aβ₄₂ alone [16]. Another theory is the amyloid threshold hypothesis, which suggests that AD pathology and symptoms appear only if a certain load of Aβ is reached [17]. In agreement with all Aβ theories, a hypothetical model of AD biomarkers was proposed by Jack et al. in 2010 [18], and has been refined several times over the years [19, 20]. In agreement with amyloid cascade hypothesis, this theory proposes that Aβ₄₂ is the first abnormal biomarker in AD which appears up to 15–20 years prior to symptom onset, followed by t-tau and P-tau accumulation, then biomarkers of neurodegeneration. Symptom severity is correlated with the later appearance of neurodegenerative markers. Utilization of biomarkers in the diagnosis and clinical progression of AD has led to the development of the AT(N) framework (amyloid, tau, neurodegeneration) [21], though ongoing discussions have highlighted the fact that AT(N) alone is likely not sufficient for the accurate clinical diagnosis of AD and proposed to expand this classification to ATX(N), where X could be markers of inflammation, synaptic dysfunction, vascular dysfunction, or another set of markers yet to be identified [22].

The standard of care for AD treatment focuses primarily on symptom management of cognitive impairment and neuropsychiatric manifestations or slowing the progression of disease. Medications consist of acetylcholine-esterase inhibitors (AChEIs), the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, and immunotherapies such as the FDA-approved agents lecanemab and donanemab. However, clinical data shows only a temporary reduction in AD progression in mild-to-moderate patients treated with AChEIs [23] and only a provisional symptomatic improvement in moderate-to-severe AD patients using memantine [24]. In the past two years, new disease-modifying therapies (DMTs; i.e., passive immunotherapies) have been introduced that can alter disease trajectory in carefully selected early stage AD patients, though their clinical efficacy remains relatively modest and serious adverse events (SAE) are a well-known risk.

Studied since 1999 as a means to reduce Aβ plaque load [25], Aβ immunotherapy approaches either stimulate the immune system via the injection of synthetic peptides that induce active immunization in the host, or deliver monoclonal anti-Aβ antibodies (mAbs) to develop passive immunity. In both situations a patient’s immune system is primed to specifically target and eliminate endogenous Aβ [26]. Briefly, active immunization is achieved either with synthetic full-length Aβ peptides or Aβ fragments to stimulate B-cell production of antibodies [27]. Benefits in AD patients have been seen, such as brain Aβ load reduction, but current adverse events (AEs) and safety concerns continue to deter FDA approval with no active immunotherapies currently in Phase IV development or having received FDA-approval. On the other hand, two medications based on passive immunotherapy have received FDA approval. Passive immunotherapy involves injecting pre-made humanized mAbs to train the host’s immune system to target and attack Aβ, which allows for greater specificity of Aβ targets and a milder side effect profile than active immunization [28]. Differences in mAbs treatment occur with different selectivity for polymorphic variants in the amyloid cascade, i.e., selectivity for Aβ conformation or a specific sequence of Aβ peptides [29]. Current problems with Aβ passive immunotherapy include: high medication costs; requirement for recurrent infusions or injections; low crossing of the blood-brain barrier (BBB; <0.1%) [30]; intracranial hemorrhage risk, mostly in APOE4 patients; immune response against the mAb; and selecting appropriate antigens to target toxic Aβ forms (e.g., oligomeric and fibrillar β sheets) so as to not interfere with neuroprotection and other physiological functions of Aβ [10 , 32]. Of note in this 25-year history of anti-amyloid drugs, FDA approval for such medications have only been awarded recently due to SAE and little to no demonstrated cognitive improvement or disease trajectory alteration for most anti-Aβ mAbs [33 –37]. The status of the few FDA approved mAbs and their clinical relevance remains a topic of debate by experts. Effectively, prior meta-analyses suggested that the benefit of anti-amyloid medications is unclear, with data suggesting changes in CSF Aβ not being correlated with clinical improvement and unfavorable AE profiles [38 –40].

Despite evident pharmacological and clinical limitations, anti-Aβ mAbs are new agents in the AD armamentarium that need to be better studied and understood, with the overarching goal of improving their efficacy and AE profile in order to develop efficient DMTs that can stop the progression of AD and its underlying pathologies in the future. This review explores passive immunotherapies that are FDA approved, are currently on stand-by seeking FDA approval, and new therapies that are progressing towards FDA approval.

MATERIALS AND METHODS

A narrative review of antibody-derived therapies limited to antibody therapies that are: FDA approved, FDA fast-tracked, pending FDA approval, or emerging antibody therapies seeking FDA approval. A major resource for searching for these therapies was Alzforum.com, a forum maintained by the Alzheimer’s Association and dedicated to networking medications by allowing academic scientists and private companies to report initiatives and products. The list was then refined to include potential drugs that showed promising early trials with targets specific to Aβ formation or degradation based on our own experience and knowledge of AD clinical trials [41]. The trial results were reviewed in-depth with additional searches on ClinicalTrials.gov and the European Union Clinical Trials registry (clinicaltrialsregister.eu), where each trial of the therapies and their design are described thoroughly. Supporting research on the clinical trials was reviewed in PubMed when available. Additional journal publications and press releases from sponsors on the individual medications, including mechanisms of action and perceived effectiveness of medication, were also reviewed to offer a comprehensive report on each of the listed medications.

FULLY FDA-APPROVED ANTIBODIES

Lecanemab

Produced by BioArctic AB, Biogen, and Eisai Co., lecanemab (also known as Leqembi and BAN2401) is a humanized immunoglobulin G1 (IgG1) mAb version of the mouse mAb158. It was observed in several preclinical studies that mAb158 binds primarily to soluble Aβ protofibrils produced from AβPP isoform 695 containing both the Arctic (E693G) and Swedish (KM670/671NL) mutations, thereby leading to a decrease in pathogenic Aβ levels, lower Aβ deposition, and selective reduction in Aβ protofibrils in transgenic mice [42 –45]. In addition to the favorable preclinical findings, Phase I (clinical trial ID: NCT01230853 and NCT02094729) and II (NCT01767311) clinical trial results gathered significant interest in lecanemab as a possible treatment for AD and instigated subsequent trials to evaluate its efficacy and safety profile [43, 46].

Of interest, lecanemab was reported in 2021 to also lower blood P-tau-181 levels [47]. This, in addition to the Phase I and II data, led the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU) team to test the first double adaptive tau-Aβ therapy combining the Eisai’s anti-tau antibody E2814 with lecanemab (NCT01760005). The DIAN-TU is an adaptive platform trial that evaluates multiple potential drugs simultaneously in individuals carrying autosomal-dominant genetic mutations associated with early-onset AD but before cognitive symptoms are present. The mutations identified affect genes like APP, PSEN1, and PSEN2, which globally represent 1–5% of AD cases [48, 49].

A dose escalation Phase III trial called the AHEAD3-45 (NCT04468659) is a prevention-oriented study combining two trials run in parallel that began in 2020 and is currently ongoing. It investigates the efficacy and safety of lecanemab in prodromal AD participants with elevated Aβ levels (A45 Trial) and prodromal AD with intermediate brain Aβ levels (A3 Trial) [50]. Participants receive 5 mg/kg of lecanemab intravenously once every 2 weeks through 8 weeks, then the dosage is increased to 10 mg/kg and administered once every 2 weeks through week 96, then lastly 10 mg/kg once every 4 weeks through week 216. The primary outcome of the A3 Trial is prevention of brain amyloid accumulation and the main secondary outcome is brain tau accumulation. These outcomes will be determined by measuring levels of Aβ and tau on PET at 216 weeks after enrolling subjects displaying 20 to 40 centiloids on their screening/baseline amyloid PET scans. For the A45 trial, the primary outcome measure is the Preclinical AD Cognitive Composite 5 scale at 216 weeks. The plan for the A45 trial is to enroll subjects with more than 40 centiloids on their screening/baseline scans and estimate PET signal levels for Aβ and tau at 216 weeks. Centiloids are a linearized scale that allows the comparison of amyloid signals despite different amyloid PET tracers and scanners used across study sites, with signals ranging from 0 for no amyloid to 100 for a typical AD patient [51]. The AHEAD3-45 trial results will be influential in indicating the clinical effectiveness of lecanemab in treating AD. However, additional long-term studies will be required to validate clinical outcomes for patients with early-to-mild AD.

In July 2018, results of a Phase IIb, blinded 18-month study (NCT01767311) showed the highest antibody dose of twice-monthly 10 mg/kg given to participants with early AD slowed cognitive decline by 30% on the Alzheimer’s disease composite score (ADCOMS; description of this scale in reference [52]). This was accompanied by a slowing of cognitive decline by 47% on the ADAS-Cog scale and a reduction in brain amyloid accumulation of up to 93% in the highest dose group [47]. However, subjects receiving the medication experienced a higher incidence of amyloid related imaging abnormalities with vasogenic edema (ARIA-E) events compared to placebo, with 48 out of 854 participants presenting at least one AE. No significant difference was seen between the placebo group and treatment group in non-ARIA events [53]. In 2021, the FDA designated lecanemab a breakthrough therapy, expediting regulatory review, and soon after, granted the fast-track designation (summarized in [41]). In 2023, the FDA approved lecanemab under the Accelerated Approval Pathway, based on evidence of an effect on the surrogate endpoint of amyloid removal in the Phase IIb trial, and a reasonable likelihood of clinical benefit [54].

In 2019, a Phase III randomized, double-blind, placebo-controlled, parallel-group, multiple-center trial called CLARITY AD (also called “Study 301”) started recruiting participants with symptomatic mild cognitive impairment (MCI) due to AD (NCT03887455). A total of more than 1900 participants received either placebo, or doses of 10 mg/kg of lecanemab administered intravenously every two weeks for 18 to 45 months to measure the drug efficacy on cognition, which is investigated via the Clinical dementia rating sum of boxes (CDR-SOB) scale between baseline and month 18. The trial is set to run through 2027. Interim results of the study showed an adjusted least-squares mean change from baseline at 18 months of 1.21 with lecanemab and 1.66 with placebo (difference, –0.45; 95% confidence interval [CI], –0.67 to –0.23; p < 0.001). The ADAS-Cog14 score was –1.44 (95% CI, –2.27 to –0.61; p < 0.001); the ADCOMS score was –0.050 (95% CI, –0.074 to –0.027; p < 0.001); and the activities of daily living for mild cognitive impairment scale (ADCS-MCI-ADL) score was 2.0 (95% CI, 1.2 to 2.8; p < 0.001). Initial adverse events included infusion-related reactions in 26.4% of participants [55]. With a significant decrease in decline in measures of cognition and function compared to placebo at 18 months being demonstrated, the FDA gave full approval in July 2023 for lecanemab to be prescribed by treating physicians and partly reimbursed by Medicare and Medicaid in the USA. The European Medicines Agency (EMA) is still evaluating lecanemab at this time with no decision on its approval being reached yet.

Controversy surrounds the FDA approval of this therapy. The primary components of these concerns consist of a suspected small beneficial effect on disease outcomes by using the medication, the potential side effects (e.g., ARIA), and the potential costs of the medication. The Phase III trials indicate at this time only a minimal clinical cognitive improvement [56]. Given the reasoning that extended trials might reveal greater significant cognitive outcomes over time, it remains important to investigate longer treatment durations than those reported in standard clinical trials to assess the sustained effectiveness and safety in a clinical context. The NIA is currently funding several trials evaluating lecanemab’s effectiveness in treating different types of AD in addition to other related dementias, including the AHEAD 3-45 and DIAN-TU trials. Regarding concerns for safety, the CLARITY AD trial resulted in 11% of participants developing symptomatic brain edema and 0.5% intracranial bleeds, evidencing concern for AE profiles [57]. Risk may be reduced by avoiding concurrent anti-platelet medications and adhering to the study’s inclusion criteria for patient populations [58]. Lastly, if all of the target population receives lecanemab in the USA, then the estimated aggregate medication expenditures would be $120 billion US dollars per year [57]. The total burden of this cost can only be appreciated if factoring in the reduction in additional healthcare services and needs (both the financial and labor resources used) that would require further clinical trials to estimate. Lecanemab will continue to be investigated for its clinical effectiveness and safety profile in a Phase IV process as it continues to be prescribed to the general public.

Donanemab

Donanemab (also termed Kisunla, LY3002813 and N3pG-Aβ mAb; Eli Lilly & Co) is a humanized IgG1 mAb developed from mouse mE8-IgG2a that targets Aβ (p3-42), which is an N-truncated pyroglutamate form of Aβ (pGlu3-Aβ, AβpE3) that is commonly aggregated in Aβ plaques [59]. Pyroglutamate-3 makes Aβ resistant to degradation, is neurotoxic, and may act as a seed for Aβ aggregation. Donanemab primarily targets Aβ already deposited in plaques rather than preventing the growth of existing plaques, with a reported ARIA profile similar to that of lecanemab [59, 60].

In a Phase I, double-blind, randomized, placebo-controlled, parallel-group, dose-escalation study that assessed participants with MCI and mild-to-moderate AD between 2013–2016 (NCT01837641), Lowe et al. found that donanemab was generally safe and well tolerated up to 10 mg/kg and reduced brain Aβ loads by 40% to 50% compared to placebo when evaluated by PET at 28 weeks [61].

In 2021, the FDA granted donanemab the designation “Breakthrough Therapy”, and allowed the sponsor to submit an accelerated approval application. However, in January 2023 the FDA rejected donanemab’s accelerated approval, citing insufficient safety data. Fewer than 100 patients had stayed on donanemab for one year in a Phase II trial, yet no other deficiencies were identified. The application for accelerated approval was dependent on data from the Phase II Trailblazer-ALZ1 trial (NCT03367403), which was an 18-month randomized, multicenter, placebo-controlled, cross-over, double-blind study ran between 2017–2021 that enrolled 272 early symptomatic AD participants presenting Aβ and tau deposition on PET and being treated with donanemab infusions every 4 weeks until testing negative for brain amyloid. Afterward, the participants were assigned randomly and equally to either receive intravenous doses of Donanemab (700 mg per patient for the initial 3 doses and 1400 mg for subsequent doses) or a placebo every 4 weeks, with a treatment duration of up to 72 weeks. In this study, participants were classified as amyloid negative if their PET scan results showed values below 11 centiloids in one scan or below 23 centiloids in two consecutive scans conducted at months 6, 12, and 18. At the 6-month mark, 40% of the group switched to a placebo, leaving 79 participants who continued to receive donanemab for one year. The study revealed that donanemab showed stronger improvements in both composite cognition and activity of daily living scores compared to placebo [62]. The primary objective of Trailblazer-ALZ1 was to assess the change in Integrated Alzheimer’s Disease Rating Scale (iADRS) scores at 76 weeks compared to baseline scores [63]. In May 2023, results from the Trailblazer-ALZ1 study found that donanemab slowed a key measure of cognitive and functional decline in a subset of early AD patients (characterized by progressive and gradual memory decline for at least 6 months, baseline Mini-Mental Status Exam [MMSE] scores ranging 20–28, and meeting criteria on amyloid and tau PET scans) by 35% over 18 months. Using the CDR-SOB scale, donanemab was found to slow the progression of AD by 29% overall and by 36% in the trial main subset of early AD patients. Brain amyloid levels were lowered by 52% after one year and 72% by 18 months, which was correlated with a reduction in plasma P-tau-217 and glial fibrillary acidic protein (GFAP) levels, but not with iADRS scores, and participants no longer required treatment [64].

In 2020, Trailblazer-ALZ2 was started as a Phase II safety and efficacy, placebo-controlled trial to test donanemab in 500 patients with early AD (NCT04437511). The primary outcome of this study was a positive change by lowering the CDR-SOB score after 18 months to evaluate cognitive and memory function changes in participants, and secondary measures included MMSE, Alzheimer’s disease assessment cognitive 13 scale (ADAS-Cog13), iADRS, and ADCS-iADL, amyloid and tau PET, and volumetric MRI, plus pharmacokinetics and measures of anti-donanemab antibodies in biofluids to assess host’s immune response against this exogenous, therapeutic mAb. The trial was scheduled to run through early 2024 at 87 sites in the United States, Canada, Japan, The Netherlands, and Poland.

Trailblazer-ALZ2 has since been expanded to a Phase III registration study with 1,800 participants with prodromal AD and mild dementia due to AD. This ongoing study has already enrolled some patients with tau-PET above 1.46 standardized uptake value ratio (SUVR), but the primary efficacy will be determined in at least 1,000 participants whose tau burden is below this cutoff. The primary outcome scale of this Phase III study has been changed to iADRS, and effectiveness will be judged using a disease-progression model. Published results indicated an overall slowing of cognitive decline in donanemab-treated patients, irrelevant of brain tau loads, after 76 weeks. Similar to the Leqembi trial, the authors reported a 24% ARIA rate in the sample population treated by the mAb versus 2.1% in the placebo group. Additionally, there was a 1.9% instance of death in the treatment arm versus 1.1% in the placebo group with 3 deaths in the treatment arm being caused by ARIA [60]. It was also announced that a 182-week Phase III placebo-controlled, double-blind prevention trial called Trailblazer-ALZ3 (NCT05026866) will be implemented between 2021–2027 to evaluate treatment on 2,600 cognitively normal subjects who are at high risk for AD based on elevated plasma P-tau-217 levels.

Using the positive results from Trailblazer-ALZ1, Eli Lilly has applied for traditional approval to the FDA. In March 2024, the FDA notified Eli Lilly that it intended to convene an advisory committee to conduct a more thorough evaluation of donanemab’s safety and effectiveness, including the implications of its unique trial design. The committee met in June 2024 and gave a favorable opinion for approval. Donanemab just received full FDA approval at the time this review was written. However, one major point of discussion in the scientific community is the overall short duration of treatment in the trials (≤5 years), which makes it difficult to assess the long-term clinical efficacy of this mAb. Another issue is the stratification of study subjects by baseline tau PET levels, which resulted in a decrease in the variable trajectories of clinical decline [62] and may not reflect the clinical effects of donanemab in the general population.

ANTIBODIES GRANTED FDA FAST TRACK DESIGNATION

PRX012

PRX012 (Prothena Corp.) is a humanized monoclonal IgG1 antibody recognizing an N-terminal epitope on Aβ protofibrils. The manufacturer suggested an affinity approximately 10 times greater than aducanumab [65]. Preclinical data of PRX012’s effect presented at the 2023 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) and Alzheimer’s Association International Conference (AAIC) indicated its ability to bind plaques in both mouse and human ex-vivo brain tissue preparations, and to mediate microglial phagocytosis of Aβ fibrils from these tissues, including pyroglutamate-modified Aβ (Aβ_pE3 - 42). PRX012 bound Aβ protofibrils with a 20-fold higher affinity than lecanemab and cleared pyroglutamate-modified Aβ_1 - 42 from brain tissues with 3–8 times the potency of donanemab. These results strongly suggest the capacity to remove brain Aβ in vivo. According to press releases from Prothena, PRX012 received FDA fast-track designation in 2022.

A Phase I randomized, double-blind, placebo-controlled trial called ASCENT-2 was started in late 2022 to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics in 50 healthy and mildly symptomatic AD subjects ranging from ages 55–85 in a single ascending dose (SAD) regimen of subcutaneous injections of up to six dose levels. The AD subject arm includes two groups, those determined to be heterozygous or non-carriers of the APOE4 allele and those homozygous for APOE4. In 2023, the sponsor indicated a partnership with Walgreens (a U.S. national drugstore chain) to improve enrollment for a multiple-ascending-dose (MAD) regimen testing doses of up to 400 mg injected once a month. Preliminary data provided by press releases suggest a reduction in brain amyloid loads after six months of treatment with a dose of 70 mg (frequency of administration not provided), with a low rate of ARIA (specific numbers not provided). The trial is expected to be completed in 2024 and detailed results are highly anticipated for this mAb, though few publications mention these clinical trials.

ANTIBODIES CURRENTLY ON HOLD

Aducanumab

Aducanumab (also called Aduhelm and BIIB037) is a humanized IgG1 monoclonal antibody against a conformational epitope of Aβ. Developed by Biogen, it is a passive immunotherapy, preferentially binding both soluble and insoluble aggregated forms of Aβ in the N-terminal region (residues 3–7) allowing the immunotherapy to target both oligomeric and fibrillar forms of Aβ [29 , 66].

Of significance, aducanumab was the first Aβ immunotherapy to be granted accelerated approval by the FDA in 2021. Preclinical experiments on Tg2576 mice were performed indicating a dose-dependent reduction in Aβ plaque size in young (9-month-old), but not in old (22-month-old) mice [65]. Such results indicated a greater effect in preventing Aβ aggregation as opposed to eliminating pre-formed Aβ plaques, which supported translation to Phase I studies. Enrolling between 2011 and 2015, a Phase I safety and pharmacokinetics study (NCT01397539) was conducted on participants with mild-to-moderate AD given a single ascending dose of 0.3 to 30 mg/kg of aducanumab for a 24-week course. With only mild-to-moderate adverse events such as headaches, diarrhea, and dizziness (not dose-dependent), the dosage was increased to 60 mg/kg [67]. However, participants taking the 60 mg/kg dose did experience SAEs of symptomatic ARIAs, though they resolved within 8–15 weeks [68]. Furthermore, increased plasma levels of Aβ₄₀ and Aβ₄₂ were noted for 3 weeks after the onset of the 60 mg/kg dose, suggesting elevated levels of aducanumab may bind soluble monomeric Aβ in humans [67]. However, after completing the trial, there was no significant difference in cognitive abilities compared to the placebo group when measured by the ADAS-Cog13 scale. On the positive side, it was determined that aducanumab has no toxicity on cognitive measures, and effects on plasma levels of Aβ₄₀ or Aβ₄₂ mirroring the results of pre-clinical studies, i.e., showing no change in plasma Aβ levels for doses ranging between 0.3–30 mg/kg, confirming a low affinity of aducanumab for soluble monomeric Aβ [67]. A promising result was seen in the Phase I multiple dose study of aducanumab in participants with prodromal or mild AD (PRIME) (NCT01677572) that evidenced a reduction in brain Aβ via PET imaging with florbetapir in both prodromal and mild cases of AD. Participants received variable low to high doses of monthly aducanumab infusions (3 mg/kg-10 m/kg) for 12 months [68].

Two Phase III clinical trials conducted at 348 sites in 20 countries were developed to assess the efficacy of two different doses of aducanumab over 76 weeks versus placebo. Named ENGAGE (NCT02477800; N = 1638 subjects) and EMERGE (NCT02484547; N = 1647), these studies used a participant sample of 50 to 85 years who displayed signs of MCI or mild dementia related to AD with confirmed amyloid pathology via PET and administered monthly doses of low dose (3 mg/kg) or high dose (10 mg/kg) of aducanumab. The primary outcome measure was CDR-SOB at week 78 [68]. Due to interim futility analysis after 50% enrollment indicating that the primary endpoints would be missed due to participants responding in the same manner across groups in both trials, these two trials were stopped in 2019 [69]. A report in late 2019 suggested the interim analysis was incorrect; analyzing each trial’s data independently showed the high dose of 10 mg/kg induced a significant reduction in the primary endpoint, causing a significant positive difference in CDR-SOB scores compared to placebo controls. Secondary endpoints of MMSE, ADAS-Cog13, and ADCS-ADL scores showed a trend of lessened decline, with the low-dose group reported to have slowed AD progression, though this observation remained below statistical significance [68, 70]. This led Biogen to submit aducanumab for FDA review in 2020 under the accelerated approval pathway. Because the submitted data demonstrated (i) an effect on brain Aβ removal; (ii) a reasonable likelihood of meaningful clinical benefit; and (iii) evidence that this benefit can be seen in a subsequent Phase IV trial, aducanumab received FDA accelerated approval in June 2021 [71]. However, in 2022, Biogen withdrew its EMA Marketing Authorization Application for aducanumab after an EMA’s committee indicated that the data provided would not be sufficient to support a positive opinion.

Post FDA accelerated program approval, safety data from the EMERGE and ENGAGE trials showed that one-third of the subjects who received Aduhelm developed ARIA and one-quarter of those were symptomatic. Study participants at greater risk of developing aducanumab-induced ARIA either suffered brain microhemorrhages at baseline or were bearing the APOE4 allele [36]. A Phase IV observational study (NCT05097131) to assess real-world effectiveness and safety began in 2021, planning to enroll 6,000 patients receiving aducanumab throughout the United States. Participants should have received follow-ups for at least 5 years, though the study was expected to take 10 years to complete. Data on changes in cognition, function, neuropsychiatric symptoms, caregiver burden, quality of life, cost of care, safety, and ARIA were expected to be collected. However, this study was terminated early in 2022 due to anticipated feasibility for enrollment after determination of limited clinical utility.

In June 2022, a Phase IIIb/IV trial labeled ENVISION (NCT05310071) began enrolling participants with early AD, who were randomized to drug or placebo for 18 months with aducanumab doses up to 10 mg/kg administered monthly intravenously. The primary endpoint was CDR-SOB scores; secondary outcomes were standard cognitive and functional measures, and amyloid and tau PET. In a surprising turn of events, Biogen announced at the beginning of 2024 that it is discontinuing the licensing of aducanumab for the treatment of AD and terminated the ENVISION study. Following this decision, the rights to aducanumab reverted to Neurimmune. Whether another sponsor will continue testing this mAb is unclear at the time we are writing the present review.

Gantenerumab

Gantenerumab (also termed RG1450 and RO4909832) was produced by Chugai Pharmaceutical Co., Ltd., and Hoffmann-La Roche. Gantenerumab is a humanized IgG1 mAb that binds with high affinity to aggregated Aβ fibrils, encompassing the N-terminal and central amino acids, in the brain parenchyma and vasculature. By using effector cell-mediated clearance inside the central nervous system (CNS) to disassemble Aβ plaques, it removes Aβ deposits via phagocytosis by microglia [72]. Gantenerumab was also found to reduce new plaque formation without altering plasma Aβ levels in 4-month-old PS2APP mice (APP751 Swedish x PS2N141I) [72].

Gantenerumab was determined to be safe in a Phase I study involving 28 healthy participants aged 40–80 years with family history of early onset AD (NCT01656525) and could be considered for at-home injections after testing randomized to a sequence of one 300-mg sub-cutaneous gantenerumab injection [73]. Seven participants experienced symptomatic ARIA, but the open-label extension baseline was not significantly different between the ARIA-E and non-ARIA-E groups. It was reported in 2019 during Phase II and III trials (NCT01224106 and NCT02051608) tested on prodromal to mild AD participants that subcutaneous doses of gantenerumab up to 1,200 mg once every 4 weeks confirmed the study’s primary endpoint of reducing Aβ loads in the brain from baseline to weeks 52 and 104 [74]. Florbetapir PET was used to evaluate gantenerumab’s efficacy. It was later reported that, at 36 months after treatment initiation in the same Phase II and III studies, subcutaneous gantenerumab injections of up to 1,200 mg also significantly reduced Aβ plaque loads in the brain [75]. Critically, clinical benefit was only observed in patients who had fast onset AD; however, the cognitive benefit was small overall [26].

An expanded Phase II, multi-site, open-label, single-arm, pharmacodynamics study (NCT04592341) with gantenerumab called GRADUATION started in 2020. This study evaluated the changes in brain Aβ accumulation from baseline to week 104. Participation criteria included prodromal-to-mild AD confirmed by amyloid PET. By a dose escalation regimen, participants received a single dose of gantenerumab at increasing doses: 120 mg subcutaneous injection every 4 weeks for 12 weeks, then 255 mg every 4 weeks for 12 weeks, then 255 mg every 2 weeks for another 12 weeks, and finally 255 mg once a week until week 104. However, the decision to terminate the development of gantenerumab due to insufficient efficacy resulted in the early termination of the GRADUATION trial in 2023.

Two efficacy, safety, and pharmacokinetics Phase III studies termed Graduate-1 (NCT03444870 and WN29922) and Graduate-2 (NCT03443973 and WN39658) began in 2018 and enrolled a combined sample of almost 2,000 participants. The studies were randomized, double-blind, parallel-group, placebo-controlled recruiting participants with prodromal to mild AD to compare gantenerumab versus placebo effect on cognition and functioning. The main evaluation of this study was comparing CDR-SOB scores from baseline to week 116. Results showed that gantenerumab has failed to slow cognitive decline on the CDR-SOB scale in these Graduate trials and cleared only half as much plaque as expected with fewer participants becoming amyloid negative on PET scans than in previous trials [33, 76]. ARIA-E was observed in 24.9% of the participants receiving gantenerumab with 5% becoming symptomatic [33]. Based on the negative results of the Graduate trials, in 2022 the Chugai Pharmaceutical Co., Ltd. and Hoffmann-La Roche announced the discontinuation of all gantenerumab trials and the status of this mAb is on hold.

DISCONTINUED ANTIBODIES

Bapineuzumab

Bapineuzumab (also referred to as AAB-001; Pfizer Inc. and Janssen) is a humanized form of a murine monoclonal IgG1 antibody. Bapineuzumab recognizes the N-terminal region of Aβ, engaging both fibrillar and soluble oligomeric forms of Aβ. This activation prompts microglial phagocytosis and cytokine production [77, 78]. Studies utilizing mouse models indicated that targeting the N-terminal residues of Aβ plaques could lower the risk of neurotoxicity, cytotoxicity, and fibrillogenesis without the neurological sequelae found in other therapies [78]. Therefore, bapineuzumab was developed to specifically target this segment of Aβ peptides in order to reduce plaque formation and improve cognitive symptoms with reduced risk of neurological adverse events. When administered intravenously to subjects with mild-to-moderate AD, bapineuzumab achieves its highest concentration within 1 to 2 h for doses of 0.5 mg/kg, 1.5 mg/kg, and 5 mg/kg. The 0.5-mg/kg dose group exhibited the highest volume of distribution and clearance compared to the 1.5 mg/kg and 5 mg/kg dose groups. With an elimination half-life ranging from 21 to 26 days, depending on the dose, Bapineuzumab was administered every 13 weeks [34].

Clinical studies with bapineuzumab began in 2006, but in 2012 all Phase III trials were terminated because two large double-blind, randomized, placebo-controlled, multi-center 18-month studies failed to demonstrate any clinical benefit of intravenous regimens of bapineuzumab. These studies evaluated the effect of bapineuzumab in a total of 2,452 patients with mild-to-moderate AD determined by MMSE scores ranging from 16–26 and MRI scans consistent with a diagnosis of AD. The first study involved 1,331 patients who were not carriers of the APOE4 allele (NCT00574132), while the second study evaluated 1,121 APOE4 carriers (NCT00676143). Bapineuzumab or placebo was administered via intravenous infusion every 13 weeks for 78 weeks with doses of 0.5 mg/kg and 1 mg/kg in the first study, and 0.5 mg/kg in the second study [78]. The inclusion of 2 mg/kg dosing was discontinued early into testing due to the finding of ARIA-E among patients receiving bapineuzumab [79]. Primary outcome measures were then evaluated utilizing the ADAS-Cog11 scale and the Disability Assessment for Dementia. Secondary outcomes included measurement of CSF P-tau-181 concentrations and amyloid PET imaging with the use of Pittsburgh compound B (PIB) [79]. It was ultimately determined that there was no significant between-group difference in primary outcomes between the 0.5 and 1 mg/kg groups. Secondary endpoint analysis found a reduction in amyloid PET signals in APOE4 carriers in mild AD patients, along with a significant decrease in CSF P-tau-181 concentrations in both APOE4 carriers and noncarriers receiving 1 mg/kg [79]. Biomarker analysis indicated that bapineuzumab engaged its intended target in these studies, but ultimately found that it had no significant effect on either cognitive or functional outcomes in the study sample [79]. Two subsequent Phase III trials scheduled to be performed following these trials and plans for other Phase III studies were then canceled and no further trials have been instigated since. Currently, there are no plans to resuscitate studies investigating the therapeutic use of this antibody, and no plans to seek FDA or EMA approval.

Solanezumab

Solanezumab (LY2062430; Eli Lilly & Co.) is a humanized IgG1 version of the mouse m266.2 mAb that targets residues 16–24 in the mid-domain of Aβ peptides [80]. It also has a higher affinity to soluble Aβ monomers than to the fibrillar and toxic conformations [81]. Solanezumab reduces brain Aβ burden by increasing CNS and plasma Aβ clearance [81, 82]. This is achieved by capturing and degrading plasma Aβ, leading to the efflux of harmful Aβ from the CNS into the bloodstream occurring via the principle of equilibrium of Aβ in the two compartments, which is referred to as the sink hypothesis [83]. Phase I studies administering single doses of 0.5, 1.5, 4.0, or 10.0 mg/kg of solanezumab to healthy volunteers and 19 patients with mild-to-moderate AD resulted in no SAEs [80]. In 2012, the DIAN-TU trial began by conducting a 5-year Phase II/III study testing a combination of solanezumab and gantenerumab (NCT01760005). The study began as a two-year Phase II biomarker study and was later expanded into a Phase III registration trial with cognitive endpoints measured after at least 4 years of treatment. The 210 participants were asymptomatic and mildly symptomatic carriers of autosomal dominant mutations in AD genes (i.e., AβPP, PSEN-1, and PSEN-2). Administration commenced with a dosage of 400 mg solanezumab every four weeks, subsequently escalating to 1,600 mg during the midway point of the trial. In 2020, study investigators announced the trial had failed to meet its primary endpoint, showing no statistically significant treatment-related change on the DIAN Multivariate Cognitive Endpoint (DIAN-MCE), a composite scale developed for this trial. While the investigators noted that both mAbs engaged their Aβ targets, no beneficial effect on cognitive measures compared to controls was observed [84]. According to biomarker data presented at the 2020 Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting, solanezumab treatment caused a steep increase in CSF Aβ₄₂, indicating target engagement. Solanezumab did not alter tau biomarkers and negatively impacted CSF neurofilament light concentrations. Adverse events included eleven participants who developed ARIA-E with 3 becoming mildly symptomatic [85].

In separate studies, the initial findings from the Expedition 1 (NCT00905372) and Expedition 2 (NCT00904683) Phase III trials similarly did not demonstrate significant clinical improvements in participants with AD treated with solanezumab for 18 months, with 6.5% of participants experiencing a non-serious adverse event [86]. However, a later data analysis of secondary outcomes discovered that solanezumab may be correlated with a slowing in the cognitive and functional deterioration of participants with mild AD utilizing the ADAS-Cog14, ADAS-Cog11, and MMSE scales despite ADCS-ADL and CDR-SOB data not showing significant differences between placebo and solanezumab groups [87]. These findings instigated a Phase III, double-blind, placebo-controlled trial termed Expedition 3 (NCT01900665), which used an adjusted study design in order to further evaluate the efficacy of solanezumab on cognition. Patients with mild AD (defined as MMSE score ranging from 20–26, and positive amyloid PET or CSF Aβ₄₂) were randomized to 400 mg solanezumab or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the ADAS-Cog14 score. However, after enrolling more than 2000 participants, this trial was discontinued in 2016 due to a lack of evidence supporting a reduction in cognitive decline in AD patients by week 80 [35]. ARIA was seen in only one participant receiving solanezumab versus two participants in the placebo group [35]. Another Phase III trial, called Expedition PRO (NCT02760602), which enrolled prodromal AD subjects, was terminated in 2017 after only recruiting 26 participants due to a lack of evidence showing positive therapeutic effects on delayed cognitive decline on the ADAS-Cog14 scale. The mixed results have dissuaded the pursuit of further investigative trials with solanezumab, and Eli Lilly have discontinued their efforts to obtain FDA or EMA approval.

Crenezumab

Crenezumab (also known as MABT5102A and RG7412) was developed by AC Immune SA and licensed to Genentech. This passive IgG4 is a monoclonal, fully humanized antibody against human Aβ peptides. Recognizing oligomeric and fibrillar species of Aβ with a high affinity and monomeric Aβ with low affinity, it targets aggregated Aβ, clears plaques, and reduces subsequent action of microglia by reducing the release of pro-inflammatory cytokines (e.g., TNFα) [88, 89]. It was theorized that this would help reduce the cytotoxic burden caused by vasogenic edema while still inducing a phagocytic clearance of Aβ. Although highly homologous to solanezumab, particularly in epitope specificity, crenezumab is the only monoclonal antibody to target the mid-region of Aβ peptides that binds multiple aggregated forms while displaying a disaggregation effect [89].

Two Phase I double-blind safety and tolerability trials (NCT02353598 and NCT02670083) were performed in 2015 on a cohort of 77 participants which evaluated three doses of intravenous crenezumab compared to placebo in subjects with mild-to-moderate AD as determined by MMSE scores ranging from 18–28. One dose of the medication was given every 4 weeks up to week 13. The outcome of this trial indicated a safe profile with no ARIA-E or cerebral microhemorrhage (ARIA-H) following crenezumab administration [90]. A Phase II multi-site trial called ABBY (NCT01998841) evaluated a low-dose subcutaneous crenezumab (300 mg) versus placebo every 2 weeks, alongside a high-dose intravenous crenezumab (15 mg/kg) versus placebo every 4 weeks in participants residing in North America and Europe for 68 weeks, totaling a participant sample of 450 who suffered mild-to-moderate AD. An open-label extension trial of 361 patients continued until 2016 but missed the primary endpoint of reducing cognitive decline assessed by the ADAS-Cog12 and CDR-SOB scales at week 73 [90]. Further analysis after study completion suggested a possible efficacy signal in mild AD with the 15 mg/kg intravenous dose every 4 weeks, but not with a 300 mg subcutaneous injection every other week [90]. This indicates the timing of doses and dosage amount may play a role in the medication’s effectiveness. An ultrasensitive immunoassay for oligomers did show a significant decline in CSF oligomeric Aβ in the treated sample (median of 43–48%) compared to placebo (median of 13%) [91]. Only one instance of ARIA-E was observed in this trial.

A similar study design was applied to the Alzheimer Prevention Initiative (API) study. This Phase II, double-blind, placebo-controlled, randomized, biomarker-based trial termed BLAZE (NCT01397578), was sponsored by Genentech and the Banner Alzheimer Institute, Phoenix, AZ. A total of 91 mild-to-moderate AD patients (MMSE score ranging from 18–26) were enrolled to receive either low-dose subcutaneous crenezumab (300 mg) versus placebo every 2 weeks, or high-dose intravenous crenezumab (15 mg/kg) every 4 weeks for 68 weeks. The primary endpoint was a change in brain amyloid PET SUVR. No significant differences in the primary endpoint were observed between drug-treated and placebo groups, though secondary outcomes suggested target engagement [92].

Another Phase II, prospective, randomized, double-blind, placebo-controlled trial was carried out on 252 young (30–60 years old) cognitively unimpaired participants (MMSE score >24) in Colombia who are members of the world’s largest group of families who carry the autosomal-dominant presenilin 1 (PSEN1) mutation E280A (NCT01998841) [93, 94]. The patients received subcutaneous placebo or 300 mg crenezumab every two weeks for at least 260 weeks. In 2015, the regimen was changed to 720 mg subcutaneously every two weeks, and in 2019 participants could opt to increase the dose to 60 mg/kg delivered intravenously every four weeks. The primary endpoint was to evaluate cognitive decline through the yearly rate of change in measures of: (i) the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease (API ADAD); (ii) the Composite Cognitive Test Total Score; and (iii) the Episodic Memory Measure: Free and Cued Selective Reminding Task (FCSRT). This evaluation spanned from baseline up to week 260, covering a total duration of 416 weeks. To note, crenezumab was the first immunotherapy treatment to be investigated for its ability to prevent or delay cognitive decline by the API study [94]. Cognitive decline was evaluated with a longitudinal analysis in two independent cohorts to establish a composite cognitive battery that is both sensitive to preclinical decline for use in ADAD and sporadic AD treatment trials. The decline in the composite cognitive test scores was sensitive to progression into the clinical stages of sporadic AD with an 80% power to detect a true effect of a 30% reduction of the mean decline in the placebo group [94]. In 2022, the NIA published an announcement that the study failed to demonstrate a statistically significant clinical benefit, and this was confirmed by the investigators during the 2022 AAIC.

Leveraging the data regarding the effect of dosage seen in previous studies in order to improve study design, two Phase III multicenter, randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety trials called CREAD (NCT02670083) and CREAD 2 (NCT03114657) recruited over 1,600 participants with prodromal to mild AD (MMSE score >22 and either low CSF Aβ₄₂ levels or amyloid PET positivity). Intravenous infusions of crenezumab (60 mg/kg) or placebo were administered every 4 weeks for 100 weeks, with an efficacy and safety analysis being performed at 52 weeks after the last dose of crenezumab. The primary outcome was the change in the CDR-SOB score from baseline [95]. Ultimately, these trials never reached completion due to Genentech/Hoffmann-La Roche’s discontinuation following an interim analysis indicating the treatment would be unlikely to meet its primary objective of statistically significant improvement in cognitive outcomes [95]. Currently, there are no plans to continue production of this mAb and the FDA status is officially discontinued. Additionally, there are no plans to pursue EMA approval status.

EMERGING ANTIBODIES

Trontinemab

In the early 2010 s, Hoffmann-La Roche began developing a new formulation for gantenerumab called Trontinemab (also known as RO7126209, RG6102, brain shuttle gantenerumab), which is a bispecific mAb. Currently in a Phase Ib/IIa, randomized, double-blind, placebo-controlled, MAD, parallel-group trial (NCT04639050), this new version of gantenerumab is designed to cross the BBB more efficiently through the binding of endothelial cell transferrin receptors found in the BBB, facilitating enhanced gantenerumab endocytosis. This technology is similar to the previous BACE1 bispecific antibody developed by the same company [96]. More than 200 participants with prodromal or mild-to-moderate AD (MMSE score ranging from 18–28 and amyloid PET positive) have been enrolled and given multiple-ascending intravenous doses with doses ranging from level 1 to level 4. The primary outcome is the percentage of participants with adverse events. The trial is estimated to be completed in 2028 [97].

Remternetug

Remternetug (also known as LY3372993; Eli Lilly & Co.) binds to pyroglutamated Aβ fibrils (N3pG-Aβ), similarly to donanemab. No published preclinical results were found during the preparation of the present review.

In 2018, the sponsor started a Phase I trial (NCT03720548) to compare intravenous infusions of single or multiple escalating doses of LY3372993 or placebo in healthy, MCI, and mild-to-moderate AD subjects (MMSE scores ranging from 18–30 and positive on amyloid PET). The primary outcome measure was the number and severity of adverse events. However, in 2019, the sponsor decided to stop the study after enrolling 36 healthy subjects. No explanation was given for this sudden stoppage and no results were released.

A second Phase I randomized, placebo-controlled, parallel-group, triple-blind trial (NCT04451408) was initiated in 2020 to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3372993 in AD (MMSE score ≥16) and healthy subjects of Japanese origin. Study participants with mild MCI received monthly single (250–2800 mg) and multiple (700–1400) escalating doses of antibody, or placebo, over nine months either intravenously or subcutaneously. As for the previous study, the primary outcome measure is the number and severity of adverse events. While the original plan was to enroll 30 subjects, over time the sponsor increased the number of participants to 224 administered drug and placebo for up to 61 weeks. Interim results on 41 subjects were presented at the 2023 AD/PD International Conference. The sponsor reported a dose-dependent decrease in brain amyloid loads detected by amyloid PET within three months. Overall, 10 ARIA events were observed, all in APOE4 carriers, though no obvious dose correlation was noted. The trial is expected to be completed in mid-2024, with the main results made public a few months later.

In 2022, the sponsor started a Phase III randomized, double-blind, placebo-controlled, multi-site, cross-over trial to evaluate the safety and efficacy of remternetug in 600 participants with early symptomatic AD (MMSE score ranging from 20–28 and positive on amyloid PET), that was coined TRAILRUNNER-ALZ1 (NCT05463731). The mAb and placebo are administered via either subcutaneous injection or intravenous infusion for 52 weeks. Then, with the cross-over design, the participants who previously received remternetug received a placebo and participants who previously received placebo receive remternetug. An additional safety cohort of 640 patients receives open-label intravenous or subcutaneous remternetug for one year (no cross-over design for this safety cohort). The primary outcome is the percentage of patients whose amyloid plaques are cleared by week 52 compared to baseline and to placebo. This trial is expected to run until the end of 2026. It is anticipated that, if results of the trial are significant, then remternetug will be submitted for FDA and/or EMA approval.

ACU193

ACU193 (Acumen Pharmaceuticals, Inc) is an experimental humanized IgG2m4 monoclonal antibody that selectively binds soluble Aβ oligomers, targeting the Aβ-derived diffusible ligands [98]. Although soluble Aβ oligomers contribute only a fraction to the total Aβ aggregates, this form is theorized to be the most neurotoxic, resulting in the cognitive deficits seen in AD dementia [99]. Preclinical data showed preferential selectivity to soluble Aβ oligomers over monomers and fibrils. The mAb blocked oligomers from interacting with cultured hippocampal neurons, with no inhibition of the mAb effect when Aβ monomers were added. In Tg2576-AD mice, ACU3B3 (the mouse parent of ACU193) lessened plaque deposition by binding soluble oligomers in brain tissues. In other AβPP transgenic mouse models, ACU3B3 improved several behavioral deficits. Because of the drug’s pharmacokinetics, it is thought that ACU193 will be more effective and less toxic than other mAbs in human subjects [99].

A Phase I trial termed INTERCEPT-AD (NCT04931459) began in 2021 to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACU193. The placebo-controlled study uses a SAD and MAD model of intravenous infusion of ACU193. Sixty-two participants were selected with a diagnosis of MCI or mild dementia due to AD (MMSE score ranging from 18–30 and positive on amyloid PET). Participants received 1–3 injections of ACU193 or placebo at doses of 2–60 mg/kg, with each cohort having 2 participants receiving a placebo. MRI was used to evaluate ARIA. Digital and imaging biomarkers, such as measuring cerebral blood flow with an MRI method was also investigated, and a computerized cognitive test battery along with Alzheimer’s Disease Rating Scale-cognition and CDR-SOB were employed to assess cognitive changes [99]. The study was designed to allow a quick decision on whether the company will proceed with a subsequent Phase II/III study. The trial was completed in 2023 and data presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) meeting indicated that ACU193 was safe and well tolerated by study subjects. It is anticipated that if data continues to prove promising, then the company will pursue FDA and/or EMA approval. Further testing is in preparation at the time this review was written.

Fig. 1

Graphical representation of amyloid antibodies on the continuum of Aβ forms. In the center are represented the production of Aβ peptides and formation of senile plaques. At the bottom are indicate the type of therapies targeting each of the steps in the amyloid continuum. On the top are listed the antibodies discussed in the present review and their antigen in the amyloid plaque formation.

DISCUSSION

The first report on an active immunization approach to reduce brain amyloid loads and improve cognition in mouse models of AD was published in 1999 [25]. Passive immunization paradigms were tested a few years later, and only 24 years later (2023) the FDA approved the first anti-Aβ mAb (Leqembi) to treat mild AD in human patients. This brief summary illustrates the difficulties faced in AD research to develop novel therapeutic interventions for this complex disease, which is emphasized by the fact that the etiology of AD (i.e., why does Aβ initially increase in the brain) remains poorly understood to date. The approval of a second mAb (donanemab) in 2024 illustrates the ambition of the FDA to support the deployment of new therapies that show potential to improve AD patients’ condition, particularly DMTs.

Despite FDA approval for two drugs and several promising emerging candidates, current anti-Aβ mAbs come with crucial limitations. First, their clinical efficacy is restricted, as Leqembi, Kisunla, and other mAbs only slow cognitive decline by 25–30% in clinical trials [37 , 100]. Because of the relatively short duration of most clinical trials (≤5 years), it is currently unknown whether these effects will be long-lasting in the general population, and whether AD patients will need to take these medications for life or can stop after a few years. A possible issue that may reduce drug efficacy is the mounting of an immune response by patients after repeated administration of anti-Aβ mAbs. It is currently unclear how many patients will develop such reaction and how it will affect long-term treatment plans. Second, most anti-Aβ mAbs induce treatment-related ARIA, or aggravate ARIA in case microbleeds pre-exist before dosing onset, which can be lethal in some cases [40]. Pathologically, ARIA have been linked to cerebral amyloid angiopathy (CAA), which is the accumulation of Aβ in the walls of blood vessels in the brain, thereby causing vessel stiffening, vessel wall fragility, and reduced perivascular clearance of Aβ. It was proposed that, when mAbs break down parenchymal plaques, part of the released Aβ increases the deposits in the walls of blood vessels (i.e., aggravates CAA), which can induce an immune response against the vasculature and increase permeability of the BBB. In addition, anti-Aβ mAbs can bind vascular Aβ, which then attracts macrophages and generate an immune response that damages blood vessel walls [101]. Of interest, the APOEɛ4 allele is a known risk factor for CAA [102] and has been suggested to increase the severity of ARIA [101]. Consequently, some clinicians prefer to not administer anti-Aβ mAbs to AD patients who bear one of two copies of the APOE4 allele along with other risk factors, such as anti-platelet medications and pre-existing brain hemorrhages [103].

The relatively limited efficacy of anti-Aβ mAbs has sparked important debates in the AD research arena. The main points of discussion are the validity of the amyloid cascade hypothesis and clinical trial study designs that integrate AT(N) biomarkers for patient stratification. An anticipated consequence of the amyloid cascade hypothesis is that the removal of brain Aβ plaques should stop the progression of AD. However, although some mAbs can reduce brain amyloid loads to a point where amyloid PET signals are below the detection threshold (e.g., aducanumab), cognitive decline is not stopped [100]. Another theory linked to the amyloid cascade hypothesis is the model of dynamic biomarkers for AD summarized in the introduction above [18]. If Aβ appears before tau and makers of neurodegeneration (i.e., the ATN framework for AD diagnosis), then a logical reasoning would be to administer anti-Aβ therapies to A+T–N–patients to prevent further progression of AD pathologies. However, many clinical trials, such as Trailblazer-ALZ1, recruited study subjects who were both amyloid and tau PET positive, and investigated the levels of plasma P-tau-217 and GFAP (i.e., A+T+N+ subjects), suggesting that the study subjects were not stratified to test the maximum clinical benefit of donanemab. Instead, anti-Aβ mAbs would likely show greater clinical benefits when administered to A+T–N–patients, i.e., at preclinical or prodromal or MCI or very early AD stages, before other AD pathologies become prominent. Such clinical trials would generate the necessary data to better assess whether the amyloid cascade hypothesis is valid, i.e., determine whether the early removal of oligomeric and fibrillar Aβ would prevent conversion to AD later in life. To note, a major issue with the testing of anti-Aβ mAbs in preclinical and prodromal subjects is the need to screen a large number of patients to find cognitively unimpaired individuals with high levels of brain amyloid loads. While amyloid PET imaging could be considered, recent reports have indicated that some races and ethnicities display lower SUVR values than non-Hispanic White individuals, which decreases diversity in clinical trials screening patients via amyloid PET [104]. Furthermore, diverse individuals are represented at a lower rate in clinical trials, including pharmaceutical companies rarely including rural residents. When clinical trials or treatment plans require frequent study visits and/or frequent administration of medications by specialists (e.g., intravenous infusion for Leqembi), rural residents simply do not have the time to travel to the nearest city, sometimes several hours away, accompanied by a study partner or caregiver. We argue that pharmaceutical companies should develop drug formulations that can be administered by rural healthcare providers and don’t require more than quarterly visits to a specialized medical center. Thus, additional methods to assess brain amyloid loads and deliver anti-Aβ mAbs should be considered to increase diversity in clinical trials and treatment plans.

In 2023, a major step was taken when the FDA fully approved the first anti-Aβ mAb as a new treatment option for AD, i.e., lecanemab. Although Leqembi is not a cure, but rather a tool to slow down disease progression, and some severe adverse events may develop, this DMT is paving the way for additional anti-Aβ medications to follow a similar regulatory path. For example, donanemab just received full FDA approval at the time we write this review. We anticipate that several emerging therapies, such as remternetug, PRX012, and ACU193 will offer promising avenues to improve both the efficacy and safety profile of mAbs to remove amyloid plaques in the brain of AD patients in carefully designed clinical trials. However, such long-awaited DMTs will likely need to be combined with other therapies directed towards additional AD pathologies, such as hyperphosphorylated tau and alpha-synuclein, which coexist alongside Aβ, to offer a cure to AD patients. In parallel, the treatments will likely need to be started early, at the prodromal phase, to prevent future conversion to AD in amyloid-positive, cognitively unimpaired patients. We predict that the coming two decades will see major improvements in the efficacy of anti-Aβ mAbs that permit the eradication of the ongoing AD epidemic accompanied by the observation of healthy aging and increased life expectancy.

AUTHOR CONTRIBUTIONS

Keith Noorda (Methodology; Writing – original draft; Writing – review & editing); Kevin Noorda (Methodology; Writing – original draft; Writing – review & editing); Marwan N. Sabbagh (Conceptualization; Funding acquisition; Project administration; Supervision; Writing – original draft; Writing – review & editing); John Bertelson (Writing – review & editing); Jonathan Singer, Ph.D. (Writing – review & editing); Boris Decourt (Conceptualization; Data curation; Funding acquisition; Methodology; Supervision; Writing – original draft; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

The authors have no acknowledgments to report.

FUNDING

The authors have received funding from the National Institute on Aging: R01AG059008, R01AG073212, and P30AG072980

CONFLICT OF INTEREST

MNS declares the following ownership interests (Stock or stock options): NeuroTau, Optimal Cognitive Health Company, uMethod Health, Versanum, Athira, Cognoptix, TransDermix, Seq BioMarque, NeuroReserve, Cortexyme. MNS also declares to be a consultant for Alzheon, Biogen, Roche-Genentech, Eisai, KeifeRx, Lilly, Synaptogenix, NeuroTherapia, T3D, Signant Health, Novo Nordisk. JB is an ad-hoc lecturer for Eisai. All other authors have no conflict of interest to report.

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