Anti-Amyloid Monoclonal Antibodies are Transformative Treatments that Redefine Alzheimer's Disease Therapeutics

The field of Alzheimer's disease (AD) therapeutics is being redefined by the approval and integration into clinical care of anti-amyloid monoclonal antibodies (MABs). Two MABs have been approved through the accelerated approval mechanism – lecanemab (Leqembi^®) and aducanumab (Aduhelm^®). One agent (lecanemab) has clinically compelling data that may lead to standard approval by the US Food and Drug Administration (FDA), and another MAB (donanemab) has promising Phase 2 data. Lecanemab and donanemab have shown marked amyloid reduction on amyloid positron emission tomography (PET) and slowing of clinical decline in clinical trials [1‐3]. Aducanumab produced dose- and time-dependent reduction of amyloid plaque in a Phase 1 trial (PRIME) and was then assessed in two Phase 3 trials (EMERGE, ENGAGE) [4, 9]. Similar amyloid lowering on PET was observed in both Phase 3 trials and a clinical response was observed in EMERGE. The ENGAGE trial demonstrated the same relationship between amyloid and clinical slowing relationship among patients who had the planned exposure of 10 mg/kg for 14 months [5].

The demonstration of disease modification in AD is a breakthrough for which neuroscientists have strived for decades. Anti-amyloid MABs are the first disease-modifying therapies (DMTs) for AD and the first DMTs for any neurodegenerative disorders except for two approved agents for the treatment of amyotrophic lateral sclerosis (ALS) [6, 7]. The advance represented by the anti-amyloid MABs reflects many years of investment in understanding the biology and treatment of AD by the National Institutes of Health (NIH), biopharmaceutical companies, and numerous other research-supporting enterprises around the world [8]. The success of these agents is a pivotal moment in the history of AD therapeutics as we celebrate the ability of neuroscience-based interventions to modify the complex biological processes of AD and slow the inevitable decline experienced by patients with this unforgiving illness. These transformative agents redefine the treatment and care of patients with AD and have many implications for patients, care partners, health care systems, payers, and the drug development process. This perspective addresses some of the foreseeable consequences of introducing unprecedented therapies into the care of patients with this common disease of aging.

Anti-amyloid MABs are DMTs whose impact on the basic neurobiological processes of AD is supported by changes in biomarkers of the MAB targets and downstream events. Randomized clinical trials have shown removal of brain plaque amyloid, often to below detection thresholds by amyloid PET [1, 2, 4, 8, 9]. In AD, there are secondary effects on other biomarkers including plasma and cerebrospinal fluid (CSF) phosphorylated tau (p-tau), plasma and CSF total tau, and CSF neurogranin [2, 5, 10, 11].

The outcomes of anti-amyloid MAB trials showed significant reduction in the rate of clinical decline as measured by cognitive and functional outcome measures. A 30% reduction in the decline in the Clinical Dementia Rating—Sum of Boxes (CDR-SB) (the primary outcome) was observed in the EMERGE and ENGAGE trials among patients with the planned treatment exposure [5]; clinical decline as measured by the integrated Alzheimer’s Disease Rating Scale (iADRS) was reduced by 32% in the Phase 2 trial of donanemab [1]. There was a 27% reduction in the decline on the CDR-SB in the 18-month Phase 3 CLARITY AD trial of lecanemab [3]. The drug-placebo differences shown on the primary outcomes have been accompanied by significant drug-placebo differences on secondary outcomes in trials powered to evaluate these measures [2, 5]. In its Phase 3 trial, lecanemab showed significant reductions in decline in cognition and function as measured by the Alzheimer's Disease Assessment Scale—cognitive subscale (ADAS-cog) and the Alzheimer's Disease Cooperative Study (ADCS) Activities of Daily Living (ADL) measure. In the Phase 2 trial of lecanemab, there was a significant drug-placebo difference (27%) in cognitive and functional decline as measured by the Alzheimer's Disease Composite Score (ADCOMS) and the ADAS-cog (56%) [2]. The Graduate I and II trials of gantenerumab (another anti-amyloid MAB) did not meet their primary end point. They did not demonstrate significant slowing of clinical decline and there was less than expected reduction in brain amyloid levels with fewer than anticipated participants reaching amyloid negativity. There was a slowing of decline in the subpopulations that met the expected levels of amyloid plaque lowering suggesting that the drug exposure in the brain was not sufficient to achieve the desired levels of amyloid lowering and the levels necessary to produce significant clinical benefit [12].

The meaningfulness of a 30% reduction in clinical decline is debated. The magnitude of the response is modest and the lack of improvement above baseline will be make it difficult for patients, families, and clinicians to perceive the benefit [13]. This degree of slowing equates to extending the mild cognitive impairment phase of AD by approximately 7.5 months [14]. Simulation modeling suggests that treatment with lecanemab will extend the mild phases of AD dementia by approximately 2.5 years with substantial cost savings [15, 16]. Delaying progression with maintenance of autonomy and avoidance of increased dependency are among the things that matter most to patients with AD and their families [17]. The 30% slowing in decline was observed in 18-month trials; it is anticipated that DMTs will permanently alter the course of AD and that the difference between treatment and no treatment will increase over time [18].

The amyloid hypothesis addresses the role of amyloid in the pathogenesis of AD [19]. This theory posits that amyloid accumulation is the key initiating event of AD and is followed by downstream effects including formation of neurofibrillary tangles, neuroinflammation, cell death, and neurotransmitter deficits. This hypothesis has been instrumental in guiding therapeutic strategies and clinical trials. Many clinical trials directed at amyloid have failed to show a drug-placebo difference and these negative outcomes have caused skepticism about the amyloid hypothesis and the viability of amyloid-beta protein (Aβ) as a target for AD drug development [20, 21]. In the history of AD therapeutics, nearly all drugs directed at any target—amyloid and non-amyloid—failed to produce clinical benefit. Of the many negative trials, Aβ was a common target but accounted for a minority of all trials [22]. Despite failures, there has been progressive refinements of the amyloid hypothesis with increasingly compelling targets within the spectrum of Aβ species and corresponding success in clinical trials [23].

There is substantial cumulative evidence supporting the amyloid hypothesis. The existence of disease-causing and disease-protecting mutations of Aβ-related genes, effects in transgenic Aβ-producing mouse models, observations in induced pluripotent stem cells (IPS cells) engineered to produce Aβ, and results of autopsy studies of Aβ in the brain in patients with AD comprise a formidable foundation for the amyloid hypothesis [24‐27]. The hypothesis gained important support from the observation that removal of amyloid plaques by anti-amyloid MABS from the brains of patients with AD significantly reduces the rate of clinical decline. Together, these many lines of evidence serve to validate amyloid as an important target for therapeutic development.

Anti-amyloid MABs reduce the rate of decline in AD by approximately 30% (detailed above). The remaining 70% may be driven by downstream and non-Aβ contributions to the pathology of AD. Further interrogation of these targets and consideration of combination therapies are warranted [28]. The goal of AD therapeutics is to maintain patient cognition and function at the highest levels for the longest period of time. The effects of anti-amyloid MABs are transformative first steps in demonstrating our ability to achieve disease modification; additional interventions will be required to achieve our ultimate therapeutic goals.

Biomarkers are making decisive contributions to drug development for AD [29]. The accelerated approvals of aducanumab and lecanemab were based on marked amyloid plaque reduction as measured by amyloid PET. The amyloid PET biomarker played multiple roles in these trials including use as an inclusion criterion to demonstrate the presence of the therapeutic target, measurement of the pharmacodynamic response to treatment with the anti-amyloid MAB, and provision of supportive evidence of disease modification. Magnetic resonance imaging (MRI) also plays a vital role in anti-amyloid MAB trials. Trial participation requires an absence of substantial ischemic or hemorrhagic cerebrovascular disease on the baseline scan. In addition, MRI is used for routine monitoring to detect asymptomatic amyloid-related imaging abnormalities (ARIA) and to determine if ARIA has occurred in patients who develop symptoms during therapy [30]. Magnetic resonance imaging is a key safety biomarker in MAB trials.

Measurement of biomarkers in CSF has provided evidence of the downstream effects of anti-amyloid MAB therapy. Biomarker changes in CSF have varied somewhat from trial-to-trial; among trials, reductions have been seen in total tau, p-tau, and neurogranin in the treatment group compared to the placebo group [10, 11]. These biomarkers function as pharmacodynamic measures and provide evidence in support of disease modification. They are consistent with the cascade of effects described in the amyloid hypothesis.

Plasma biomarkers have made marked progress. Plasma tau phosphorylated at threonine 217 or threonine 181 are elevated in individuals with brain amyloid accumulation [31]. The p-tau elevations may reflect tau-related neuritic changes induced in the peri-plaque environment. These p-tau measures declined in the treatment group compared to the placebo group in concert with amyloid plaque reduction in several trials in which they were measured [5, 11]. Plasma p-tau measures can be used as monitoring biomarkers or pharmacodynamic biomarkers and provide evidence of disease modification. They are being used to screen patients for clinical trials and could be used to stratify patients in statistical analysis plans [32].

Plasma biomarkers have the greatest promise of transitioning from clinical trial application to clinical care. These biomarkers could be used to establish the presence of AD pathology in patients with mild cognitive impairment and might eventually be used to identify patients in the preclinical phase of AD before symptoms appear and when preventive therapies can be introduced [19]. These potentially transformative biomarkers will require workflow adjustments in clinical care for optimal use and to ensure equitable availability of these remarkable new tools across populations.

The apolipoprotein E ε4 (APOE4) gene increases the risk of AD and decreases the age of onset [33, 34]. Routine testing for APOE4 carrier status has been discouraged since no adjustments for prevention or treatment of AD could be based on this information. In anti-amyloid MAB trials, APOE genotyping provides actionable information. Amyloid-related imaging abnormalities are associated with anti-amyloid MAB treatments, and ARIA are more frequent among APOE4 carriers. Most ARIA events have no associated symptoms, but some have serious consequences and deaths have occurred. For example, in the trials of aducanumab, 43% of APOE4 gene carriers and 20.3% of APOE4 non-carriers developed ARIA with edema (ARIA-E). These changes were most frequent in APOE4 homozygotes (66%) [35]. Given the known additional risk for ARIA in APOE4 carriers, APOE genotyping is recommended prior to treatment to allow informed risk discussions with potential therapy candidates and their care partners [36]. Apolipoprotein E genotyping provides information relevant to treatment with anti-amyloid MABs, and patients have expressed a desire to receive genetic information if the information informs practice [37]. Apolipoprotein E genotyping has implications for the patient’s siblings and children since they may be gene carriers of familial genes and at increased risk for development of AD. Genetic counseling must be available before and after genotyping to avoid misunderstandings and assist in decision making [38]. Genotyping is a new aspect of care for AD patients required for the informed use of anti-amyloid MABs.

The FDA used the mechanism of accelerated approval to allow aducanumab and lecanemab to be marketed while additional clinical data were generated [39]. Accelerated approval requires that a biomarker change be considered reasonably likely to predict clinical benefit. A confirmatory trial is typically required when the accelerated approval pathway is used. The relationship between amyloid plaque lowering demonstrated by amyloid PET and slowing of clinical decline was supported by observations in trials of lecanemab, donanemab and one of the aducanumab trials. The relatively consistent association across trials between plaque lowering and reduction in cognitive and functional decline supports the conclusion that plaque lowering is reasonably likely to predict beneficial clinical changes. The FDA required a confirmatory trial of aducanumab and is currently examining data from the confirmatory trial for lecanemab (CLARITY AD) [3].

Accelerated approval is commonly used for provisional approval of treatments across therapeutic areas [40]. Its use in AD provides early access to promising agents for patients who have this life-threatening illness. The precedent encourages accrual of data on other biomarkers that might be viewed as reasonably likely to predict a clinical response and might eventually be the basis for accelerated approval for AD or other neurodegenerative disorders.

Current anti-amyloid MABs have important limitations. They are administered intravenously at 2- to 4-week intervals. As noted, they produce ARIA, which is usually without accompanying symptoms but may occasionally produce severe impairment or death. The MRI scanning required to monitor ARIA increases the inconvenience of treatment with these agents [36]. Anti-amyloid MABs that can be administered less frequently, are less likely to produce ARIA, require less monitoring, are more convenient to administer, and produce greater slowing of clinical decline are all goals for evolving anti-amyloid MAB development programs. Anti-amyloid MAB trials included patients with mild cognitive impairment due to AD and mild AD dementia; the use of these agents in individuals with preclinical AD or more severe AD has not been assessed and the lack of this information represents an important gap in our understanding. Further definition of the targets of anti-amyloid MABs is needed. Plaque-lowering MABs may have non-plaque Aβ targets that contribute to the therapeutic benefit. Lecanemab, for example, markedly lowers plaques as shown by amyloid PET but also preferentially targets amyloid protofibrils and effects on protofibrils may contribute to efficacy [41].

Other anti-Aβ approaches will be stimulated by the success of the amyloid-reducing MABs. Anti-amyloid vaccines might avoid some of the challenges that occur with anti-amyloid MAB therapies [42]. Small molecule drugs that can be taken orally are more convenient than biological approaches and will be encouraged by the success of anti-amyloid MABs and the validation of Aβ as a therapeutic target [43, 44].

The demonstration that disease modification is a feasible goal for drug development programs will facilitate advancing drugs with other targets in the pathophysiology of AD. Interventions directed at aspects of tau biology, neuroinflammation, neuronal metabolism and energetics, oxidative stress, proteostasis, autophagy, vascular features of AD, epigenetics changes, apolipoprotein E and lipid abnormalities, synaptic plasticity, neuroprotection, and hormonal features of AD are all potential therapeutic targets that warrant investigation. Reductions in plasma and CSF p-tau and total tau following removal of the Aβ plaques suggests that tau-related changes may be important components of the response to anti-amyloid MABs. This observation will encourage the development of treatments directly targeting tau biology. Anti-amyloid MABs activate microglia to remove amyloid and direct targeting of these cells may be a plausible therapeutic approach. The success in producing disease modification with removal of Aβ plaques will likely stimulate the development of drugs targeting aggregated proteins in other diseases such as tau proteins in tauopathies, alpha-synuclein protein in Parkinson's disease, and TAR DNA-binding protein 43 (TDP43) in amyotrophic lateral sclerosis and frontotemporal dementia.

The success of anti-amyloid MAB development will increase the confidence of pharmaceutical companies, private investors, venture capital companies, philanthropy, and federal programs in supporting research aimed at disease modification [45]. The anti-amyloid MABs herald a new era in the development of disease-modifying therapies for AD and other neurodegenerative diseases.

Approval of the anti-amyloid MABs will require reconsideration of AD clinical trial designs [46, 47]. Most clinical trials, including those conducted for MABs, allow participants to be on the standard of care with cholinesterase inhibitors or memantine. The approvals of aducanumab and lecanemab and the potential approval of other anti-amyloid MABs suggest that these drugs may become the standard of care, at least for some patients with mild cognitive impairment or mild AD dementia. Designing trials that allow for this contingency is complex and a variety of strategies can be considered. Active comparator studies would allow the comparison of an approved anti-amyloid MAB with an experimental MAB or other therapy; trials could allow anti-amyloid MABs to be added on to the treatment of participants in the active treatment and placebo arms of ongoing trials with modification of sample size to account for the effects of the add-on therapy; patients on existing anti-amyloid MAB therapy can be randomized to drug or placebo with appropriate sample size and outcome measure adjustments; delayed start trials can be considered where an anti-amyloid MAB is systematically introduced after a period of observation without MAB therapy in one arm of a trial; biomarkers might define unique patterns of response or identify populations more likely to respond to specific therapeutic regimens. Other neurological disorders such as multiple sclerosis have several approved DMTs and have developed clinical trial methodologies that are ethical and practical and have provided the basis for approval of new therapies in the context of existing therapies [48]. Experience derived from treatments in non-AD therapeutic areas can assist in planning clinical trials in these new circumstances.

Patients and their care partners in consultation with knowledgeable clinicians will be the decision makers regarding treatment with anti-amyloid MABs. An informed decision will require substantial learning by the patient-care partner dyad. Whether a 30% reduction in disease progression is sufficiently desirable to accept the inconvenience and potential harm associated with anti-amyloid MAB therapy will be a challenging decision for most patients and care partners. Treatment discussions will include APOE genotyping, which may have implications for the patient’s siblings and children [38]. Magnetic resonance imaging monitoring in the first year of therapy as part of ARIA management increases demands and inconvenience of treatment. These requirements may increase uncertainty for patients considering treatment with a MAB. The demands of MAB treatment will be weighed against the alternative of an unaltered and inevitable decline to more severe cognitive impairment. These decisions are not unlike those facing many cancer patients whose therapies provide modestly improved survival and have substantial toxicity. The decision process and the required decision supports are new to AD care.

The US Centers for Medicare and Medicaid Services (CMS) made a policy decision to reimburse the costs of aducanumab only if the agent is given in a CMS-approved clinical trial. This greatly limited the availability of aducanumab to those participating in a confirmatory trial or who are capable of self-pay for the agent. Given these severe constraints, aducanumab is rarely used. This was an unusual decision by CMS; many oncology agents and treatments for other diseases approved through the accelerated pathway have received funding through CMS while confirmatory trials were ongoing [49]. The purpose of accelerated approval is to make promising drugs available based on preliminary biomarker evidence while additional clinical evidence is being accrued. The CMS decision is at variance with the purpose of accelerated approval and with the intent to make emerging treatments for life-threatening illnesses available to patients as soon as possible.

Transformative therapies such as the anti-amyloid MABs can benefit patients only if they are readily available and most of the cost of the therapy is reimbursed [50]. The costs of these therapies and responsible pricing by pharmaceutical companies must be part of the dialogue about reimbursement [51]. Anti-amyloid MABs currently under review and meeting the traditional requirements for approval based on clinical evidence of the benefit of slowing cognitive and functional decline must be reimbursed to become generally accessible. These transformative therapies require changes in health care policy, payment strategies, mechanisms to identify patients who can benefit from therapy, and processes to administer and monitor treatment [52]. Our society traditionally values the health, well-being, and dignity of older individuals. Older persons deserve the same access to excellent care and advanced therapies afforded other citizens. Progress in science must be accompanied by a concomitant receptivity to integrating new discoveries into health care by the social and political mechanisms that can make these advances available to patients in urgent need of treatment.

Anti-amyloid MABs are redefining AD care. They are extraordinary therapies that offer previously unavailable benefits to patients on the inevitable downward trajectory of AD. They have shown that disease modification is possible and define pathways for the development of other DMTs and combination therapies. Anti-amyloid MABs are the result of relentless application of neuroscience knowledge to solve the problems of humankind. These unprecedented breakthrough therapies are associated with new requirements for the many stakeholders involved with AD and the care of older citizens of our society. Global social and medical care innovations are needed to accommodate these transformative therapies. Anti-amyloid MABs are an advance to be celebrated as they open a new era of addressing the challenges to our most precious global resource, the human brain.