Therapeutic Spotlight: New Evidence Brings Cautious Optimism to Alzheimer’s Disease Treatment

By Xcenda

After another promising Alzheimer’s disease treatment seemingly fails, a broader data review brings aducanumab back in the spotlight, setting the stage for a landmark FDA decision with major implications for patients with Alzheimer’s disease, the amyloid-β disease model, and the influence of post hoc analyses on health authorities.

HTA Quarterly | Fall 2020

New Evidence Brings Cautious Optimism to Alzheimer’s Disease Treatment 

By: Robin Tan, PhD; Anne Loos, MA; Eldon Spackman, PhD; Kimberly Ruiz, EdM

Alzheimer’s disease is a progressive neurodegenerative disorder that causes loss of cognitive functioning, changes in behavior, and interference in daily functioning, and is the leading cause of dementia around the world with a global prevalence of 43.8 million. Alzheimer’s disease places a significant economic burden on healthcare systems. Overall healthcare costs for Alzheimer’s and other dementia diseases in the United States (US) are projected to be $305 billion, and the costs of care provided by family members and other unpaid caregivers are estimated at $244 billion. Despite the substantial investment in understanding its pathophysiology and developing treatments, currently approved therapies for Alzheimer’s disease only temporarily reduce symptoms and do not slow disease progression. However, a novel treatment being developed by Biogen may be the first therapy to reduce the clinical decline in patients with Alzheimer’s disease. After initially reporting negative trial results and discontinuation of phase 3 trials evaluating aducanumab, Biogen announced late last year that they will file for market approval based on positive findings from a new analysis of a larger dataset. The Food and Drug Administration (FDA) is now set to make a historic decision on a therapy that could bring new hope to those affected by Alzheimer’s disease. To understand how aducanumab fits in the current market landscape and how it is likely to be viewed by health authorities, this article provides an overview of current Alzheimer’s disease models, the treatment landscape, and the evolution of aducanumab as a prospective first-in-class treatment.

Theoretical Models and Current Treatment Landscape

Prior to the early 2000s, several theoretical treatment models emerged to potentially explain the Alzheimer’s disease pathology, including the involvement of acetylcholine and N-methyl-D-aspartate (NMDA) receptors, and have been used to guide the development of effective therapies. However, the 5 current FDA-approved treatments (donepezil, rivastigmine, galantamine, memantine, donepezil/memantine), which consist of acetylcholinesterase inhibitors and NMDA receptor antagonists, are only able to treat associated symptoms, and none are able to prevent or slow the progression of the disease. Given the limited effectiveness of currently approved drugs, researchers have shifted to developing new therapeutic strategies that target disease modification. Disease-modifying therapies are thought to produce enduring change in the clinical progression of Alzheimer’s by altering the underlying pathophysiological mechanisms of the disease. As direct observation of changes in the brain is not feasible, disease modification is a concept that is inferred based on evidence of an enduring effect generated from clinical trials using clinical outcomes and biomarkers. The emerging evidence over the past 2 decades suggests that the neurological changes found in Alzheimer’s disease may be related to abnormal amyloid plaques and tau proteins. Research has shown that the accumulation of amyloid and tau are related to neurodegeneration and cognitive decline, which are common symptoms of Alzheimer’s. Therefore, many new treatment strategies are focusing on disease modification by targeting the removal of amyloid and tau, even though the exact molecular mechanisms are unknown. Despite evidence of the involvement of amyloid and tau in Alzheimer’s and the massive investment in treatments targeting these pathways, almost all phase 3 clinical trials conducted under this model have failed to meet pre-specified endpoints.

Challenges of Clinical Trials

Because of the substantial challenges in designing Alzheimer’s clinical trials, it is difficult to ascertain whether clinical trial failures are associated with the treatment under investigation or factors relating to the study design itself. While there are several challenges of Alzheimer’s trials, the most prominent of which is the selection of relevant trial endpoints that can capture change within the clinical trial setting. FDA and European Medicines Agency (EMA) guidelines state that early-stage Alzheimer’s clinical trials should use a co-primary outcome measures approach in which a drug demonstrates efficacy on both a cognitive and functional or global assessment scale (FDA 2018; EMA 2018). The Alzheimer’s Disease Assessment Scale-Cognition subscale (ADAS-Cog) is still the most commonly used cognitive measure in Alzheimer’s trials, despite concerns that the ADAS-Cog does not cover all aspects of cognitive decline, may underestimate within-person changes and differences between treatments and control groups for early Alzheimer’s and trials of shorter duration, and may be administered and scored inconsistently from trial to trial. The Clinical Dementia Rating Sum of Boxes (CDR-SB) is another common outcome measure used in Alzheimer’s trials and assesses both cognitive and functional aspects of Alzheimer’s. Although the CDR-SB has shown promise for use in trials of early Alzheimer’s, there are still several limitations, such as floor effects, administrative burden, the potential for interrater variability, and a high dependency on the reliability and accuracy of a single observer informant throughout the clinical trial. 

Patient selection (eg, inclusion/exclusion criteria) is also an issue, as the only way to make a definitive Alzheimer’s diagnosis is after death via examination of brain tissue from an autopsy. The timing of treatment is another challenge, as treating symptomatic Alzheimer’s may be too late in the disease course for any disease-modifying therapy to be effective. Evidence from imaging, biomarker, and neuropsychological studies of symptomatic patients have shown that amyloid buildup followed by other pathological changes have already been in progress and peak when subtle clinical symptoms begin to emerge; therefore, patients with preclinical Alzheimer’s should be targeted for treatment. Any or all of these factors combined may be contributing to the failure of Alzheimer’s trials.

A Promising Treatment: Aducanumab

Clinical Trial Findings 

Despite many failed anti-amyloid trials, there is one anti-amyloid drug that offers some promise for reducing the clinical decline of Alzheimer’s disease. Aducanumab, a human monoclonal antibody that selectively targets aggregated amyloid-β (Aβ), while facing some initial stumbling blocks, has recently shown some positive results from two identical phase 3 trials (Figure 1). 

Figure 1. Timeline for Aducanumab
Timeline for Aducanumab

Key: AD – Alzheimer’s disease. 

Phase 1 trial results (n=165) showed that aducanumab reduced Aβ plaques in the brain (as measured by positron emission tomography [PET] imaging) and slowed cognitive decline in patients with prodromal or mild Alzheimer’s disease for those receiving the highest dose (10 mg/kg) over 1 year. The main safety concern was amyloid-related imaging abnormalities-edema (ARIA-E), which typically resolved within 4 to 12 weeks. 

Following these promising phase 1 results, Biogen began enrolling 3,200 early-stage Alzheimer’s disease patients for two identical phase 3 trials, ENGAGE and EMERGE, which started in August and September 2015, respectively. Then, in March 2019, these trials were discontinued based on results of a futility analysis conducted by an independent data monitoring committee that indicated the trials were unlikely to meet their primary endpoint upon completion. The futility analysis was based on those participants who had completed 18 months of follow-up by December 2018, which was approximately half of the total number enrolled. Biogen also decided at that time to discontinue all ongoing trials of aducanumab, including the EVOLVE phase 2 safety trial, the PRIME phase 1b long-term extension trial, and the planned phase 3 secondary prevention trial.

In a major turn of events, Biogen announced in October that they planned to submit a regulatory filing with the FDA in early 2020 after consulting with external advisors and the FDA. At that time, Biogen also released the results of an analysis based on more complete data from the ENGAGE and EMERGE trials showing positive clinical results for aducanumab. Between December 2018 (the data cutoff for the futility analysis) and March 2019 (the time of trial discontinuation), an additional 179 EMERGE and 139 ENGAGE participants completed 18 months of follow-up, bringing the total for the updated analysis of the larger dataset cohorts to 982 and 1,084 participants, respectively. Biogen stated that the results of the smaller, earlier futility analysis were inaccurate, and the new analysis of the larger dataset showed that aducanumab reduced clinical decline in patients who received sufficient exposure to high doses; however, no further details were provided by Biogen. 

Across pre-specified primary and secondary endpoints, the larger aducanumab dataset demonstrated a statistically significant reduction of clinical decline in EMERGE for patients exposed to a high dose. Table 1 shows the primary endpoint results (ie, CDR-SB) from EMERGE and ENGAGE. Although ENGAGE clinical endpoints were not significant for high-dose aducanumab patients, Biogen believes that data from a subset of these patients (ie, patients with ≥10 uninterrupted 10 mg/kg dosing intervals at steady-state) support the significant findings from EMERGE and the phase 1 trial (Figure 2).

Table 1. EMERGE and ENGAGE Primary Endpoint (CDR-SB) Results from the Larger Dataset and Total Population.

EMERGE and ENGAGE Primary Endpoint (CDR-SB) Results from the Larger Dataset and Total Population.

a Subjects who had the opportunity to complete Week 78 visit by March 20, 2019.
b All subjects’ data (data after March 20, 2019 are censored for efficacy analyses).
c Difference in change from baseline vs placebo at Week 78. Negative percentage means less decline in the treated arm. 
Note: Numbers of all randomized and dosed subjects that were included in the analysis. Placebo = 548 (intent to treat) and 313 (opportunity to complete).
Key: CDR-SB = Clinical Dementia Rating-Sum of Boxes.


Figure 2. EMERGE and ENGAGE Primary Endpoint (CDR-SB) and Amyloid PET Results for Patients With Sufficient Exposure to High-Dose (10 mg/kg) Aducanumab.
EMERGE and ENGAGE Primary Endpoint (CDR-SB) and Amyloid PET Results for Patients With Sufficient Exposure to High-Dose (10 mg/kg) Aducanumab

Key: ADU – aducanumab; CDR-SB – Clinical Dementia Rating-Sum of Boxes; PBO – placebo; PET – positron emission tomography. 

The safety and tolerability profile of aducanumab from EMERGE and ENGAGE was consistent with previous studies of aducanumab, with the most common adverse events being ARIA-E (35%) and headache (20%). The majority of patients who experienced ARIA-E (74%) did not have symptoms during the episode, and those who did had their episodes generally resolved within 4 to 16 weeks, typically without long-term clinical sequelae. 

Key Considerations on Interpretation of Clinical Trial Finding

Given the aforementioned challenges of clinical trials in Alzheimer’s disease, there are a number of possible explanations for why there were negative findings from the initial futility analysis from ENGAGE. Discrepancies in phase 3 results may be related to systematic differences between trials, differences in subgroup responses, endpoint selection, improper patient selection, dose- and time-dependent effects of aducanumab, among other reasons. Biogen has investigated these as possible explanations for the differences in ENGAGE and EMERGE results and suggested that differences are due to dose- and time-dependent effects of aducanumab. Specifically, Biogen suggests that subset analysis results from ENGAGE of patients who achieved sufficient exposure to high-dose aducanumab support the findings of EMERGE, and that differences between EMERGE and ENGAGE results can mostly be accounted for by greater exposure to high-dose aducanumab in EMERGE (Biogen 2019d). Biogen noted that patients included in the initial futility analysis had earlier enrollment dates and, due to protocol amendments that had been put in place in March 2017, had lower average exposure to aducanumab. Because the ENGAGE trial began enrollment 1 month prior to EMERGE, Biogen believes that the protocol amendment may have had differential effects due to the relative timing of enrollment. 

There have been several criticisms of the re-analysis and explanations of discrepant trial results. There are concerns that the updated results may be an example of post hoc fallacy, particularly given that the re-analyses were based on participants that were preferentially selected based on treatment compliance. Clinical trial results that are not part of pre-specified statistical analyses can be susceptible to bias. Given that these analyses were not pre-specified and part of multiple tests that were performed, these re-analysis results may not actually provide sufficient evidence of causation. The clinical significance of these updated results has also been questioned, as the absolute difference in CDR-SB score may not be clinically relevant. Additionally, one published commentary raised concerns regarding Biogen’s explanation of trial result differences and argued that without seeing the data, it is unlikely that EMERGE’s later start date of one month would convincingly explain the discrepant results. 

Implications for Health Technology Assessment (HTA)

The aducanumab data package is complex and complicated by termination due to a pre-specified futility analysis and timing of recruitment that impacted the distribution of patients with exposure to the high dose. In EMERGE, high-dose aducanumab reduced clinical decline as measured by primary and secondary endpoints. Biogen believes that these data combined with data from a subset of ENGAGE support the efficacy and an FDA filling. However, agencies like the FDA, EMA, and HTA have historically placed great weight on evidence from pre-specified endpoints of appropriately planned and rigorously conducted randomized control trials. These appraisers are generally cautiously skeptical around any findings from re-analyses or post hoc analyses. Further, agencies responsible for the reimbursement of technologies and achieving value for spend desire high certainty around the estimated benefit, which is generally limited with the bias of post hoc analyses. 

If Biogen can demonstrate that aducanumab is clinically effective, HTA bodies and payers will then need to decide if the treatment represents a good value. Aducanumab is likely to be expensive. In addition to PET scans to measure the amyloid levels in the patient’s brain, the risk of ARIA-E would require magnetic resonance imaging to monitor safety. Furthermore, it may be difficult for HTAs and payers to interpret the findings from the various analyses, as well as translate CDR-SB scores and measures of cognition and function into health utility estimates. 

Differences in results between EMERGE and ENGAGE are likely to result in high uncertainty in terms of cost-effectiveness, which may lead to unfavorable coverage decisions by some HTAs and payers, but this will also be heavily influenced by how the drug is priced. Although aducanumab may receive more favorable coverage from HTAs and payers such as Germany’s Federal Joint Committee/Institute for Quality and Efficiency in Health Care (G-BA/IQWiG), who base their assessment largely on clinical comparative effectiveness, aducanumab is likely to be costly to health systems and may not bring many immediate cost benefits. As aducanumab would presumably reduce or delay the level of care needed for Alzheimer’s patients, value assessments using a societal perspective or considering the overall public health impact may support a higher value-based price of aducanumab. 

Given the considerable uncertainty around efficacy and cost-effectiveness, aducanumab may make for an interesting case study for conditional coverage options, such as the National Institute for Health and Care Excellence’s (NICE) decisions of “only in research” or “approval with research.” These conditional coverage options may help to preclude approving a treatment that fails to meet expected positive net health effects or rejecting a treatment that would later, as a result of additional evidence, demonstrate a greater-than-expected net health effect. These exceptions would allow for continued research of aducanumab that would serve to clarify questions around efficacy by extending the research and development process for a drug that has shown promising, albeit inconsistent, results. 


If approved, aducanumab will become the first treatment to potentially reduce clinical decline in Alzheimer’s disease and demonstrate that reduction of Aβ plaques leads to better outcomes for patients with Alzheimer’s disease. The FDA will likely be the first regulatory agency to determine whether there is enough evidence to indicate that the benefits of aducanumab outweigh the risks, which will also have important implications for clinical pathways to target for future research. Although there have been many failed phase 3 clinical trials examining a number of these potential pathways, aducanumab’s success would breathe life back into the amyloid hypothesis. However, expectations should be tempered until the full analyses from the phase 3 aducanumab trials are available, as there is substantial uncertainty around the validity and clinical significance of these trial results, particularly given the prior negative findings from the futility analysis. If aducanumab is approved by regulatory agencies, HTA agencies and payers will have to navigate the complexity of the dataset and analyses in determining aducanumab’s value for coverage decisions. While many questions remain, the results from Biogen’s updated phase 3 analysis are encouraging, particularly for those patients, their families, and the medical community involved in the long, uphill battle to find an effective treatment for altering the course of Alzheimer’s disease. 


The article should be referenced as follows: 

Tan R, Loos A, Spackman E, Ruiz K. New evidence brings cautious optimism to Alzheimer’s disease treatment. HTA Quarterly. Fall 2020.

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