Biogen Unveils New Aduhelm Data at AAIC 2021; Experts Issue Clinical Use Recommendations

At today’s Alzheimer’s Association International Conference (Alzheimer’s Association International Conference, AAIC-2021), Biogen and Eisai presented the latest data on their Alzheimer’s antibody therapy, Aduhelm (aducanumab). Meanwhile, multiple groups of experts have published their perspectives on the treatment strategies for this therapy in authoritative journals. In today’s article, we will compile this information and share it with our readers.

What information has Biogen updated?

In a poster presentation, researchers analyzed the relationship between aducanumab-induced reduction in cerebral amyloid-beta (Aβ) deposition, changes in downstream Alzheimer's disease (AD) pathological biomarkers, and the slowing of clinical cognitive decline.

In the PRIME, EMERGE, and ENGAGE clinical trials, population-level analysis demonstrated a positive correlation between the reduction in Aβ deposition detected by PET scans and the slowing of clinical decline measured by the CDR-SB across different dose groups in the respective trials (except for the high-dose group in the ENGAGE trial).

Furthermore, in the EMERGE clinical trial, a greater reduction in brain Aβ deposition was associated with greater reductions in tau protein and other neurodegeneration-related biomarkers in the cerebrospinal fluid (CSF), and with a slower rate of decline in clinical endpoints. However, these associations were not significant in the ENGAGE trial.

The third analysis found that, in the PRIME, EMERGE, and ENGAGE clinical trials, patients whose brain Aβ deposition levels were reduced below the threshold for amyloid negativity experienced a smaller decline in clinical endpoints.

The press release states that, taken together, these results are consistent with the proposed mechanism of action of aducanumab, supporting that the changes in AD pathophysiological biomarkers induced by aducanumab are associated with an attenuation of decline in clinical endpoints.

In other posters, further analyses of the EMERGE clinical trial demonstrated that high-dose aducanumab treatment produced consistent effects on prespecified endpoints assessing cognition, function, and behavior, respectively. The trial met its primary, secondary, and tertiary clinical endpoints. Across 13 patient subgroups stratified by six different factors, including ApoE ε4 status and baseline disease severity, aducanumab resulted in a dose-dependent reduction in Aβ deposition levels. Assessment of the primary adverse event associated with antibody therapy, amyloid-related imaging abnormalities (ARIA), revealed that 76% of patients treated with aducanumab who developed ARIA remained asymptomatic. Furthermore, the majority of ARIA cases were of mild or moderate radiographic severity and were transient.

How is this therapy recommended to be used?

Following the US FDA approval of aducanumab for the treatment of AD, physicians require guidance on the appropriate use of this novel therapeutic option. At the AAIC, a panel of six AD experts issued recommendations on the use of aducanumab. These recommendations were concurrently published in The Journal of Prevention of Alzheimer's Disease.

Recommendation 1: Which patients are eligible for treatment?

Since the pivotal clinical trials of aducanumab were conducted in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia, and these patients were confirmed via PET scans to have amyloid plaque deposition in the brain, the expert panel recommended that the use of aducanumab be restricted to a similar patient population in whom the efficacy and safety of this therapy have been studied.

Recommendation 2: Initial Dose and Maximum Dose

The expert panel recommends that the initial dose of aducanumab be 1 mg/kg, followed by gradual escalation to a target dose of 10 mg/kg. During dose titration, physicians should inquire about any ARIA-related symptoms following each administration.

▲Aducanumab Dose Titration Recommendations (Image source: Reference [4])

Recommendation 3: Potential Risks and Management

The most common adverse reaction to aducanumab therapy is ARIA. In the high-dose treatment group, the incidence of ARIA was 35.2%, compared with 2.7% in the placebo group. It is more common in APOE ε4 allele carriers. The expert panel recommends MRI monitoring prior to treatment initiation, during dose titration, and following infusion of the highest dose of aducanumab. If a patient develops symptoms suggestive of ARIA, such as headache, nausea/vomiting, or dizziness, an immediate MRI evaluation should be performed. Treatment should be suspended if ARIA causes clinical symptoms or if radiological severity is moderate or severe. Treatment should be permanently discontinued if ARIA results in severe clinical symptoms (e.g., seizures, stroke).

▲ Flowchart for Risk Assessment and Management of Aducanumab Treatment (Image source: Reference [4])

Recommendation 4: When to Discontinue Treatment

In addition to treatment discontinuation due to adverse effects, the expert panel also provided recommendations regarding discontinuation for other reasons. The experts noted that the timing and strategies for treatment discontinuation have not yet been formally studied. The decision to discontinue treatment may be influenced by various factors, including lack of clinical efficacy, inability to adhere to the treatment regimen, and concerns regarding ARIA.

It is worth noting that experts have pointed out that aducanumab has not been evaluated in patients with moderate or severe Alzheimer's disease (AD). Therefore, if an early-stage patient's disease progresses to moderate dementia following appropriate treatment with aducanumab, clinicians should carefully review the evidence regarding the benefits and risks of further treatment with the patient.

What do the experts think about the recommendations for use?

*The Journal of Prevention of Alzheimer's Disease* concurrently published commentaries from multiple expert panels on this recommendation for use.

Regarding treatment initiation, two experts from McGill University stated that the "recommendations for use" clearly define patient eligibility based on the characteristics of participants enrolled in phase 3 clinical trials. Additionally, the "recommendations for use" specifically address patients under 50 years of age with familial autosomal dominant AD and those with Down syndrome, noting that these populations require independent randomized controlled trials to determine the effective dosage and safety profile of aducanumab. The recommendation to exclude patients "based on stroke evidence" requires further clarification, as many symptomatic early-stage AD patients present with asymptomatic lacunar infarcts in non-strategic brain regions.

In a commentary, two experts from Amsterdam University Medical Centers (Amsterdam UMC) noted that it is not surprising that the "use recommendations" specify a real-world patient population for aducanumab that is identical to the participants in the EMERGE and ENGAGE clinical trials.

Importantly, although the Aduhelm label does not explicitly state it, the "Recommendations for Use" section clearly specifies that patients eligible for Aduhelm treatment must be amyloid-positive. This can be established using an approved amyloid imaging agent, as interpreted by an experienced imaging specialist, or alternatively, through abnormal CSF biomarker levels. The authors of the commentary emphasize that both CSF Aβ1-42 and p-tau181 must be abnormal to confirm a diagnosis of AD.

Regarding when to discontinue treatment, two experts from McGill University stated that the "use recommendations" have made some efforts to define when to stop treatment, including specifying instances where ARIA results in severe clinical symptoms, the therapeutic dose cannot be achieved, or clinical and brain imaging monitoring cannot be maintained, among others. However, the authors of the "use recommendations" did not explicitly state that treatment should be discontinued once patients progress to moderate dementia. Insurance companies may require such a criterion. In the forthcoming usage guidelines, moderate dementia may be defined as a CDR global score of 2, an MMSE score below 19 on at least two separate occasions, and a loss of essential independence in activities of daily living.

Two experts from Amsterdam University Medical Centers (Amsterdam UMC) stated that the "Recommendations for Use" provide important guidance for monitoring ARIA. It should be emphasized that among clinical trial participants, 75% of ARIA cases were asymptomatic. In real-world clinical practice, this proportion may be lower, as trial participants are specifically queried about adverse effects. Nevertheless, treating physicians should remain vigilant for adverse events. If ARIA occurs, treatment should be temporarily suspended or the dosage reduced in accordance with the criteria outlined in the "Recommendations for Use." In cases of severe clinical symptoms, corticosteroid therapy is typically highly effective.

Two experts from McGill University added that these guidelines were issued in the absence of published, peer-reviewed pivotal Phase 3 clinical trial papers. Therefore, these recommendations may need to be revised once all the data are made public.

Impact on Alzheimer's Disease Research, Development, and Care

“Recommendations for Use” states that all patients considering the use of aducanumab need to understand that its expected benefit is to slow the rate of cognitive and functional decline, and it does not improve the patient's current clinical condition.

*The Journal of Prevention of Alzheimer's Disease* concurrently published commentaries by multiple experts, exploring the impact of aducanumab's approval on Alzheimer's disease research, development, and care.

In terms of research and development, expert articles note that the approval of aducanumab will help shift public perception of AD. Previously, many believed that cognitive decline and dementia associated with aging were inevitable, which may have deterred patients and their families from seeking diagnosis and treatment. The authors hope that the attention generated by aducanumab’s approval will help educate the public, encourage more patients to seek treatment, and facilitate greater patient participation in clinical trials.

Another positive impact of Aducanumab's approval is the potential for increased investment in neurodegenerative disease research, as well as further development of diagnostic methods for AD.

However, experts are also concerned that in the short term, the approval of aducanumab may make ongoing observational AD studies and randomized clinical trials more difficult to conduct. As patients may seek aducanumab therapy, they might withdraw from clinical trials, and resources currently dedicated to clinical research will be diverted to support the clinical use of aducanumab.

Regarding Alzheimer's disease (AD) care, experts note that aducanumab represents only one component of AD treatment and care. Currently, the majority of AD patients require comprehensive care, yet there remains a severe shortage of professionals in this field. Aducanumab can only slow the decline of clinical symptoms in a subset of patients; it is not a curative therapy. Until innovative disease-modifying therapies become widely accessible to patients, public health strategies for AD will continue to play a critical role. These strategies include promoting prevention, early detection, and accurate diagnosis, comprehensive care, and support for caregivers.

Note: The original text has been abridged.

References:

[1] Biogen and Eisai Announce ADUHELM™ (aducanumab-avwa) Data Presentations at Alzheimer’s Association International Conference 2021. Retrieved July 27, 2021, from https://www.eisai.com/news/2021/news202162.html

[2] Biogen and Ionis report positive topline clinical data on investigational Alzheimer’s disease treatment at AAIC. Retrieved July 27, 2021, from https://investors.biogen.com/news-releases/news-release-details/biogen-and-ionis-report-positive-topline-clinical-data

[3] Gauthier and Rosa-Neto, (2021). The US Expert Panel on the Appropriate Use Recommendations of Aducanumab in Clinical Practice. The Journal of Prevention of Alzheimer's Disease, https://doi.org/10.14283/jpad.2021.44

[4] Cummings et al., (2021). Aducanumab: Appropriate Use Recommendations. The Journal of Prevention of Alzheimer's Disease, https://doi.org/10.14283/jpad.2021.41

[5] UNLV Alzheimer’s Researcher and Expert Panel Present First-Use Recommendations For Aducanumab. Retrieved July 27, 2021, from https://www.newswise.com/articles/unlv-alzheimer-s-researcher-and-expert-panel-present-first-use-recommendations-for-aducanumab

[6] Weiner et al., (2021). How Will Aducanumab Approval Impact AD Research? The Journal of Prevention of Alzheimer's Disease, https://doi.org/10.14283/jpad.2021.46

[7] Kallmyer et al., (2021). Impact of Aduhelm Approval on Care and Policy. The Journal of Prevention of Alzheimer's Disease, https://doi.org/10.14283/jpad.2021.42

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