The Food and Drug Administration (FDA) has granted accelerated approval to aducanumab (Aduhelm) for the treatment of Alzheimer's disease. Aducanumab is the first new drug to treat Alzheimer's disease since 2003. Aducanumab is a human immunoglobulin gamma 1 monoclonal antibody directed at amyloid beta plaques, the accumulation of which is a defining pathophysiological feature of Alzheimer's disease. Accelerated approval is granted to drugs that treat serious conditions for which no other effective treatment exists. If the phase 4 clinical trials required to demonstrate aducanumab efficacy are unsuccessful, the FDA can remove the drug from the market.

Aducanumab's approval was controversial. The FDA's Advisory Panel for Peripheral and Central Nervous System Drugs, which met virtually November 6, 2020, did not recommend approval of the drug because of a lack of adequate clinical trial evidence demonstrating its effectiveness.1 Accelerated approval was not an option the panel was asked to consider. Although the FDA is not required to follow the advisory panel's advice, it generally does. The Alzheimer's Association, patients, and caregivers, however, strongly supported aducanumab and lobbied for the drug's approval during and after the advisory panel meeting.2 Nurses should be aware of the facts regarding this controversy so they can best assist patients and their families in making treatment decisions.

Clinical trial data. Two trials with essentially the same design were conducted to prove aducanumab's efficacy: trials 301 (1,647 patients) and 302 (1,638 patients). The trials were initiated in 2015, with a planned midpoint examination for futility in early 2019. Both were multicenter, randomized, double-blind, placebo-controlled parallel-group trials of high- or low-dose aducanumab versus placebo in patients with early symptomatic Alzheimer's disease who were positive for brain amyloid pathology, as assessed by positron emission tomography. Globally, 181 centers participated. The primary end point of both studies was a reduction in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.

During the planned midpoint examination for futility, the studies were stopped because neither had a positive effect, as determined by the study criteria. However, while the midpoint analysis was underway, some patients in trial 302 continued to receive the high aducanumab dose. When the data from this group were examined, the manufacturer, Biogen, determined that the drug had had a positive effect.1

After Biogen ended the clinical trials for futility, it sought assistance from the FDA to reevaluate the data from both studies.1 The FDA and Biogen concluded that the studies' early termination did not compromise the interpretation of their efficacy results and that the negative findings from trial 301 did not negate the positive effect seen in trial 302.1 The FDA and Biogen found that study 302's high-dose treatment effect had reached statistical significance, and they estimated a 22% relative reduction in the CDR-SB score with the high dose of aducanumab compared with placebo.

The FDA considered the findings of trial 302 as proof of aducanumab's effectiveness and supported its approval.1 However, this position was not accepted by any member of the advisory panel (12 members voted no and one voted uncertain). The advisory panel was split on whether aducanumab's ability to decrease amyloid beta plaques in the brain would likely improve the clinical outcome of Alzheimer's disease (seven voted yes and six voted that a change in outcome was uncertain). To read the full transcript of the November 6, 2020, advisory panel meeting, see http://www.fda.gov/media/145691/download.

Controversy over approval. Some critics think the FDA was too helpful to Biogen in reexamining the trial data and that the agency had decided on its action prior to the advisory panel meeting. Some members of the panel found the FDA's practice without scientific basis and so unusual that they published an opinion piece in the March 30 JAMA, where they concluded that "the post hoc analyses regarding aducanumab provided limited information useful in deciding the benefit of this new drug and these post hoc analyses should not be the basis for FDA approval."3

After the FDA announced it would grant aducanumab accelerated approval, three panel members resigned in protest. In public statements, they expressed their disapproval of the FDA's failure to listen to the panel's concerns regarding the lack of efficacy data and their feeling that the decision set a poor precedent regarding the need for sufficient data to demonstrate efficacy prior to drug approval, which could erode the public and health care providers' trust that drugs for sale in the United States were safe and effective.4

The FDA, in support of its decision, has provided more information than usual to explain its rationale for granting aducanumab accelerated approval. In a news release (http://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treat) and a memorandum to the advisory panel (http://www.fda.gov/media/149903/download), the agency emphasized that it followed normal procedures when faced with complex clinical trial data, in this case that one trial did not meet clinical outcomes and the other trial did. In deciding to grant accelerated approval to aducanumab, the FDA stated that since both trials found a reduction in amyloid beta plaques, there was reason to hope for improved clinical outcomes, although the agency admitted that this cause and effect had not yet been seen. The fact that aducanumab is the first drug to significantly reduce amyloid beta plaques, providing a new mechanism for treating Alzheimer's disease, was important in the FDA's decision-making. Patient comments were also a key factor.

Cost and other issues. Adding to the controversy over the approval of aducanumab is its proposed cost. Biogen determined the cost of treatment to be $56,000 per year. The company has been criticized for such a high price for a drug that hasn't been proven clinically effective.

The final aspect of the controversy concerned the labeling information describing the drug's intended patient population. Although the clinical trials of aducanumab were limited to those with early Alzheimer's disease, the drug's label originally stated it was "for the treatment of Alzheimer's disease." Then, less than a month after its approval, the FDA revised the drug's label to add that it was appropriate for use in those with "mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials."

Drug information. Aducanumab is administered as an intravenous infusion every four weeks. Its most common adverse effects are amyloid-related imaging abnormalities (ARIA), which often present as swelling and bleeding in the brain and are frequently asymptomatic. ARIA includes ARIA-edema (in 35% of patients treated with aducanumab compared with 3% given placebo), ARIA-H microhemorrhage, and ARIA-H superficial siderosis (a buildup of iron after bleeding into the brain). An excess of ARIA-H was noted in those who also had ARIA-edema and was present in 21% of patients treated with aducanumab compared with 1% of patients given placebo. Other common adverse effects include headaches and falls. Hypersensitivity reactions are also possible, as are diarrhea, confusion, delirium, altered mental status, and disorientation.

Because of the ARIA noted after aducanumab use, a magnetic resonance imaging (MRI) scan of the brain should be obtained prior to initiating treatment. Follow-up MRIs prior to the seventh infusion (the first 10 mg/kg dose) and 12th infusion (the sixth 10 mg/kg dose) are also required per the label's instructions. Nurses should confirm that these tests have been completed prior to administering aducanumab.

For the revised prescribing information for aducanumab, go to http://www.biogencdn.com/us/aduhelm-pi.pdf.

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