Alzheimer’s disease (AD) is devastating. There is no cure and existing treatments don’t slow or stop its progression. In June 2021, the FDA approved aducanumab (pronounced a-due-KAN-you-mab, brand name Aduhelm) for the treatment of AD. It’s the first new AD med since 2003 and is the only treatment that directly attacks a component of AD’s purported underlying pathology. The approval has brought hope to those dealing with the illness, but the FDA’s decision has also been controversial.

What are the indications? How does it work?
Initially, aducanumab was approved for all stages of AD, but the FDA updated its endorsement in July. Aducanumab is now recommended only for mild cognitive impairment (MCI) and mild AD, which is the population in which it was originally studied.

Aducanumab is an intravenous (IV) antibody infusion. It targets and helps to break down clumps of beta-amyloid in the brain. Beta-amyloid, along with pathological tau, are the two problem proteins found in AD. Unfortunately, the role of beta-amyloid in AD is unclear, and multiple trials of other drugs that do the same thing have already failed.

Does it work?
The efficacy of aducanumab was evaluated in two double-blind trials, totaling 3285 patients with either MCI or mild AD. Patients were randomized to receive low-dose (3 or 6 mg/kg) ­aducanumab, high-dose (10 mg/kg) aducanumab, or placebo IV every four weeks for 18 months. The primary endpoint was slowing of cognitive decline and functional impairment with aducanumab compared to placebo. This was evaluated by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. This scale measures memory; orientation; judgment and problem solving; and functioning in the community, at home, in hobbies, and in personal care. The manufacturer stopped both trials early after a preliminary analysis concluded that the drug was not more effective than placebo. However, in both studies, aducanumab significantly reduced beta-amyloid deposits in the brain (Aducanumab (Aduhelm) for Alzheimer’s Disease, Med Lett Drugs Ther 2021;63(1628):105–106).

Controversy erupted when the manufacturer later reanalyzed a portion of the data and found that in one trial, but not the other, the highest dose of aducanumab was associated with reduced clinical decline compared to placebo in the CDR-SB score and other tests of cognitive function. This occurred only in the last week, week 78. The reduction was statistically significant, though the actual difference was small and of uncertain real-life significance (Biogen, Aduhelm prescribing information, revised 6/2021).

Rather than conduct a new study with this subgroup, the company applied for FDA approval. Critics have argued that cherry-picking the data after the study was stopped early does not pass scientific rigor and is not statistically valid (Alexander GC et al, JAMA 2021;325(17):1717–1718).

Why was it approved?
Technically, aducanumab isn’t fully approved. It was accepted under the FDA’s accelerated approval pathway. This track is used for medications targeting serious or life-threatening illnesses that may provide therapeutic benefit over existing treatments. To qualify, a drug must show that it changes the biology of the disease in a way thought to likely benefit patients. If post-marketing data show that the drug provides clinical benefit, then the FDA will grant traditional approval for the drug. If the data are negative, the FDA could remove it from the market.

What are the side effects?
Aducanumab causes amyloid-related imaging abnormalities (ARIAs). These are visible on MRIs and fall into two categories: 1) brain swelling and 2) small brain bleeds. Because of this, people taking blood thinners or who are otherwise prone to bleeding should avoid taking aducanumab.

ARIAs can occur at any time during treatment and are fairly common. Thus, patients on aducanumab require frequent brain MRIs to monitor for ARIAs. At the treating dose, brain edema occurred in 35% of patients (vs 3% on placebo) and microhemorrhages in 21% (vs 1% on placebo). About one in four patients with ARIAs had clinical symptoms associated with them, including headache (13%), confusion (5%), dizziness/vertigo (4%), visual disturbance (2%), and nausea (2%). Most of these symptoms (88%) were self-resolving and only 0.3% fell in the serious range, although the long-term impact of ARIAs is unknown.

Other common adverse reactions were falls (15%) and diarrhea (9%), and according to the Aduhelm prescribing information one patient developed signs of an allergic reaction (angioedema and urticaria).

How is it given? How expensive is it?
Aducanumab is administered as an IV infusion given over one hour every four weeks. The medication is titrated gradually over six months toward a target dose of 10 mg/kg. Most patients require chronic treatment for dementia, although the studies only stretched out to 78 weeks. A brain MRI should be obtained before starting treatment and before the seventh and twelfth infusions to monitor for adverse events.

Aducanumab is priced at $56,000 annually for the drug alone, excluding costs from doctor visits, associated imaging, or administration at infusion centers. Several private insurers have already declined to cover it and several hospital systems won’t offer it, arguing that the cost/risk does not outweigh its tenuously proven benefit. Medicare and Medicaid are reviewing their coverage decisions.

TCPR Verdict: Aducanumab has unclear evidence of benefit, and it can cause brain swelling and bleeding. To date, just over a hundred patients have received it. There are significant barriers to prescribing it, including high cost, side effect monitoring, obtaining insurance coverage, and arranging for its administration in infusion centers. For now, aducanumab isn’t ready for prime time.