A Promising Frontier in Alzheimer’s Treatment
June 30, 2023
By Seema Gupta, MD, MSPH
Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV
SYNOPSIS: In a multicenter, head-to-head trial, donanemab demonstrated superiority over aducanumab for early symptomatic Alzheimer’s disease patients.
SOURCE: Salloway S, Lee E, Papka M, et al. TRAILBLAZER-ALZ 4: Topline study results directly comparing donanemab to aducanumab on amyloid lowering in early, symptomatic Alzheimer’s disease (S26.009). Neurology. Apr 28, 2023.
Alzheimer’s disease (AD) is the most common type of dementia, with an estimated 6.7 million Americans age 65 years and older living with it. The number of people living with the disease doubles every five years beyond age 65 years. Without major medical breakthroughs to prevent, slow, or cure AD, this number is expected to double by 2060.1 AD affects family caregivers financially and places them at higher risk for emotional distress as well as negative mental and physical health outcomes. The total payments for healthcare, long-term care, and hospice services for patients age 65 years and older with dementia are estimated to be $345 billion in 2023.
Medical treatment can improve quality of life for patients living with AD and for their caregivers. In mild-to-moderate AD, treatment of symptoms with cholinesterase inhibitors (galantamine, rivastigmine, and donepezil) can assist patients (and caregivers) with comfort, dignity, and independence for a longer period. However, as AD progresses, the brain produces less acetylcholine and, over time, these agents eventually lose their effectiveness. In recent years, immunotherapies, such as lecanemab and aducanumab, have received FDA approval to treat early AD.2,3 The target for these drugs is the protein beta-amyloid, a hallmark of brain change in AD.
In the case of lecanemab, study results demonstrated slowed rates of cognitive decline among participants over the course of 18 months and a reduction in the levels of amyloid in the brain. For aducanumab, data showed a similar reduction in amyloid buildup in the brain but uncertainty remains in the drug’s ability to slow cognitive decline. However, at higher doses, aducanumab demonstrated a modest slowing of cognitive decline among patients with mild cognitive impairment or early-onset AD.4
More recently, Salloway et al reported the early results of the multicenter, head-to-head, Phase III TRAILBLAZER-ALZ 4 trial, which was conducted at 31 sites across the United States. The authors enrolled 140 patients age 50 years to 85 years with early and symptomatic AD. Subjects were randomized 1:1 to receive either donanemab or aducanumab at escalating doses for 18 months.
Researchers found that after six months of treatment, PET scan analyses revealed 37.9% of patients treated with donanemab achieved amyloid clearance compared with only 1.6% of those who received aducanumab (P < 0.001). Among patients with intermediate tau levels (n = 27 for donanemab and n = 28 for aducanumab), 38.5% of those who received donanemab achieved amyloid clearance compared with only 3.8% of patients in the aducanumab group (P = 0.008).
Researchers also found amyloid levels were 65.2% lower in donanemab patients, while levels in patients receiving aducanumab were lower only by 17% (P < 0.001). Among those with intermediate tau, amyloid levels decreased by 63.9% in patients who took donanemab and 25.4% with those who took aducanumab (P ≤ 0.001). Adverse events remained similar between groups, since 62% of donanemab-treated participants and 66.7% of aducanumab-treated participants reported an adverse event.
COMMENTARY
The results of TRAILBLAZER-ALZ 4 provide significant active comparator data on amyloid plaque clearance in patients living with early symptomatic AD. Will lowering amyloid plaque levels preserve cognitive function when treated early enough (or at least slow the decline)? Here, significantly more participants reached amyloid clearance and amyloid plaque reductions with donanemab vs. aducanumab at six months. What does this mean for those drugs already approved via accelerated pathway (lecanemab and aducanumab)?
FDA approval would make donanemab the third new AD treatment in two years. However, there are several factors in play, including cost, access, insurance coverage, and an adverse effect profile. Thus, it will be important to understand how this progress and this new frontier will translate to a higher standard of patient care for an important disease, both in the United States and around the world. The clinical possibilities for cure of dementia are within reach.
REFERENCES
1. [No authors listed]. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement 2023;19:1598-1695.
2. U.S. Food & Drug Administration. FDA grants accelerated approval for Alzheimer’s drug. June 7, 2021.
3. U.S. Food & Drug Administration. FDA grants accelerated approval for Alzheimer’s disease treatment. Jan. 6, 2023.
4. Beshir SA, Aadithsoorya AM, Parveen A, et al. Aducanumab therapy to treat Alzheimer’s disease: A narrative review. Int J Alzheimers Dis 2022;2022:9343514.
In a multicenter, head-to-head trial, donanemab demonstrated superiority over aducanumab for early symptomatic Alzheimer’s disease patients.
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