From the Journal of the American Medical Association.
The underlining is mine.
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Are New Alzheimer Drugs Better Than Older Drugs?Author Affiliations Article Information
JAMA Intern Med. Published online July 31, 2023. doi:10.1001/jamainternmed.2023.3061
In July 2023, the US Food and Drug Administration (FDA) provided full approval for an amyloid-β–directed antibody, lecanemab (Leqembi), for treating Alzheimer disease. The prescribing information states that treatment, which is administered as an intravenous infusion, should be initiated in patients with mild cognitive impairment or the mild dementia stage of the disease, which is the population in which the treatment was studied in clinical trials. Lecanemab is the second monoclonal antibody targeting β-amyloid protein to be approved; the first was aducanumab (Aduhelm) in 2021. The FDA approved lecanemab via its accelerated approval program in January 2023 based solely on the decline in β-amyloid as estimated on positron emission tomography scans in the brains of patients taking the drug compared with placebo. The agency granted full approval of lecanemab based on clinical efficacy data from a clinical trial with 1795 participants.1 Advocacy groups were pressuring the US Centers for Medicare & Medicaid Services to pay for the drug.
In the lecanemab trial reported by van Dyck et al,1 the primary outcome measure was the change from baseline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) scale, a commonly used scale of cognition and daily function (range, 0-18). The mean decline from baseline over 18 months was 1.21 points with lecanemab and 1.66 points with placebo, an absolute difference of 0.45 points (95% CI, −0.67 to −0.23), which was reported as a 27% slower decline with lecanemab than with placebo.1
Studies of the cholinesterase inhibitors, the first class of drugs approved for treating Alzheimer disease, showed similar effect sizes. In 1996, the FDA approved the commonly prescribed cholinesterase inhibitor, donepezil (Aricept). In the most recent Cochrane review (from 2018), the 2 longest randomized, placebo-controlled trials of donepezil (10 mg daily for 24 weeks) that used the CDR-SB as an end point2 reported mean differences of 0.67 and 0.5 points, favoring donepezil. Both studies included patients with mild and moderate dementia; 1 also included patients with more severe dementia, which is considered harder to treat.
The similarities in outcome measures between donepezil and β-amyloid protein antibodies for treating Alzheimer disease have been previously noted.3 Historical comparisons among studies are imperfect and can be misleading given factors such as the differences in inclusion criteria and duration of the studies. Also, many participants in the lecanemab trial1 had mild cognitive impairment; it may be more difficult to detect changes in outcome measures earlier during the course of disease. Ideally, clinical trials would directly compare new drugs with older drugs.
A statistically significant change on a test or scale does not mean that the change is clinically significant, such that patients or their families would see a benefit in their daily lives. On the CDR-SB scale, a minimal clinically meaningful difference is generally thought to be between 1.0 and 2.5 points annually. In a federally funded study in which participants were tested annually, the mean change in CDR-SB score considered to be clinically meaningful for those with early Alzheimer disease was 1.63 points per year.4 This difference is greater than the change found in any of the lecanemab or donepezil studies to date.
Stated another way, neither the lecanemab trial1 nor the donepezil trials4 found clinically significant beneficial effects of Alzheimer drugs. Only about half of trials evaluating drugs for dementia have reported the clinical significance of their results, and to our knowledge the field has not established a standardized method for estimating clinically relevant change.3,4 As Liu et al3 stated, the lack of consensus and guidance from the FDA means that “sponsors are motivated to power trials to detect statistical significance for only small and potentially inconsequential effects on clinical outcomes.”
What is a clinician to do? For cholinesterase inhibitors, the American Geriatric Society’s Choosing Wisely recommendation states, “Although some randomized control[led] trials suggest that cholinesterase inhibitors may improve cognitive testing results, it is unclear whether these changes are clinically meaningful… If the desired effects (including stabilization of cognition) are not perceived within 12 weeks or so, the inhibitors should be discontinued.”5 However, these drugs are also prescribed to patients with mild cognitive impairment, although studies have shown lack of benefit.6
In Alzheimer disease research, the cholinergic hypothesis and the amyloid hypothesis have had similar trajectories; each dominated the field for years and focused on drugs for a single biochemical/molecular target. Although the cholinesterase inhibitors targeted a neurochemical deficit and aimed for symptomatic relief, an increasing number of Alzheimer disease researchers coalesced around the amyloid hypothesis as the 1990s progressed. The belief was that β-amyloid protein underlay the pathology of the disease and that reducing the amount of the protein might slow or even stop disease progression. In the lecanemab study, such a slowing of progression was indicated by the diverging trajectories of decline between the drug treatment and placebo groups; over 18 months, the differences increased on the primary end point (CDR-SB) and some (although not all) of the other outcome measures.1
Although many researchers believe that β-amyloid is involved in the pathology of Alzheimer disease, as of June 2023, the protein has never been proven to be the cause. In clinical trials, drugs that targeted (and successfully reduced) β-amyloid failed to show any benefit.7 Like many diseases of aging, Alzheimer disease is a multifactorial disease: a mix of neurodegenerative, genetic, metabolic, and vascular pathologies, as well as environmental factors.7,8
Aducanumab and lecanemab are associated with brain edema and sometimes fatal brain hemorrhages (3 patients taking lecanemab in the open-label extension of the trial died of brain hemorrhages). The brain atrophies even with normal aging, and with dementia, even more so. A 2023 review and meta-analysis of 31 randomized clinical trials of drugs that target amyloid-β reported that the drugs appeared to accelerate ventricular enlargement and brain atrophy so that patients with mild cognitive impairment who were treated with anti–amyloid-β drugs were projected to have a material regression toward the brain volumes typical of Alzheimer dementia about 8 months earlier than if they were untreated.9 Over 18 months, those taking the dose of lecanemab approved by the FDA had an average of 28% greater loss of brain volume than those taking placebo.9
When administered at the recommended dosage of 10 mg/kg once every 2 weeks, the annual cost of lecanemab is about $26 500 a year.10 The cost of the drug does not include the costs of administering the medication; monitoring for potential adverse effects, such as with baseline and periodic brain magnetic resonance imagery; and treatments for adverse effects.
In 2021, about 6.2 million people in the US were estimated to be living with Alzheimer disease. A recent report estimated that lecanemab and associated ancillary services could add $2 to $5 billion annually to Medicare spending, with substantial out-of-pocket costs for beneficiaries lacking supplemental coverage.10
Focusing on drugs for Alzheimer disease with at best marginal efficacy distracts from the use of drugs with clear benefits for diabetes, hypertension, and depression. The treatment of these diseases is associated with a substantially decreased risk of developing Alzheimer disease and other dementias (as well as many other diseases).7 According to a 2020 report on preventable risk factors for dementia, interventions that target 12 modifiable risk factors could prevent or delay around 40% of cases, especially in lower-income and middle- income groups, for which the condition is more prevalent.7 Hearing loss is the most prevalent preventable risk factor. At present, drugs for Alzheimer disease have unproven clinical benefits and proven harms. Billions of dollars spent on hearing aids, smoking cessation, encouragement of healthy lifestyles, and treatment of hypertension, diabetes, and other modifiable risk factors may benefit patients more than spending on these drugs.
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