Monoclonal Antibodies May Cause Serious Harm for Patients with Alzheimer

Key Takeaways

Limited Clinical Benefit: Monoclonal antibodies targeting amyloid in Alzheimer patients offer only marginal benefits on cognitive and functional scales. These benefits fall below the minimal clinically important difference (MCID), indicating a lack of substantial clinical impact.
Significant Harms and Risks: The use of monoclonal antibodies for Alzheimer treatment is associated with serious risks, including cerebral edema, hemorrhage, and other adverse events. The potential harms may outweigh the perceived benefits, raising concerns about the overall safety of these treatments.
High Financial Costs: Monoclonal antibody treatments for Alzheimer come with a hefty price tag, ranging from $26,500 to $28,000 per year. The study questions the cost-effectiveness of these treatments, especially considering the limited clinical benefits and potential risks involved.
FDA Approval Based on Intermediate Markers: The article criticizes the FDA's approval process for monoclonal antibodies like lecanemab and aducanumab. These approvals were primarily based on improvements in medical imaging and biomarkers, without demonstrating substantial improvements in clinical outcomes. This approach is deemed inappropriate and may set a concerning precedent for drug approvals.
Meta-analysis Findings: The meta-analysis, involving data from 23,202 participants across 24 studies, revealed no quantitative evidence supporting significant improvement in cognitive or daily functional abilities beyond the MCID. The lack of robust clinical efficacy across multiple studies raises questions about the overall effectiveness of monoclonal antibodies for Alzheimer treatment.

New research suggests amyloid-reducing monoclonal antibodies in patients with Alzheimer dementia may cause more serious harm than benefits.^1,2

"We identified 19 reports of 24 studies of monoclonal antibodies targeting amyloid depositions in patients who largely had mild cognitive impairment and mild Alzheimer disease," investigators wrote. "In no case did the results of any single study, of all combined studies for an individual drug, or of all combined studies overall find a change in cognition or function that exceeded the MCID for that scale"

Although hailed as revolutionary by some, the new study, which was a systematic review and meta-analysis of multiple databases, suggests use provided "small" benefits on cognitive and functional scales far below the minimal clinically important difference, with some accompanied by clinically meaningful harms.

Not only do monoclonal antibodies for Alzheimer treatment have harmful risks including cerebral edema, hemorrhage, serious adverse events, and death, but the drugs are expensive, ranging from $26,500 – $28,000 per year. To compare the clinically meaningful benefits and harms of monoclonal antibodies for patients with Alzheimer, investigators, led by Mark H. Ebell, MD, MS, from the department of epidemiology and biostatistics at the University of Georgia in Athens, Georgia, conducted a meta-analysis to see if the harms outweighed the benefits.

Due to the theory of amyloid deposition being a part of the pathway in the development of Alzheimer, monoclonal antibodies were developed to reduce amyloid deposition. The Food & Drug Administration (FDA) approved the monoclonal antibodies after seeing improvements in medical imaging and biomarkers. However, the monoclonal antibodies failed to demonstrate significant improvement in reducing mortality and morbidity.

“The FDA has previously argued that decisions about drug approvals should be based on the MCID,” investigators wrote. “Lecanemab and aducanumab, however, were both approved based primarily on their effect on imaging and biomarkers, without any meaningful improvement in clinical outcomes. We feel that this is inappropriate and sets a bad precedent for the agency, not only for Alzheimer disease but also for other conditions wherein intermediate markers are easily measured but may not reliably predict clinical outcomes.”

The team leveraged data from 19 placebo-controlled randomized trials, obtained from PubMed, Cochrane CENTRAL databases, and 5 trial registries. The trials evaluated the effects of 8 different monoclonal antibodies, most lasting 18 to 19 months.

In total, the meta-analysis included 23,202 participants with either mild cognitive impairment or mild or moderate Alzheimer disease. Studies included in the meta-analysis evaluated the use of monoclonal antibodies at a dose consistent with the dosage used in Phase 3 or FDA-approved trials.

None of the observed studies demonstrated quantitative evidence to support monoclonal antibodies improving cognitive or daily functional abilities past the measure of minimal clinically important differences (MCID). MCID is the smallest change in a scale measuring cognition or function that is noticeable by a patient or a caregiver—and previous research decided the MCID should be a standardized difference of 0.5.

The investigators noted “small” improvements over placebo in the Alzheimer’s Disease Assessment Scale with a standardized mean difference of -0.07 (95% confidence interval [CI], -0.10 to -0.04), a Mini Mental State Examination score of 0.32 points; 95% CI, 0.13 to 0.50), Clinical Dementia Rating-Sum of Boxes scale score with a mean difference of -0.18 points (95% CI, -0.34 to -0.03), and a combined functional scores with a standardized mean difference of 0.09 (95% CI, 0.05 to 0.13).

The team noted statistically significant improvements in cognitive scores for solanezumab (standardized mean difference [SMD] = 0.07; 95% CI, -0.12 to -0.02), aducanumab (SMD = −0.11; 95% CI, −0.19 to −0.02), and lecanemab (SMD = −0.11; 95% CI, −0.19 to −0.02). Yet, for the FDA-approved antibodies, the mean difference for lecanemab did not exceed the MCID of 4 to 5 points (-1.8 points; 95% CI, -3.1 to – 0.52) for the Alzheimer’s Disease Assessment Scale.

Likewise, the mean difference for aducanumab did not exceed the MCID of 3.75 points (-0.98; 95% CI, -1.77 to -0.18). As for donanemab, still waiting for an FDA decision, had a mean difference of -1.41 points (95% CI, -2.11 to -0.70).

The Mini Mental State Examination also showed statistically significant mean differences for anti-amyloid antibodies and donanemab but not for solanezumab and aducanumab. Furthermore, none of the mean difference improvements exceeded the MCID. As for the Clinical Dementia Rating-Sum of Boxes scale, they found an improvement with lecanemab and donanemab—but the differences did not exceed the MCID.

Moreover, harms of amyloid-reducing monoclonal antibodies significantly increased risks of amyloid-related imaging abnormalities edema (relative risk [RR], 10.29) with 9 instances needed to harm, hemorrhage (RR, 1.74) with 13 instances needed to harm, and symptomatic edema (RR, 24.3) with 86 instances needed to harm.

The investigators observed no significant difference between treatment and control groups regarding all-cause mortality (RR, 1.15; 95% CI, 0.85 to 1.56). The drug bapineuzumab was linked to a significant increase in mortality (RR, 1.76; 95%, CI, 1.03 to 3.00). They found no significant difference between treatment and control groups in serious adverse events (RR, 1.02; 95% CI, 0.92 to 1.12).

Limitations the investigators highlighted were requiring participants to have positron emission tomography scanning and cerebrospinal fluid analyses for amyloid which are not done in typical clinical practice. Additionally, the studies did not report the percentage of participants receiving clinically meaningful differences in cognition or function from baseline. Moreover, studies had various inclusion criteria for the severity of the disease at baseline, which could have altered results.

“Alzheimer disease causes tremendous suffering in those afflicted, serious burdens to their families and caregivers, and enormous costs to the health care system,” investigators concluded. Each of these groups hope for effective tools to alleviate these burdens and to extend the time of meaningful life. But our meta-analysisshows that monoclonal antibodies targeting amyloid do not provide a clinically meaningful benefit, are associated with significant harms, and come at a high cost.”