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Meta-Analysis Questioning Benefit of Anti-Amyloid Alzheimer's Drugs Gets Critical Reception

3D illustration showing amyloid plaques in Alzheimer's disease

NEW YORK – A recent systematic review of beta-amyloid-targeting Alzheimer's drugs raised questions about the clinical meaningfulness of the treatments, but critics have found it difficult to glean definitive conclusions since the analysis considered a wide range of drugs, some that failed trials and other that didn't.

In the paper, published in the Annals of Family Medicine last month, study authors selected 19 publications presenting data from randomized-controlled trials comparing an anti-amyloid monoclonal antibody with placebo. Cumulatively, the studies included data from more than 23,000 patients who received one of eight anti-amyloid drugs. Researchers not only analyzed changes in cognitive and functional scales between treatment and placebo groups, but they also considered whether the changes met a measure of minimal clinically important difference (MCID) — in other words, would the improvement in points measured by these scales following anti-amyloid treatment be noticed by patients or their caregivers. 

The analysis suggested that while most studies reported statistically significant improvements in measurements from these cognitive and functional scales with anti-amyloid treatment compared to placebo, that may not make much perceptible difference in patients' everyday living.

"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," study authors wrote in the paper. "Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms."

In contrast, the study authors noted that the drugs carry an increased risk of amyloid-related imaging abnormalities, require patients to spend substantial time on treatment, and have high price tags. Eisai and Biogen's Leqembi (lecanemab), for example, has a list price of $26,500 a year and a recommended dose frequency of once every two weeks.

"It's important that patients are given all the information that they need to make an informed decision," said Mark Ebell, lead author of the paper and a professor of epidemiology and biostatistics in University of Georgia's College of Public Health. "I really wish these [treatments] worked better, but I don't think we should sell false hope."

The monoclonal antibodies in question are developed based on the amyloid hypothesis, which posits that the root cause of Alzheimer's is accumulation of beta-amyloid proteins in the brain that hinder communication between cells. Experts in the field have been at loggerheads for years over whether beta-amyloid clusters in the brain are the right target, and multiple drugs designed to employ that strategy have failed clinical trials.

The first anti-amyloid drug to achieve US Food and Drug Administration approval in 2021, Biogen and Eisai's Aduhelm (aducanumab), was met with skepticism after the agency went against a recommendation from its advisory committee, in which 10 of 11 experts advised against approving the drug due to inconclusive evidence that clearing amyloid would result in meaningful clinical benefits. In the wake of slow sales and limited reimbursement, Biogen last month said it would discontinue commercialization of Aduhelm and return global rights to Neurimmune, the drug's original developer.

However, for many in the biotech industry, last year seemed to mark a milestone for anti-amyloid drugs with the approval of Leqembi and Eli Lilly's announcement that it would seek traditional FDA approval for its drug donanemab. Many experts in the Alzheimer's space argue that this new generation of drugs is built on lessons learned from the previously failed candidates.

Leqembi and donanemab, like others in the anti-amyloid space, aim to slow the rate of cognitive deterioration for those with early symptomatic Alzheimer's disease; neither stop progression or restore function in this patient population. Leqembi, which originally garnered accelerated approval on the basis of its ability to clear beta-amyloid, later became the first anti-amyloid drug to earn traditional approval after the FDA decided that Leqembi's clinical benefits were confirmed in the CLARITY AD Phase III trial. Investigators in the trial evaluated patients' cognitive decline using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), an 18-point scale in which higher scores represent disease progression. In CLARITY AD, after 18 months on Leqembi, patients experienced an average increase of 1.21 points from baseline, while those on placebo averaged 1.66 points.

Determining whether that 0.45-point difference represented a clinically meaningful benefit was the key question the FDA put forth to its Peripheral and Central Nervous System Drugs Advisory Committee in June 2023. In a 6-0 vote, the panel unanimously agreed that the data submitted by Eisai and Biogen verified that Leqembi was benefiting Alzheimer's patients.

However, the authors of the Annals of Family Medicine paper remain unconvinced.

The paper included studies of not only Leqembi, Aduhelm, and donanemab but also gantenerumab, crenezumab, solanezumab, bapineuzumab, and ponezumab, five anti-amyloid drugs that failed clinical trials. To qualify for inclusion in the meta-analysis, studies had to test drugs at the same doses that the FDA approved, or the drug doses had to be evaluated in a Phase III trial, and investigators had to report at least one clinically relevant benefit or harm after a year or more.

Based on their analysis, the authors found that there were "small improvements" when comparing treatment groups to placebo groups according to various cognitive and functional scales used to measure Alzheimer's progression, such as the Alzheimer’s Disease Assessment Scale (ADAS), Mini Mental State Examination (MMSE), and CDR-SB. However, "none of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID," study authors wrote.

"In all cases, the benefit was not even close to a minimal clinically important difference," Ebell said. For example, across groups, treated patients had an average change in score from baseline that was just one-third of a point higher than for patients in control groups on the 30-point MMSE, a scale in which lower scores represent cognitive impairment. And on the CDR-SB scale, across studies, the difference between the average change in score for patients who received an anti-amyloid drug compared to those who didn't was just 0.18 points. 

Clifford Saper, a neurologist at Beth Israel Deaconess Medical Center and a professor of neurology and neuroscience at Harvard Medical School in Boston, doesn't think the paper has any implications for patient care. "I wouldn't put any weight on it," said Saper, who was not involved in the meta-analysis.

According to Saper, a meta-analysis isn't the appropriate way to evaluate the impact of these drugs since it isn't accounting for the differences in the design and mechanism of the different monoclonal antibodies, several of which represented early attempts at targeting beta-amyloid that drugmakers have already determined not to work. 

For example, Roche has shuttered many trials of gantenerumab and last month returned global rights to crenezumab to AC Immune. Lilly ended development of solanezumab last year. Pfizer stopped development of ponezumab in 2011. The earliest paper included in the systematic review, published in 2009, evaluated bapineuzumab, a collaboration between Elan, Pfizer, and Johnson & Johnson that ended in 2012. 

It doesn't make sense to analyze the three drugs that have been approved or are under review by the FDA alongside those that have been found to have little or no effect, Saper said, adding, "There's been a progression of the field." 

In an emailed statement, the Alzheimer's Association shared a similar sentiment. "The analysis includes early (first generation) monoclonal antibodies as well as more recent [or] more advanced (second generation) compounds," the statement reads. "This shows a lack of scientific sophistication, and an unfamiliarity with the Alzheimer's field and its science."

A Lilly spokesperson criticized the use of MCID thresholds to compare group-level changes over time. Those thresholds are designed to assess an individual patient's disease progression, the spokesperson said, pointing to a recent paper on interpreting clinical meaningfulness from an Alzheimer's Association work group. "The MCID threshold is not intended to evaluate whether the group-level differences shown in a clinical trial are meaningful," the spokesperson said.

Eisai, which is leading development efforts for Leqembi, stressed in an emailed statement that the results from the CLARITY AD trial had the vote of confidence from the FDA's advisory committee in terms of the drug's clinical meaningfulness and risk-benefit profile. "Importantly, patients value preservation of function and slowing of decline, and patient focus groups have indicated that personal meaningfulness should be considered alongside clinical meaningfulness when assessing treatments," an Eisai spokesperson said. A Biogen spokesperson pointed to Eisai's statement and declined further comment.

Despite his criticisms of the meta-analysis, Saper acknowledged that none of the currently available anti-amyloid drugs are a "magic bullet" and more research is needed. He'd like to see more data on long-term outcomes from Alzheimer's patients who have received newer drugs and investigations into whether early administration could prevent disease onset in presymptomatic Alzheimer's patients.

But "mixing up a bunch of drugs that work with a bunch of drugs that don't work, and then coming up with an average for all of them, is not … a valid way to approach this subject," he said.

While Ebell acknowledged that there "certainly were differences between specific drugs," he pointed out that even when homing in on the drugs with statistically significant findings in studies, the improvements were quite small. On the CDR-SB scale, for example, two of the eight drugs had statistically significant improvements: Leqembi, with 0.43 points, and donanemab, with 0.59 points. However, a clinically meaningful difference would need to be 1 or 2 points, according to the study authors.

While there's still more to learn about these monoclonal antibodies, Ebell said he hopes the findings from the Annals of Family Medicine paper will spur more informed discussions between physicians and patients. He worries that patients may be under the impression that these new drugs — the first in a class of disease-modifying medications for Alzheimer's — are "some sort of a miracle drug." 

"Patients should really understand what the limits are of [these agents] … and understand that there are also harms and burdens," such as side effects, time, and cost, he said. "I'm not saying that nobody should ever take [these drugs], but people who take [them] should be well informed on the limitations," Ebell said.