- Many older adults would not be eligible for the Alzheimer’s treatment Leqembi, based on the inclusion and exclusion criteria used in the drug’s clinical trial.
- Physicians have some leeway in determining which patients should receive this monoclonal antibody, as long as basic criteria are met.
- Experts say patients should work with their doctor to decide whether Leqembi is appropriate for them.
Only a small fraction of older adults in the early stages of Alzheimer’s disease would be eligible for the monoclonal antibody treatment Leqembi if the criteria used in the clinical trial of this drug were followed, say Mayo Clinic researchers.
Leqembi, known by the drug name lecanemab, targets
These plaques may also be present in people with preclinical Alzheimer’s disease or mild cognitive impairment due to early Alzheimer’s disease, but are not seen in people with mild cognitive impairment due to other conditions.
Results from a large phase 3 clinical trial found that the drug, given as an IV infusion every two weeks, slowed cognitive decline in people with early forms of Alzheimer’s disease by about 27%, compared to those who received an inactive placebo.
In January 2023, the Food and Drug Administration granted accelerated approval of Leqembi, and converted it to full approval in July. The agency included a warning on the prescribing information about the potential risks of Leqembi, such as brain bleeding and swelling.
“For a treatment that is logistically intensive for patients and where there is the potential for severe side effects, in order to optimize care it is critical to understand which patients are most likely to benefit and least likely to be harmed,” said study author Dr. Vijay Ramanan, a clinical neurologist and assistant professor of neurology at Mayo Clinic in Rochester, Minnesota.
“The clinical trial criteria for lecanemab serve as important guideposts here, because these define the conditions where data on the efficacy and safety of treatment were drawn from,” he told Healthline.
The new study, published August 16 in Neurology, the medical journal of the American Academy of Neurology, included 237 people, ages 50 to 90.
All participants had mild cognitive impairment or mild dementia due to Alzheimer’s disease, with confirmed presence of beta-amyloid plaques — the patient population that the FDA approved the drug for.
Researchers looked at the eligibility criteria for the lecanemab clinical trial to see how many of their study participants would have been eligible for the trial.
The inclusion criteria for the trial required people to have a body mass index (BMI) between 17 and 35, and to have specific scores on thinking and memory tests. Researchers found that 47% of the 237 participants would meet these criteria.
The clinical trial also had exclusion criteria, which would make people ineligible to participate. This included cardiovascular disease, stroke, a history of cancer, or brain scans showing previous small brain bleeds or brain injuries due to not enough blood getting to the brain.
These exclusion criteria further narrowed the pool of participants eligible for the lecanemab trial to 8%, researchers found.
However, if all people with mild cognitive impairmentand increased brain amyloid burden by PET scanwere included — without additional cognitive tests — 17.4% of participants would have been eligible for the clinical trial.
Researchers found similar results for aducanumab (brand name Aduhelm), another monoclonal antibody treatment for Alzheimer’s disease. This drug received accelerated approval from the FDA in 2021 but has yet to receive full approval.
This new study highlights “that many individuals with symptomatic Alzheimer’s disease may not be ideal candidates for these treatments,” said Ramanan, “reinforcing the need to consider all appropriate avenues of care for individuals dealing with a devastating illness.”
Dr. S. Ahmad Sajjadi, a neurologist and associate professor of neurology at the UCI School of Medicine in Orange County, Calif., who was not involved in the new research, said physicians generally follow a drug’s FDA prescribing information when deciding which patients to prescribe a drug to.
The prescribing information for lecanemab closely matches the clinical trial’s inclusion and exclusion criteria, he said, but is “more permissive” in terms of patients’ cognitive status.
This allows “a discretionary approach, as determined by clinicians, when it comes to exclusion criteria,” he told Healthline.
Ramanan said as physicians gather more real-world data, what is considered appropriate clinical use of lecanemab may change.
“However, in the meantime, it will remain important for clinicians and patients to engage in shared decision-making about whether lecanemab is the right option for that individual,” he said.
“Those discussions will likely rely on a combination of clinical experience and judgment, patient goals and values, and what is both known and unknown at the present time,” he added.
The goal of clinical trials is to test treatments in a group of people who closely resemble patients who would show up in a clinic.
But trials are also designed to control as many variables as possible that can affect the outcome — such as other medical conditions, medication use, and sometimes age. People may also be excluded from a study if they can’t complete study requirements such as brain imaging or taking medication regularly.
As a result, “it’s a highly selected population that gets tested in phase 3 clinical trials,” said Dr. David Merrill, a geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center in Santa Monica, Calif., who was not involved in the study.
Previous studies have found that clinical trial participants tend to be healthier, younger, have higher education, and are less diverse in race and ethnicity, compared to the general population. So using a drug in different populations — such as less healthy or more diverse groups — may result in different safety or effectiveness outcomes.
Although clinical trial criteria can guide physicians, Sajjadi said Leqembi may still be appropriate for people who might not have been eligible for the trial, “as long as basic inclusion and exclusion criteria are met.”
Scientists will continue to monitor the benefits and risks of Leqembi in different groups. Some data will come from the patient registry required by the Centers for Medicare & Medicaid Services as part of its decision to cover Leqembi.
“This [registry] will allow for studies of less-represented groups,” said Sajjadi.
Merrill said one of the challenges of rolling out Leqembi is “proceeding in a way that’s safe and offers the chance of benefits to patients, but is also fair and not reckless.”
The drug is not a cure for Alzheimer’s disease. It also doesn’t stop the disease from getting worse; it modestly slows down cognitive decline in people with early stages of the disease.
In addition, Leqembi requires biweekly infusions, and carries a risk of brain bleeding and swelling, said Merrill. As a result, “it remains to be seen how widely these infusion treatments will be adopted,” he said.
He also suggests that removing amyloid plaques in the brain — which is how Leqembi is thought to work — may not be enough, because this may not address the complex underlying mechanisms of Alzheimer’s disease.
“Even if you clean up the plaques, if you haven’t addressed the root cause of what led to the plaques being produced in the first place, that could explain why people are not getting better [on Leqembi],” he said.
In spite of that, “these drugs may still have an important role,” he said. “But it may be later in the treatment process, after you’ve resolved whatever’s driving their dementia.”
Merrill agrees that more research needs to be done, not specifically on Leqembi, but looking at what is causing the deposition of amyloid plaques in the brain.
“This would be a different type of study,” he said, “not focusing on a silver bullet approach, but more like silver buckshot, where you’re looking to improve somebody’s overall health.”
Patient criteria for the clinical trial of Alzheimer’s treatment Leqembi excluded many older adults based on age and other medical conditions.
If these criteria were followed in the real world, a small percentage of older adults would be eligible for the drug.
However, doctors are able to prescribe the drug to a wider range of patients, as long as they meet basic inclusion and exclusion criteria.