Researchers now have a first look at the phase III clinical trial data for a highly acclaimed experimental Alzheimer’s drug –. Although the data supports a moderate cognitive benefit, scientists are concerned about its safety.
The results, presented on 29 November at the Clinical Trials on Alzheimer’s Disease conference in San Francisco and simultaneously published in the New England Journal of Medicine, confirmed that the treatment, a monoclonal antibody called lecanemab, slowed cognitive decline by 27% relative to placebo in an 18-month study of nearly 1,800 participants. The antibody’s developers–pharmaceutical firm Eisai, based in Tokyo, and biotechnology firm Biogen, based in Cambridge, Massachusetts–announced these topline findings in September in a press release.
The disclosure comes amid media reports suggesting that lecanemab may have caused the deaths of two people involved in the trial. This adds to the ongoing debate about whether the modest benefits of the experimental drug are worth the associated safety risks. Eisai denied that lecanemab was involved in one of the deaths, but has yet to determine if it played a role in the second.
” “It’s quite complicated balancing act for risk and benefits,” says Rob Howard of University College London, a psychiatrist who specializes in dementia. He is concerned about how families and patients who are desperate to find Alzheimer’s treatment will weigh the options, if lecanemab gets approved by regulatory agencies.
“All the available safety information indicates that lecanemab therapy is not associated with an increased risk of death overall,” Eisai said in a 29 November statement.
If a link between lecanemab and deaths is found, it could pose a “real conundrum” to the US Food and Drug Administration (FDA). This could be because it has to decide how to rule on lecanemab. Caleb Alexander, an intern-medicine specialist and epidemiologist at Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland and an advisory committee member of the FDA, said that it could cause confusion for the FDA. In January, the FDA will decide whether to grant special authorization for the experimental drug.
Benefits and risks
Researchers were pleased to see the publication of the trial data for lecanemab. Some have previously criticized the rollout of another monoclonal antibody treatment for Alzheimer’s: aducanumab. Similar to lecanemab and aducanumab, aducanumab was developed to remove clumps a protein called Amyloid-b from the brain. Many researchers believe this protein is the root cause of Alzheimer’s. Biogen also developed aducanumab. The FDA approved it last year, but there was no evidence that it had any cognitive benefits.
Lecanemab, however, is the first drug to slow down mental decline in a clinical trial. Clarity AD was a clinical trial in which clinicians administered the treatment to more than a dozen people with early-stage Alzheimer’s. Half of the patients received intravenous lecanemab infusions biweekly, while the rest received placebo. Scientists assessed people’s cognition primarily with a metric called the Clinical Dementia Rating-Sum of Boxes (CDR-SB), which evaluates a person’s abilities in six areas, including memory and problem solving, using an 18-point scale.
After 18 months, participants receiving lecanemab scored, on average, 0. 45 points better on the CDR-SB than those receiving placebo. Other cognition tests were used in the study to confirm these results. The treatment group had a lower amyloid and other biomarkers.
However, some researchers are questioning whether this shift is noticeable enough to be noticed in a person. Howard states that a one-point difference in the CDR-SB score is sufficient to be considered clinically significant.
“It is a modest benefit,” said Brent Forester, director, Geriatric Psychiatry Research Program, McLean Hospital in Belmont (Massachusetts), who was involved in the clinical trial for lecanemab. Safety is his main concern. About 20% of people receiving lecanemab had brain-scan abnormalities that indicated swelling or bleeding–although less than 3% of those who received the antibody experienced symptoms related to these abnormalities.
This safety profile is superior to that of aducanumab. In phase III clinical trials, 40% of those who received the antibody showed brain swelling in scans. Forester is still concerned that lecanemab, if approved, would be given to people with relatively high functioning who are in the early stages Alzheimer’s. Their quality of life could be affected by complications.
During Clarity AD, 13 people taking lecanemab developed symptomatic brain bleeds–or strokes–whereas only 2 people in the placebo group did, according to the conference presentation. Howard states that this is only 1.4% of the treatment group. However, it is a serious risk profile.
Further exploration required
Both deaths were reported in the media during Clarity AD’s ‘open label extension’. This is a period when a trial has officially ended but participants who were being given placebo can still opt for the experimental treatment. Both were related to stroke.
In one case, reported by STAT News, a participant who used a prescribed anticoagulant, or ‘blood thinner’, for a heart condition, died after a heart attack and four mini-stroke-like events. The other individual, reported by Science, died from a brain bleed after she received an emergency stroke medicine. According to both outlets, scientists believe that lecanemab could cause brain damage by removing amyloid protein from the blood vessels. The medications could have also helped to cause bleeding.
Due to the tie with anticoagulants, it’s not easy to determine if lecanemab was involved in the deaths. Marwan Sabbagh, an Arizona-based neurologist at the Barrow Neurological Institute, presented data at the conference. He said that “these things are still being explored.” He said that although brain hemorhage rates are low with lecanemab it does increase with anticoagulants.
” I would honestly be in the camp of not prescribing Monoclonal Antibodies to People on Anticoagulation [Medications],” says Liana Apostolova. She is a neurologist at the Indiana University School of Medicine, Indianapolis and has consulted for Eisai as well as Biogen.
Alexander states that it is unclear if the deaths will impact the FDA’s decision to approve lecanemab. The FDA’s decision is scheduled for 6 January. Alexander says that the FDA will decide whether to grant the drug candidate an “accelerated approval” based on phase II clinical trial data that shows lecanemab removes amyloid-b. The approval would be subject to Eisai and Biogen performing follow-up studies to confirm clinical benefits, which Clarity AD should fulfil.
If lecanemab is approved by Forester, he says, “I would suppose that there will be recommendations to careful monitoring.”
This article is reproduced with permission and was first published on November 30 2022.