Leqembi, a monoclonal antibody, receives accelerated FDA approval: it reduces amyloid plaques in the brain, but raises questions about the important side effects. The expert: The clinical benefits are modest
The U.S. Food and Drug Administration (FDA) has granted accelerated approval for a new drug for Alzheimer’sil Lekmbi (lecanemab-irmb).
The drug, a monoclonal antibody, promises to slow the progression of Alzheimer’s disease if taken in the early stage, i.e. when the disease is still mildly manifested.
The data from the phase 3 study (anticipated in September with a press release from the two companies that developed it, Eisai e Biogenwhich had also made their shares soar) were highly anticipated and have recently been published in the New England Journal of Medicine by a group of scientists from Yale University.
The results of these studies, according to the FDA release, support the decision to grant accelerated approval. Eisai has announced that the list price for Leqembi will be $25,500 a year (just under €25,000), but an independent organization that assesses the value of medicines in the United States (the Institute for Clinical and Economic Review) has judged that the price is too high and does not meet typical cost-benefit thresholds.
However, according to the authors of the work, lecanemab was associated with less clinical decline in cognitive and functional abilities than placebo, but there were adverse effects and longer studies will be needed to determine the drug’s efficacy and safety. The package leaflet of the drug reports possible serious adverse effects such as cerebral edema and cerebral hemorrhage, in particular for those who use blood-thinning drugs or those with a particular genetic mutation.
The drug, Eisai said, will be launched at an annual cost of $26,500.
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I study
The drug, given by infusion every two weeks, has been tested for 18 months out of 1,795 adults between 50 and 90 years oldthose affected by a mild cognitive impairment: 900 volunteers were given lecanemab, the other half a placebo (substance without active ingredients).
The test data show that patients who received il lecanemab they then had a recorded cognitive decline 27% slower compared to patients treated with placebo. On a dementia rating scale, which rates people from 0 to 18 on memory, problem solving, and other tasks, patients treated with the drug scored by only 0.45 points less (minor development).
In detail, at the beginning of the study, both groups had a clinical dementia score of 3.2, consistent with early Alzheimer’s disease. After 18 months, the score increased by 1.21 points in the lecanemab group and by 1.66 in the placebo group. Cognitive decline occurred in both groups, but was slower among those taking lecanemab.
Enthusiasm and caution
the first time that in a clinical trial with a drug intended for Alzheimer’s is registered a slowing of cognitive decline and this is the reason for the accelerated approval by the FDA.
For authors, led by Christopher van Dyckdirector of the Yale Alzheimer’s Disease Research Center, this result could mean extra months to recognize spouses, children and grandchildrendelaying cognitive and functional decline, just as life-prolonging treatments do for those with terminal illnesses.
However among the scientific community there is a lot caution why this slight reduction and it is not actually clear whether it has daily implications that can really be noticed by patients and their families.
The result certainly statistically significant in favor of the drug but of of little clinical relevance and it might not mean much for the patients to move the score from a starting 3.2 to a 4.4 with the drug and a 4.8 with a placebo, also taking into account the huge number of patients involved, the fairly long period of the study , a year and a half, and the important side effects notes the professor Albert AlbanianHead of the Neurology Unit at the Humanitas Institute in Milan and Professor of Neurology at the University CAttolica of Milan.
The study is well done and encouraging – comments Alfredo Berardelli, professor of neurology at the La Sapienza University of Rome and president of the Italian Society of Neurology – and even if it does not offer a definitive datum and should be taken with the right prudence, the right stimulus needed to continue the research: advances in science are made in this way, in small steps.
The amyloid plaques
The drug targets theamyloid
, a protein that accumulates in the brain forming the typical plaques, hallmark of the degenerative disease. In a smaller number of patients (688) the load of amyloid plaques in the brain of the volunteers was measured thanks to imaging techniques and it was seen a significant reduction in amyloid among those treated with lecanemab.
At study entry, participants’ average amyloid level was 77.92 centiloids in the lecanemab group and 75.03 centiloids in the placebo group. After 18 months, the mean amyloid level dropped by 55.48 centiloids in the lecanemab group and rose by 3.64 centiloids in the placebo group. Demonstrating that with a therapy the accumulation of protein substances can be counteracted in theory is an important result. Previous studies had only shown that with monoclonal antibodies the formation of plaques was slowed down, underlines Alfredo Berardelli. He strikes that there was one important reduction of amyloid plaques – adds Alberto Albanese – but the therapy should have been a “sweeper”, and take away all the amyloid plaques which evidently continue to form, albeit more slowly and with clinical implications yet to be investigated.
The fear of adverse effects
Since from a clinical point of view the differences compared to placebo do not appear so significant, many experts are wondering whether it is worth offering treatments of this type, which are very expensive and with important adverse effects come cerebral edema (13% of patients versus 2% of placebo recipients) e brain hemorrhages (17% of patients compared to 9% of those taking the placebo).
Circa i6.9% of study participants in the lecanemab group discontinued the trial due to adverse events. The study did not report a different incidence of deaths: six among 898 patients treated with lecanemab and seven among 897 patients treated with placebo. The authors wrote that no deaths were considered related to lecanemab is that in no case did cerebral edema or bleeding occur.
However, in recent months, the death of three patients from edema and cerebral hemorrhage after 18 months of clinical trials has caused discussion (which is why they were not included in the recently published report). It is not known whether the two deceased patients had taken the drug or the placebo, however all the participants at the end of the 18 months of observation chose to take the drug and actively participate in the trial which will continue for at least another five years. One patient was a 65-year-old female who had undergone a stroke treated with anticoagulants, before dying of one cerebral hemorrhage. A neuropathologist who conducted an autopsy at the request of the woman’s husband told STAT that lecanemab likely weakened her blood vessels leaving them vulnerable. The second patient who died was an octogenarian who was taking a anticoagulants for a heart problem and shortly before his death he had had ischemia and had fallen several times.
In a press release, Eisai, citing the clinical histories of the two patients, concluded that the two deaths could not be linked to the intake of lecanemab, raising many perplexities on the part of the experts. In the real world, patients are likely to suffer from multiple diseases (as well as Alzheimer’s) and need to take blood thinners, so there are concerns about adverse effects. The question to be asked is whether it is worthwhile, making a careful analysis of costs and benefits, to offer this drug to patients. On this point the study makes no statements, the authors conclude that further investigations will be needed, but a study involving almost 1800 people that is already very large reflects Albanese
Biological progress and the difficulties on clinical benefits
As is often the case in neurodegenerative disease research, in the biological field we see important results, which however do not yet translate into clinical benefits: It is becoming more and more difficult – concludes Professor Albanese – a convert these discoveries into effective therapiesthat deliver tangible results for patients. A hiatus between the biological and clinical aspects for neurological diseases is increasingly emerging. In studies, such as happened in the latter on lacanemab, we often see that the biological mechanisms improve just as much, the “indicators of degeneration” are reduced, but then the patients do not improve clinically, and this is very frustrating. We are in this transitional stage of research, but not bad news. Getting here is an important step forward if we think that 5 years ago we had no results or very modest effects. This research represents a step that should not be underestimated.
January 6, 2023 (change January 6, 2023 | 21:55)
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