Hope for dementia patients: A new monoclonal antibody shows promise against early-stage Alzheimer’s disease. In a clinical phase 3 study, the drug lecanemab reduced the harmful amyloid plaques in dementia patients and slowed down mental decline by around 27 percent, as the researchers report. Also important: Severe side effects such as cerebral hemorrhage and edema occurred significantly less frequently than with two previously tested antibody preparations against Alzheimer’s.

There is currently no cure for Alzheimer’s dementia: the progressive breakdown of brain cells caused by misfolded amyloid and tau proteins cannot be stopped and can hardly be slowed down. Although many active ingredients have been successful in animal studies, they have mostly performed disappointingly in human tests. They could not slow down the dementia significantly or had side effects that were too strong.

So far, this has also applied to the latest hope in the fight against dementia: antibodies. These laboratory-made immune proteins are specially adapted to attach to and destroy the misfolded proteins typical of Alzheimer’s disease. In fact, antibody preparations such as aducanumab, donanemab or gantenerumab have shown initial positive effects on the amyloid plaques of Alzheimer’s patients in clinical studies.

The problem, however, is that although these antibodies reduced amyloid plaques in clinical studies, they often did not succeed in slowing down dementia. In addition, all antibody preparations have significant and sometimes serious side effects: They cause cerebral edema and microbleeds, which in extreme cases even lead to death. Because the benefits and risks are disproportionate, the European Medicines Agency (EMA) recently rejected the approval of the antibody preparation aducanumab.

But now there is new hope: A team led by Christopher van Dyck from the Yale School of Medicine in New Haven has developed another antibody against Alzheimer’s, which has now been successful in a phase 3 clinical trial. Lecanemab contains monoclonal antibodies that target amyloid beta protofibrils. These threadlike, misfolded proteins are thought to be the early precursors to the larger amyloid plaques.

For the study, 1,785 Alzheimer’s patients with mild dementia received an infusion of the lecanemab antibodies or a placebo every two weeks. Over a period of 18 months, the researchers repeatedly examined the density and amounts of amyloid deposits in the test subjects’ brains using positron emission tomography (PET). In addition, all patients underwent a variety of standardized tests of mental performance at baseline and periodically thereafter.

The result: over the course of the 18-month treatment, the patients treated with the antibody developed significantly fewer amyloid plaques in the brain than the control group. Their mental decline also slowed down by 0.45 points on the 18-point CDR-SB score. This corresponds to a slowdown in dementia by an average of 27 percent, and even by 37 percent in activities of daily living, as reported by van Dyck and his team.

“Of the three antibodies aducanumab, gantenerumab and lecanemab, the present study on lecanemab shows the clearest evidence of efficacy,” comments dementia researcher Stefan Teipel from the German Center for Neurodegenerative Diseases (DZNE), who was not involved in the study encouraging study.” The patient probably only notices a little of this effect in everyday life at first.

“However, you also have to consider a longer period of time: If the effect persists, the difference would diverge even further over time and become more relevant.” In fact, over the course of the 18-month study, it became apparent that the differences to the placebo group increased over time.

However, the side effects are also decisive for a possible approval. Similar to previous antibody preparations, excessive immune reactions also occurred with lecanemab immediately after the infusion, but these were mostly transient and not severe and transient. However, there have also been cases of cerebral edema and microbleeds with lecanemab. Their frequency was 21.3 percent, as the scientists report. However, most of them did not cause any symptoms and could only be detected by a brain scan.

Overall, lecanemab apparently causes less cerebral edema and microbleeding than the previously tested antibody preparations. “Overall, the incidence of such ARIA with lecanemab is low compared to other antibodies. This comparatively low risk has a favorable effect on the benefit-risk ratio of lecanemab,” comments neurologist Jörg Schulz from the University Hospital of RWTH Aachen University.

But what do these results mean for a possible approval of lecanemab as an Alzheimer’s drug? Typically, a Phase 3 trial is the last step before submitting an application. However, van Dyck and his team are cautious in this regard: They recommend that further, longer-term investigations be carried out first. “However, if I take this sentence literally, it would mean that we cannot yet apply for approval with this study,” comments Teipel.

In contrast, Schulz thinks it is quite possible that lecanemab will soon go through an approval process. “The data are so convincing and consistent and the reported side effects comparatively low that there can (hopefully) be no doubt about a positive decision,” says Schulz. Whether the research team sees this the same way and submits an application for approval or whether they are still waiting remains open for the time being.

Regardless of this, the new antibody preparation marks progress in this still young form of Alzheimer’s therapy, as Christian Haass from the Ludwig Maximilian University in Munich agrees: “Even if the term is perhaps used too frequently at the moment: These results mark a turning point.” Because they show that newer antibody therapies are getting closer to the goal of destroying the amyloid plaques and slowing down dementia.

The authors of the study and the commenting researchers see the main advance in the fact that lecanemab is not directed against the finished amyloid plaques, but already on their precursors, the protofibrils. These misfolded amyloid beta threads are considered to be particularly damaging to cells and probably also contribute to the spread of dementia in the brain.

“It is quite likely that early forms of Alzheimer’s plaques trigger the process of damage to the nerve cells and thus trigger Alzheimer’s disease,” explains the neurologist Walter Schulz-Schaeffer from the Saarland University Hospital in Homburg, who was not involved in the study. “The plaques, on the other hand, are an expression of the successful disposal process of the damaging early forms and should therefore be left alone. (New England Journal of Medicine, 2022; doi: 10.1056/NEJMoa2212948)

Quelle: New England Journal of Medicine, Science Media Center

This article was written by Nadja Podbregar

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The original of this article “Reduced by 27 percent: Novel drug against Alzheimer’s gives hope” comes from scinexx.