A “promising” drug, which “excites the experts” and would even offer… “hopes for a cure (sic)“. The publication, at the beginning of May, by the American laboratory Eli Lilly of a press release announcing the “effectiveness” of donanemab against Alzheimer’s disease sparked a wave of rave reviews in the media. And for good reason: according to the industrial, injections of its product “would reduce the cognitive decline of treated patients by 36%. Their ability to carry out their daily activities would also deteriorate less quickly than those of patients on placebo. After decades of failure, these results, in the same vein as those presented a few months ago by the Japanese firm Eisai with lecanemab, mark a historic turning point: “Alzheimer’s now appears to be a disease accessible to treatment”, rejoices Prof. Marie Sarazin, head of the unit Neurology of Memory and Language at Sainte-Anne Hospital in Paris.
This new generation of drugs, monoclonal antibodies, acts by eliminating the amyloid proteins which form the famous “senile plaques” in the brain which are characteristic of the disease. By “cleaning up” these toxic molecules, the hope is to prevent millions of people from developing this neurodegenerative pathology which affects memory and leads to a total loss of autonomy. However, despite the apparently spectacular figures put forward by the laboratories, most specialists show great caution. “The study is positive and, even if it is only a press release for the moment, I, as a scientist, welcome this breakthrough. But the doctor who I am is also more reserved, because the real benefit for the patients probably remains quite modest”, summarizes Dr Nicolas Villain, neurologist at the Pitié-Salpêtrière hospital (AP-HP), in Paris.
These products will not cure patients already in advanced stages of dementia. “When the disease progresses, it destroys the neurons, and we do not know, for the moment, how to regenerate them”, confirms Professor Philippe Amouyel, director general of the Alzheimer Foundation. It will therefore be necessary to treat the patients as soon as possible, at a time when they are still in a relatively preserved cognitive state, in order to hope to keep them there as long as possible. “It would already be a huge progress”, underlines the neurologist Marie Sarazin. But between the vagueness of the real effectiveness of these treatments and their sometimes very severe side effects, doctors, patients and their loved ones could quickly find themselves faced with complicated choices when these drugs arrive on the market – if they do. . In the United States, the Food and Drug Administration (FDA) has already issued a provisional authorization to the lecanemab of the Japanese Eisai, on which it must rule definitively in the coming weeks. However, it is difficult to say that the same will happen in Europe and France, as there are still many uncertainties.
“The absolute effect is not miraculous”
“A result given as a percentage does not mean much. It can even be misleading”, warns Professor Marie Sarazin, of Sainte-Anne Hospital. In fact, Eli Lilly indicates that patients on placebo saw their symptoms worsen by 1.9 points on average in eighteen months, against 36% less for treated patients. Or in absolute value… 0.68 points less. “On a scale of 18, we understand that the effect is not miraculous. It’s barely better than the Alzheimer’s drugs delisted in 2018 in France”, notes Dr Nicolas Villain. The big difference between these old purely symptomatic treatments and this new class of products? The possibility that by acting on a key parameter of the disease, the famous amyloid proteins, the benefit observed after eighteen months is amplified over time. “But, for the moment, we do not have enough hindsight, this has not been demonstrated”, recognizes Bruno Dubois, professor emeritus of neurology and former head of the Institute for Memory and Alzheimer’s Disease. at the Pitié-Salpêtrière.
In this slowly evolving pathology, the challenge is to know what the effect of the drugs will be beyond the eighteen months of the study. The scientists’ hope rests on the “amyloid cascade” hypothesis, according to which the accumulation of this protein in the brain triggers a series of deleterious processes involved in the disease. With in particular the modification of another protein inside neurons, the tau protein, which would also become toxic. By blocking this cascade with the drug, we would stop this process and the patients would no longer deteriorate, or much more slowly. “But we also know that dysfunctions of the tau protein can become autonomous. In this case, the disease would continue to evolve, even if there is no more amyloid. And the reality is that the current data do not allow to decide”, specifies Dr Nicolas Villain, from Pitié-Salpêtrière.
Treat patients even earlier?
The age of the patients included in the trial also questions. “These are people who started Alzheimer’s disease before the age of 70, when it often starts later, after 75 or 80 years old”, notes Professor Pierre Krolak-Salmon, neurologist and geriatrician, ex-head of service at the Hospices Civils de Lyon, on availability since the end of 2022 as medical director of the Orpea group. A major difference, according to this expert: “Older patients tend to also have other lesions, vascular in particular. In this case, we will be less likely to have a clinical benefit by targeting only amyloid”, he points out.
To obtain greater efficiency, some imagine using drug combinations in the future. “Molecules are being developed to block abnormalities in the tau protein, to modulate immunity, suspected of also playing a role in the disease, or to protect neurons. But this remains very preliminary”, notes Professor Philippe Amouyel, of the Alzheimer’s Foundation. Others plan to prescribe monoclonal antibodies at even earlier stages than today, in prevention, in people with amyloid lesions but showing no symptoms. “Perhaps we would then block the entry into the disease”, hopes Professor Bruno Dubois.
It will still be necessary to know how to identify these patients. This is the whole purpose of an ambitious project led by this scientist: he is developing a new research center within the Pitié-Salpêtrière hospital, specializing in the search for biomarkers and algorithms that could one day serve as screening tests. A complex question, since we still do not know the exact causes of the disease. “Amyloid lesions are a necessary but not sufficient condition: you can very well have plaques and never develop the pathology. Other factors must be at play, but we don’t know which ones”, continues Professor Dubois, who hopes to raise a corner of the veil thanks to his work.
Cerebral edema and haemorrhage
One thing is certain, however: these drugs are anything but harmless. For example, they would reduce the volume of the brain of patients – a phenomenon that worries scientists all the more because they are still struggling to explain it. Of the patients treated in Eli Lilly’s trial, 1.6% also had severe cerebral edema or hemorrhage, and three died. “These data are comparable with those of lecanemab (from Eisai), for which three deaths were also reported during the extension phase of the clinical trial”, underlines neurologist Nicolas Villain. Several explanations have been put forward. Adverse effects appear to be more common in patients also taking blood thinners, or in those carrying two copies of a genetic variant called “APOE4”, a known genetic risk factor for Alzheimer’s disease. Or when amyloid weakens the blood vessels of patients, which seems to be the case for half of them. So many situations where the drug will probably not be prescribed.
“We will have to be very careful in selecting patients, then in monitoring them,” insists the director of the Alzheimer Foundation, Philippe Amouyel. Their follow-up promises to be costly, with various examinations including MRIs at regular intervals to identify possible adverse effects. To this will be added the budget linked to the administration of treatments, by intravenous injections in the hospital, once or twice a month. Not to mention the very high price of the drugs themselves: in the United States, Eisai’s lecanemab is billed at $26,000 per year and per patient. “In France alone, 66,000 to 1 million patients could be affected. Taking into account all the costs, these products risk blowing up any health system”, worries Dr. Villain. Taking the American tariff, the sums at stake would represent at European level up to half of all drug expenditure in the various Member States, according to calculations presented at a recent scientific conference. Unsustainable.
“Today, we would have neither the human resources nor the infrastructure to administer these treatments to all patients”, confirms Professor Sarazin. To all these difficulties is added another, specific to donanemab: the need to perform an examination called “PET-tau” to select patients. Eli Lilly has in fact enrolled in his trial only patients who already have an abnormal amount of tau protein. However, the conditions for placing a drug on the market must normally follow those of the clinical trial. “The problem is that PET-tau are not available in Europe outside of research protocols,” recalls Nicolas Villain, from Pitié-Salpêtrière. As the American laboratory also has the license for the product used for PET-tau, there is no doubt that it will ask for its marketing in Europe at the same time as that of donanemab. But that will add to the bill even more…
If authorized, these drugs will therefore profoundly disrupt the organization of care. Without waiting, doctors are already preparing: “The Federation of Memory Centers has launched a working group. The basic principle is to recommend that, at least initially, any prescription decision be subject to a consultation meeting with several specialists”, announces Nicolas Villain. The evolution towards severe dementia taking an average of five to fifteen years, the patients concerned would still have several years of autonomy ahead of them, and the decision to expose them or not to the risks associated with the treatments promises to be delicate. Some patients degrade faster than others, caregivers would like to reserve the molecules for them. But, today, they don’t know how to identify them… Moreover, no one really knows either how long these products should be taken: for eighteen months, as in clinical trials? Longer ? for life ? Mystery. “The most likely will be that they are interrupted after the elimination of the plaques, even if it means resuming them if they reappear”, imagines Professor Bruno Dubois.
If the uncertainties remain numerous, if the risk-benefit ratio remains mediocre, this first success could have at least an immense interest: to push scientists and laboratories to seek other, even more effective treatments. It would already be a lot, in the face of this disease which has so far held science in check.
