Dr. Giuseppe Di Fede (Milan): “We are talking about a complex and multifactorial pathology: the mere reduction of amyloid plaques may not be enough”
There are neurological pathologies, among whichAlzheimer, to which the adjective “incurable”, unfortunately, has always remained associated, with the consequence that the most desired therapy – a regeneration of nervous tissue – ends up seeming like a dream that only characters like Marvel’s Doctor Strange seem to be able to realize. Without a doubt, the rekindling of the synapses is still a distant horizon; nevertheless, in recent years, researchers have developed therapies which, unlike the current standard of care, promise to affect the course of the disease. These are monoclonal antibodies, the challenge of which seems to have been won but, as we know, precisely “when you are close to the goal, the ground begins to collapse under your feet”. out of metaphor, we have tried to take stock of the pros and cons of these innovative therapeutic solutions for Alzheimer’s disease, summarizing its path to commercialization.
To do this, we turned to dr. Joseph DiFede, Head of the Dementia Genetics and Biochemistry Laboratory at the Besta Institute in Milan, with whom we recently studied the topic of frontotemporal dementia. In the case of Alzheimer’s disease, the hot topic is that of monoclonal antibodies, synthetic substances with the ability to specifically destroy cancer cells; in fact, the characteristic of the antibodies circulating in the body is that they are equipped with various types of receptors, i.e. those structures capable of recognizing the antigens on the surface of viruses and bacteria. Normally it is precisely the antigenic diversity that creates a broad spectrum of protection, but in the case of monoclonal antibodies the greater efficiency is linked to a unique relationship: a monoclonal antibody recognizes a specific receptor on the surface of the tumor cell and engages it in a targeted manner, destroying the cell itself. Monoclonal antibodies they are currently used against various types of tumors but have also been studied against certain neurodegenerative diseases.
“In Alzheimer’s, monoclonal antibodies are mostly directed against the protein beta-amyloid, one of the main protagonists of the pathogenesis of this form of dementia,” explains Dr. Faithful. “The two most discussed and known of this category of drugs are aducanumab and lecanemab, the clinical results of which have been widely discussed in recent months and which continue to be discussed following the approval received by the Food and Drug Administration ( US FDA).
ADUCANUMAB
On June 7, 2021, the FDA cleared the market for aducanumab, which thus became the first monoclonal antibody to be officially approved for the treatment of Alzheimer’s disease. “It is a molecule designed to reduce accumulations of beta-amyloid in the brains of people with Alzheimer’s dementia,” says Di Fede. In 2007, the Neurimmune company, which originally developed aducanumab, sold the rights to the drug to Biogen (which is currently developing it together with Eisai) and Phase I trials began in 2011, which was followed, in 2012, a Phase Ib study to evaluate its safety and tolerability. “Subsequently, Two Phase III clinical trials were designed, randomised, controlled with placebo and intended for patients with mild Alzheimer’s disease”, continues the Milanese neurologist. “It’s about the studies ENGAGE ed EMERGE, designed to compare the clinical efficacy of different doses of aducanumab in a population of approximately 3,000 patients. Unfortunately, the preliminary results of the two clinical trials appeared conflicting: in fact, based on the conclusions of EMERGE, aducanumab proved to be able to slow down the cognitive decline of patients, while the results produced in the ENGAGE study did not reach the primary endpoint”. However, in both studies the drug was shown to be able to decrease the accumulation of beta-amyloid protein in the brain. “Not negligible side effects have also emerged, as in approximately 40% of the patients treated, the magnetic resonance showed focal cerebral edema (ARIA-E, Amyloid-Related Imaging Abnormalities-Edema), i.e. small extravasations of fluids from the blood vessels to the surrounding brain tissue”, he specifies Faithful. “In a smaller fraction of patients the presence of ARIA-H (Amyloid-Related Imaging Abnormalities-Haemorrages) was found, i.e. cerebral micro-haemorrhages which, in some cases, proved to be serious. The mechanism by which these events occur is not sufficiently clear but it is hypothesized that the link between monoclonal antibodies and the beta-amyloid protein, located on the walls of the cerebral vessels, induces damage through an inflammatory or mechanical stimulation, removing the adherent plaques and opening micro-gaps through which fluids and blood pass”. The extent of these phenomena has contributed to making aducanumab a real case, given that the drug’s approval process in the United States has been bitterly contested: in fact, a panel of FDA experts did not find the monoclonal antibody’s clinical data convincingspeaking out against its marketing, but the US supreme regulatory body still granted the drug conditional approval. “We will have to wait for the definitive data to get an idea of the safety and real efficacy of aducanumab,” says Di Fede. “In fact, if the drug destroys the beta-amyloid plaques without halting the patient’s cognitive impairment, the treatment goal cannot be said to have been achieved”.
LECANEMAB
According to FDA leaders, the reduction of beta-amyloid protein deposits should reasonably lead to important benefits for patients with Alzheimer’s, and this has led many companies to focus on the development of drugs with this purpose. One of them is lecanemab, a monoclonal antibody capable of binding with high affinity to amyloid-beta protein aggregates; developed by BioArtic Neuroscience, the drug was licensed to Eisai who then established a collaboration with Biogen to oversee its development and commercialization. “The mechanism of action is the same as aducanumab but, in this case, in addition to the reduction of amyloid plaque, a clinical effect is observed, revealed by the analysis of the data obtained through special score scales used to evaluate the patient’s cognitive decline”, explains Di Fede. “The results of a Phase III clinical study published in the prestigious journal The New England Journal of Medicine show the drug’s efficacy in reducing both amyloid plaque and cognitive decline, with a better safety profile than aducanumab.” Once again, the Food and Drug Administration has expressed a favorable opinion, authorizing the use of the monoclonal antibody through accelerated approval, procedure usually intended for those drugs that are expected to provide a clinical benefit in the treatment of particularly serious medical conditions orphans of cure.
DONANEMAB
A third actor on the stage of monoclonal antibodies is donanemabdeveloped by the pharmaceutical multinational Eli Lilly: as in the case of lecanemab, this drug also seems to show the ability to break down beta-amyloid protein and a promising clinical effect of slowing the progression of the disease. Unfortunately it was the same pharmaceutical company, in a Press release a few weeks ago, underlining that the side effects observed with other monoclonals are also present in a significant number of patients treated with donanemab, effects which, therefore, must be carefully monitored. Currently, the small number of patients treated with Eli Lilly’s drug in the Phase III clinical trial TRAILBLAZER ALZ 2 it was not deemed sufficient by the FDA for accelerated approval of the drugeven if the clinical effects of the treatment appear to be decidedly encouraging.
REDUCTION OF AMYLOID PLAQUE ALONE MAY NOT BE SUFFICIENT
“Comprehensive and definitive data from Phase III trials will be needed to get a definitive answer on the safety and efficacy of these new drugs in the treatment of Alzheimer’s disease”, comments Di Fede, recalling the cases of other monoclonal antibodies, such as solanezumab (Eli Lilly) or gantenerumab (Roche), whose development process has suffered an abrupt halt following the failure to achieve the relative objectives to slowing the cognitive decline of patients. “From aducanumab onwards, the main difference compared to the older generations of monoclonal antibodies is linked to the epitope, i.e. the region of the beta-amyloid protein towards which the new drugs are directed. In fact, some molecules have produced a better result by targeting the oligomeric or fibrillar forms of beta-amyloid, from which the typical plaques that damage the brain of patients then derive”.
With the reduction of the amyloid plaque, doctors and researchers thought they had found the ‘crack’ in the defensive barrier of Alzheimer’s but, as it has been possible to ascertain, this therapeutic strategy is not always associated with a clinically significant effect. “Monoclonal antibodies such as aducanumab, lecanemab and donanemab act in the early stages of the disease; however, there is no evidence that they can be equally effective in the more advanced stages, when the damage produced by Alzheimer’s on the brain is extensive and irrecoverable”, adds Di Fede. “The pathogenetic mechanisms of this form of dementia are intricate and may not fully resolve with the destruction of beta-amyloid clusters. Although a reduction in cognitive impairment such as that reported in clinical trials can be considered an important success in the therapeutic history of the disease, the level of complexity of Alzheimer’s suggests that a direct approach against a single molecular target is not sufficient”.
In addition to investigating the real safety and efficacy of these new monoclonal antibodies, it will therefore be necessary to turn attention also to further therapeutic approacheslike the one based on oligonucleotidi antisenso, or treatment strategies that look not only at amyloid-beta protein but also at other factors involved in Alzheimer’s disease, such as the tau protein. “It is essential to have a clear vision of which targets to hit”, concludes Di Fede. “And since there are many players involved, it will probably be necessary to reflect on the possibility of using, and evaluating within specific clinical trials, new combined strategies, aimed not only against the beta-amyloid protein but also involving other molecular targets”.