The world population is aging and with this trend comes an increased risk of mild cognitive impairment and dementia, which is why the availability of safe and effective treatments to treat Alzheimer’s disease is an urgent challenge given the global change in the increase in hope of life. In this context, drugs are emerging, such as donanemab, developed by the company Lilly which, like the other two new medications to treat Alzheimer’s aducanumab (Aduhelm) and lecanemab (Leqembi)—the first fully FDA-approved that slows the course of the disease—is a monoclonal antibody that works by attacking the plaques that beta amyloid protein forms in the brain, which in turn cause the propagation of another protein called tau, and that are related to the development of this neurodegenerative disease.
A few months ago, the pharmaceutical company had already announced that donanemab effectively eliminated amyloid plaques in patients who were in the early stages of Alzheimer’s disease and had amyloid deposits in the brain and intermediate levels of tau, according to the results of a clinical trial that, however, had not yet been published in a scientific journal.
Now, Journal of the American Medical Association (JAMA) publishes phase 3 TRAILBLAZER-ALZ 2 trial results showing that treatment with donanemab slows cognitive decline associated with Alzheimer’s by 35% compared to placebo in patients with low to intermediate brain tau levels.
From Lilly they emphasize that this study included patients with a broader range of cognitive scores and amyloid levels than other recent trials of therapies directed against amyloid plaque, who were stratified according to their level of tau – a predictive biomarker of the progression of amyloid. disease – in a “low-medium tau” group (sometimes referred to as intermediate tau) and in a “high tau” group, which represents a more advanced pathological phase of the disease. They then assessed all participants over 18 months using scales that measure cognitive and functional decline, including the Alzheimer’s Disease Integrated Assessment Scale (iADRS) and the Clinical Dementia Rating Table (CDR- SB, for its acronym in English).
“He donanemab treatment –they affirm– significantly slowed deterioration by 35% according to the iADRS Scale and by 36% based on the CDR-SB. Among all study participants with early Alzheimer’s symptoms and the presence of amyloid plaque (n=1,736), donanemab treatment significantly slowed deterioration by 22% on the iADRS and 29% on the CDR-SB. In turn, the additional data presented at AAIC reinforce the fact that, regardless of the baseline clinical or pathological stage of the disease, treatment with donanemab generates benefits at a cognitive and functional level compared to placebo”.
Hopeful therapeutic option against Alzheimer’s… with risks
“The positive data from TRAILBLAZER-ALZ 2 brings hope to people with Alzheimer’s disease who urgently need new treatment options. This is the first phase 3 trial of a therapy that modifies the course of the disease that reproduces the positive clinical results obtained in a previous study”, stated Anne WhiteExecutive Vice President of Eli Lilly and Company and President of Lilly Neuroscience, who added: “If approved, we believe that donanemab may provide clinically significant benefits to people with this disease.”
For its part, the Alzheimer’s Association has declared in the mouth of Maria C. Carrillo, scientific director, that “with this more complete picture, there is additional and convincing scientific evidence that the complete elimination of beta amyloid from the brain is associated with a slowing significant increase in disease progression in people living with early Alzheimer’s.” “The results illustrate that starting treatment as early as possible allows for the possibility of a greater beneficial effect, but also that there is the potential to slow disease progression even when treatment is started later in disease progression.” Cheek. “These benefits are real and significant, giving people more time to participate in daily life, remain independent, and make future health care decisions.”
However, not all experts have been impressed with the promising results. Although donanemab was very effective in clearing brain amyloid, “the clinical effect was comparatively weak,” Jennifer Manly, of Columbia University Irving Medical Center, and Kacie Deters, of the University of California, Los Angeles, said in a paper. editorial accompanying the data in JAMA.
The drug, a treatment given once a month intravenously, however, has also caused Adverse effects, such as transient inflammation in one or several areas of the brain, or microhemorrhages, in both cases detected by magnetic resonance imaging and which can be serious, and even fatal in certain cases. Donanemab also decreased whole brain volume – as also occurs with Lecanemab – and increased ventricular volume. Therefore, these risks must be taken into account and follow-up and monitoring with magnetic resonance imaging must be carried out in order to intervene if necessary. Serious infusion-related adverse reactions and anaphylaxis also occurred.
“Disease progression slowed between 4.4 and 7.5 months over 18 months. The drug appears to have significant benefit, at least for some patients.”
Liz Coulthard, Associate Professor of Dementia Neurology at the University of Bristol (United Kingdom) considers that “The results are encouraging and mean that in one or two years we will be able to offer patients a series of treatments that slow the progression of the disease Alzheimer’s. Some patients did not significantly worsen during the trial and, on average, the disease progression slowed between 4.4 and 7.5 months over 18 months. The drug seems to have a significant benefit, at least, for some patients”, according to what he declared to Science Media Center Spain.
Although he points out: “We still do not know if this benefit would continue after 18 months. There were significant side effects and patients will have to be aware of the risks of treatment so that they can choose whether to take these drugs or not”, and stresses that “adopting this sophisticated treatment implies changes and requires enormous resources. We need to transform our access to brain scans and infusion rooms and train qualified staff to administer these treatments.”
Ivan Koychev, principal clinical investigator and neuropsychiatrist at the Dementia Platform UK and the University of Oxford (United Kingdom), explained in statements to the same medium that “The study stands out for the additional evidence that therapy in the earliest phases of the disease (that is, when there are still low levels of tau protein accumulation in the brain) brings the greatest benefits.” And he concludes that: “The next stage is to find out what the long-term results of those who have followed the therapy are: we still do not know when patients would stop treatment in the real world. This will be of enormous importance when it comes to economically justifying the availability of this type of drug in the NHS. [sistema nacional de salud de Reino Unido]”.