A new investigational drug joins the next generation of advanced therapies to curb Alzheimer’s disease. Pharmaceutical company Lilly has announced positive results for donanemab, a monoclonal antibody that targets amyloid protein, a precursor to degenerative disease. According to the company, the drug delays cognitive decline by 35% in patients with early-stage symptomatic disease in its latest clinical trial, which has not yet been published. As the full study is unknown and the results will be published in a peer-reviewed scientific journal, the experts consulted celebrate the “encouraging” results but urge caution: they do not cure or stabilize the disease, they only buy part of the progress Time irreversible treatment of this neurodegenerative disease. Donanemab naturally joins the therapeutic arsenal that in recent months has revolutionized the outlook for a disease that affects 50 million people around the world and for which there is currently no cure.
Alzheimer’s is a disease that develops silently for 15 to 20 years before showing symptoms. Appear late when the neurological damage has already been done and for the time being it is impossible to undo it. Not even previous attempts to halt its progression have been effective. The scientific community is increasingly focused on tackling the disease from its earliest stages, even before the first symptoms appear, and remains focused on the role of these amyloid protein plaques that accumulate in the brain and promote neurological damage. “The accumulation of amyloid is the earliest lesion, but these plaques are outside of the neurons. Over time, these neurons degenerate, producing the TAU protein that damages the brain synapse. [la conexión entre neuronas]“, explains Albert Lleó, Head of Neurology at the Hospital Sant Pau in Barcelona. From a biological point of view, the neurologist adds, people with more amyloid and more TAU are at a more advanced stage of the disease.
More information
Donanemab acts precisely against the amyloid protein: it binds to the amyloid plaques and marks them so that the immune system recognizes and eliminates them. In a phase III study involving more than 1,700 people between the ages of 60 and 85 with symptomatic Alzheimer’s disease, but at an early stage, the researchers found, Lilly explains in a statement, that this drug slows down cognitive and cognitive function functional decline.
This drug is expected to be the fourth in a group of anti-amyloid protein monoclonal antibodies that have emerged in recent years to help stop Alzheimer’s. After the controversial aducanumab, which hit the streets with much ado and further doubts about its effectiveness, others emerged, like gantenerumab, which didn’t get the results expected, and lecanemab, which slowed cognitive decline by 27%. Lilly’s drug follows the latter and confirms “the class effect,” in the words of Raquel Sánchez Valle, head of neurology at Hospital Clínic de Barcelona. “That monoclonal antibodies that can eliminate amyloid have a clinical effect. There isn’t enough data to say if one is better than the other. The design is different and that can push us to learn things,” he points out.
Unlike previous studies, this study stratified participants based on their TAU scores, a predictive biomarker of disease progression. “It appears that those with a less biologically advanced disease [menos niveles de TAU]they had a greater impact,” says Sánchez Valle.
Specifically, in a subgroup of more than 1,100 participants with brain amyloid deposits and mean TAU levels, the experimental drug reduced cognitive decline by 35% at 18 months. This means that compared to the group of patients receiving a placebo, those who received this monoclonal antibody retained their cognitive and functional abilities longer, parameters measured by scales that measure their ability to perform activities of the body everyday life, such as managing your finances, driving a car or chatting about current affairs. Forty-seven percent of patients receiving the drug had no clinical disease progression at one year, compared to 29 percent in the placebo arm.
In the other subgroup of patients, just over half a thousand, who had amyloid deposits and higher levels of TAU, the researchers already expected that the response would be worse, since the high presence of the TAU protein initially indicated a more advanced stage indicates the disease. The company does not disclose the drug’s effect in this specific group, but when both groups are taken together (those with moderate and high TAU levels), the reduction in cognitive decline in patients taking donanemab is slightly less, at 29% . . This number is more similar to the results of the other drug, lecanemab, which also showed favorable results a few months ago.
Lleó celebrates the dates provided by Lilly, although he assures that they were already “expected”. “We knew that donanemab was very effective in terms of reducing amyloid in the brain,” he says, emphasizing the value of stratifying participants based on TAU levels and response to the drug: this supports the idea that it administered in earlier stages of the disease will have more results. Pascual Sánchez, secretary of the Spanish Society of Neurology’s Study Group on Behavior and Dementia, agrees: “This tells us that we need to move towards early diagnosis. The sooner we give the drugs, the better.”
In practice, however, it remains to be seen what this slowdown in cognitive decline means and what clinical extent it will have. “That’s the big question: What does that mean for the patient,” admits the clinic’s neurologist. The idea is to keep the patient with autonomy or little dependence for as long as possible, stresses Sánchez Valle. Lleó also warns of caution when it comes to extrapolating the meaning of this data to the real life of the patient: “In degenerative diseases, one cannot speak of an improvement because it is a progressive disease. The disease progresses the same way, but more slowly than without treatment. For better understanding, lecanemab, which reduced cognitive deterioration by 27%, was said to delay the development of the disease by six months,” emphasizes the neurologist.
side effects
The neurologist from Sant Pau also points out that these drugs are not without risk. There are risks and you must consider them. In fact, the company has admitted that there are side effects—commonly known as amyloid-related magnetic resonance imaging abnormalities (ARIAs)—such as cerebral edema (swelling) and microbleeds: 24% of donanemab-treated patients had brain swelling, however, only 6% had symptoms,31 4% in the drug group and 13.6% in the placebo group also had microbleeds.
“Removing amyloid from the brain can cause brain inflammation, which is usually asymptomatic and transient, but people taking this need MRIs,” Lleó explains. Lilly has reported the deaths of three people, two of whom were directly attributed to these serious effects and a third died after suffering one of these images. “We are encouraged by the potential clinical benefits that donanemab may offer, although as with many effective treatments for debilitating and deadly diseases, there are associated risks that can be serious and life-threatening,” Mark Mintun, group vice president for research, donanemab , admitted in a statement by Lilly Neurosciences and Development.
Another reported effect of anti-amyloid drugs like lecanemab or donanemab is a reduction in brain size. A study published a few months ago in the journal Neurology described this accelerated reduction in brain volume in patients taking these drugs. The lead author claimed that these were “worrying” results and had unknown long-term consequences, but Lleó lowered the alarm: “This pseudoatrophy is attributed to a reduction in amyloid-associated inflammation. When the amyloid plaques go away, the brain reduces inflammation,” he explains.
The risk of possible serious side effects “concerns” professionals, admits Sánchez Valle: “The big handicap is that these are drugs that must be controlled and we must see if we can identify subjects more susceptible to these effects . ” Pascual Sánchez agrees that they need to be closely “monitored” and understand why these serious phenomena occur, but he insists that the introduction of these treatments “represents a turnaround,” and he’s optimistic: “It doesn’t mean “These drugs will be the solution for Alzheimer’s, but we’re on the right track. You have to be patient,” he concludes. Sánchez Valle reckons that these first-generation anti-amyloid treatments “may not be the definitive drugs because their effectiveness needs to be further refined, but they open the door for new generations that are more effective, safer and easier to administer, and that will change the disease landscape.”
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