From gene-silencing therapies to drugs disguised as Trojan horses: experts at the Alzheimer’s Association International Conference discuss future therapies to treat the disease.
What will Alzheimer’s treatment look like in five years? At 2024’s Alzheimer’s Association International Conference in Philadelphia, experts provided a sneak peek into the future of drug development. These new experimental approaches could complement therapies like Leqembi and Kisunla that clear beta-amyloid plaques from the brain, and bring us closer to a future in which people living with Alzheimer’s have multiple treatment options.
Targeting the Tau
Beta-amyloid isn’t the only toxic protein that builds up in the brains of people with Alzheimer’s; many researchers and drugmakers are zeroing in on tau tangles, another type of protein that wreaks havoc.
Although researchers have tested 15 tau-targeting antibodies, almost half have failed in trials. But Mark Mintun, senior vice president of neuroscience at Eli Lilly, remains optimistic about this approach. Some of the drugs, according to Mintun, didn’t stick to the right part of the tau protein, and as a result, the treatment didn’t stop tau from building up. The antibodies currently being tested in Phase 2 trials stick to a different part of the tau protein and help the brain’s immune system clear them out. The results of some of these anti-tau drugs are set to come out by the end of next year.
Another approach showing promise involves what Mintun calls “mRNA knockdown therapies” — also known as gene-silencing therapies. Genes typically provide a recipe, called mRNA, that tells cells how to make a specific protein. If more mRNA for a gene is floating around, the cells will make more of that protein. Gene silencers destroy the mRNA, reducing the number of tau proteins made down the line. Biogen’s gene silencing drug, BIIB080, is entering Phase 2 trials, with results expected by 2027.
Lilly is also developing gene-silencing drugs targeting tau. “We have really exciting data on the mRNA knockdown of tau and the potential for slowing the disease by decreasing tau,” Mintun said.
The future looks bright for prevention trials
Although scientists have conducted many clinical trials trying to prevent Alzheimer’s disease in people with genetic forms of Alzheimer’s or amyloid biomarkers, all the trials to date have failed.
Jessica Langbaum, senior director at the Alzheimer’s Prevention Initiative, discussed why she’s optimistic about the future of prevention trials. “There’s a relationship between the amount of amyloid you remove from the brain and cognitive impairment,” Langbaum explained. “[But] the drugs that failed in previous trials weren’t very good at removing beta-amyloid from the brain.” She is optimistic because the four ongoing prevention trials are testing Leqembi and Kisunla, which are much better at removing those amyloid plaques. One of the ongoing studies is testing a combination therapy of Leqembi and an experimental anti-tau antibody called E2814. The results of these studies are expected by 2027 and 2028.
Blood tests are also making these studies easier to run since they make it much faster to find people with evidence of amyloid plaques in the brain.
Breaching the blood-brain barrier
One of the significant challenges of treating brain diseases is getting the actual drug into the brain, due to a protective structure called the blood-brain barrier which prevents drugs in the blood from reaching the brain.
Geoffrey A. Kerchner, a vice president at Roche, spoke about the development of Trontinemab, an anti-amyloid antibody with a “brain shuttle” attached to it. It works like a Trojan horse, tricking the blood-brain barrier into letting the drug into the brain. Once inside, it sticks to the beta-amyloid and summons the immune system to clear plaques.
Early trials of the drug have been promising — five of eight participants in the study who received a high dose of the drug cleared all the amyloid in their brains after three infusions. Less than one in 20 participants developed brain swelling or brain bleeds in the early trial. Having such a low rate of these side effects is a big deal — they’re one of the major drawbacks of approved anti-amyloid drugs. The two approved anti-amyloid drugs, Leqembi and Kisunla, cause brain swelling or brain bleeds in 20 and 40 percent patients, respectively. Roche is extending the study to include more participants before moving to Phase 3 in the next few years.
Treating people with multiple health conditions
Most people with Alzheimer’s have a multitude of other health conditions or comorbidities like high blood pressure, diabetes, and stroke which affect the progression of the disease. “Around 54 percent of the patients with Alzheimer’s disease have five or more comorbidities,” Theresa Leon Colombo, a scientific vice president at Novo Nordisk, said.
As a result, many people with Alzheimer’s are also taking other medications to manage their health conditions. People with mild cognitive impairment and beta-amyloid in the brain — who are at high risk of transitioning to mild Alzheimer’s — take an average of three different medications to treat these health conditions. The cognitive impairment may also cause some patients to forget their medication, worsening their overall health. Many patients also have mixed forms of dementia, meaning that they have other types of protein plaques in addition to beta-amyloid and tau in the brain.
Future trials need to focus on effectively including and treating patients with multiple health conditions. Ultimately, Colombo thinks patients will receive treatments that treat not only Alzheimer’s but also their other health conditions.
“I think the future of Alzheimer’s disease is not going to be one pill or one treatment, it will need a cocktail of treatments,” she said.
