Crenezumab

Removing amyloid beta plaques in the brain has been a leading treatment approach in Alzheimer's disease for many years, but it's failing to move the needle even after many attempts, a group of researchers contends. Top drugmakers have spent more than a decade investigating and advancing anti-amyloid Alzheimer's medicines in clinical studies, generating enough evidence to support FDA approvals for three of them so far. But a new analysis throws more cold water on the treatment approach after years of doubts—and some successes.Medicines in this class, which include Biogen and Eisai's Leqembi and Eli Lilly's Kisunla, "likely have no clinically meaningful positive effects," according to a press release from the nonprofit health research organization Cochrane. Further, the meds likely increase the risk of brain swelling, the group's review found.To reach this conclusion, the team compiled results from 17 studies assessing seven different amyloid‐beta‐targeting monoclonal antibodies, including the failed Aduhelm, Leqembi, Kisunla and several medicines that failed to reach the market. The studies, which all used placebo control cohorts, altogether enrolled more than 20,000 people.Overall, the results showed the drugs "probably result in little to no difference" on measures of cognitive function and functional ability, the team said. On dementia severity, the drugs "may result in little to no difference," according to the assessment."The effect of amyloid‐beta‐targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease is trivial, while on functional ability, it is small at best," the researchers concluded."Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease," the team added. "Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action."Besides Aduhelm, Leqembi and Kisunla, the Cochrane team looked at the clinical track record for bapineuzumab, crenezumab, gantenerumab and solanezumab. Each of those drugs saw high-profile trial setbacks over the years.It's important to note that while the group has had its share of clinical blemishes, Leqembi did show a statistically significant reduction in clinical decline in a placebo-controlled trial, enabling the FDA to convert its initial FDA nod into a full approval. Likewise, Kisunla boasts a full approval and proved its worth by demonstrating a statistically significant reduction in clinical decline in its own placebo-controlled study.A spokesperson for Eli Lilly said the review is "built on an inherently flawed methodology.""It pools data from across multiple amyloid-targeting therapies as a class, including molecules that did not achieve their clinical trial endpoints and were never granted regulatory approval," Lilly's spokesperson added. "Combining data on unsuccessful molecules with approved medicines artificially dilutes the observed benefit and produces class-level conclusions that do not reflect the evidence for any individual approved therapy."On the subject of safety, the amyloid-targeting drugs "probably result in a small increase in the occurrence of any ARIA E," the shorthand for amyloid-related imaging abnormalities-edema, or brain swelling or fluid that's visible on an MRI. The meds aren't associated with any significant difference in symptomatic ARIA E, the analysis found.As for ARIA H, or brain bleeding, three studies assessing the side effect showed divergent results, which prevented a pooled analysis, the team noted. Researchers have been studying amyloid beta plaques and their potential ramifications for patients with Alzheimer's disease for decades. Within biopharma, treating the disease by targeting these plaques has yielded several high-profile drug candidates—with most failing to make the grade in the clinic. In 2022, it was revealed that a vast amount of research in the field appeared to contain fabricated materials, adding to doubts about anti-amyloid treatments and calls for drugmakers to look elsewhere in the quest for future Alzheimer's drugs.

A new report trying to settle a decades-old debate about Alzheimer’s disease has reached a dramatic conclusion: Antibody drugs that target sticky amyloid beta proteins in the brain simply don’t work. The meta-analysis, which compiles data from more than 20,000 patients across 17 clinical trials, determined that treatment with amyloid antibodies resulted in “little to no difference” in cognitive function, dementia severity and functional ability. The authors concluded that future Alzheimer’s drugs “should focus on other mechanisms of action.” But the study is filled with limitations sure to send many neuroscientists who have devoted their lives to these drugs into a tizzy. It overlooks the strongest arguments about why so many older attempts have failed; it ignores recent technological breakthroughs in delivering these kinds of drugs into the brain more efficiently; and it skirts over bigger and longer clinical trials that are still ongoing but promise to provide the most conclusive evidence on amyloid drugs yet. “I don’t think this changes the overall view of these therapies,” Eric McDade, a neurologist who studies these drugs and others at the WashU Medicine Memory Diagnostic Center in St. Louis, told Endpoints News . When asked if the meta-analysis would move the needle on the broader debate about the amyloid hypothesis, he said he “highly doubts it.” The study , published in the Cochrane Database of Systematic Reviews on Wednesday night, quickly spurred numerous headlines proclaiming the amyloid drugs useless or suggesting that the study will further fuel the ongoing debate about whether the marginal benefits of the medicines outweigh their risks, which can include brain bleeding and swelling. But several researchers contacted by Endpoints News were quick to point out what they see as a major methodological flaw. Only two clinical trials included in the review centered on the two amyloid antibodies that are commercially available in the US: Leqembi, sold by Biogen and Eisai; and Kisunla, made by Eli Lilly. Twelve clinical trials in the meta-analysis focused on drugs that failed their pivotal trials, including Genentech’s crenezumab, Johnson & Johnson’s bapineuzumab, Lilly’s solanezumab and Roche’s gantenerumab. Another three studies focused on Aduhelm, the controversial Biogen drug that the FDA approved against the will of its scientific advisors because it failed one of its two pivotal studies. The drug was subsequently withdrawn from the market after abysmal sales. “It should be no surprise that if you average 15 studies for drugs that don’t work with two studies for drugs that do work, that the average result shows that, as a class, these drugs don’t work,” Andrew Budson, associate director of the Boston University Alzheimer’s Disease Research Center, told Endpoints. “I just don’t think that this review is relevant for people living with Alzheimer’s disease.” For decades, much of the Alzheimer’s field has centered on the problematic protein known as amyloid beta. Scientists now know that the protein begins accumulating in our brains a decade or two before the first signs of memory loss set in. By that point, amyloid has formed plaques in the brain that trigger a cascade of other problems, including toxic tangles of a protein called tau and rampant inflammation. At least, that’s the gist of what scientists who adhere to the amyloid hypothesis of Alzheimer’s believe is happening. It’s an interpretation backed by reams of laboratory data and tantalizing genetic clues. Yet despite the billions of dollars that drugmakers have spent trying to clear out amyloid, they’ve barely made a dent in the disease. The dispute over whether amyloid has led the field astray — or worse, hijacked and blocked out promising alternative theories — has been roiling for years. Neuroscientists who are sticking to their guns often note that the earliest studies of amyloid-targeting drugs were tested in people already in the throes of dementia. In retrospect, scientists say those treatments were too little too late. There’s a variety of other arguments for why earlier attempts to target amyloid have failed. Some studies were done in people who had memory loss but turned out to not have amyloid plaques in the brain. Today, many companies use imaging molecules to make sure the patients they enroll in their studies actually have brains full of the plaques they are trying to remove. The type of amyloid that the drug targets may be important too. Older drugs like Lilly’s solanezumab that targeted free-floating forms of the protein failed to show a benefit in clinical studies. The commercialized drugs targeting smaller clumps of the protein, like Leqembi, or specific forms of the plaques, like Kisunla, showed modest but statistically significant slowing of cognitive decline. An Eisai spokesperson told Endpoints that the Cochrane review was “scientifically deeply flawed by inappropriately combining ineffective antibodies and failed studies with effective, regulatory-approved anti-amyloid treatments.” A Lilly spokesperson echoed that sentiment and said that pooling failed drugs with approved ones “dilutes the observed benefit and produces class-level conclusions that do not reflect the evidence for any individual approved therapy.” But combining data from disparate drugs may have had an unintended effect: making the medicines look safer than they really are. The risks of brain bleeding and swelling have only become prominent with the FDA-approved medicines. The Cochrane review concluded that there was probably “little to no difference” in symptomatic brain bleeding and swelling, risks that have been at the heart of the debate about whether the modest benefits of the drugs are worth it. McDade said that pooling all these studies together “underestimates the risk and benefit” of the two commercialized medicines, which “have the most consistent clinical benefit, which was modest and has been recognized as modest.” The Cochrane review authors, based at the Institute of Neurological Sciences of Bologna in Italy, did not immediately respond to questions from Endpoints. Whether the amyloid hypothesis proves to be the right one, drugmakers are marching down that road as ardently as ever. The trials included in the Cochrane review focused on people with mild cognitive impairment or in the early stages of dementia. Eisai and Lilly believe that their drugs will work better when given even earlier. Both companies are conducting large and lengthy clinical trials in seemingly healthy people who have evidence of amyloid accumulation, but no outward signs of memory loss. They hope that treating these so-called asymptomatic patients will more dramatically slow the disease. Results could come in the next couple of years. Other companies, including Roche, are working on next-generation versions of amyloid antibodies designed to better cross the protective blood-brain barrier — something that the existing medicines do rather poorly. Early results from Roche’s drug suggest greater and faster amyloid plaque reduction with far lower rates of brain bleeding and swelling. Several big pharma companies, including AbbVie, Bristol Myers Squibb and Novartis, have begun their own work on similar brain-targeting amyloid antibodies. Dozens of smaller companies have jumped on the trend as well. Marc Diamond, founding director of the Center for Alzheimer’s and Neurodegenerative Diseases at UT Southwestern Medical Center, doesn’t think the Cochrane review’s conclusions have any bearing on these new kinds of studies that are rejuvenating the often-dreary field. And although it’s too soon to know whether they will find success where so many others have failed, he is hopeful. “Stay tuned,” he said. “It is likely they will have a bigger effect.” Endpoints is fielding the next Biopharma Sentiment Index (BPSI) — a concise, three-minute survey that distills thousands of industry views into a clear quarterly benchmark. This year is pivotal for biopharma, and we need your perspective on where things are going. Take the survey here.