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MONDAY, July 17, 2023 -- Another experimental drug meant to slow the damage of Alzheimer’s appears poised to join a growing arsenal of new treatments for this memory-robbing disease. In research published online Monday in the Journal of the American Medical Association and presented simultaneously at the Alzheimer's Association International Conference in Amsterdam, the drug donanemab slowed memory and thinking declines in early symptomatic Alzheimer’s patients by more than one-third. About 47% of those taking the medication had no decline on a key measure of thinking over a year, compared to 29% of patients on a placebo. "If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as 6 months once their amyloid plaque is cleared," Anne White , executive vice president of Eli Lilly and president of Lilly Neuroscience, said in a company news release . "We must continue to remove any barriers in access to amyloid-targeting therapies and diagnostics in an already complex healthcare ecosystem for Alzheimer's disease ." The company added that it has already completed an application for traditional approval from the U.S. Food and Drug Administration. "People living with early, symptomatic Alzheimer's disease are still working, enjoying trips, sharing quality time with family — they want to feel like themselves, for longer," Dr. Mark Mintun , group vice president of neuroscience research & development at Lilly, said in the company news release. "The results of this study reinforce the importance of diagnosing and treating disease sooner than we do today." About 52% of the patients in the trial were able to stop taking the medication by one year because of its effectiveness. About 72% could do so by a year and a half, the company said. In the trial, a group with intermediate levels of a brain protein known as tau had a 35% slowing in cognitive and functional decline. In the intermediate group combined with a group with higher tau levels, slowing in decline was 22%. Despite the promising results, four editorials that were published alongside the trial results raised concerns about cost, access and safety risks. "The modest benefits would likely not be questioned by patients, clinicians or payers if amyloid antibodies were low-risk, inexpensive and simple to administer," wrote experts led by Dr. Eric Widera , from the University of California, San Francisco (UCSF). "However, they are none of these." Other editorials also offered caveats on the findings. "Donanemab was very effective at eliminating its target, cerebral amyloid, but the clinical effect was comparatively weak," wrote Jennifer Manly and Kacie Deters , from the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University and the University of California, Los Angeles, respectively. "By the end of the trial (76 weeks), amyloid plaques were cleared in 80% of the treatment group. Overall, cognition and daily function continued to decline in all participants, but treatment with donanemab delayed progression on the primary outcome... by about 4 months," they noted. "While the slowing of clinical decline seen in this trial represents an important start, and may be deemed clinically meaningful for some patients, development of more impactful and safer treatments is still needed," wrote Dr. Gil Rabinovici and Renaud La Joie , from UCSF's Memory and Aging Center. "Current trials are evaluating whether [amyloid]-targeting monoclonal antibodies may be more effective at the preclinical stage of AD [Alzheimer's disease], and ultimately it seems likely that a combination of drugs targeting additional molecular pathways involved in AD pathophysiology will be needed to more profoundly affect the trajectory of disease," they added. Another new Alzheimer's drug, Eisai and Biogen’s Leqembi, was fully approved earlier this month. But that drug carries similar risks, Widera's team noted. "The harms include infusion reactions and amyloid-related imaging abnormalities [ARIA]," his team wrote in the editorial. "Although ARIA may often be asymptomatic to mild in nature, they can lead to life-threatening events, including what was likely 3 treatment-related deaths in each of the donanemab and lecanemab studies." Apart from safety risks, there is the issue of cost and access, a fourth editorial pointed out. "Both the potential for high out-of-pocket costs and the fact that treatment with donanemab will require trips to a provider with infusion and advanced imaging capacity are likely to serve as unequally distributed barriers to access," wrote Meredith Rosenthal , from the department of health policy and management at the Harvard School of Public Health, in Boston. "Particular concern may be warranted for rural patients, those with lower incomes who do not qualify for Medicaid (a larger concern in states with less generous Medicaid programs, such as those that have not participated in the Affordable Care Act expansion) and those who lack reliable transportation," Rosenthal noted. "Moreover, Black patients, who are disproportionately diagnosed with [Alzheimer's disease], are 1.5 times more likely to be uninsured than white patients, which could make treatment with donanemab inaccessible given the overall cost of treatment," she added. Donanemab is given by infusion once monthly. Its price is expected to be $28,000 a year, Rosenthal noted, while Leqembi’s price is $26,500 annually. Sources Journal of the American Medical Association, July 17, 2023 Eli Lilly & Co, news release, July 17, 2023 Posted July 2023

With yet a third new Alzheimer's drug expected to be approved by the Food and Drug Administration (FDA), the field is beginning to show progress in the fight to slow the disease. With yet a third new Alzheimer's drug expected to be approved by the Food and Drug Administration (FDA), the field is beginning to show progress in the fight to slow the disease. But the drugs work best for those in the earliest stages of Alzheimer's, and other therapies will be needed to help those with advanced disease, according to Gil Rabinovici, MD, director of the UCSF Alzheimer's Disease Research Center. This is likely "just the opening chapter in a new era of molecular therapies for Alzheimer's disease and related neurodegenerative disorders," Rabinovici wrote in a July 17, 2023, JAMA editorial that is being published along with the results of the latest drug, donanemab. Rabinovici was not involved in the trial. Donanemab is a monoclonal antibody, like the two earlier Alzheimer's drugs, aducanumab (Aduhelm) and lecanemab (Leqembi). These drugs attack plaques in the brain that are made of a protein called amyloid. They disrupt cell function and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of Alzheimer's disease. The trial showed donanemab slowed cognitive decline by 35% compared with placebo in patients with low-to-intermediate levels of tau in the brain. These results are similar to those reported with Leqembi, which received FDA approval earlier this month. In the donanemab trial, patients also experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia. Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi. It reduced tau concentrations in the blood, but not in a key area of the brain. While these results are encouraging, Rabinovici said an in-depth analysis still is needed to understand how these findings affect patient outcomes. Not much benefit for those with more serious disease Patients with more advanced disease showed little to no benefit compared to those who received the placebo. Together with the drug's potentially serious side effects, this should push experts to "aim higher in developing more impactful and safer treatments," wrote Rabinovici, who is affiliated with the UCSF Memory and Aging Center, departments of Neurology, Radiology and Biomedical Imaging, as well as the Weill Institute for Neurosciences. Donanemab should be restricted to patients with low-to-intermediate levels of tau, which indicates mild disease. Other trials are evaluating how well monoclonal antibodies work in the earliest phase of the disease before symptoms appear. Like the two other new Alzheimer's drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities that may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three deaths. Risks were higher among patients with the APOE4 gene, which is related to an increased risk for Alzheimer's. For that reason, Rabinovici said, genetic testing should be recommended prior to monoclonal antibody treatment. While ARIA has generally been managed safely in clinical trials, Rabinovici urged caution as these drugs enter into real-world practice. He suggested limiting access to patients with normal pre-treatment MRIs, repeating MRIs at regular intervals and stopping or suspending treatment when ARIA occurs. Lack of racial and ethnic diversity was a major limitation of the trial. Just 8.6% of the 1,251 U. S. participants were non-white. Rabinovici said this raises ethical concerns about the "generalizability of results to populations at highest risk," noting studies that have shown higher rates of dementia in Black and Latino populations. Given the anticipated high cost of donanemab and high patient demand, Rabinovici said it might make sense to limit the treatment duration to the time needed to clear amyloid plaques from the brain, which is the approach pioneered in the trial. He said this could "greatly enhance the feasibility of treatment for patients, clinicians, insurers and health systems." Funding: Rabinovici is supported by NIH P30-AG062422, R35-AG072362, U01-AG057195, R56-AG075744 and Alzheimer's Association ZEN-21-848216. La Joie is supported by NIH P30-AG062422, K99AG065501, and Alzheimer's Association AARG-22-926899.