Donanemab

Pictured: Abstract visualization of human brain/iStock, bawanch An FDA advisory committee on Monday unanimously voted for the approval of Eli Lilly’s anti-amyloid antibody donanemab, concluding that the benefits outweighed the risk for Alzheimer’s disease patients. At the same time, thousands of physicians, technologists, lab professionals, scientists and others attended the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2024 annual meeting in Toronto. Many of the speakers at SNMMI 2024 discussed donanemab and other anti-amyloid drugs and the urgent need to properly diagnose Alzheimer’s so these therapies will benefit patients. Despite other targets, amyloid beta and tau remain critical to the Alzheimer’s treatment landscape, with Eisai and Biogen’s Leqembi in July 2023 becoming the first ever anti-amyloid antibody and disease-altering treatment to be granted traditional FDA approval. Mary Ellen Koran, assistant professor of radiology in the Nuclear Medicine Section at the Mayo Clinic Arizona, emphasized in an SNMMI 2024 presentation that the imaging of brain pathologies is critical, particularly with the advent of anti-amyloid drugs. “It turns out that clinically diagnosing Alzheimer’s disease is very difficult,” Koran said at SNMMI 2024. “Even in specialized dementia centers, there’s a misdiagnosis of Alzheimer’s disease of over a quarter of patients. This is really important now that we have therapies that are actually targeting these pathologies.” Koran pointed to a study published in JAMA Neurology that found as many as one-third of patients clinically diagnosed with mild to moderate Alzheimer’s disease had minimal amyloid accumulation in their brains and risked having limited or no benefit from anti-amyloid treatment. “If you’re giving them a drug based on clinical diagnosis, you’re not giving these patients the right drug, and you’re not giving the right patients the drugs for the clinical trials,” she said. “This is where imaging becomes so important.” The Amyloid PET Quandary Positron emission tomography (PET) scans are a particularly critical component of the diagnosis and treatment of Alzheimer’s disease (AD). Last week, ahead of Monday’s advisory committee meeting, FDA staffers noted that donanemab treatment “demonstrated a statistically significant effect on change from baseline in brain amyloid plaque as measured by PET.” The agency also said that “the use of reduction of amyloid plaques on PET as a surrogate endpoint [is] reasonably likely to predict clinical benefit in patients with early symptomatic stages of AD.” The Alzheimer’s Drug Discovery Foundation (ADDF) has called Lilly’s TRAILBLAZER-ALZ 2 donanemab trial “emblematic of a new era” in research in which patients most likely to benefit from treatment are identified in the early stages of AD. “A unique aspect of this trial was the use of both the Amyvid and Tauvid PET scans to enroll patients with confirmed amyloid plaques, allowing investigators to confirm clearance or reduction of the pathology in later scans,” according to ADDF. At SNMMI 2024, Koran similarly commented that in Lilly’s TRAILBLAZER-ALZ 2 trial, “there were multiple amyloid PET images taken throughout the course of treatment,” which is “pretty cool” for the Alzheimer’s imaging community as such “quantification” of images “may actually inform therapy.” On the reimbursement side, an October 2023 decision by the Centers for Medicare and Medicaid Services (CMS) expanded coverage of PET imaging for diagnosing AD, potentially enabling greater access to new therapies for patients. “It makes us, as nuclear medicine physicians, very relevant to the treatment of these patients,” Koran said. However, Satoshi Minoshima, chair of the Department of Radiology and Imaging Sciences at the University of Utah, provided a sobering assessment at SNMMI 2024 of the challenges facing anti-amyloid therapy in the U.S., including limited scanner capacity, shortages of radiologists and cognitive disorder specialists and unreliable PET interpretation. “Resource limitation is a major challenge for the health system,” Minoshima said, noting it’s a problem that will only get worse as anti-amyloid antibodies like donanemab come to market. The new CMS policy to pay for amyloid PET scans beyond clinical trials is already having a big impact. Minoshima provided a chart with the latest nationwide data on patient volume in the U.S., which showed a 5- to 10-fold increase since October 2023. “Amyloid PET imaging use is really escalating nationally,” he warned. It seems the dam is about to break. Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

The analysts noted an area that donanemab may have an edge over Leqembi Eli Lilly looks set to make the long-deserted Alzheimer’s disease market a two-horse town—but that may be a good thing for Biogen and Eisai. William Blair analysts are tipping the anticipated approval of a rival anti-amyloid therapy to boost Leqembi by helping raise awareness, although they also see possible risks to the early frontrunner after Lilly waltzed through its advisory committee.  The FDA highlighted a range of issues for the experts to dig into ahead of the meeting but Lilly navigated the discussion successfully, emerging with unanimous votes in its favor on two key questions about the efficacy and risk-benefit profile of donanemab. Jefferies and William Blair analysts now expect Lilly to win approval with a broad label that allows physicians to prescribe the drug without assessing tau levels. “We see this as a net positive for Biogen’s/Eisai’s AD franchise, attempting to recover from the Aduhelm fallout, given donanemab provides further support that anti-amyloid antibodies provide an efficacious option for combating AD, despite concerns with ARIA,” the William Blair analysts said. “A rising tide lifts all boats, in our view, at this very early stage of anti-amyloid antibody commercialization.”  However, the analysts noted an area that donanemab may have an edge over Leqembi. Donanemab is currently given less frequently than Leqembi—every four weeks rather than every two weeks—and takes less time to administer. Patients can spend up to four hours receiving Leqembi, an hour infusion followed by a three-hour waiting period. Donanemab requires a 30-minute infusion and a 30-minute wait.  “We will see if these factors play into a competitive advantage in the long term, but our view currently is that the more anti-amyloid therapy approvals, the better the disease awareness/therapeutic education will be, and this should be a tailwind for the ongoing Leqembi launch,” the analysts said. Applications for monthly and subcutaneous dosing of Leqembi could eliminate Lilly’s administration advantages.  The analysts added that they believe Leqembi’s “first-to-market status will continue to reap benefits past a donanemab approval date.” Exactly when donanemab could win approval is unclear, with its original PDUFA date being tossed out after the FDA called an advisory committee.