Less than two weeks after an Alzheimer's drug developed by Biogen and Eisai won full approval from the US Food and Drug Administration (FDA), Eli Lilly's monoclonal antibody donanemab has been shown to significantly slow the progression of the disease if treated early. Lecanemab, a monoclonal antibody sold under the name Leqembi, was granted “accelerated” approval this January for its ability to reduce amyloid beta protein plaques in the brain — a defining feature of Alzheimer's — and got full approval this month after later-stage results demonstrated 27% slowing of cognitive and functional decline over 18 months in comparison to a placebo. On Monday, data on a 1,736-person trial released by Eli Lilly showed 47% of patients who were started on donanemab in the earliest stages of the disease had no disease progression on some measures after a year, compared with 29% for placebo. While clinicians have welcomed the new therapies for a condition that has long been without a targeted drug, conversations have begun on the costs and benefits of bringing them to hospitals in India. “.The modest benefits would likely not be questioned by patients, clinicians, or payers if amyloid antibodies were low-risk, inexpensive, and simple to administer. However, they are none of these,” an editorial published alongside the phase III data on donanemab in the journal JAMA said. Real-world challenges Therapy with donanemab would require an early diagnosis, careful selection of patients, screening the eligible among them, and following up with expensive tests while watching for severe adverse events that may lead to death. Those being screened would have to be tested for the APOE4 gene, which has been associated with a higher risk of adverse events. The JAMA editorial pointed to the need for validated tools and expertise so that the disease may be suspected by primary care physicians and diagnosed through biomarkers in specialty dementia clinics. It said special and expensive PET scans, the availability of which are limited in clinical settings, would be needed to stage protein abnormality levels in the brain before and during the treatment. “The costs will be substantial, not just for the medication itself, but also for the biomarker and imaging workup,” the editorial said. Weighing the benefits The phase 3 study with 1,736 patients, 860 of whom received the infusion every four weeks till the amyloid clumps cleared, showed that donanemab slows down cognitive decline in early Alzheimer’s patients by 35.1% in 76 weeks. “The slower decline is measured by tests that look at memory and motor skills, which translate into small daily activities like talking to another person. The therapy slows the progression of the disease, but does not ultimately treat it,” Dr Pravat K Mandal, senior researcher at the National Brain Research Centre, Gurgaon, said. While the phase 3 trial results of lecanemab and donanemab cannot be compared directly — they used different scales for measuring cognitive decline — Monday's results suggest that donanemab may have slightly higher adverse events. Other than infusion-related reactions, the main adverse effect with drugs that clear out amyloid beta proteins is amyloid-related imaging abnormalities (ARIA) such as swelling or bleeding in the brain, most of which is asymptomatic. The study showed that 24% participants had ARIA involving brain swelling, and 19.7% involving brain bleeds. The study reported three treatment-related deaths. Donanemab might still be preferred for the reason that infusion needs to be given every four weeks instead of two weeks with lecanemab. The patients switched over to placebo after there was a certain level of protein clearance in the donanemab study. “This is a welcome difference for patients and payers, limiting infusion-related burdens as well as longer-term costs,” the JAMA editorial said. Dr Mandal said that given the huge costs, “it is inadvisable to administer the therapy for limited benefits; unless someone has the money and really wants to go for it”. He underlined that the therapy does not cure, which means “the benefits will be for a limited time”. Dr P K Sethi, neurologist at Sir Ganga Ram Hospital, said: “It is a very new drug; we still do not know all the adverse effects it may have. We have to see what happens when the drug is administered to a large number of people. Also, this is high-cost therapy, and we have to do a cost-benefit analysis.” Testing other modalities Despite the excitement about the trial data, there is a continuous search for something better. “Alzheimer’s has multiple modalities and we need various therapies to address them. While the amyloid beta protein therapy has been at the forefront, there is a need to investigate other targets as well,” Dr Mandal, whose team is investigating the impact of iron build-up and oxidative stress in the brain as a result of declining levels of an antioxidant called glutathione, said. Dr M V Padma Srivastava from the All India Institute of Medical Sciences had told the Indian Express earlier that most of the earlier research had been “off bull’s eye” — which was one of the reasons for the excitement about the new therapies. “But there are more drugs in the pipeline with several different targets,” Dr Srivastava had said. The JAMA editorial said: “Ultimately it seems likely that a combination of drugs targeting additional molecular pathways involved in Alzheimer’s disease pathophysiology will be needed to more profoundly affect the trajectory of disease.”
