Anand Kumar writes: “We are ill-served by overinterpreting statistical significance, heralding the false dawn and expediting the approval of ineffective, inadequately tested drugs under the umbrella of “cutting-edge science.
U.S. Food and Drug Administration offices in Silver Spring, Maryland, on Dec. 10, 2020. The FDA recently approved a new drug for the treatment of Alzheimer’s disease. This month, the Food and Drug Administration approved a new drug, lecanemab, for the treatment of Alzheimer’s disease.
The drug, sold under the brand name Leqembi, was developed by Japanese pharmaceutical company Eisai and will be marketed commercially in partnership with American pharmaceutical company Biogen. Biogen, notably, is the maker of the drug Aduhelm, whose earlier rollout and marketing were a fiasco from scientific and public relations perspectives. Lecanemab is a humanized monoclonal antibody that binds to and lowers brain levels of amyloid beta, the protein suspected of contributing to Alzheimer’s. came from a multicenter study that enrolled 1,795 participants diagnosed with mild Alzheimer’s. While the disease progressed in both groups, research subjects who were randomized to the lecanemab group showed slower progression of the disease when compared with subjects in the placebo group. Brain scans showed a significant lowering of amyloid in the lecanemab group when compared with the placebo group. Brain swelling and hemorrhage were greater in the active drug group when compared with the placebo group.There was jubilation among members of the press. Based on the data, it was argued that the disease progressed 27% slower in the active treatment group when compared with the placebo group. The study was hailed as “momentous and historic” by theThis is the first amyloid-lowering drug that slows disease progression when compared with a placebo. The exuberance is understandable. However, we need to take a clear-eyed look at the data beyond the headlines. A thoughtful editorial published Dec. 3 in the prestigious medical journal The Lancet, “,” argues that the 27% difference in disease progression between the drug and placebo groups translates to a much smaller objective difference in cognitive decline, estimated using the Clinical Dementia Rating sum of boxes scale that quantifies a range of cognitive and functional domains.The difference between the two groups is 0.45 on the 0 to 18 scale, a difference so subtle that patients who receive the drug and their family members who care for them will not be able to notice the clinical difference. In other words, the difference is statistically significant but not necessarily clinically meaningful.In addition, the side effects are potentially serious and will require close medical monitoring. The cost of this biweekly intravenous drug is estimated to be $26,500 per year. An image provided by Eisai in January 2023 shows vials and packaging for the medication Leqembi. On Jan. 6, 2023, U.S. health officials approved Leqembi, a new Alzheimer’s drug that modestly slows the progression of the disease. On Nov. 3, 1906, German psychiatrist Alois Alzheimer presented the clinical features of Auguste Deter — the first patient diagnosed with the disease — together with the neuropathological features that included brain shrinkage and the presence of a protein found between brain cells and the Tau protein identified within the brain cell. Today, more than 115 years later, Alzheimer’s is a major health problem globally, and the amyloid hypothesis — that amyloid accumulation causes dementia — dominates the research community. This hypothesis has guided drug development, and pharmaceutical companies saw a huge opportunity. Lecanemab is the first drug that lowers brain amyloid levels and ostensibly slows progression. That being said, that proof of principle is tenuous in this case. The Lancet editorial appropriately states, “Whether lecanemab is the game changer that some have suggested remains to be seen.” The next step will be determined by the Centers for Medicaid & Medicare Services. Unlike the FDA, the CMS has a broader mandate and set of responsibilities. The agency examines the broad clinical impact of drugs and medical devices in the community factoring in cost–benefit analyses as it decides whether to cover the cost of new drugs. It is estimated that approximately 6.5 million Americans 65 and older live with Alzheimer’s. Much of the cost of any dementia drug will fall on Medicare given the age-associated risk for the disease. While there is considerable pressure from advocacy groups, Big Pharma and elected officials to approve new drugs, the premature approval of expensive drugs with modest clinical impact does not serve the community well. It has the additional risk of setting a dangerous precedent and opening the floodgates for similar expensive compounds that do not discernibly affect the course of the disease. There are five FDA-approved drugs on the market that have been demonstrated to slow cognitive decline in Alzheimer’s based on pivotal phase 3 clinical trials — head-to-head comparison with a placebo. These drugs are less expensive; have relatively mild, non-life-threatening side effects; and can be taken orally. The advantages of lecanemab over these treatments, if any, are unclear. It will therefore be prudent to conduct larger, community-based effectiveness studies with more representative patient populations with coexisting medical disorders. Clinical impact and side effects must be examined before a final decision is made regarding lecanemab and whether taxpayer dollars are justified to pay for this drug. While the world eagerly awaits an effective treatment for Alzheimer’s, we must be intellectually honest about our research endeavors and prudent in our scientific investments. We are ill-served by overinterpreting statistical significance, heralding the false dawn and expediting the approval of ineffective, inadequately tested drugs under the umbrella of “cutting-edge science.” The authors of the New England Journal of Medicine paper do note that “longer trials are warranted to determine the efficacy and safety of Lecanemab in early Alzheimer’s disease.”During the Aduhelm crisis, CMS leadership stood up to public pressure and deferred making final decisions about coverage pending larger community-based studies. Let us hope they step up again and follow the recommendations of the authors of this impactful scientific article.Dr. Anand Kumar is head of the psychiatry department at the University of Illinois at Chicago. He previously was president of the American Association for Geriatric Psychiatry.
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