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When the U.S. Food and Drug Administration (FDA) granted accelerated approval for the use of lecanemab-irmb (Leqembi) for the treatment of Alzheimer\u2019s disease last month, patients diagnosed with Alzheimer\u2019s, their families, caregivers, and clinicians met the news with a mixture of hope and hesitation.<\/p>\n
Decades without progress in therapeutic options have made the Alzheimer\u2019s community especially eager for anything new. Perceived policy missteps in the last two years have made it cautious.<\/p>\n
There are an estimated 6 million Americans living with Alzheimer\u2019s. Initially impacting memory, cognition, and language, the disease eventually completely robs individuals of their ability to function independently.<\/p>\n
The most common age-related neurodegenerative disease, Alzheimer\u2019s is also the tenth leading cause of death<\/a> among U.S. adults and the fifth leading cause of death for those 65 and over. It is estimated<\/a> to cost the U.S. $321 billion annually.<\/p>\n Alzheimer\u2019s is also among the most feared diseases in the United States. For family members caring for Alzheimer\u2019s patients, the burden of care is compounded by their anxiety<\/a> over eventually developing the disease themselves.<\/p>\n Given the financial and social burdens associated with Alzheimer\u2019s and its growing incidence among an aging population, the disease has become a national research priority, with annual National Institutes for Health (NIH) funding for Alzheimer\u2019s research increasing three-fold between 2008 and 2019.<\/p>\n Lecanemab is a human immunoglobulin gamma 1 (IgG1) monoclonal antibody (mAb) developed by Japanese pharmaceutical company Eisai in cooperation with U.S.-based Biogen. It is delivered by infusion once every two weeks and has been shown to bind to the amyloid \u03b2-protein (A\u03b2) soluble protofibrils associated with Alzheimer\u2019s.<\/p>\n For the Alzheimer\u2019s community, these data are the basis for both hope and<\/em> hesitation.<\/p>\n While the precise etiology of Alzheimer\u2019s remains unknown, its pathology is distinctive. When Alois Alzheimer first presented \u201cA peculiar severe disease process of the cerebral cortex<\/em>\u201d to colleagues in 1906, he remarked upon the plaques and neurofibrillary tangles in the brain of a patient who died five years after first presenting with memory loss and confusion.<\/p>\n It wasn\u2019t until the 1980\u2019s that researchers<\/a> isolated the specific protein involved in the formation of these plaques.<\/p>\n In 1992, John A. Hardy and Gerald A Higgins proposed the amyloid cascade theory<\/a>, positing that the \u201cdeposition of amyloid B protein (ABP), the main component of the plaques, (was) the causative agent of Alzheimer’s pathology and that the neurofibrillary tangles, cell loss, vascular damage follow as a direct <\/em>result.\u201d<\/p>\n While not all<\/a> researchers embrace the amyloid cascade theory, in the last three decades amyloid-\u03b2 protofibrils have moved from being biomarkers<\/a> of Alzheimer\u2019s to becoming target<\/a> of experimental therapies.<\/p>\n The FDA granted accelerated approval for Lecanemab based on its efficacy in removing amyloid plaque in a Phase 2 trial. However, the results of a Phase 3 clinical trial published<\/a> in the January 5 issue of The New England Journal of Medicine<\/em>, that may support full approval of Lecanemab, are generating the most conversation around the drug.<\/p>\n The 18-month long study included 1795 participants with early Alzheimer\u2019s disease, defined as \u201cmild cognitive impairment or mild dementia due to Alzheimer\u2019s disease\u201d with evidence of amyloid on positron-emission tomography (PET) or through testing of cerebrospinal fluid.<\/p>\n Lecanemab reduced amyloid markers in the brains of those taking it, with the greatest difference and clearing of amyloid plaques observed between three and nine months after treatment was initiated. Importantly, it also slowed the progression of cognitive decline as measured by Clinical Dementia Rating\u2013Sum of Boxes (CDR-SB) compared to a placebo group.<\/p>\n More serious adverse events included amyloid-related imaging abnormalities (ARIA) and cerebral microhemorrhages and macrohemorrhages, which are believed to result from plaque clearing. This can have serious implications for patients on anticoagulation therapy. Monitoring of patients using lecanemab will necessarily require regular PET scans.<\/p>\n The FDA label<\/a> for Leqembi, the name under which lecanemab is marketed, specifies that the drug is for use in \u201cpatients with mild cognitive impairment or mild dementia stage of disease,\u201d with the presence of amyloid beta pathology confirmed before the initiation of treatment.<\/p>\n Despite the side effects, many patients and caregivers are finding a new sense of optimism<\/a> in the drug\u2019s availability.<\/p>\n Even as lecanemab inspires hope, it carries the echoes of another Alzheimer\u2019s treatment from Biogen and Eisai which was granted accelerated approval by the FDA: aducanumbab (Adulhelm).<\/p>\n When the FDA approved aducanumab \u201cfor the treatment of people with Alzheimer\u2019s disease\u201d in June of 2021, there was only one study suggesting <\/em>that it slowed cognitive decline. Biogen and Eisai had halted other ongoing studies of the drug \u201cbased on results of a futility analysis conducted by an independent data monitoring committee.\u201d \u00a0Ten of the eleven members of the independent Peripheral and Central Nervous Systems (PCNS) Drugs Advisory Committee had recommended against the drug\u2019s approval, with the eleventh uncertain.<\/p>\n Yet the FDA proceeded with aducanumab\u2019s approval declaring that it had \u201creviewed clinical trial findings with a fine-tooth comb,\u201d and citing<\/a> its authority to grant accelerated approval to the drug because it was \u201cshown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.\u201d For the FDA, the observed reduction in amyloid plaque in study participants was a sufficient surrogate for impact on clinical decline.<\/p>\n One of the three CPNS panel members who resigned in protest, called<\/a> the approval \u201cprobably the worst drug approval decision in recent U.S. history.\u201d And a subsequent congressional investigation<\/a> of the approval process found it \u201crife with irregularities.\u201d<\/p>\n Biogen and Eisai originally priced Aduhelm at $56,000 a year. But for Alzheimer\u2019s patients and their caregivers across the country, the hope offered by the first new Alzheimer\u2019s treatment in nearly two decades was invaluable.<\/p>\n In Maine<\/a> a woman said she \u201cwould spend every cent of (her) savings\u201d in return for one more good year with her 61-year-old husband who had been diagnosed with early onset Alzheimer\u2019s. \u201cNow (I) have something to look forward to,\u201d one patient told<\/a> The Los Angeles Times.<\/p>\n The executive director of the Georgia Chapter of the Alzheimer\u2019s Association, summed up the optimism<\/a> of many when she declared, \u201cThis is the first drug treatment that provides a new future for us and a chance to slow the progression of disease.\u201d<\/p>\n The enthusiasm was short-lived. The controversy over the drug\u2019s approval continued and Aduhelm failed to gain coverage by insurers. When Bloomberg<\/a> surveyed private insurance companies in November of 2021, none of the 25 which responded deemed Adulhelm \u201cmedically necessary.\u201d<\/p>\n The larger question remained whether it would be covered by Medicare.<\/p>\n Writing in The Atlantic in 2021, law professors Nicholas Bagley and Rachel Sachs characterized<\/a> Aduhelm as \u201cthe drug that could break American healthcare,\u201d pointing to the hundreds of billions of dollars coverage could cost Medicare and Medicaid. As Applied Policy\u2019s President and CEO Jim Scott wrote<\/a>, CMS was “not prepared” for Aduhelm.<\/p>\n In November of 2021, before making a coverage determination, CMS announced a 14.5% increase in the Medicare premium for 2022, citing<\/a> rising health care prices and utilization, Congressional action, and \u201cpotential costs from Aduhelm.\u201d The next month, Biogen announced that it was cutting the wholesale acquisition cost (WAC) to $28,200 to improve patient access to the drug.<\/p>\n Yet, large scale availability and use of Aduhelm were never realized.<\/p>\n In a national coverage determination (NCD) on Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer\u2019s Disease<\/em><\/a> released in April of 2022, the Centers for Medicare & Medicaid Services (CMS) specifically limited Medicare coverage for mAb\u2019s approved under the accelerated approval pathway to individuals enrolled in randomized clinical trials. This Coverage with Evidence<\/a> (CED) model limited access to all but a relative few.<\/p>\n The next month, Biogen announced plans to \u201csubstantially eliminate commercial infrastructure for Aduhelm.\u201d Major medical centers, including the Cleveland Clinic and Mount Sinai, had announced<\/a> that they would not administer the drug. United Healthcare, one of the country\u2019s largest private insurers, limited coverage to those enrolled in clinical trials. Neither Japan<\/a> nor the European Union<\/a> approved Aduhelm.<\/p>\n The hope had faded.<\/p>\n Lecanemab is subject to CMS\u2019s Monoclonal Antibody NCD and is therefore currently only available for Medicare beneficiaries enrolled in clinical trials.<\/p>\n Following announcement of the \u00a0FDA\u2019s accelerated approval of lecanemab, CMS issued a statement<\/a> that if the drug \u201creceives traditional FDA approval, CMS would provide broader coverage using the framework we announced last year, under coverage with evidence development, on the same day.\u201d<\/p>\n That timeline isn\u2019t soon enough for some. On a letter<\/a> dated January 30, 2023, 74 members of the U.S. House of Representatives petitioned Health and Human Services Secretary Xavier Becerra and CMS Administrator Chiquita Brooks-LaSure to reconsider the CED requirements for mAb for the treatment of Alzheimer\u2019s and to make lecanemab available to all Medicare beneficiaries.<\/p>\n They cited the \u201cenormous physical and financial burden\u201d CED requirements pose for rural Medicare beneficiaries with Alzheimer\u2019s who would have to travel \u201ccountless hours\u201d in order to participate in trials at the limited number of research institutions conducting them for lecanemab.<\/p>\n In contrast, the advocacy group Doctors for America has expressed concern that the lessons of aducanumbab are being forgotten. The group has called upon<\/a> the FDA to \u201cput patients first and commit to holding an Advisory Committee meeting before any decision is made on the full approval of (lecanemab).<\/p>\nLecanemab<\/strong><\/h3>\n
The Amyloid Cascade Hypothesis<\/strong><\/h3>\n
Efficacy in a Phase 3 clinical trial<\/strong><\/h3>\n
A problematic predecessor <\/strong><\/h3>\n
Medicare coverage of lecanemab<\/strong><\/h3>\n
Hope springs eternal<\/strong><\/h3>\n
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