When the U.S. Food and Drug Administration (FDA) granted accelerated approval for the use of lecanemab-irmb (Leqembi) for the treatment of Alzheimer’s disease last month, patients diagnosed with Alzheimer’s, their families, caregivers, and clinicians met the news with a mixture of hope and hesitation.

Decades without progress in therapeutic options have made the Alzheimer’s community especially eager for anything new. Perceived policy missteps in the last two years have made it cautious.

A heavy burden

There are an estimated 6 million Americans living with Alzheimer’s. Initially impacting memory, cognition, and language, the disease eventually completely robs individuals of their ability to function independently.

The most common age-related neurodegenerative disease, Alzheimer’s is also the tenth leading cause of death among U.S. adults and the fifth leading cause of death for those 65 and over. It is estimated to cost the U.S. $321 billion annually.

Alzheimer’s is also among the most feared diseases in the United States. For family members caring for Alzheimer’s patients, the burden of care is compounded by their anxiety over eventually developing the disease themselves.

Given the financial and social burdens associated with Alzheimer’s 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’s research increasing three-fold between 2008 and 2019.

Lecanemab

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 β-protein (Aβ) soluble protofibrils associated with Alzheimer’s.

For the Alzheimer’s community, these data are the basis for both hope and hesitation.

The Amyloid Cascade Hypothesis

While the precise etiology of Alzheimer’s remains unknown, its pathology is distinctive. When Alois Alzheimer first presented “A peculiar severe disease process of the cerebral cortex” 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.

It wasn’t until the 1980’s that researchers isolated the specific protein involved in the formation of these plaques.

In 1992, John A. Hardy and Gerald A Higgins proposed the amyloid cascade theory, positing that the “deposition 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 result.”

While not all researchers embrace the amyloid cascade theory, in the last three decades amyloid-β protofibrils have moved from being biomarkers of Alzheimer’s to becoming target of experimental therapies.

Efficacy in a Phase 3 clinical trial

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 in the January 5 issue of The New England Journal of Medicine, that may support full approval of Lecanemab, are generating the most conversation around the drug.

The 18-month long study included 1795 participants with early Alzheimer’s disease, defined as “mild cognitive impairment or mild dementia due to Alzheimer’s disease” with evidence of amyloid on positron-emission tomography (PET) or through testing of cerebrospinal fluid.

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–Sum of Boxes (CDR-SB) compared to a placebo group.

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.

The FDA label for Leqembi, the name under which lecanemab is marketed, specifies that the drug is for use in “patients with mild cognitive impairment or mild dementia stage of disease,” with the presence of amyloid beta pathology confirmed before the initiation of treatment.

Despite the side effects, many patients and caregivers are finding a new sense of optimism in the drug’s availability.

A problematic predecessor

Even as lecanemab inspires hope, it carries the echoes of another Alzheimer’s treatment from Biogen and Eisai which was granted accelerated approval by the FDA: aducanumbab (Adulhelm).

When the FDA approved aducanumab “for the treatment of people with Alzheimer’s disease” in June of 2021, there was only one study suggesting that it slowed cognitive decline. Biogen and Eisai had halted other ongoing studies of the drug “based on results of a futility analysis conducted by an independent data monitoring committee.”  Ten of the eleven members of the independent Peripheral and Central Nervous Systems (PCNS) Drugs Advisory Committee had recommended against the drug’s approval, with the eleventh uncertain.

Yet the FDA proceeded with aducanumab’s approval declaring that it had “reviewed clinical trial findings with a fine-tooth comb,” and citing its authority to grant accelerated approval to the drug because it was “shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.” For the FDA, the observed reduction in amyloid plaque in study participants was a sufficient surrogate for impact on clinical decline.

One of the three CPNS panel members who resigned in protest, called the approval “probably the worst drug approval decision in recent U.S. history.” And a subsequent congressional investigation of the approval process found it “rife with irregularities.”

Biogen and Eisai originally priced Aduhelm at $56,000 a year. But for Alzheimer’s patients and their caregivers across the country, the hope offered by the first new Alzheimer’s treatment in nearly two decades was invaluable.

In Maine a woman said she “would spend every cent of (her) savings” in return for one more good year with her 61-year-old husband who had been diagnosed with early onset Alzheimer’s. “Now (I) have something to look forward to,” one patient told The Los Angeles Times.

The executive director of the Georgia Chapter of the Alzheimer’s Association, summed up the optimism of many when she declared, “This is the first drug treatment that provides a new future for us and a chance to slow the progression of disease.”

The enthusiasm was short-lived. The controversy over the drug’s approval continued and Aduhelm failed to gain coverage by insurers. When Bloomberg surveyed private insurance companies in November of 2021, none of the 25 which responded deemed Adulhelm “medically necessary.”

The larger question remained whether it would be covered by Medicare.

Writing in The Atlantic in 2021, law professors Nicholas Bagley and Rachel Sachs characterized Aduhelm as “the drug that could break American healthcare,” pointing to the hundreds of billions of dollars coverage could cost Medicare and Medicaid. As Applied Policy’s President and CEO Jim Scott wrote, CMS was “not prepared” for Aduhelm.

In November of 2021, before making a coverage determination, CMS announced a 14.5% increase in the Medicare premium for 2022, citing rising health care prices and utilization, Congressional action, and “potential costs from Aduhelm.” The next month, Biogen announced that it was cutting the wholesale acquisition cost (WAC) to $28,200 to improve patient access to the drug.

Yet, large scale availability and use of Aduhelm were never realized.

In a national coverage determination (NCD) on Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease released in April of 2022, the Centers for Medicare & Medicaid Services (CMS) specifically limited Medicare coverage for mAb’s approved under the accelerated approval pathway to individuals enrolled in randomized clinical trials. This Coverage with Evidence (CED) model limited access to all but a relative few.

The next month, Biogen announced plans to “substantially eliminate commercial infrastructure for Aduhelm.” Major medical centers, including the Cleveland Clinic and Mount Sinai, had announced that they would not administer the drug. United Healthcare, one of the country’s largest private insurers, limited coverage to those enrolled in clinical trials. Neither Japan nor the European Union approved Aduhelm.

The hope had faded.

Medicare coverage of lecanemab

Lecanemab is subject to CMS’s Monoclonal Antibody NCD and is therefore currently only available for Medicare beneficiaries enrolled in clinical trials.

Following announcement of the  FDA’s accelerated approval of lecanemab, CMS issued a statement that if the drug “receives traditional FDA approval, CMS would provide broader coverage using the framework we announced last year, under coverage with evidence development, on the same day.”

That timeline isn’t soon enough for some. On a letter 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’s and to make lecanemab available to all Medicare beneficiaries.

They cited the “enormous physical and financial burden” CED requirements pose for rural Medicare beneficiaries with Alzheimer’s who would have to travel “countless hours” in order to participate in trials at the limited number of research institutions conducting them for lecanemab.

In contrast, the advocacy group Doctors for America has expressed concern that the lessons of aducanumbab are being forgotten. The group has called upon the FDA to “put patients first and commit to holding an Advisory Committee meeting before any decision is made on the full approval of (lecanemab).

Hope springs eternal

Jason Karlawish, a professor of medicine and co-director of the Penn Memory Center at the University of Pennsylvania, Perelman School of Medicine, captured the conflicting feelings of many about lecanemab on a recent episode of the GeriPal podcast. Applauding the show’s cohost for his performance of “The Times, They are A’Changin’” at the outset of a discussion of whether it is “time for geriatricians to get onboard with lecanemab,” Karlawish smiled.

An equally good selection, he suggested, would have been, “Don’t get fooled again.”