Dementia Insights: The World Turned Upside Down:
July 2023—A Remarkable Month in the World of Alzheimer Disease Diagnosis and Treatment

Legend says that following the surrender that effectively ended American Revolutionary War in 1781, a British Army band played a tune titled “The World Turned Upside Down” to signify the unexpected change in the world order. While the historical record does not support the veracity of this event, July 2023 might turn out to be a “World Turned Upside Down” transition point for the diagnosis and treatment of Alzheimer disease (AD). It was certainly a whirlwind month (see Figure).

On July 6, 2023, the US Food and Drug Administration (FDA) announced “traditional approval” for the anti-amyloid monoclonal antibody lecanemab (Leqembi; Eisai, Tokyo, Japan; Biogen, Cambridge, MA) for treatment of patients with “early Alzheimer disease” based on clinical efficacy demonstrated in a phase 3 double-blind, placebo-controlled trial.¹ That study (CLARITY AD, NCT03887455), involving over 3500 participants, demonstrated slowing in the rate of decline across multiple clinical endpoints, including global ratings and cognitive test scores. The magnitude of the slowed progression was remarkably consistent across the endpoints, generally in the 25% to 35% range. Similar to an earlier study that identified the effective dose for amyloid plaque clearance,² the phase 3 study showed robust removal of amyloid plaque as visualized on florbetapir (amyloid) PET scans. The earlier study’s PET biomarker results had previously led to the FDA’s “accelerated” limited approval of lecanemab in January 2023. This was the same level of approval that generated considerable controversy when the agency gave the green light to another anti-amyloid monoclonal antibody, aducanumab (Aduhelm; Biogen, Cambridge, MA), in June 2021.³ The Centers for Medicare & Medicaid Services (CMS) determined in both cases that the evidence for clinical efficacy was insufficient to support payment for use of the agents in patients without additional data.⁴ Without Medicare approval, there was very limited uptake of these medications into clinical practice. But the July 6th announcement changed all of that.

A second seminal July 2023 event in AD therapeutics was preordained when lecanemab achieved accelerated approval by the FDA in January 2023. At about the same time, CMS published a statement indicating that if and when the FDA granted traditional (full) approval to lecanemab based on direct measures of clinical efficacy, CMS would provide payment under a “coverage with evidence development” (CED) plan that it had previously outlined. Even so, CMS’s statement of coverage with the full approval of lecanemab in July was still a big deal.⁵ Medicare patients–who constitute a large portion of people diagnosed with AD–would now have coverage for this expensive medication. However, the CMS decision also places significant burden on neurologists (and other prescribers) because it requires patients to be enrolled in a CMS-approved registry to qualify for coverage. I don’t usually like to write in the passive voice, but my choice of the phrasing “to be enrolled” was very intentional. That’s because the prescriber (a physician “with an appropriate clinical team” is specified) will need to sign up and enter the patient’s information, then report results of cognitive and functional measures every 6 months during the first 2 years of treatment, along with any adverse events.⁶ Prescribers can expect to report adverse events aplenty because amyloid-related imaging abnormalities (ARIA) such as cerebral edema (ARIA-E) or hemorrhage (ARIA-H) occurred in about 40% of treated patients depending on their apolipoprotein E genotype status.¹ Although costs for the drug, infusion sessions every 2 weeks, and regular safety monitoring will be covered in varying degrees by CMS and other insurers, prescribers do not receive additional compensation beyond the usual Evaluation and Management (E&M) codes for fulfilling these new documentation requirements.

The third big event happened less than 2 weeks later when positive results for a phase 3 trial of another anti-amyloid monoclonal antibody, donanemab (Eli Lilly and Company, Indianapolis, IN), were published in the Journal of the American Medical Association (JAMA). The efficacy findings from the TRAILBLAZER-ALZ-2 study (NCT04437511) were quite similar to those reported in trials of lecanemab, with reduced progression in the 25% to 35% range across multiple outcomes.⁷ Although overall efficacy appeared comparable between donanemab and lecanemab, factors such as dose frequency, acute side effects, severity of disease, and cost will likely play large roles in neurologists’ prescribing decisions between the 2 options if donanemab achieves full FDA approval as expected by 2024.

On the same day as the publication of results of the study of donanemab therapy, CMS announced a major change in policy regarding use of the PET scans that allow visualization of amyloid plaque in the brain.⁸ Since 2013, CMS had covered payment for amyloid PET scans only under a CED decision for FDA-approved imaging ligands. After inviting public commentary in 2022, CMS’s 2023 statement opened another 30-day public commentary period on a “proposed decision memo” before sunsetting the national CED rule. This effectively turned payment decisions over to local Medicare Administrative Contractors. The proposal to end the CED arose from results of several studies conducted under the program; these generally supported utility of amyloid PET in guiding treatment decisions for people who might have AD.^9-11

The CMS determination regarding PET scan coverage also cited the clinical trials for lecamemab and donanemab that used amyloid PET results to establish eligibility to receive therapy. There is a potentially important, but understated, financial consideration in the decision to open up payment for amyloid scans. In a substudy embedded in a clinical trial of bapineuzumab, an early anti-amyloid therapy, initiated before amyloid PET was routinely used as a qualifying variable, about 20% of participants meeting clinical criteria for probable AD in mild and moderate stages did not demonstrate pathological amyloid burden on PET scan.¹² The scope of the FDA’s approval for the use of anti-amyloid drugs in “early AD” includes patients with mild cognitive impairment, a population with even lower rates of amyloid positivity.¹³ When translated to clinical practice, this might mean more than 1 in 5 people being considered for anti-amyloid therapies would not qualify for drug treatment because of negative amyloid PET results. Thinking only of list prices, Medicare might save more than $20,000 for each negative PET scan that directs a patient away from starting anti-amyloid antibody therapy.^14-16 Phrased another way, a PET negativity rate of 1 in 6 probably would save costs that CMS would otherwise be expected to cover.

Previously, even under the CED, only 1 amyloid PET scan was permitted during a Medicare beneficiary’s lifetime. However, perhaps because the anti-amyloid clinical trials used PET measures of plaque clearance to assess the biological effectiveness of the drugs, CMS has proposed eliminating the “once in a lifetime” restriction. The utility of sequential scans was reinforced by results indicating that 30% of patients treated with donanemab achieved amyloid negativity after only 6 months of therapy. By 18 months, 75% had cleared their plaque burden below treatable levels.⁷ Data on early PET scan results for lecanemab have not been published, but significant amyloid removal was demonstrated at 18 months.¹ These results suggest that rescanning to determine whether treatment should continue would be appropriate for both agents, perhaps as early as 6 months into the course of therapy to reduce patient burden, the risk for complications of treatment, and overall costs to the health care system.

As if this was not enough news for one month, an additional biomarker approach to AD diagnosis, namely blood based testing, rose to new prominence with a paper that was accepted for publication on July 9.¹⁷ Monane and colleagues reported that commercial mass spectrometry methods, measuring amyloid subtypes and apolipoprotein E prototypes, significantly influenced clinical diagnosis and treatment decisions in a sample of neurologists providing care to more than 350 patients. The test results altered the physicians’ treatment choices regarding anti-amyloid therapies in a substantial proportion of patients, suggesting that there may be lower cost alternatives to PET scans for initial decisions about whether to route a patient toward anti-amyloid therapies. Computer modeling of starting with a blood based biomarker for AD suggested that it could reduce costs and speed recruitment into AD clinical trials,¹⁸ and this method has already been adopted in a large scale trial of AD prevention.¹⁹ If the blood-based approach demonstrates success in the clinical trials realm, transition to using blood work to screen for anti-amyloid therapy eligibility seems likely to translate into routine clinical practice for neurologists in the near future.

So, to borrow an old movie quotation that’s become a staple on social media, “that escalated quickly.” It seems like over the course of a month—in actuality, a little less than 2 weeks—the core elements of AD diagnosis and treatment in the United States went topsy turvy. Of course, these breakthroughs are the culmination of decades of research to clarify the mechanisms of the disease and stubbornly chip away at the complexities of AD. Nonetheless just like the sudden end of fighting in the American Revolutionary War after long years of conflict, a lot of things came together all at once to make it seem that the world of AD has indeed turned upside down.