Rising Leqembi Prescriptions Are Straining Clinic Capacity

Part 1 of 2. Click here for Part 2. As Alzheimer’s clinicians across the U.S. started offering a disease-modifying treatment to their patients, uptake at first was slow but is now speeding up. Six months after Eisai’s anti-amyloid antibody lecanemab received traditional approval from the U.S. Food and Drug Administration, approximately 2,000 to 3,000 people across the country are currently on it. So far, this is happening mostly at larger neurology centers that have clinical trial experience with such antibodies, with each site treating a handful to several dozen new patients. To date, the rollout has had smooth sailing, and prescribers express cautious optimism that lecanemab will help certain people.

  • Many U.S. dementia clinics have dozens of patients on lecanemab.
  • So far, the rollout has gone smoothly, with an emphasis on safety.
  • Next hurdle: treatment at less-experienced clinics.

“It has changed the face of our practice,” Erik Musiek at Washington University in St. Louis told Alzforum. “There is a path forward after a diagnosis.”

Rougher seas may lie ahead. Demand for the drug is accelerating and will soon outstrip the capacity of specialized dementia clinics to take on new patients. AD researchers agree that general neurology clinics will have to step up to meet the demand. Having less experience with immunotherapy, these clinics will have to learn to identify the right patients and manage the safety monitoring. This is crucial, because the amyloid-related imaging abnormalities (ARIA) that accompany amyloid immunotherapy can cause serious side effects, even death (see related story).

Alzforum contacted prescribing clinician-researchers for a snapshot of clinical use at this early timepoint. Despite some concerns, they see the treatment as progress. “In our practice, we’re very excited about it,” said James Noble at Columbia University in New York. “We’ve been working toward this as a field for decades.”

Up Up Up. Lecanemab prescriptions at Washington University in St. Louis have grown steadily from July 2023 to the present (dotted line). Nearly 70 patients have received their first dose (red dots), and a few are in double digits (purple). Two patients have stopped treatment due to ARIA (A), two for reasons unrelated to drug (N). [Courtesy of Suzanne Schindler, Washington University, St. Louis.]

Insurance Coverage Opens Door for Broad Use
Though the FDA first approved lecanemab under its accelerated program in early 2023, the Centers for Medicare and Medicaid Services did not cover it until it received traditional approval in July (Jan 2023 news; Jul 2023 news). This opened the floodgates. In a November earnings call with stockholders, Eisai said that the number of people on the drug has been rising since summer, to 800 by the end of October and projected to reach 10,000 by the end of March (Endpoints story). Eisai will release updated numbers at its next earnings call in February.

At Alzheimer’s clinics, the speed of the rollout varies, with some programs underway since July and others still starting up. WashU was among the first to jump in, and now has 68 patients taking the drug, some of whom have had 13 treatments (see image above). Other large centers, such as Columbia University, Emory University in Atlanta, and the Mayo Clinic in Rochester, Minnesota, also have several dozen people on treatment. The number continues to climb. “A few times now, we’ve lined up more than one patient in a day for lecanemab, whereas before it was one patient every few weeks,” Noble told Alzforum.

Elsewhere, uptake has been slower. For example, Banner Alzheimer’s Institute in Phoenix does not yet have lecanemab on its formulary, noted Pierre Tariot there. Doctors can prescribe it, but patients have to go elsewhere for infusions, which has led some to decide against taking the drug at this time. At Yale-New Haven Health, the clinical pathway for lecanemab was finalized earlier this month, Chris van Dyck told Alzforum, clearing the way for initial administration, which is expected shortly. Across the U.S., about 60 percent of large healthcare systems had approved lecanemab as of November, according to Eisai’s partner BioArctic (see press release).

Even at a given site, clinicians use the drug differently. For example, Michael Greicius, a professor at Stanford’s Center for Memory Disorders, told Alzforum, “I won’t be using lecanemab, because I am not convinced there is any true clinical benefit.” Greicius points to the poor correlation between amyloid removal and clinical benefit in individual patients in aducanumab trials, and to the potential for participants with ARIA to have realized they were on the drug and experienced a placebo effect (Digma et al., 2023). Other neurologists at Stanford do prescribe lecanemab. The program recently infused its first patient, with 40 more people undergoing eligibility screening, Irina Skylar-Scott at Stanford told Alzforum.

Patient attitudes run the gamut as well. Many have heard of the drug and want to find out more. “Over recent months we have been receiving numerous phone calls, in-basket messages, and questions at office visits,” Vijay Ramanan at the Rochester Mayo Clinic wrote to Alzforum.

Once patients hear the details, about a quarter of those eligible decide lecanemab is not for them, Musiek said. Some are put off by the risk of side effects or the cost, others by the amount of time required. Between the twice-monthly infusions and multiple MRI scans, 18 months of treatment could require about 40 days spent visiting a doctor’s office. “For the relative benefit, they’re not sure it’s worth it, and they’d rather spend that time with their grandchildren,” Noble noted.

Those who go through with it tend, on average, to be in good general health, since any chronic health conditions have to be well-controlled to qualify for lecanemab treatment. Overall, these first patients resemble clinical trial participants, being largely non-Hispanic whites who are better educated and wealthier than the general population. “We need to work on broadening access to people in underserved communities,” Joy Snider at WashU told Alzforum.

How Much Does It Cost?
Even with insurance coverage, lecanemab treatment is costly. Medicare picks up 80 percent of the $26.5K per year price for lecanemab. Supplemental insurance plans help with the rest but do not always fully cover the co-pay. Medicare Advantage plans often reimburse at lower rates than does traditional Medicare. Patients too young for Medicare rely on private insurance, but not all private payers are following CMS’ lead. A December 2023 analysis by Tufts Medical Center in Boston found that, at this early point, more than half are denying coverage (Neurology Today article). “Thus, [our] patients with Medicare have been more likely to receive this treatment,” noted John Dickson, Michael Erkkinen, Liliana Ramirez-Gomez, Kirk Daffner, and Teresa Gomez-Isla at the Mass General Brigham (MGB) Alzheimer Therapeutic Program, a combined initiative of the two hospitals. More than 30 patients there are taking lecanemab.

In Japan, Leqembis’ list price is lower than in the U.S., and requires a 10 to 30 percent co-pay from patients (Dec 2023 industry news).

Besides the cost of the drug and infusions, lecanemab treatment requires additional testing. Qualifying patients need to have evidence of amyloid plaque buildup in their brains. For that, CSF tests tend to be cheapest; for example, Medicare reimburses up to $300 for the FDA-approved Lumipulse CSF test (May 2022 community news).

Doctors or patients who reject lumbar sampling can opt for amyloid PET, which is also FDA-approved. Scans can run up to $6,000 and, as of October, started being covered by CMS (Oct 2023 community news). This announcement sparked another surge in demand for lecanemab. “Before, people opted out [of treatment] for that reason,” Russell Swerdlow of Kansas University Medical Center in Kansas City told Alzforum. “Once scans were covered, that reduced barriers.” About two dozen patients at his institution are taking lecanemab.

Insurance coverage for amyloid PET is often incomplete. In hospital settings, CMS caps the cost at around $1,500, meaning the co-pay won't exceed $300. At free-standing PET clinics, CMS reimburses separately for the scan and the tracer, and co-pays can run higher. Such varying decisions by insurers add up to an unequal patchwork of coverage across the country.

Spurred on in part by the advent of immunotherapy and its associated testing cost, blood tests are starting to be evaluated in real-world settings outside of carefully curated clinical trials (see Jan 2024 news).

How Can Doctors Keep Patients Safe?
Beyond price, patients and physicians are concerned by the potential risk of the treatment. About one in eight people develop ARIA. A quarter of those are symptomatic. Most ARIA symptoms are mild, but three deaths in lecanemab's Phase 3 open-label extension have been blamed on the drug (Jan 2023 news). Emerging data suggest that most such catastrophic outcomes occur in APOE4 homozygotes, who are more prone to develop vascular amyloid.

At some centers Alzforum contacted, for example Columbia, Emory, the University of Pennsylvania, and the University of Southern California, clinicians hew as closely as possible to the Phase 3 inclusion and exclusion criteria, which allowed in APOE4 homozygotes and people on anticoagulants. Their reasoning? All of the findings to date pertain to this population, and were the basis for drug approval, hence holding to those criteria and the FDA label offers the firmest ground. For its part, Eisai, too, recommends that physicians follow the FDA label, spokesperson Libby Holman told Alzforum.

Alas, not everyone in the trial population fared equally well. Clarity results showed a sixfold higher risk of developing ARIA in E4 homozygotes, and a threefold higher risk of intracerebral hemorrhage in those on anticoagulants (Jun 2023 community news). Because of these results, the FDA label for lecanemab includes a black-box warning for APOE4 homozygotes (Jul 2023 community news).

Many centers, such as WashU, Columbia, and Kansas, leave the final decision of whether to prescribe lecanemab in these cases up to clinicians and patients. Swerdlow counsels patients about the dangers and assesses their risk tolerance, but lets them proceed if they are otherwise a good fit for the drug, without other risk factors, and eager to take it. Musiek noted, “At our center, it’s up to each practitioner to decide how comfortable they are in those gray-area cases.”

Meanwhile, the American Geriatrics Society recommends its members follow the more conservative appropriate-use recommendations issued by a quorum of experts. The AURs advise against prescribing lecanemab to people on anticoagulants (Apr 2023 conference news). The AGS provides a tipsheet that lists inclusion/exclusion criteria and suggests how best to manage use of the drug. Like Greicius, this doctors’ association notes reservations about the antibody’s clinical benefits.

“The AGS considers the evidence insufficient to inform many of the prescribing scenarios our members will face,” the tipsheet said. The organization offered a May 3 preconference at its 2023 annual meeting, held May 4-6 in Long Beach, California, to help its members understand recent advances in AD diagnosis and treatment and incorporate them into their practices. In addition, the AGS Health in Aging Foundation, its public education arm, will develop materials to assist patients and their families in making decisions about the new treatments, according to spokesperson Jennifer Fisher.

About two-thirds of the programs Alzforum contacted, including the Rochester Mayo Clinic, MGB, Stanford, and Butler Hospital in Providence, Rhode Island, strictly follow the AURs. “We’re being conservative—safety first,” Ron Petersen at the Rochester Mayo Clinic, an author on the AURs, told Alzforum. About 50 patients there are taking lecanemab.

Petersen tells his patients to call if they experience new headaches, dizziness, or confusion, and will have them come to the emergency room for an MRI to check for ARIA. Because ARIA symptoms can sometimes look like stroke, many programs have alerted emergency room personnel at their institution to ask if a patient is taking lecanemab, and to avoid clot-busting drugs in those situations.

Likewise, at MGB, physicians do not prescribe lecanemab to anyone on full-strength anticoagulation or dual antiplatelet therapy. For APOE4 homozygotes, a multidisciplinary team carefully reviews prospective patients to identify potential red flags for ARIA risk, Gomez-Isla and colleagues at the Alzheimer Therapeutic Program wrote to Alzforum. The team discusses cases at a weekly consensus conference, which includes neuroradiologists who go over the results of amyloid PET and MRI scans.

To improve safety, the program has an AD specialist on call 24/7, and patients are given the specialist’s pager number when they start the drug. They also receive a handout that lists ARIA symptoms and tells them when to call. MGB has developed institutional policies that include guidelines for managing severe ARIA, as well as ischemic stroke, in patients on lecanemab. In addition to coordinating with emergency room personnel, the program is also developing alerts within the electronic health record system to flag potential drug interactions, such as prescription of an anticoagulant to a patient on lecanemab.

With most patients early in their treatment, doctors at these institutions have seen little ARIA so far. Of WashU’s 68 patients, two have stopped treatment due to ARIA, and two for reasons unrelated to lecanemab. At Kansas University, there has been no ARIA yet, but most patients have been taking the drug for only a few weeks. “We haven’t gotten to the period when we’d be expecting ARIA,” Swerdlow said.

Registry Requirement: No Big Deal
One worry that was overblown? The CMS requirement that clinicians enter patient data into a registry in order to be reimbursed for services (Jun 2023 community news). This is not proving to be a hurdle. On the same day the agency granted lecanemab traditional approval, its own registry went live. All clinicians Alzforum spoke with said they were using that registry. Most of the items it requires are data the clinics already tracked, although two sites said they had to add a formal Functional Activities Questionnaire to comply. Data entry takes little time per patient. “The easiest part of [administering] lecanemab is probably the CMS website,” Noble quipped.

On the flip side, the slim data means the registry will have limited capacity to assess the harms and benefits of lecanemab. “We’d like a more robust dataset to see how well this medication works,” Snider said.

One option is ALZ-NET, developed in 2021 by the Alzheimer’s Association and hosted by the American College of Radiology (Aug 2022 conference news). It gathers much more data, is CMS-approved, and can be used in place of the CMS registry to obtain coverage approvals. The hitch is that this registry qualifies as a clinical study and involves sharing patient data, therefore AD centers need approval from Institutional Review Boards to participate.

Several programs, such as WashU, MGB, Stanford, and Mayo, said they plan to transition to ALZ-NET. Clinicians at Butler, which has four patients currently on lecanemab, are already entering data there. Still, many researchers expressed concern about the time it will take. Snider noted that clinics cannot bill for the time spent entering data, incurring additional cost for institutions. Several have hired new personnel to help manage lecanemab patients and enter data. Snider is investigating whether data entry could be partially automated, populating from a patient’s medical record. “We’re looking for models to make this work,” she said.

More than half the programs Alzforum spoke with, including Rush University and the University of Texas Southwestern, said they do not plan to switch from the CMS registry. Gomez-Isla noted that some patients do not want to use ALZ-NET due to data privacy concerns; for those MGB will continue with the CMS one. Meanwhile, Emory University, which has 65 people on lecanemab, plans to transition to a local option, the Georgia Memory Net Anti-Amyloid Monoclonal Antibody Registry, Chad Hales at Emory told Alzforum.

What Happens When Clinics Reach Capacity?
As lecanemab use ramps up, clinicians expect demand to overwhelm the staff at most memory clinics. At WashU’s Knight Alzheimer Disease Research Center—one of the larger centers in the country—the staff comprises 12 physicians and four physician assistants or nurse practitioners. Patients wait three to four months to start lecanemab, Snider said, with 100 patients in the queue at this point. At Stanford, there can be a nine-month wait to see a neurologist and start the screening process, Skylar-Scott told Alzforum.

A dearth of infusion centers is also holding things up. At the Wisconsin ADRC in Madison, many infusion facilities were already full before lecanemab arrived on the scene. Five patients there are receiving lecanemab, while another 15 are waiting for infusion chairs to become available, according to Robert Przybelski at the University of Wisconsin. “I am sending patients more than 100 miles away from their homes to get the twice-monthly infusions, braving hazardous winter driving conditions,” he wrote to Alzforum.

One upcoming development may ease crowding at infusion centers. Eisai plans to submit an FDA application for a subcutaneous formulation in the first quarter of 2024 (Nov 2023 conference news). That will enable at-home injections, reducing the travel burden on patients. WashU participated in the clinical trial of this formulation. “We have patients using the autoinjector, and they really like it,” Snider noted.

Overall, however, the treatment bottleneck is likely to tighten. In the U.S., 1 to 2 million people have early AD, of whom up to 17 percent are estimated to meet the lecanemab Phase 3 inclusion and exclusion criteria (Pittock et al., 2023).  That would net between 170,000 to 340,000 people, around 100 times more than those currently being treated. Their number stands opposite 550 certified cognitive neurologists in the U.S., or one for every 600 patients (Neurology Today article).

To serve the need, treatment will branch out from dementia clinics, which tend to be tertiary care referral centers, to broader neurological practices. As of now, most of those are not ready. Neurologists need training in how to identify patients at early stages of AD and safely manage lecanemab treatment. This requires specialty knowledge, for example reading amyloid PET and MRI ARIA scans. “We’ve found radiologists in the community are not very accurate in their positive or negative diagnoses,” noted Lon Schneider at the University of Southern California, Los Angeles.

Despite these growing pains of a new drug rollout, most clinicians are pleased to have one available. “It has been rewarding for our clinicians to be able to offer this option to patients where it makes sense to do so,” Ramanan wrote. All hastened to add that they need more treatments to go after other aspects of AD, from tangles to inflammation and co-pathologies such as Lewy bodies. “This is a step in the right direction, but it’s just the first step,” Petersen said.—Madolyn Bowman Rogers

Comments

  1. At Mayo Rochester we began use of lecanemab in eligible patients in late fall. It’s a positive step for our patients to have an additional treatment option to slow early Alzheimer’s disease, and it has been rewarding for our clinicians to be able to offer this option to patients where it makes sense to do so. Many patients with cognitive symptoms have heard about lecanemab through news reports and other avenues, and over recent months we have been receiving numerous phone calls, in-basket messages, and questions at office visits.

    Very often this initial interest is at the level of early curiosity, and we provide value at that stage by filling out patient/family understanding of what the drug is trying to accomplish, what we know (and don’t yet know) from clinical trials, side effects and other risks, and the “nuts and bolts” logistics of receiving what is a fairly intensive treatment. Even among patients who are eligible for lecanemab (which itself is a relatively small fraction of patients with Alzheimer’s disease), we have found shared decision-making to be of high value as not every eligible patient may ultimately see lecanemab as the right option for them. It’s very hard to know the right “denonimator,” which includes patients who do not proceed with lecanemab treatment, in part because many who are ineligible (for various reasons) are in effect filtered out in primary care or general neurology settings prior to being seen in a subspecialty clinic.

    In our clinic, we do adhere closely to the major conditions of the lecanemab clinical trials and to the principles outlined in the appropriate use recommendations. Because of how complex the drug is, we have been deliberate to ensure that we only treat at volumes that we can safely manage, though we hope to grow this over time. 

    We are not using lecanemab in patients on anticoagulant medications or in those who have cerebral amyloid angiopathy.  At present, we are also recommending against lecanemab treatment in patients homozygous for APOE ε4 until there is additional data to guide safety and efficacy in those patients. We’ve also placed heavy emphasis on multidisciplinary engagement (e.g., with radiology, emergency medicine, hospital neurology, and others) at our institution, both to ensure that we are offering lecanemab to those patients most likely to benefit and least likely to be harmed, and also to prepare in case of ARIA or other complications.

    Infusion reactions were quite common in the clinical trials and we have had similar observations particularly with the initial infusions in these early stages. Educating patients upfront and having options for symptom management or even pretreatment have been helpful. We are using the CMS registry but are continuing to explore options.

    View all comments by Vijay Ramanan

  2. This is wonderful news, thanks to all who shared their clinical data. Finally, we are implementing a treatment for this fatal disease. It took hard work and the sacrifice of every subject and their caregivers. Cheers all around.

    With respect, isn't not treating based on other failed trials an association fallacy? It is true that many drugs in the class failed, but what does that have to do with a drug that met primary and secondary outcomes? Every failed trial built upon the last, so we got to the right target, dose, biomarker, patient, and outcome measurement.

    This article highlights the fact that we need more people in the field ASAP. I'm sure this will happen because, as Dr. Ramanan points out, it is personally and professionally rewarding to be able to help these patients.

    Upcoming trials will be easier to enroll now that there's some wind in the sails, and also no rationale for nihilism, less cultural stigma.

    View all comments by David Weisman

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References

News Citations

  1. U.S. FDA Gives Green Light to Leqembi, aka Lecanemab
  2. FDA Grants Traditional Approval to Leqembi
  3. FDA Approves Fujirebio’s CSF Test for AD—Quest Diagnostic Offers Plasma Test
  4. After a Decade, Amyloid PET Scans Receive Broad Insurance Coverage
  5. AD Blood Tests Are Here. Now, Let's Grapple With How to Use Them
  6. Should People on Blood Thinners Forego Leqembi?
  7. Shrunken FDA Advisory Committee Is Unanimous: Leqembi Works
  8. Next Goals for Immunotherapy: Make It Safer, Less of a Hassle
  9. CMS Sticks to Its Guns on Amyloid Immunotherapy Coverage
  10. Bringing Aduhelm—and Antibodies to Come—Into Practice
  11. Gotta Get Rid of It All: Total Plaque Clearance Key for Clinical Benefit

Therapeutics Citations

  1. Aduhelm

Paper Citations

  1. Digma LA, Winer JR, Greicius MD. Substantial Doubt Remains about the Efficacy of Anti-Amyloid Antibodies. arXiv:2310.15456 [q-bio.TO], November 19, 2023 Cornell University, Quantitative Biology
  2. Pittock RR, Aakre JA, Castillo AM, Ramanan VK, Kremers WK, Jack CR Jr, Vemuri P, Lowe VJ, Knopman DS, Petersen RC, Graff-Radford J, Vassilaki M. Eligibility for Anti-Amyloid Treatment in a Population-Based Study of Cognitive Aging. Neurology. 2023 Nov 7;101(19):e1837-e1849. Epub 2023 Aug 16 PubMed.

Other Citations

  1. here

External Citations

  1. Endpoints stor
  2. press release
  3. Neurology Today article
  4. Dec 2023 industry news
  5. tipsheet
  6. Neurology Today article

Further Reading

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