Gaining a Foothold: Amyloid Immunotherapy in Clinical Practice

Little by little, amyloid immunotherapy is finding more use at U.S. clinics, with procedures in place to smooth patients’ experience. Two new developments may simplify things. First, Eisai and Biogen recently requested marketing approval for maintenance dosing of lecanemab. If the Food and Drug Administration agrees, patients whose plaque has been cleared could rachet back from biweekly to monthly intravenous injections, halving the expense and time required for treatment. Second, on May 14, Eisai announced the start of a “rolling” application for subcutaneous maintenance dosing. Rolling applications allow companies to send findings to the FDA as they come in. Transitioning to a subcutaneous auto-injector would enable patients to dose themselves at home. This would ease the logistical burden of treatment, and also pave the way for the initial lecanemab dosing to eventually be injected under the skin, as well.

  • For Leqembi, Eisai has applied for approval of maintenance and subcutaneous dosing.
  • Clinical use projected to ramp up more quickly in 2024.
  • Donanemab AdComs date set for June 10.

Such a move could expand Leqembi’s reach. Clinical use in the U.S. remains sparse, with a few thousand people on it nationwide, but is now starting to accelerate. Lecanemab is also being prescribed in Japan, was recently approved in China, and applications are pending in 14 additional countries or regions.

In an April 19 Nature Aging perspectives article, Dennis Selkoe at Brigham and Women’s Hospital, Boston, reviewed the history that brought the field to this point and reflected on the significance of the current moment. “Society is entering an era in which the unchecked devastation of AD is no longer inevitable … The implications of this moment for medicine and society are profound,” he wrote.

Lecanemab is the only FDA-approved anti-amyloid antibody currently on the market in the U.S., but donanemab may soon join it. Importantly, the FDA has recognized amyloid clearance as a surrogate endpoint in its new guidance on developing drugs for early AD. This could facilitate accelerated approvals of future antibodies. One such up-and-coming antibody is Lilly’s remternetug, newly selected for the Dominantly Inherited Alzheimer Network’s primary prevention trial.

Next Steps: Maintenance and Subcutaneous Dosing
One unanswered immunotherapy question is whether dosing should stop once plaque has been completely cleared. In lecanemab long-term extension studies, fluid biomarkers such as plasma p-tau181 and Aβ42/40 gradually worsened again after people stopped taking the drug at 18 months, even if they had been amyloid-negative by PET at that point. Eisai researchers believe this was due to the continuing presence of synapse-damaging soluble oligomers and protofibrils. Modeling based on these extension data suggested that a maintenance dose of 10 mg/kg monthly, half the therapeutic dose, would suffice to keep biomarkers flat (Mar 2022 conference news).

The company is now trying to put this plan into action with its March 31 submission of a supplemental Biologics License Application to the FDA for a 10 mg/kg monthly maintenance dose, given intravenously. In a press release, Eisai noted it is still discussing with the FDA where to set the exact amyloid threshold for shifting from initial to maintenance dosing.

IV dosing is invasive and burdensome, requiring patients to travel frequently. It also creates a barrier, since not everyone lives near an infusion center; even for those who do, such centers have limited capacity. For this reason, Eisai has been exploring a subcutaneous formulation, which can be taken at home via auto-injector. For maintenance dosing, this means a weekly injection of 360 mg Leqembi. Because this formulation is new, the FDA has requested additional data on its immunogenicity, leading Eisai to start the rolling application. To initiate it, Eisai had to first apply for a Fast Track designation for the subcutaneous formulation, which delayed the submission from March to May. Eisai will apply in 2025 for approval to use subcutaneous injections for the initial treatment phase, as well, Michael Irizarry at Eisai told Alzforum.

Clinical Foundation Laid
The clinical rollout of lecanemab was slow to gather steam after it received traditional FDA approval last summer (Jul 2023 news). This is, in part, because the companies, hospitals, and payors all struggled with the complicated logistics of this new treatment. It requires confirmation of amyloid positivity, sufficient infusion center capacity, and frequent MRIs for safety monitoring—the cost of all of which must be borne by somebody. Biogen CEO Chris Viehbacher told industry reporters the launch has been “extraordinarily difficult” due to all the new procedures that had to be put in place at medical centers, including hiring new personnel and developing business plans (Endpoints story).

More medical centers are now set up. In a May 15 earnings call with investors, Eisai reported that 97 out of 100 large healthcare systems it targeted, and 82 percent of infusion centers, now have procedures in place for prescribing and administering lecanemab. Clinical uptake is speeding up, with U.S. sales of the drug nearly tripling from the last quarter of 2023 to the first quarter of 2024. Put another way, Eisai went from selling 800 vials of lecanemab per week in October 2023 to 6,500 per week now. It is unclear how many patients are taking the drug, as the last number Eisai reported—2,000—was from the end of January. The company projects that its U.S. revenue from lecanemab will be $283 million in 2024, 15 times that of 2023.

Alzheimer’s centers contacted by Alzforum noted steady progress in the last four months, with processes becoming more streamlined (Jan 2024 news). James Noble at Columbia University in New York said PET imaging is often done on-site now, and scans are read the same day. More infusions are being done locally as well. The wait time from deciding to take the drug to getting the first infusion is generally a few weeks, Noble told Alzforum. Likewise, Russell Swerdlow at Kansas University Medical Center, Kansas City, said lecanemab use is becoming more routine there, with a wait time around two months. The center’s number of patients on the drug has doubled from 20 to 40 since January. At Emory University in Atlanta, more than 100 people are now on lecanemab, up from 65 in January, Chad Hales there told Alzforum. Hales and Swerdlow both said the ARIA rate has been consistent with what was reported in the Phase 3 trial.

At the Mayo Clinic in Rochester, Minnesota, a few patients have now been on lecanemab for longer than six months. A handful have chosen to stop, due to the major lifestyle changes associated with frequent treatments and testing, Vijay Ramanan at Mayo told Alzforum. “This again highlights the importance of detailed and individualized counseling upfront to ensure that this treatment option is the right fit,” he wrote to Alzforum.

Other programs are just getting started. Banner Alzheimer’s Institute in Phoenix has recently begun administering lecanemab, with nine people on the drug so far. “Extensive planning and an interdisciplinary approach have facilitated smooth functioning thus far,” Ganesh Gopalakrishna at Banner told Alzforum.

How many people in the U.S. could eventually take the drug? It depends whom you ask. A recent paper calculated that 17 percent of the estimated 1 to 2 million Americans with early AD would qualify for lecanemab, meaning that fewer than half a million people would take it (Pittock et al., 2023). A newer study sets the estimate higher, predicting that up to 2 million Americans and 6 million Europeans might be eligible, based on data from a birth cohort in Gothenburg, Sweden (Dittrich et al., 2024). Lecanemab is not yet available in Europe, but a decision is expected from the European Medicines Agency by the end of June.

What about other countries? Lecanemab was approved for use in Japan last September. Eisai reported the rollout there has gone better than in the U.S., with lecanemab already being prescribed at 600 facilities. The drug was approved in China in January, and prescriptions are expected to start in July. Eisai has also applied for approval in Australia, Brazil, Canada, Great Britain, Hong Kong, India, Israel, Russia, Saudi Arabia, Singapore, South Korea, Switzerland, and Taiwan.

Up Next: Additional Antibodies, and Efforts at Prevention
Eisai and Biogen might soon face competition. Lilly’s donanemab is expected to receive marketing approval this year, based on Phase 3 results (May 2023 news; Jul 2023 conference news). The FDA has now set the date for its advisory committee meeting for Monday, June 10.

Why convene a separate AdComs for donanemab? Researchers note several differences between lecanemab and donanemab for which the FDA might want input to help determine the label.

One concerns safety. Donanemab has about twice the rate of ARIA-E as lecanemab, 24 percent versus 12. A recent paper correlates ARIA rates with an antibody’s binding affinity for cerebral amyloid angiopathy fibrils, suggesting this could be an intrinsic difference between the molecules (Söderberg et al., 2024; Nov 2023 conference news). Donanemab causes less ARIA than aducanumab, which scored an accelerated approval based on plaque removal, suggesting this difference may not sink the drug with regulators.

Regulators may also seek advice on whether to require tau imaging before donanemab use. The Phase 3 trial found much greater benefit in people who started with tangle loads below 1.46 SUVr than in those above that cutoff, but requiring tau imaging would increase the cost and difficulty of obtaining donanemab. Another question is whether donanemab should be stopped once plaque is gone. This was done in the Phase 3 trial, but there is little information on how well cognitive benefits were maintained long-term once dosing stopped.

Lilly has a newer antibody with a similar mode of action coming up behind donanemab. Remternetug also targets pyroglutamate Aβ, but does not prompt the anti-drug antibodies and infusion reactions that plague donanemab (Apr 2023 conference news). Remternetug has been developed from the beginning as a subcutaneous formulation, making it easier to take.

DIAN recently announced it has chosen remternetug for its primary prevention trial, arguably the vanguard of amyloid immunotherapy clinical research. This trial had earlier selected gantenerumab, before Roche plugged the plug on that antibody when it fell short in Phase 3. The prevention trial enrolls people who carry their family’s APP or presenilin mutation, but have no significant plaque buildup yet. The goal is to see if preventing plaque accumulation can halt the disease. Because autosomal-dominant populations lay down plaque quickly, the fast action of remternetug, which clears plaque faster than even donanemab, could be an advantage.

Does Plaque Clearance Nip Early Alzheimer’s in the Bud?
In March, the FDA issued revised guidance on developing drugs for early AD. For the first time, this guidance discusses using amyloid clearance as a surrogate endpoint that is likely to predict clinical benefit. Aducanumab was approved on this basis in 2021, before such guidance had been issued, in a highly controversial decision (Jun 2021 news; Jun 2021 news). The new guidance incorporates learnings since then. It is still a draft, and the FDA is accepting comments until June 10.

In his Nature Aging article, Selkoe argued that because plaque clearance ameliorates downstream biomarkers of inflammation and tau pathology, such plaques represent the key pathological lesions of AD. He speculated that in the future, plaque removal alone might suffice to earn traditional FDA approval.

Echoing the DIAN approach, Selkoe believes that presymptomatic plaque clearance could stop Alzheimer’s from developing altogether. “The outright prevention of AD has become a realistic goal,” he wrote. He predicted that other neurodegenerative diseases are poised for similar advances, writing, “Progress over the next decade on previously untreatable diseases of the nervous system is likely to have a major positive impact on the enormous personal and societal burden of age-related neurodegeneration.”

In commenting on Selkoe’s essay, Philip Scheltens at EQT Life Sciences Dementia Fund highlighted his argument for the clinical meaningfulness of even the slight slowing of cognitive decline seen in trials. “Selkoe convincingly shows, using data from population-based studies, that the results in [Phase 3] trials could indeed lead to reduction in years lived with dementia,” he wrote to Alzforum.

Recommending the essay particularly to a broader audience, Christian Haass at the German Center for Neurodegenerative Diseases in Munich praised Selkoe’s summary of the key developments in AD research that have led to today. “All newcomers in our field—students, journalists, science managers, and politicians—would be well-advised to carefully read this perspective to avoid the pitfall of drawing hasty conclusions about success or failure in AD research,” Haass wrote (comments below).—Madolyn Bowman Rogers

Comments

    • User Profile Image Christian Haass
      Biomedizinisches Centrum (BMC), Biochemie & Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
    • Posted:

    How do young investigators and newcomers in the AD field identify the most relevant findings when, every day, a large number of papers is published? They do not even have the time to read all of the new ones, much less easily judge which of these publications is correct, trivial, novel, or flawed. When I started in AD research 34 years ago, I went on Saturdays to the Harvard library, copied all papers on the cellular and molecular biology of AD, on Sunday I read all of them, and on Monday I started to work in the lab. Nowadays, this is totally impossible. The problem is made worse, as personal opinion, jealousy, badly overinterpreted results breaking all cell biological principles, and sometimes overt hostility prevent a clear data-based judgement of research.

    Even in 2024, when disease-modifying therapies in humans are capable of breaking the amyloid cascade, and consistently slow cognitive decline at least to a modest extent, some colleagues maintain that we need a paradigm change in AD research. They claim, falsely in my view, that even after more than 100 years of AD research we have no clue about its cellular mechanisms. To put things into the correct perspective, we need scientists with lifelong experience in AD research to write thorough perspectives and review articles, which give objective insight in the truly relevant developments of our research field. Certainly, an obvious person to do this is Dennis Selkoe. He not only followed the field basically from the identification of Aβ-peptide in the ’80s until today, but also made numerous pivotal findings, which paved the way to develop the very first disease-modifying therapies. If all this were not enough, Dennis has incredible skills for science writing.

    The major chapter of his perspective is divided into three parts, where Dennis explains what is required to achieve successful disease modification. First, one needs to have a precise molecular and cellular understanding of the etiology of the disease. This included the identification of Ab, its proteolytic processing, the identification of the secretases, the identification of autosomal-dominant mutations and their effects on amyloid metabolism, the Icelandic mutation, which reduces Aβ generation and thus protects from AD, and the gene dosage effect caused by the triplication of chromosome 21 in Down’s syndrome which increases Aβ generation due to an additional copay of its precursor, just to name a few.

    Second, one needs to develop pharmacological agents that are capable to break the cascade, and third, one needs well-designed clinical trials, to demonstrate that such pharmacological agents reduce the pathology and simultaneously slow cognitive decline.

    Dennis sheds critical light on the development of secretase inhibitors and the corresponding clinical trials. Although promising inhibitors were developed, which in vitro and in animal models efficiently prevented amyloid production, all failed to work in humans. This prompted criticism and even ridicule in the press. But, in none of these cases had the drug reached its target, since amyloid burden was not significantly lowered by any of them. Similarly, active and passive anti-amyloid immunotherapeutic strategies also failed at the beginning. The reasons were also explainable: active vaccination caused an inflammatory reaction, and anti- amyloid-based therapies were given too late during the progression of the disease.

    This has now changed with lecanemab, which efficiently removes amyloid plaque pathology and slows cognitive decline by about 27 percent. Dennis acknowledged that we all want more protection or, even better, a complete stop of cognitive decline. But as Dennis recently wrote in another perspective in Science: “In therapeutics, as in life, one must walk before one can run.”

    In his current perspective, Dennis makes yet another important point; that is, even with the current 27 percent reduction of cognitive worsening, which some believe is not much, there could be already substantial societal benefits. Selkoe expects savings in healthcare expenditures, and major reductions of frequent systemic syndromes of the elderly, which are major burdens for patients, their families and their caregivers.

    All newcomers in our field—students, journalists, science managers, and politicians—would be well-advised to carefully read this perspective to avoid the pitfall of drawing hasty conclusions about success or failure in AD research. I just want to remind everybody of the Aβ56* story, which led some to conclude that the entire amyloid-based AD research over decades was totally flawed. AD researchers in Germany were even asked by the authorities how much money they had “wasted” on amyloid research. Only serious scientific knowledge—and understandable, critical, objective discussion of our research (including its failures)—can avoid such dramatically misleading conclusions. We should all thank and support Dennis for describing the advent of AD treatments and their consequences for our aging society so lucidly, and with wisdom.

    On a more personal note, here’s my plea to all: Let’s leave hateful discussions behind. Let’s celebrate major success in understanding AD etiology and the consequent development of first disease-modifying therapies. And as Dennis points out, let’s never forget Dale Schenk, who initiated successful treatment with a breakthrough experiment.

    View all comments by Christian Haass
    • User Profile Image Philip Scheltens
      Alzheimer Center Amsterdam; Head EQT Life Sciences Dementia Fund
    • Posted:

    In this Nature Aging article, the “eminence grise” of Alzheimer’s gives his perspective on the advent of AD in a concise and well-conceived way. I guess figures 1 and 2 will soon make their way into powerpoints of many colleagues in the field, showing the timeline of AD research and the various AD targets for therapy, respectively. 

    Besides offering an excellent overview of the current landscape, Selkoe makes a few points worh mentioning. Addressing possible combination therapies, he highlights the recurrence of γ-secretase modulators (note: not inhibitors) as possible adjuncts to monoclonal antibodies after the amyloid has been reduced substantially. By shifting the products of Aβ cleavage from the longer forms to the shorter forms that are less prone to aggegation, such a treatment would slow down or prevent further plaque buildup. Initial results presented by Roche at ADPD seem to strengthen this idea, and many other GS’s are being studied to enter human trials in the not too distant future.

    On the issue of “clinical meaningfulness” of the changes in CDR as shown in the Clarity AD and Trailblazer studies, Selkoe convincingly shows, using data of population-based studies, that the results in these trials could indeed lead to reduction in years lived with dementia and even be cost-effective, postponing costs made in the severe stage of the disease.

    Lastly, a bit hidden in the text, he argues that, without making concrete reference to other disease areas where this is already standard practice, given the advent of being able to measure the disease process of AD so accurately nowadays using biomarkers, changes in these markers with a therapeutic intervention (i.e., lowering amyloid burden) should not only lead to accelerated approval, but in fact full approval. More work on this is needed for sure, but the path forward is laid out clearly.

    View all comments by Philip Scheltens
    • User Profile Image Michael Weiner
      San Francisco Veterans Affairs Medical Center
    • Posted:

    This paper is a masterpiece. It’s a fabulous review by the foremost proponent of the amyloid hypothesis, filled with valuable information for experts and beginners.

    View all comments by Michael Weiner

  4. We submitted a late-breaking abstract to AAIC summarizing our experience. In brief, we are treating more patients now than at the beginning of this year. Wait times from the decision to actually start drug are quite brief, perhaps a few weeks in general now, and that step has not been a major factor in getting started. Since January, we have more sites in our local hospital network providing infusions.

    We’ve seen a pretty dramatic increase in amyloid-PET imaging ordered and done at our center, and these are accomplished quite quickly. Once someone sees us, our workflow from first encounter through workup and making a decision to start lecanemab is happening a bit more quickly because data returns more quickly. E.g. a PET read is the same day, CSF results not that long ago took a few months to return. We are working to adapt to this revised timeline.

    I have patients who get infused at outside centers and others infused in our building. The ability to drop in to see someone during their infusion is both helpful from a medical standpoint (if any concerns arise), and it’s also a pleasure to get to see patients as they are being treated.

    I can recall as a fellow meeting patients in the bapineuzumab trial 16-17 years ago, a few floors away from where we infuse our patients now, wondering if, and when, such a day would come. Here we are. It is exciting to be a part of it.

    View all comments by James Noble

  5. Since January, we have gone from about 20 clinic patients on leqembi to about 40. By the numbers, therefore, the rate of enrollment over the past four months has not clearly accelerated since the close of 2023. This might be a little misleading, as it is possible a group of patients who were eagerly awaiting leqembi got on it fairly quickly and boosted the initial numbers.

    The process around getting patients evaluated for eligibility, and getting them on the drug if they qualify and if they wish to pursue it, is getting more routine from the care provider side. Thus far our enrollment numbers have not been robust enough to strain our health system’s infusion infrastructure.

    The time from deciding to pursue the required biomarker, genotyping, and MRI safety testing has not changed much. It takes time to get these tests done. The time that elapses from deciding to fully pursue eligibility, and start the treatment in those who qualify and want to pursue, is about two months.

    So far we’ve seen side effects, including infusion reactions and ARIA. The frequency of ARIA is perhaps not that different than what the Clarity trial reported. Maybe we will see an uptick as patients are on it longer, although we are not pushing APOE4 homozygotes toward the drug and that might help keep ARIA rates lower than they might otherwise be.

    Our clinic has historically struggled to keep up with the number of referrals we get. The availability of leqembi is perhaps exacerbating this to a small degree. Adding a discussion of leqembi to potentially eligible patient visits certainly puts a time strain on those visits. In general even before leqembi there was a lot to cover during a visit. Now there is even more ground to cover during the course of a visit.

    View all comments by Russell Swerdlow

  6. We have about 30 patients on lecanemab at present, including a small handful now beyond six months of treatment. For most, the process has been fairly smooth. Insurance coverage denials fortunately have been rare, but when they have occurred, have been stressful for all involved.

    There have been a few patients who, through shared decision-making, elected to discontinue infusions after initially starting them, typically in relation to the major lifestyle changes associated with frequent treatments and testing. I suspect this is in line with similarly administered medications elsewhere in neurology and in other parts of medicine, but again highlights the importance of detailed and individualized counseling up front to ensure that this treatment option is the right fit.

    View all comments by Vijay Ramanan

  7. Dennis Selkoe’s article in Nature Aging is an informative and unbiased account of a very complicated subject. He provides a well-written description of the amyloid problem and a convincing assessment of anti-amyloid treatment as being a realistic option for the future.

    I've always been concerned that we really don't know how Aβ peptides are pathogenic, and we still don't know what amyloid oligomers are. The idea that they disrupt synaptic activity is an attractive one but still largely an educated guess. Amyloid must play some pathogenic role, but how and when is still unclear.

    Functional impairments of brain activity are likely to be as important as the pathology that we recognize, and the function of the brain most critical to neuronal activity is the ability of neurons to signal to each other. Recent studies describe how voltage-gated ion channels generate action potentials in collaboration with the skeletal proteins ankyrin and spectrin, making them candidates for axonal transmission defects, since defects of their genes have been described in children with many neurological diseases. Mutant proteins that contribute to reduced axonal transmission might precede the accumulations of toxic proteins and could be biomarkers of functional defects that offer new approaches to diagnosis and treatment (Marchesi, 2023).

    References:

    Marchesi VT. Impaired electrical activity of the brain explains the onset of dementia in aging people. FASEB J. 2023 Nov;37(11):e23249. PubMed.

    View all comments by Vincent Marchesi

  8. We have about 50 patients on lecanemab now, compared to zero in January. The process is gradually working more smoothly as issues are worked out. However, we will need to continue to monitor as numbers increase further.

    View all comments by Christopher van Dyck

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References

Therapeutics Citations

  1. Leqembi
  2. Donanemab
  3. Remternetug
  4. Aduhelm
  5. Gantenerumab

News Citations

  1. Using Lecanemab Trial Data to Determine Maintenance Dose
  2. FDA Grants Traditional Approval to Leqembi
  3. Rising Leqembi Prescriptions Are Straining Clinic Capacity
  4. And Then There Were Three: Donanemab Phase 3 Trial Positive
  5. Donanemab Data Anchors Upbeat AAIC
  6. Unlocking Blood-Brain Barrier Boosts Immunotherapy Efficacy, Lowers ARIA
  7. Next Goals for Immunotherapy: Make It Safer, Less of a Hassle
  8. Aducanumab Approved to Treat Alzheimer’s Disease
  9. Aducanumab Approval Sparks Backlash

Paper Citations

  1. 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.
  2. Dittrich A, Westman E, Shams S, Skillbäck T, Zetterberg H, Blennow K, Zettergren A, Skoog I, Kern S. Proportion of Community-Dwelling Individuals Older Than 70 Years Eligible for Lecanemab Initiation: The Gothenburg H70 Birth Cohort Study. Neurology. 2024 May 14;102(9):e209402. Epub 2024 Apr 9 PubMed.
  3. Söderberg L, Johannesson M, Gkanatsiou E, Nygren P, Fritz N, Zachrisson O, Rachalski A, Svensson AS, Button E, Dentoni G, Osswald G, Lannfelt L, Möller C. Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities. Sci Rep. 2024 May 13;14(1):10868. PubMed.

External Citations

  1. announced
  2. press release
  3. Endpoints story
  4. announced
  5. revised guidance

Further Reading

Primary Papers

  1. Selkoe DJ. The advent of Alzheimer treatments will change the trajectory of human aging. Nat Aging. 2024 Apr;4(4):453-463. Epub 2024 Apr 19 PubMed.

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