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

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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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