29 Aug 2024

Now that lecanemab has been in clinical use in the U.S. for a little over a year, doctors are asking how long they should treat. This remains an open question. Drug maker Eisai has proposed to the FDA, in a supplemental biological license application, that patients stay on past 18 months and switch to half as frequent a dose once plaques and other, more sensitive biomarkers, have changed. Eisai is in discussions with the agency about that. What is the evidence for this proposal, and how would doctors know when to switch? These are the questions clinicians discussed at last month’s Alzheimer’s Association International Conference in Philadelphia.

When a patient comes off Leqembi, biomarkers and cognition worsen at placebo rates.
This might be due to the return of toxic protofibrils.
Modeling suggests monthly maintenance dosing will keep biomarkers flat.

Several talks showed how fluid biomarkers rebound after patients stop taking the drug. Likewise, cognitive decline returned to placebo levels, even in amyloid-negative patients. Scientists argued that this is due to the rebound of Aβ protofibrils in the brain. Lecanemab targets this species linked to synaptic damage and neurodegeneration. Eisai’s quantitative model predicted that 18 months of lecanemab will mop up most protofibrils in the brain. The same model projected that maintenance dosing would be sufficient to keep protofibrils low, biomarkers flat, and maintain cognitive benefits. These data stand in contrast to findings for donanemab, which targets fibrillar amyloid and can be discontinued once plaque is gone.

Other news from AAIC? Long-term lecanemab dosing in open-label extensions now goes out to three years, and continues to support the idea that the antibody slows disease progression. On cognitive measures, the treatment group maintains its edge over the former placebo group, as is expected for a disease-modifying drug, and people at the earliest disease stages reap the biggest cognitive benefits. Perhaps as Alzheimer’s disease progresses, non-amyloid processes come to dominate and immunotherapy is less helpful, Eisai’s Michael Irizarry told the audience.

Sustained Benefit? People on lecanemab for three years (green) maintain a cognitive edge over those who transitioned from placebo at 18 months (black to green); both do better than matched controls from ADNI (pink). [Courtesy of Eisai.]

Biomarkers Worsen Off Drug, Even in Absence of Plaque
Data from lecanemab trials offer a glimpse into what happens in the brain after dosing stops. After the Phase 2 trial ended, participants had to wait about two years before entering an open-label study. Most were amyloid-negative at the time. Scientists previously reported that plaque and plasma p-tau181 rose during the gap, creeping about a quarter back toward baseline levels, while plasma Aβ42/40 rebounded faster, halfway toward the baseline value (Mar 2022 conference news).

In Philadelphia, Eisai’s Larisa Reyderman showed more data. During the gap, the inflammatory marker plasma GFAP rose by nearly a third, similar to the rate of p-tau181. Plasma p-tau217, which reflects both plaques and tangles, rose more slowly, by 13 percent. These rates of worsening were similar to those seen in the placebo group. In effect, without lecanemab, disease progression resumed its usual pace.

How long before the treatment effect is lost? Half of it would be gone in six months for plasma Aβ42/40, and in less than two years for plasma p-tau181 and GFAP, Reyderman calculated. For plaque, it would take 12 years to move halfway back toward a patient’s load at trial baseline. Fluid biomarkers are more sensitive indicators of pathology than plaque, Reyderman concluded.

The picture changed once treatment resumed in the OLE, noted Charlotte Teunissen of Amsterdam University Medical Center. Biomarkers began improving again at the same rate as in the clinical trial, both in previously treated people and in the former placebo group.

In contrast to these Phase 2 data, in the Phase 3 Clarity study, participants transitioned directly into the OLE without a gap. For them, biomarkers responded continuously, with additional plaque clearance and further normalization of plasma Aβ42/40, p-tau181, p-tau217, and GFAP over six months of open-label treatment. “The biomarker data support continued treatment,” Teunissen said.

Off Treatment, Cognition Craters. During a dosing gap (middle), cognition declines at the same rate in the previous treatment (blue) and placebo (black) groups, but the numeric difference between them persists (red lines). The groups remain separated during open-label dosing (right). [Courtesy of Eisai.]

Cognition Tracks with Fluid Biomarkers
What about cognition? It followed suit. During the treatment gap after Phase 2, performance on the CDR-SB worsened at the same rate in the former treatment and placebo groups, Reyderman said. Nonetheless, the treatment group maintained its numerical advantage over placebo controls. The group difference persisted after 18 months of OLE treatment, as well (image above). That pattern is expected for a disease-modifying therapy, because people who were treated first remain at an earlier disease stage than those whose treatment started later.

This pattern occurred when there was no treatment gap, as well. Chris van Dyck of Yale School of Medicine in New Haven, Connecticut, showed 18-month OLE data from Clarity. These represent three years of continuous treatment with lecanemab. During the OLE, cognition on the CDR-SB slipped faster than during the trial, but the difference between the former treatment and placebo groups stayed constant, with the lines paralleling each other.

How does this compare with what would have happened off treatment? To approximate a placebo group, van Dyck compared these trajectories to those of matched controls from the ADNI observational study. For the 18-month core trial, ADNI trajectories overlaid those of the placebo group. During the OLE, however, the ADNI line steepened, diverging from the OLE curves. Cognitive decline is known to accelerate as disease progresses. At the end of three years, the difference in CDR-SB scores between the ADNI and original treatment groups was 0.95 points, twice as large as the 0.45 difference between treatment and control groups at 18 months (see image at top of story).

This is what would be expected for a disease-modifying therapy, where treated patients should continue to diverge from controls over time. Slicing the data another way, people on drug were 30 percent less likely to progress to a higher CDR-SB score than ADNI participants. External controls are less reliable than a true placebo group. Even so, van Dyck said, the data hint that lecanemab continues to slow cognitive decline over three years of treatment.

Benefits were bigger for people who entered the trial at very early disease stages, when their tau PET scans were below 1.06 SUVR. Previously, scientists had reported six-month OLE data from this “no-tau” subgroup (Nov 2023 conference news). In Philadelphia, van Dyck added 18-month OLE data. Again, the former treatment and placebo groups remained separated throughout the OLE. After three years of continuous treatment, 59 percent of these participants had lost no ground on the CDR-SB; 51 percent had improved their scores over baseline values. This compares with 76 and 60 percent, respectively, at the end of the placebo-controlled period, reinforcing again that AD does continue to progress even in these treated early stage patients.

Early Patients, Slow Decline. In a subgroup of Phase 3 participants with low amyloid burden, those who started on lecanemab (green) maintain separation at three years from those who switched to lecanemab (black to green). [Courtesy of Eisai.]

Because few people got tau PET scans in this trial, the groups were tiny, at 40 to 50 people each, and the data were noisy. To eke out a bit more statistical reliability, van Dyck selected early stage patients from the full cohort by using baseline amyloid loads of below 60 centiloids as a proxy for low tangle load. This resulted in about 150 people each from the former treatment and placebo groups. Again, their CDR-SB curves remained apart from and paralleling each other throughout the OLE, with less noise in the data and error bars separated (image above). After three years of continuous treatment, 46 percent of people in this larger group had stayed stable, 33 percent were above their baseline.

The apparent relative stabilization of cognition in this group, compared with the steepening decline in the overall cohort, highlights the importance of starting amyloid immunotherapy at an early disease stage, van Dyck said. Eisai’s Brian Willis agreed, noting that at later stages, pathological progression is driven by factors other than amyloid.

Dual Mechanism of Action—Plaques and Protofibrils
Why does lecanemab treatment matter after plaques are gone? Speakers evoked the antibody’s modus operandi, saying it both clears plaque and removes soluble protofibrils. Lecanemab has a higher affinity for protofibrils than do other antibodies (Nov 2021 conference news). Among plaque-clearing antibodies, aducanumab and gantenerumab bind soluble species more weakly than does lecanemab; donanemab only binds plaque.

Small species such as oligomers and protofibrils cause much synaptic toxicity, said Dennis Selkoe of Brigham and Women’s Hospital, Boston. His lab reported that oligomers isolated from AD brain inhibit long-term potentiation in hippocampal slices and blunt memory when infused into rat brain (May 2023 news). In cultured human neurons, they promote tau phosphorylation and trigger neurites to degenerate; neutralizing them delays tau pathology. Selkoe believes that this is why lecanemab continues to benefit the brain even in the absence of plaques. “Lecanemab’s dual mechanism of action supports continued dosing,” he said in Philadelphia.

For his part, Kenjiro Ono of Kanazawa University, Japan, linked Aβ protofibrils directly to neurodegeneration. To measure protofibrils in human cerebrospinal fluid, he first isolated them using lecanemab conjugated to magnetic beads, then quantified them via immunoassay. He found that protofibrils were significantly higher in CSF from 34 people with MCI-AD and 64 people with AD dementia than they were in 56 amyloid-negative people.

Curiously, however, protofibrils did not correlate with plaque load. Instead, they correlated with markers of neurodegeneration. Protofibrils were associated with CSF total tau, at r=0.6, and with neurogranin, at about r=0.45, but not with p-tau181, p-tau217, or Aβ42/40. The data suggest that protofibrils may directly promote neurodegeneration, Ono said. Eisai researchers collaborated on the study.

Staying Low. Modeling predicts that stopping lecanemab at 18 months would cause biomarkers to rebound (pink), and that maintaining therapeutic (aqua) or maintenance (blue) dosing would keep them flat. [Courtesy of Eisai.]

Modeling How Amyloid, Tau, and Cognition Interact
To try to predict what its antibody will do, Eisai has developed a quantitative systems pharmacology model (Mar 2022 conference news). In Philadelphia, Eisai’s Youfang Cao said the model integrates what is known about amyloid and tau pathology and their effect on cognition with the published literature on amyloid production, clearance, and tau kinetics and spread. Its 11 equations and 74 parameters attempt to simulate the AD pathological cascade, though without inflammatory components.

Next, the scientists plugged in data on lecanemab’s binding affinities for both protofibrils and plaque. Using data from ADNI and lecanemab’s Phase 2 and 3 studies on a total of 4,056 participants, they predicted how lecanemab would affect six outcomes ranging from amyloid and medial-temporal tau PET, plasma Aβ42/40, and p-tau181, to CDR-SB and ADAS-Cog scores. In every case, the model closely predicted actual trial results, Cao said.

Cao noted the model also predicts factors that cannot yet be easily measured, such as protofibril concentration, tau seeds, and neuronal loss. It estimated that 18 months of lecanemab treatment would clear 70 percent of a person’s starting plaque load, and 94 percent of protofibrils. The scientists will test this prediction by directly measuring protofibrils in stored CSF samples.

The scientists also tested the model on other antibodies, entering known data on the binding affinities of aducanumab, gantenerumab, and donanemab to predict final amyloid PET and CDR-SB values in those trials. Again, the model matched reported outcomes.

This model, then, helped Cao and colleagues determine a maintenance dose for lecanemab. If the drug were discontinued at 18 months, the model shows protofibrils rising 30 percent of the way back to control levels over the next 2.5 years, while medial-temporal tau PET would rise about a quarter back toward the level in the placebo group over the same time frame. If dosing continued at 10 mg/kg biweekly, protofibrils and tangles would remain flat. Ten mg/kg monthly would do the same (image above). Eisai requested marketing approval for that latter dose from the U.S. Food and Drug Administration (May 2024 news).

If approved, at what point should doctors transition their patients? In Philadelphia, Reyderman said their modeling suggests doing so at 18 or 24 months would be equally effective. Even for people who still have some amyloid at 18 months, monthly dosing would continue to clear plaque, and the clinical outcomes after four years would be nearly identical, she said. This means doctors could move to maintenance monthly dosing without needing to order an expensive amyloid PET scan to confirm amyloid negativity. Eisai’s Lynn Kramer said the company is in talks with the FDA about the best transition point. No final decision has been made.

Attendees in Philadelphia asked when to stop dosing. To that, Irizarry had a simple answer: when patients have progressed to moderate dementia stages. Accumulating evidence from multiple antibody programs indicates that amyloid immunotherapy does little good once cortical tau pathology takes off.—Madolyn Bowman Rogers

Leqembi: The Case for Long-Term Dosing

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