Leqembi: Side Effects No Worse in Clinical Use Than They Were in Trial

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2024 - 17th:

Lecanemab has been in clinical use in the U.S. for nearly two years, and in Japan for not quite a year. How is it going? At the Clinical Trials on Alzheimer’s Disease conference, held October 29 through November 1 in Madrid, speakers offered a snapshot. In the U.S., about 9,000 people have been treated, most of them white city dwellers. Clinicians are following the recommended schedule of MRIs for safety monitoring, and ARIA rates have been comparable to those in the trials, despite these real-world patients having more underlying health conditions than did trial participants.

  • ARIA rates in clinical practice are the same as in trials.
  • This is despite a broader population of patients being treated.
  • In Japan, use has been growing faster, but may soon hit a ceiling.
  • EMA follows UK, pivoting toward approval

In Japan, clinical use is climbing faster, with about 4,500 people now on the drug. ARIA rates in Japan are half those in the U.S., which was also the case in the Phase 3 Clarity trial.

Meanwhile, use in other countries is beginning, with lecanemab approved this year in China, South Korea, Hong Kong, Israel, the United Arab Emirates, and the United Kingdom. One problem in the UK: The country's National Health Service will not cover the cost, meaning access will be limited to wealthier people.

Not all countries are giving it the green light, however. In July, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) said no to the drug; in October, Australia's did. In August, the U.K. approved lecanemab but, striking a compromise, excluded APOE4 homozygotes, who have the highest risk of ARIA. Also last summer, drug maker Eisai asked the CHMP to reconsider, and today, on November 14, it did just that. Following the UK's example, EMA is now recommending that the European Commission approve lecanemab except for APOE4 homozygotes. At CTAD in Madrid, one talk suggested that non-carriers and heterozygotes reap a greater benefit from lecanemab, while having a lower risk (see below).

The other approved anti-amyloid antibody, donanemab, went on the market in July and has begun to enter clinic use, with around 700 people in the U.S. on it so far (see next story in this series).

Heading Up. The number of lecanemab infusions (colored dots) at Washington University, St. Louis, has grown steadily over a year. Most ARIA-A occurs around the fifth infusion. [Courtesy of Joy Snider, WashU.]

In the U.S., lecanemab has been on the market longest. In Madrid, Marwan Sabbagh of the Barrow Neurological Institute in Phoenix offered a bird’s eye view, by showing administrative claims data from the Komodo Health research database, which collects these records from more than 150 insurers representing 165 million patients. The data covered the period from January 2023, when lecanemab obtained accelerated FDA approval, through June 2024.

This analysis cohort comprised 3,155 people who had received at least one lecanemab infusion and had health insurance, i.e., about one-third of everyone treated in the U.S. In this group, 84 percent were non-Hispanic white, 93 percent lived in urban areas. Their average age was 75; 56 percent were women. Sixty percent were diagnosed as having mild cognitive impairment, indicating that the majority of the cohort were at an early disease stage, as expected. Four percent were taking anticoagulants, considered a risk factor for more serious side effects (Jan 2023 news; Aug 2023 conference news).

More than 90 percent of these patients started lecanemab after October 2023, when usage took off in the U.S. On average, it took nearly five months from their confirmatory amyloid test to starting infusions, indicating that the process remains slow. The average time on lecanemab in this early cut of real-world data was 129 days, or a little over four months. Most patients received their doses and scans per protocol, with the average time between infusions 16 days, and the first MRI done at 47 days, after the fourth infusion. “Lecanemab is being used appropriately,” Sabbagh concluded.

Sabbagh also noted that 85 percent of patients were still taking lecanemab at their four-month follow-up appointments. “Patients are highly motivated to stay on these drugs once they understand the consequences of treatment and nontreatment,” Sabbagh said. He has about 50 patients on lecanemab.

Reports from individual medical centers add detail to this broad-brush picture. Lawrence Honig of Columbia University, New York City, previously reported that among the first 122 people treated at Columbia, 7 percent developed ARIA-E, fewer than expected (Aug 2024 conference news). In Madrid, Honig updated the numbers.

By now, 162 patients have received an average of 13 lecanemab infusions each. Honig noted that many of them live far away, some even in Europe. They go to local infusion centers and MRI sites. As was seen in the Komodo Health database, 90 percent are non-Hispanic whites, and 60 percent have an MCI diagnosis. Their average age is 73. Most were genotyped for APOE, with 44 percent being E4 heterozygote and 14 percent homozygote. Typically, amyloid positivity was confirmed by cerebrospinal fluid biomarkers. Honig prefers that to PET, because a CSF analysis includes three biomarkers and gives him greater confidence in the diagnosis.

How have they fared? Eleven percent developed ARIA-E, about the same rate as in the Clarity trial. ARIA-E was typically mild and asymptomatic. In two cases, clinicians continued giving infusions, while in 14 others, dosing was paused until the edema cleared up. One person discontinued treatment due to ARIA-E, two due to ARIA-H. There have been no deaths since the previously reported case.

ARIA being quite manageable is notable, Honig said, because these patients have more co-morbidities than did trial participants. So far, Honig has treated one person on anticoagulants, three with prior cortical strokes or bleeds, and four with vascular malformations. He has also treated two patients with pacemakers, devices that can be affected by MRI scans. Radiologists are able to handle this, Honig said, often by having a cardiology nurse present.

His talk inspired a lively debate in Madrid over how conservative clinicians should be during this initial transition to immunotherapy when they make decisions about the treatment eligibility of the person across the table from them (Nov 2024 conference news).

Both Sabbagh and Honig emphasized that their institutions have put protocols in place to ensure that MRI monitoring is done appropriately, with infusions and scans prescribed in sets. For each set, the prescribing neurologist must sign off that the MRI has been done before a patient can receive their next infusion. “We instituted that as a solid stop. There has not been one violation,” Honig said.

Other health systems report similar experiences. Sutter Health in California employs more than 100 neurologists serving 3.5 million patients, and has thus far treated 234 people with lecanemab, according to neurologist Shawn Kile. All were screened either at one of the system’s two memory clinics, or by general neurologists using a review board. Neurologists followed the published AUR, with few exceptions, Kile said. All patients had APOE genotyping; 133 were heterozygote, 14 homozygote. Recipients’ average age was 70; 30 percent had mild dementia, the rest MCI.

So far, 15 patients have had ARIA-E; at 6 percent, this is half the rate of the clinical trial. Three of them had ARIA that was severe on MRI and caused confusion and headaches. One person had a lasting neurological deficit, a loss of vision in one-fourth of his or her visual field. Three people who stopped lecanemab due to ARIA developed a macrohemorrhage one to three months later, suggesting that side effects can occur with a delay. However, there were no deaths related to lecanemab treatment.

Likewise, Joy Snider of Washington University, St. Louis, offered an update from her medical center. At the beginning of the year, clinicians there had treated 68 people (Jan 2024 news). By a July 2024 data cut, the number of patients had risen to 186. As at other centers, nearly all were non-Hispanic white, with an average age of 74. Similar to in the trial, 13 percent developed ARIA-E, two-thirds of whom were mild and asymptomatic. Seven people had symptoms, two of those severe enough to require hospitalization. Notably, the majority of ARIA occurred around the fifth infusion; this was also seen at other institutions (image above).

Restricted Use in the U.K., Growing Numbers in Japan
With the U.K. limiting lecanemab use to non-homozygotes, Richard Perry of Imperial College London, working with Eisai scientists, showed how removing this group from the Clarity trial data would affect trial results. Without E4 homozygotes, there were 1,521 participants. Amyloid removal was the same as in the full cohort, at 59 centiloids per person. Cognitive outcomes were slightly better, with decline on the CDR-SB slowed by 33 percent, versus 27 percent in the full cohort, and other measures similarly nudged. The difference in ARIA was more notable. ARIA-E was lower by a fourth, from 13 to 9 percent, as was ARIA-H, falling from 17 to 13 percent. The rate of microhemorrhages nudged downward from 14 to 10 percent, superficial siderosis from 6 to 4 percent.

The EMA's CHMP committee cited Perry's analysis in its reconsideration, saying that, for this restricted group, the benefit of lecanamab treatment outweighed the risks (EMA announcement).

In Japan, lecanemab was approved in September 2023, and received insurance coverage at the end of that year. Thus, it has been in clinical usage for about 10 months. In Madrid, Takeshi Iwatsubo of the University of Tokyo told the audience that more than 600 clinics and 900 doctors now prescribe it. Iwatsubo noted that lecanemab use is restricted to major medical centers able to manage the multiple needs of patients, including MRI monitoring.

Another wrinkle: APOE genotyping is required for lecanemab use, but is not covered by insurance. As a workaround, patients enroll in a registry maintained by academic centers, which takes care of genotyping.

An estimated 4,500 prescriptions have been filled in 2024 so far, Iwatsubo said. About 80 percent of patients have mild cognitive impairment, the rest have mild dementia. Most are in their 70s, and almost two-thirds are women. Confirmation of amyloid positivity is done by PET two-thirds of the time, cerebrospinal fluid the rest.

Curiously, in the Clarity trial, ARIA occurred at only half the rate in Asian participants compared with other geographic regions in this global study. There were only 10 cases among 153 participants, for a rate of 6.5 percent. For the 88 Japanese participants, the rate was even lower, at 4.5 percent. In clinical usage so far, ARIA rates have matched that, with around 5 percent of patients developing ARIA-E or ARIA-H, Iwatsubo reported.

Though the rollout has been smooth so far, Iwatsubo noted hurdles to future expansion. In this country of 124,000 million people, with its aging society, only about 2,400 physicians are licensed to prescribe anti-amyloid antibodies. There is also a shortage of infusion sites. Among the 10 million Japanese people with MCI or AD, about 1 million are estimated to be eligible for treatment. Only a small proportion of them will be able to get lecanemab, Iwatsubo said, adding that more treatment options for AD are needed.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Donanemab

News Citations

  1. Finally, Therapeutic Antibodies Start to Reduce Tangles
  2. Should People on Blood Thinners Forego Leqembi?
  3. Is ARIA an Inflammatory Reaction to Vascular Amyloid?
  4. Two New Deaths on Leqembi Highlight Need to Better Manage ARIA
  5. Donanemab: Small Tweak in Titration, Big Gain in Safety?
  6. Rising Leqembi Prescriptions Are Straining Clinic Capacity

External Citations

  1. EMA announcement

Further Reading

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