New Leqembi Data Illuminate Longer-Term Effects, Tau Reduction

As researchers, doctors and biopharma professionals gathered in Philadelphia this week for the Alzheimer’s Association International Conference, expectations were high. Among the most-anticipated presentations were several studies by Eisai on its Alzheimer’s therapy Leqembi that suggest the drug should be given early in the disease’s progression and continuously, and that it affects levels not only of amyloid but of tau tangles as well.

Leqembi, the anti-amyloid therapy Eisai co-developed with Biogen, received full FDA approval in July 2023. Among the questions Eisai has continued to investigate is: what happens if patients stop taking the drug? On Tuesday, it shared a mass of long-term data on this and more.

In one of its presentations, Eisai shared data from a study that included a gap period where both arms stopped taking either the placebo or drug for an average of two years. During the initial treatment period prior to the pause, Leqembi elicited a positive effect on cognition compared to placebo. During the gap, participants in both groups showed cognitive decline at the same rate, said Lynn Kramer, chief clinical officer of deep human biology learning at Eisai.

Kramer compared Alzheimer’s to other progressive, chronic conditions like rheumatoid arthritis. Treatment “calms” the disease process down, but upon stopping, “it’ll flare back up,” he told BioSpace. During the no treatment period, biomarkers showed immediate worsening of disease, according to Eisai. Once treatment resumed, the decay flattened as it had in the beginning of the trial, Kramer said.

Another trial presentation showed the effects of an early versus a delayed start of Leqembi, compared to longitudinal data from an observational cohort set up by the NIH to follow the natural progression of Alzheimer’s disease. Participants in this trial were specifically selected by Eisai to match Alzheimer’s patients in the observational cohort.

In the double-blind trial, the first 18 months showed a 27% slowing of cognitive decline for patients treated with Leqembi versus those on placebo. Then at 18 months, the placebo group was switched to Leqembi and showed an improvement in cognitive decline compared to the observational group over the following year and a half.

“The important thing to see is that people who started on placebo don’t catch up to the patients who are on [Leqembi] continuously,” said Christopher van Dyck, director of the Alzheimer’s research unit at Yale, who presented the results alongside Kramer. “And that’s really important evidence that [Leqembi] is disease-modifying.”

More than 50% of patients who started treatment with Leqembi in the earliest stages of Alzheimer’s continued to show improvement after three years, Eisai reported.

A third study showed that in addition to clearing amyloid plaque from the brain over time—the drug’s primary target—Leqembi also has an impact on tau protein, the other key pathological feature of Alzheimer’s. Eisai studied areas of the brain where the first significant abnormal tau accumulation occurs.

“In the medial temporal, meta temporal and temporal lobe regions, all show significant benefit of [Leqembi] through the slowing of tau accumulation,” van Dyck told BioSpace, adding that patients with the lowest tau levels at the start of treatment appeared to do the best.

This was the only study on the early-stage patient group, Kramer added, because other companies felt these patients would deteriorate too slowly to demonstrate an effect. He noted that 40% of the patients in the sub-study had very low or no tau at the beginning of the study.

Eisai and Biogen have a pending FDA submission for maintenance dosing to reduce the frequency of Leqembi to once a month instead of every two weeks. A subcutaneous formulation of Leqembi has also been granted Fast Track designation. Kramer said the entire packet is expected to be submitted for approval in 2024.

This year’s conference is generating an unprecedented level of excitement among attendees.

“Research has finally caught up with drug development” in the Alzheimer’s space, said Howard Fillit, co-founder and chief scientific officer at the Alzheimer’s Drug Discovery Foundation (ADDF). With two disease-modifying drugs now on the market, researchers can now discuss the use of safe and effective Alzheimer’s drugs “for really the first time in a meaningful way,” he told BioSpace.

The Eisai data will make for a “beautiful segue” into the next thing, which could be identifying and treating cognitively normal patients before they ever show symptoms, van Dyck said.

While amyloid beta and tau had been the primary AD targets for decades, the R&D landscape has shifted significantly in recent years, with around 75% of drugs now in clinical development targeting the biology of aging, Fillit said.

One key area where Fillit expects to see novel approaches presented at AAIC is around the inflammatory component of Alzheimer’s. Neuroinflammation not only causes harmful symptoms but also leads to neurodegeneration and progression of the disease, he noted.

GLP-1 agonists—the darling of the diabetes and weight-loss markets—have also shown promise in treating Alzheimer’s. Fillit attributes this to an improvement in the metabolism of the brain, as metabolic decline, a natural part of aging, can lead to neurodegeneration. Novo Nordisk is currently studying semaglutide in people with early Alzheimer’s disease, and Fillit noted an ADDF-supported study using another GLP-1 drug, liraglutide. Results from this study, presented Tuesday, showed that treatment with liraglutide slowed cognitive decline by as much as 18% in people with early-stage Alzheimer’s disease.

New tools for clinicians are also of interest this year as novel blood tests and speech technology are being developed to accelerate disease identification and quantify progression. Both Fillit and van Dyck expressed excitement over p-tau217 blood tests. A recent study showed the blood test combined with amyloid probability score had a high diagnostic accuracy for disease identification among patients with cognitive symptoms.

“We’re also going to hear discussion about combination therapy,” Fillit said, adding that with two antibodies, as well as cholinesterase inhibitors, on the market, the industry will need to determine how to do combination studies. Fillit anticipates a lot of conversation around trial design, biomarkers and precision medicine approaches to identify the right patients for each trial.

Fillit said that historically, the AAIC conference was “often not a very optimistic type setting” due to the lack of drug development. That has now changed. “We’ve succeeded in bringing disease-modifying drugs to market as a field, and I think that’s going to make a huge difference in how the field goes forward.”