PHILADELPHIA – Eisai executives took the stage at the Alzheimer's Association International Conference on Tuesday to report data they say support using its beta-amyloid-targeting drug Leqembi (lecanemab) as a chronic maintenance treatment for Alzheimer's disease.
The US Food and Drug Administration approved Leqembi last year for patients with early Alzheimer's and evidence of beta-amyloid pathology, a hallmark of the neurodegenerative disease, based on the drug's ability to slow patients' rate of cognitive decline. Patients can receive intravenous infusions of the drug every two weeks, according to the FDA-approved label. Eisai earlier this year submitted a supplemental biologics license application (sBLA) seeking Leqembi's approval as a lower-dose maintenance treatment, which patients would receive monthly after completing an initial regimen of biweekly infusions. The FDA is expected to decide whether to approve this sBLA by January 2025.
"Alzheimer's disease, like any other chronic and progressive disease, requires a long-term therapeutic strategy," said Larisa Reyderman, Eisai's VP of translational science, during a featured research session at AAIC.
Eisai and Biogen, which codeveloped Leqembi and split product revenue and cost of sales, have recently been talking up their drug's "dual-acting" mechanism, emphasizing that it targets not only beta-amyloid plaque but also protofibrils, which they say is an especially toxic form of beta-amyloid. That underpins the drugmakers' reasoning for why it's important to continue taking the drug even after plaque is removed, since these protofibrils can cause neuronal injury and increase formation of plaque.
However, some neurologists have said they want to see more data supporting Leqembi's use as a maintenance treatment.
At the session Tuesday, Reyderman and colleagues shared some additional data. They noted that Eisai's sBLA primarily contains data around two clinical trials: an off-treatment period between a Phase II trial and open-label extension, and a Phase III trial and open-label extension, which they compared to a natural history study.
After the company's Phase II trial of Leqembi, called Study 201, patients had the option to enroll in an open-label extension study. Before the extension portion, patients went off treatment for an average period of two years. During that gap, patients who had previously been receiving Leqembi on average maintained better scores on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale than their placebo counterparts, which Reyderman attributed to the boost these patients got from the slower progression of disease during the 18-month core study. However, their rate of cognitive decline — the measurement of how quickly their condition continued to deteriorate — during the gap period sped up and matched the rate seen in the placebo group. That is, they did not maintain the slowed rate of cognitive decline after they stopped treatment, Reyderman said.
Beta-amyloid also reaccumulated during that period, as did other biomarkers of neurodegeneration. Based on PET scans, beta-amyloid increased by 21 percent during the gap period, and blood tests showed that the amyloid-beta 42/40 ratio worsened by 47 percent. Phosphorylated tau (p-tau) 181 also reaccumulated by 24 percent and p-tau 217 by 13 percent.
That indicates "discontinuation of anti-amyloid treatment results in reaccumulating of Alzheimer's disease pathology," Reyderman said.
She added that Eisai developed multiple pharmacokinetic and pharmacodynamic models based on data from the Phase II and Phase III trials and their open-label extensions, which the company used to conduct simulations to identify a maintenance dosing regimen that sustained clinical efficacy and prevented biomarkers from reaccumulating, while reducing the frequency of dosing.
According to these models, if Leqembi is discontinued, "half of the treatment effect is lost in 12.1 years on amyloid PET," Reyderman said, adding that since fluid biomarkers reaccumulate at a faster rate than amyloid PET, half of the treatment effect on the plasma amyloid-beta 42/40 ratio "will be lost in six months."
Based on these analyses, she said Eisai determined patients would likely be able to switch to monthly dosing after 18 or 24 months of the initial biweekly treatment regimen. Eisai is discussing the length of the biweekly treatment initiation phase with the FDA and has not yet determined a specific time at which patients would convert to maintenance dosing.
Dennis Selkoe, codirector of the Ann Romney Center for Neurologic Diseases at Brigham and Women's Hospital and a professor of neurologic diseases at Harvard Medical School, said it makes sense that patients would continue to take Leqembi to target protofibrils, a form of beta-amyloid that he said accounts for a substantial portion of synaptic toxicity.
"There's extensive evidence for a dual lecanemab mechanism supporting the rationale for continued dosing not only for plaque reduction," he said during a presentation on the role of beta-amyloid protofibrils during the same conference session Tuesday.
Christopher van Dyck, director of the Alzheimer's Disease Research Unit and a professor of neurology and neuroscience at Yale School of Medicine, during a presentation of data on long-term Leqembi treatment noted that between Eisai's Phase III CLARITY AD study and open-label extension, there's now data on Leqembi's efficacy through more than three years.
The FDA approved Leqembi based on results from the randomized, controlled CLARITY AD study, which illustrated a 27 percent slower rate of cognitive decline among patients treated with Leqembi than those in a placebo group, based on Leqembi-treated patients on average scoring 0.45 points better than patients on placebo on the 18-point CDR-SB after 18 months.
The difference in CDR-SB scores reached 0.95 points when researchers compared patients who received Leqembi for three years in the open-label extension against untreated patients in the Alzheimer's Disease Neuroimaging Initiative, a natural history study at the University of Southern California.
During a Q&A session following the presentations, James Lah, a neurologist at Emory Healthcare, asked whether physicians on the panel thought continued dosing would be needed for Eli Lilly's Kisunla (donanemab), another drug that targets beta-amyloid plaque. The FDA approved Kisunla earlier this month, but unlike Leqembi, Lilly said patients can potentially stop taking it if they reach a certain threshold of beta-amyloid plaque removal, as measured by PET imaging.
"I don't want to get into conflicts between antibodies," van Dyck said. He said he would like to see more data to support the ability to stop treatment before doing so with patients.
Earlier in the day Tuesday, during a separate presentation on Lilly's Phase III TRAILBLAZER-ALZ 2 trial on Kisunla, Lilly's global imaging platform leader Emily Collins presented data that she said supports the company's limited-duration dosing approach. In the randomized, controlled TRAILBLAZER-ALZ 2 trial, patients receiving Kisunla were switched to placebo once beta-amyloid plaque was removed. Nearly half of the patients in the treatment group, 46.6 percent, were able to stop receiving the drug by week 52, for example, and those patients continued to maintain improvements on the CDR-SB, compared to those on placebo, even after they stopped treatment.
Collins said beta-amyloid levels stayed low after patients switched to placebo, and the rate of beta-amyloid reaccumulation at that point was similar to the natural rate of accumulation in beta-amyloid negative individuals.
Neill Graff-Radford, a neurologist at the Mayo Clinic, asked during the Q&A session on Leqembi maintenance dosing whether Eisai planned to do a randomized, controlled trial of maintenance dosing compared to stopping treatment. Taking Leqembi long term can be expensive for patients and usurp already limited resources within health systems, he suggested.
Leqembi given as biweekly infusions has a list price of $26,500 per year. Eisai hasn't yet announced a price for maintenance dosing.
"It's a tremendous commitment," Graff-Radford said. "A real use of resources that are very limited, so that many patients won't be treated if we continue treating everybody without really good evidence."
Eisai doesn't plan to conduct a new clinical trial evaluating the impact of continued treatment after 18 months, said Michael Irizarry, deputy chief clinical officer within the firm's neurology group. He noted that Eisai also initiated a rolling submission of a BLA seeking approval of a subcutaneous version of Leqembi that could be used as a weekly maintenance treatment, which would be more convenient than intravenous infusions. Eventually, Eisai hopes to reduce the need for intravenous infusions in the treatment initiation phase and plans to submit another application with the FDA for a subcutaneous Leqembi formulation that can be used in this setting.
"The rationale for maintenance is based on the data from the Phase II study that supported the detrimental effect of stopping treatment and the ongoing separation from a natural history cohort in Phase III," Irizarry said. "That will serve as the basis for the recommendation for maintenance dosing that's under review by the FDA."