Background

BAN2401 is the humanized IgG1 version of the mouse monoclonal antibody mAb158, which selectively binds to large, soluble Aβ protofibrils. This therapeutic antibody grew out of the discovery of the “Arctic” mutation in APP, which leads to a form of clinically typical Alzheimer's disease that is marked by particularly high levels of Aβ protofibrils and relative absence of amyloid plaques (see Nilsberth et al., 2001). mAb158 was originally developed at Uppsala University, Sweden (Englund et al., 2007).

In its preclinical development, mAb158 was found to reduce Aβ protofibrils in brain and CSF of Tg-ArcSwe mice (Lord et al., 2009; Tucker et al., 2015). Subsequent studies in mouse neuron-glial co-cultures showed that mAb158 may protect neurons, i.e., reduce Aβ protofibril toxicity, by counteracting the pathological accumulation of these protofibrils in astrocytes (Söllvander et al., 2018). In a direct comparison with the anti-amyloid antibodies aducanumab and gantenerumab, lecanemab was reported to bind most strongly to Aβ protofibrils, while the others preferred more highly aggregated forms (Nov 2021 conference news). Lecanemab was shown to bind to diffusible Aβ fibrils and protofibrils from human brain tissue (Nov 2022 news; Johannesson et al., 2024). It bound to cerebral amyloid angiopathy fibrils less avidly than other Aβ antibodies (Soderberg et al., 2024). In aged Tg2576 mice, mAb158 lowered Aβ protofibrils within four weeks, and later reduced Aβ plaques; both effects reversed after treatment was stopped (Rizoska et al., 2024). Lecanemab was also reported to interfere with the binding of Aβ protofibrils to fibrinogen, which may offer additional protection against clotting abnormalities and synaptotoxicity that occur in AD (Singh et al., 2024).

BAN2401 was licensed to Eisai, which in March 2014 signed a collaboration agreement with Biogen for joint development of this therapeutic antibody.

While clinical trials are being conducted in Alzheimer's (see below), preclinical research with postmortem Down's syndrome brain sections indicates binding of lecanemab to Aβ deposits in this disease, as well (Johannesson et al., 2021). In another study of postmortem tissue from 15 people with DS, lecanemab bound extensively to both amyloid plaques and vascular amyloid (Liu et al., 2024).

A hexavalent antibody based on mAb158 is being developed, with the goal of enhancing binding strength selectively to Aβ protofibrils (Rofo et al., 2021).

Findings

A multicenter Phase 1 trial tested the safety, tolerability, and pharmacokinetics of single and multiple ascending intravenous doses of BAN2401 in 80 people with mild to moderate AD. Changes in Aβ levels were also measured. BAN2401 was well-tolerated at all doses tested, up to 10 mg/kg every two weeks for four months, with amyloid-related imaging abnormalities (ARIA-E, ARIA-H) occurring at the same rate in both placebo and BAN2401. The antibody entered the CSF and showed dose-dependent exposure, though with a short serum elimination half-life of seven days and no clear effect on CSF biomarkers. Results were published (Logovinsky et al., 2016).

Subsequently, a Phase 2, 18-month U.S. trial tested five different intravenous doses of BAN2401 in a Bayesian adaptive design. Allocation of subsequent enrollees to different groups was adjusted in response to frequent interim analyses, the first to be done in late 2015 after the first 196 patients had entered the trial, and again every time 50 more people had enrolled (for detailed description of this innovative trial design see Satlin et al., 2016). This trial enrolled 856 people who had either early stage AD as defined by the proposed NIA-AA diagnostic criteria or mild cognitive impairment due to AD, or who met NIA-AA criteria for probable AD and whose diagnosis was confirmed by a positive amyloid PET scan. As primary outcomes, the trial measured 12-month change from baseline in the new ADCOMS composite of cognitive tests (Wang et al., 2016), and safety.

In 2017 the sponsors announced that BAN2401 had shown no cognitive benefit at this 12-month time point. However, futility conditions had not been met either at the 17 interim analyses conducted until then. Therefore the trial continued to full enrollment of 856 participants, and out to the full treatment period of 18 months (Dec 2017 news). In February 2018, the trial protocol was amended to offer up to five years of additional treatment in an open-label extension phase, in which change on the ADCOMS will be measured at each visit. 

The sponsors announced top-line results of the blinded 18-month treatment phase in July 2018 (see July 2018 news). The highest antibody dose of twice-monthly 10 mg/kg slowed progression on the ADCOMS and reduced brain amyloid accumulation, according to a press release from BioArctic. Full results of this Phase 2b study were presented at AAIC (Jul 2018 news). The antibody reduced brain amyloid by up to 93 percent in the highest-dose group. This dose slowed cognitive decline by 47 percent on the ADAS-Cog, and by 30 percent on the ADCOMS. The next-lower dose, 10 mg/kg monthly, showed a trend toward slower cognitive decline that was not statistically significant. In an analysis of CSF from a subgroup of patients, the treatment caused a dose-dependent rise in CSF Aβ42. MRI scans detected ARIA in just under 10 percent of participants overall, and in fewer than 15 percent of those with ApoE4 in the highest-dose group. Most ARIA occurrences were asymptomatic.

The results were complicated by uneven distribution of ApoE4 carriers between placebo and treatment groups, which was caused by an EMA request during the trial. A subgroup analysis, presented at CTAD, suggested that the treatment benefit was not due to this imbalance (Nov 2018 conference news). Full results were subsequently published (Swanson et al., 2021). Additional analysis of the three cognitive endpoints with six different statistical methods found a consistent positive effect of treatment (Nov 2021 conference news).

An open-label extension to this trial re-enrolled its participants to deliver the highest antibody dose for up to two years total. As reported at AD/PD 2019 in Lisbon, Portugal, Eisai/Biogen planned to treat up to 250 people in this extension, which was to run until August 2021 (May 2019 conference news). Baseline data from 35 participants suggested that brain amyloid load had remained steady during a two-year pause in antibody dosing, but that cognition declined when BAN2401 was discontinued (Dec 2019 conference news). One-year brain imaging data from 76 participants, presented in December 2020 at CTAD, indicated that people previously treated with placebo had large decreases in their brain amyloid since entering the OLE, while those previously treated with antibody maintained low levels of brain amyloid. ARIA-E incidence was comparable to the core study. Most ARIA-E was asymptomatic and resolved within four to 12 weeks. Continuing to dose people with mild to moderate ARIA-E appeared to pose no additional safety issues (Nov 2020 conference news). More one-year OLE data on 180 participants were presented in March 2021 at AD/PD. Brain amyloid fell fastest in those who began the OLE with the highest amyloid. By the end, 80 percent of participants were judged amyloid-negative, with SUVRs below 1.17 (Mar 2021 conference news).

At the July 2021 AAIC, Eisai reported 18-month OLE data on 100 people. It suggested a slowing of cognitive decline in the open-label phase, compared to ADNI historical data. CSF Aβ42/40, which had increased with treatment during the placebo-controlled phase of the trial, started to decline during the dosing gap, but rose again in all participants after open-label treatment began. A post hoc analysis across the entire study duration suggested cognition declined more slowly in people on lecanemab than in those on placebo (Aug 2021 conference news). More data presented at the Nov 2021 CTAD showed a correlation between plaque clearance and slowed decline on ADCOMs in the OLE (Nov 2021 conference news). At the same conference, Eisai reported that changes in plasma ptau181 tracked with changes in amyloid PET and plasma Aβ42/40. OLE results were formally published (McDade et al., 2022), as were details on ARIA in the completed study (Honig et al., 2023), and an explication of the advantages of the Bayesian design (Berry et al., 2023).

In March 2019, Eisai began a Phase 3 trial called Clarity AD, to be run at 250 sites across the world. It aimed to enroll 1,566 people with early symptomatic AD, who received 10 mg/kg drug or placebo infusion every two weeks for 18 months, followed by a two-year open-label extension. The primary outcome in the core study was change in CDR-SB at 18 months, with secondary outcomes of brain amyloid, ADCOMS, and ADAS-Cog14 subscale. In the extension phase, primary outcomes were change in CDR-SB as well as safety. Change in the CSF biomarkers neurogranin, neurofilament light chain, Aβ(1-42), total tau, and phospho-tau from baseline up to 45 months were originally listed as primary outcomes in the trial registration, but dropped in July 2019. Plasma and CSF biomarkers, as well as amyloid and tau PET, are being assessed in optional longitudinal substudies.

As of October 2020, Clarity AD had randomized 1,222 participants, with demographic and cognitive scores similar to the Phase 2 study (Nov 2020 conference news). By March 2021, it had exceeded its enrollment goal, at 1,794 patients, the company announced (press release). In 2022, the extension added an option for a weekly subcutaneous injection of 720 mg. It is set to run until 2027.

In February 2020, the Alzheimer’s Therapeutic Research Institute announced that the Alzheimer's Clinical Trial Consortium (ACTC) would conduct a large Phase 3 study of lecanemab, called AHEAD 3-45 and co-funded by the NIH and Eisai (press release). It started in July 2020 as a four-year trial that comprises two sub-studies in a combined 1,400 people who are cognitively normal but have elevated brain amyloid. A3 is enrolling 400 people whose amyloid is below the brain-wide threshold for positivity; they will receive 5 mg/kg titrating to 10 mg/kg BAN2401 or placebo every four weeks for 216 weeks, and their primary outcome will be change in brain amyloid PET at that time. A45 is enrolling 1,000 participants who have a positive amyloid PET scan. They will receive BAN2401 titrated to 10 mg/kg every two weeks for 96 weeks, followed by 10 mg/kg every four weeks through week 216. Their primary outcome is change from baseline on their Preclinical Alzheimer Cognitive Composite 5 (PACC5) score, also at week 216. Secondary outcomes for A45 include change in brain amyloid PET and cognitive function. Both studies will measure change in tau PET as a secondary outcome. This new study will use blood Aβ42/40 measures to rule out participants unlikely to have elevated brain amyloid before proceeding to PET imaging (for details, see Rafii et al., 2022).The first person was dosed in this trial in September 2020; as of the July 2021 AAIC, 77 people had been randomized. As of November 2022, 107 sites were recruiting around the world. In early 2024, a two-year open-label extension was added, with trial completion expected in February 2031.

In June 2021, the FDA designated lecanemab a breakthrough therapy, expediting regulatory review, and soon after, Eisai/Biogen began their application for marketing approval (press release; Oct 2021 news). In December 2021, the agency granted fast-track designation (press release).

In September 2021, Eisai began a Phase 1 evaluation of lecanemab subcutaneous administration. The study compared the pharmacokinetics, bioavailability, and safety of a single 700 mg injection under the skin in the abdomen to 10 mg/kg given intravenously in 60 healthy people; it was completed in January 2022. In September 2022, a Phase 1 study started evaluating bioequivalence of a subcutaneous formulation delivered with an auto-injector device; it enrolled 160 healthy participants and finished in January 2023.

In November 2021, the DIAN-TU announced its choice of lecanemab for the first DIAN-TU anti-amyloid/anti-tau concurrent trial (Nov 2021 conference news). It will pair lecanemab with the anti-tau antibody E2814 in the Tau NexGen prevention study in 168 people with familial AD mutations. All will receive lecanemab, while half will get E2814, and half a matching placebo, against a primary outcome of change in tau PET. This trial will run at 40 sites in the Americas, Australia, Japan, and six European countries, until 2027 (Mar 2021 news). As of July 2024, the trial was fully enrolled with 197 participants.

In May 2022, Eisai/Biogen completed lecanemab’s FDA submission, based on the Phase 2 data (May 2022 news). In July 2022, the FDA granted priority review status to the application, with a decision date of January 6, 2023 (Jul 2022 news). 

On September 27, 2022, Biogen and Eisai reported positive top-line results on all primary and secondary outcomes of the Phase 3 Clarity AD study (Sep 2022 news). Results were presented in December at the 2022 CTAD conference, and published the same day (Dec 2022 conference news; van Dyck et al., 2023). Lecanemab slowed decline on the CDR-SB by 27 percent compared to placebo at 18 months. Key secondary endpoints, including the ADAS-Cog14, ADCOMS, and ADCS MCI-ADL, all showed a similar slowing of decline. Two-thirds of the treated group became PET-amyloid negative at 18 months. Tau PET indicated a significant slowing of tangle accumulation in the medial temporal lobe, and trended toward slowing in other brain regions. The astrocytosis biomarker GFAP was reduced on treatment, but markers of neurodegeneration were mixed. Safety was in line with past studies, with amyloid-related ARIA-E detected in 12.6 percent of treated participants versus 1.7 percent of the placebo group. About one-quarter had symptoms, which were typically mild and transient. Three people had severe symptoms, but the company did not say what they were. Full safety data were published (Honig et al., 2024).

Three deaths from brain hemorrhage have been reported in the lecanemab open-label extension (Jan 2023 news). Two of the three people had received blood thinners. In Clarity, macrohemorrhages, defined as any brain bleed larger than 1 cm, occurred in 0.6 percent in the treatment group, and 0.1 percent in the placebo group; for people on anticoagulants and lecanemab, this rate increased to 2.4 percent. According to a news article, the third fatality was a 79-year old woman with pre-existing cerebral amyloid angiopathy (Piller, 2023). Published in December 2023, her autopsy report detailed fatal cerebral, Aβ-related arteritis after her third dose of lecanemab (Solopova et al., 2023; Jan 2024 news). A 65-year-old woman who received three doses of lecanemab died after being treated with tissue plasminogen activator for acute stroke symptoms; her brain autopsy revealed inflammation in blood vessels with cerebral amyloid angiopathy. The examination also showed evidence of phagocytic clearance of vascular Aβ and parenchymal Aβ plaques, and other changes suggesting Aβ and tau clearance (Castellani et al., 2023; Reish et al., 2023).

On January 6, 2023, the FDA approved lecanemab under the Accelerated Approval pathway, based on evidence of effect on the surrogate endpoint of amyloid removal in the Phase 2 trial, and a reasonable likelihood of clinical benefit (FDA press release; Jan 2023 news). Lecanemab is sold under the brand name Leqembi.

In March 2023 , the U.S. Veterans Health Administration announced it would cover the cost of lecanemab for veterans in the early stages of AD, excluding those with two copies of APOE4 (press release; VA use criteria).

Additional efficacy data from the Clarity trial, presented at the March 2023 AD/PD conference and subsequently published, showed benefit on self-reported outcomes capturing quality of life and caregiver burden (April 2023 conference news; Cohen et al., 2023). 

In March 2023, Leqembi Appropriate Use Recommendations were published (Cummings et al., 2023). They stipulate that it not be prescribed for people taking anticoagulants, or those with a clotting disorder, strokes, or seizures. People on lecanemab should not be treated with acute thrombolytics such as tPA, though common antiplatelet medications such as aspirin or clopidogrel are allowed. The AUR recommend APOE genotyping prior to therapy, so clinicians can discuss risks with patients, but allow treatment for APOE4 homozygotes. A schedule of monitoring MRIs is recommended to include scans at baseline, and before the fifth, seventh, and 14th biweekly infusions. Scans are recommended at one year for APOE4 carriers and people with any ARIA during the first year. By January 2024, approximately 2,000 to 3,000 patients in the U.S. were receiving Leqembi (Jan 2024 news). Extrapolation from Swedish population data indicated that about 5.9 million European and 2.2 million U.S. patients might be eligible for treatment (Dittrich et al., 2024).

In June 2023, Beth Israel Deaconess Medical Center in Boston registered a prospective comparative study of monoclonal antibodies for the treatment of AD. This study creates a patient registry, as required for Medicare coverage of Leqembi or other antibodies once approved (see CMS Decision Summary; Jun 2023 news). The study will enroll up to 500 patients at the hospital’s Cognitive Neurology Unit, and follow them for 30 months to determine if the antibodies slow cognitive and functional decline, to identify associations between patient characteristics and side effects, and to establish the time to clinical benefit. In early 2024, Emory University in Atlanta began enrolling 735 patients for a similar study. In January 2024, Health Partners Institute Neurology Clinic in St. Paul, Minnesota, began a 20-patient study of the feasibility of lecanemab treatment and outcomes.

On July 6, 2023, the FDA granted lecanemab a traditional, full approval (Jul 2023 news).

At the November 2023 CTAD conference, Eisai presented results on subcutaneous dosing of lecanemab in the open-label extension phase of Clarity (Nov 2023 conference news). Participants were administered 720 mg weekly, in two doses, using either an injector pen or syringe and needle. After six months, subcutaneous delivery resulted in 11 percent higher blood exposure and more stable blood levels, compared to IV administration. Amyloid removal increased by 14 percent, and ARIA was slightly higher, both attributed to higher drug exposure.

At the same conference, post hoc analyses from Clarity's tau-PET substudy indicated that, among participants who began the study with low tau tangle load, more participants improved on the CDR-SB who were on lecanemab than were on placebo (Nov 2023 conference news). Lecanemab treatment stopped tangle accumulation over the course of the study, according to data presented at the 2024 AD/PD conference (Mar 2024 conference news). This occurred regardless of baseline tau load.

In February 2024, Eisai began post-marketing tracking of lecanemab safety in Japan, where it was approved in late 2023. This study will investigate ARIA and how it affects treatment continuation in 5,000 patients receiving lecanemab as part of routine clinical care. It will follow patients for three years. Completion is set for the end of 2027.

In March 2024, Eisai and Biogen applied for FDA approval of monthly maintenance infusions of lecanemab for patients previously treated on the biweekly regimen. The company also began to send data to the FDA on subcutaneous maintenance dosing. If approved, this would allow patients to dose themselves at home (May 2024 news).

In June 2024, DIAN-TU began an open-label study of lecanemab in people with early onset, familial AD who had completed a study with the discontinued amyloid antibody gantenerumab. The Amyloid Reduction Trial (ART) expects to enroll 65 people to receive intravenous lecanemab biweekly for a minimum of five years, against a primary outcome of time to progression on the CDR-SB. ART will also examine long-term safety and rates of ARIA, plaque removal, and downstream biomarkers. Completion is planned for November 2029.

On July 26, 2024, the European Medicines Agency recommended against approving Leqembi for use in Europe. Eisai has requested re-examination of the opinion (press release). In August 2024, Leqembi was approved in the United Arab Emirates. That month it was also approved in the United Kingdom, though the national health service will not cover its cost. China approved lecanemab in January 2024, South Korea in May, Israel in July.

At the August 2024 AAIC, Eisai presented data to support monthly maintenance dosing in trial participants who had cleared amyloid plaque (Aug 2024 conference news). When these patients stopped treatment, biomarkers of Aβ, tau, inflammation, and cognition worsened at the same rate as in placebo-treated patients, but in the open-label extension, treatment still slowed disease progression after three years. People treated at the earliest stages of AD had the biggest benefit. Disease modeling suggested 10 mg/kg monthly would be sufficient to sustain lecanemab’s effects on biomarkers and cognition.

Also according to reports at AAIC, two people died while receiving Leqembi in clinical care (Aug 2024 conference news). Both developed severe ARIA-E, possibly resembling cerebral amyloid angiopathy-related inflammation. In a published case, ischemic stroke and seizures were reported in a 71-year-old man who developed ARIA after lecanemab treatment (Gibson et al., 2024).

For all clinical trials of Leqembi/lecanemab, see clinicaltrials.gov.

Clinical Trial Timeline