In the current Alzheimer’s disease therapeutic space, the two approved disease-modifying therapies (DMTs) have differing treatment strategies despite both being anti-amyloid-beta (Aβ) monoclonal antibodies (mAbs). Eisai/Biogen’s Leqembi (lecanemab) is approved for continuous treatment (beyond 18 months) until progression to moderate Alzheimer’s, whereas Eli Lilly’s Kisunla (donanemab) is being positioned as a finite treatment option that can be discontinued once significant amyloid clearance has been achieved. As such, at the AD/PD 2026 International Conference on Alzheimer’s and Parkinson’s diseases and Related Neurological Disorders, both Eisai and Biogen have focused on demonstrating and promoting the benefits of continued treatment with Leqembi.
On 18 March, during a symposium sponsored by Eisai, the company presented four-year data from its open-label extension (OLE) period of its Phase III CLARITY-AD (NCT03887455) trial of Leqembi for the treatment of early Alzheimer’s (mild cognitive impairment (MCI) and mild Alzheimer’s). This was the first time that the presented data covered patients who are apolipoprotein E (APOE) ε4 phenotype heterozygotes or non-carriers, which matches the specific patient population that Leqembi is approved for in the EU. In the US, Leqembi is approved for all early Alzheimer’s patients regardless of their APOE4 status.
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At four years, continued Leqembi treatment resulted in slowed disease progression compared with untreated controls as measured by Clinical Dementia Rating – Sum of Boxes (CDR-SB) score. This is equivalent to a 9.8-month delay in progression when compared to untreated controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Patients treated with Leqembi also remained at an earlier disease stage compared with untreated controls, as measured by time to worsening on CDR-SB, with 52.9% of the Leqembi-treated patients progressing to the next stage compared with 68.4% in the ADNI group. An additional post-hoc analysis in patients with early Alzheimer’s and low tau showed that 73% had no decline in CDR-SB at four years, and 61% had an improvement in CDR-SB at four years. While there were low patient numbers for the post-hoc analysis, continued treatment with Leqembi could be particularly beneficial in patients with low tau, which could be an important factor for patients deciding if they would like to initiate treatment. Importantly, there were no new safety findings across the OLE period, and Leqembi was generally well tolerated, with many of the side effects, such as infusion-related reactions and amyloid-related imaging abnormalities (ARIA), being most common within the first 12 months of treatment.
As part of the panel discussion during the symposium, it was noted by Eisai that even once amyloid plaque clearance has been achieved, as seen on a positron emission tomography (PET) scan, continued treatment with Leqembi was expected to continue to provide benefit due to its mechanism of action. The drug preferentially targets Aβ protofibrils that do not always show up on amyloid PET scans. Therefore, continued maintenance treatment with Leqembi allows for continued clearance of Aβ protofibrils thus preventing the formation of Aβ plaques. In contrast, Kisunla targets the already formed Aβ plaques to achieve amyloid clearance.
The long-term persistence of intravenous (IV) Leqembi in the US, based on an analysis of claims data, was presented on 20 March, during a symposium on “real-world outcomes and mechanistic insights in anti-amyloid treatment”. The high long-term persistence that was demonstrated was hypothesised to correlate with the treatment continuing to offer a benefit, as patients are not thought to want to continue the treatment unless they are seeing a benefit, which also supports the long-term continued use of Leqembi.
While the data presented at AD/PD 2026 is important for showing clinicians, patients, and insurers that the continued use of Leqembi does continue to provide a benefit to patients without increasing safety concerns, it is not enough to point to the Leqembi treatment strategy being better than that of Kisunla. Questions remain over even longer-term continued use of Leqembi in patients whose disease continues to remain stable rather than progressing, as well as the benefit versus the cost of continued treatment. It will also be interesting to see how the recent approval and uptake of the subcutaneous (SC) formulation of Leqembi, Leqembi Iqlik, for maintenance treatment will impact patient willingness to remain on long-term therapy. Eisai and Biogen have also submitted a supplemental application for Leqembi Iqlik for the initiation phase of the treatment. If approved, this would allow SC dosing for the whole treatment period, thereby reducing patient burden. Additionally, Eli Lilly is also continuing to evaluate how stopping treatment with Kisunla once amyloid clearance is achieved affects the disease course over the long term. More of this data is important to advance the understanding of Kisunla’s treatment strategy. Ultimately, as the use of Leqembi and Kisunla increases globally, longer-term real-world data will provide a deeper understanding of the advantages and disadvantages of the mechanisms and treatment strategies of these drugs, as well as patient and provider preferences for each option.
