New clinical data demonstrates three years of continuous treatment with dual-acting Leqembi (lecanemab-irmb) continues to significantly benefit early Alzheimer’s disease patients presented at AAIC 2024

Three Years of continuous lecanemab treatment reduced clinical decline by -0.95 on CDR-SB showing continued clinically and personally meaningful benefit for early AD Patients.

Clarity AD was a global Phase III placebo-controlled, double-blind, parallel-group, randomized study in 1,795 people with early AD (Lecanemab group: 10 mg/kg bi-weekly IV treatment: 898, placebo group: 897). 95% of patients who completed the core study (18 months) chose to continue in the open-label extension study (OLE). In the Clarity AD core study, the mean change from baseline between the lecanemab treated group and the placebo group was -0.45 (P=0.00005) on the primary endpoint of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) global cognitive and functional scale. Over three years of treatment across the core study and OLE, lecanemab reduced cognitive decline on the CDR-SB by -0.95 compared to the expected decline based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) group. A change from 0.5 to 1 on the CDR score domains of Memory, Community Affairs and Home/Hobbies is the difference between slight impairment and loss of independence, such as people’s ability to be left alone, remember recent events, participate in daily activities, complete household chores, function independently and engage in hobbies and intellectual interests.

Safety Matters No new safety findings have been observed with continued lecanemab treatment over three (3) years. Most Amyloid-related imaging abnormalities (ARIA) occurred in the first six months of treatment. After the first six months, ARIA rates are low and similar to ARIA rates on placebo. Most patients who had ARIA had CDR-SB assessments after the event. Sensitivity analyses showed ARIA had no impact on cognition or function. From these results ARIA was not associated with accelerated long-term progression. As stated in the FDA product label, the incidence and timing of ARIA vary among treatments.

More than 50% of patients who started treatment in the earliest stage of AD continued to show improvement after three years of lecanemab treatment. The Clarity AD study included an optional tau PET substudy and used the tau PET probe MK 6240 to identify patients with no tau or a low accumulation of tau in the brain. As tau begins to accumulate in the brain, cognition and function start to decline; therefore, patients with no tau or low tau in the brain represent an early stage of AD. After three years of lecanemab treatment, 59% of these patients (24/41) showed improvement or no decline, and 51% (21/41) showed improvement from baseline on the CDR-SB. On the ADAS-Cog14 measurement scale, 63% of patients showed improvement or no decline and 61% showed improvement. On the ADCS MCI-ADL, 63% of patients showed improvement or no decline and 59% showed improvement. This suggests that earlier initiation of treatment with lecanemab may have a significant positive impact on disease progression and may provide continued benefits to patients with early AD over the long-term.

Even after plaque clearance, AD continues to progress when treatment is stopped. Study 201 is a multicenter, double-blind, placebo-controlled, Phase IIb trial conducted in 856 patients with early AD. Appropriate patients participated in the OLE after an off-treatment period of 9-59 months (mean: 24 months) following the 18-month core study. During the off-treatment period lecanemab’s clinical effect was maintained but the rate of decline (slope) in patients who stopped therapy reverted back to the rate of decline in patients on placebo as measured by CDR-SB. This indicates that even after Abeta plaque is removed, AD continues to progress, and reverts to the placebo rate of decline when treatment is stopped.

After plaque removal, dual-acting lecanemab continues to positively impact biomarkers over the course of treatment. The key AD fluid biomarkers Abeta42/40, pTau181, pTau217, and glial fibrillary acidic protein (GFAP) are more sensitive indicators of amyloid and tau development than Amyloid PET and have been shown to re-accumulate at a faster rate when treatment is discontinued. Modeling data from the Study 201 (Phase II), Clarity AD (Phase III) and respective OLE studies showed that the half-life of the treatment effect on the fluid biomarkers plasma Abeta42/40 ratio, pTau181, and GFAP are lost within 0.5 year, 1.6 years and 1.7 years, respectively, while the half-life of the treatment effect on amyloid plaque is gradually lost in 12.1 years. When lecanemab treatment was resumed in the Study 201 OLE after off-treatment period, fluid biomarkers Abeta42/40 ratio, pTau181, pTau217 and GFAP improved. These results suggest that AD continues to progress when treatment is stopped, even after plaque has been cleared. Patients continue to benefit by remaining on treatment as lecanemab maintains improvement in the fluid biomarkers of amyloid pathophysiology.

Lecanemab’s dual action on protofibrils and plaques impacts amyloid and slows Tau spread, offering patients a continuous, long-term treatment for this chronic and progressive disease. Lecanemab is the only widely available early AD treatment that offers a dual mechanism of action designed to selectively target highly toxic protofibrils in addition to amyloid plaques. Protofibrils accumulate early in the AD brain and lead to nerve cell function loss, abnormal nerve processes, inflammation, and memory loss. In nonclinical studies, antibodies against protofibrils prevented protofibril-mediated neuronal dysfunction and memory loss. Lecanemab preferentially binds to toxic protofibrils with the highest affinity. After rapidly clearing plaque and existing protofibrils, lecanemab continuously clears the protofibrils that continue to develop and damage neurons. Protofibrils also play a role in tau spread.5 In the tau PET substudy, continuous lecanemab treatment slowed the rate of increase in tau accumulation across all brain regions as measured by tau PET. CSF MTBRtau243 has high correlation with tau PET and increases with the progression of AD pathology. Treatment with lecanemab slows the increase in CSF MTBR-tau243. Additionally, lecanemab improved pTau217 and other biomarkers related to neuroinflammation and neurodegeneration. This indicates a potential disease-modifying effect on tau pathophysiology.

Protofibrils are thought to be the most toxic Abeta species that contribute to brain damage in AD and play a major role in the cognitive decline of this progressive and devastating disease. Protofibrils can cause neuronal damage in the brain, which can subsequently adversely affect cognitive function through multiple mechanisms. The mechanism by which this occurs has been reported not only by increasing the formation of insoluble Abeta plaques, but also by directly damaging signaling between neurons and other cells. It is believed that reducing protofibrils may reduce neuronal damage and cognitive impairment, potentially preventing the progression of AD.