Additional Detailed Analyses From Phase 2 Study 201 of Lecanemab Published as Three Papers in Peer-Reviewed Journals

Tokyo and Cambridge, Mass. — Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (Nasdaq: BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Christopher A. Viehbacher, “Biogen”) announced that three additional detailed analyses from the Phase IIb clinical study (Study 201), evaluating the efficacy and safety of lecanemab for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD), were published in the peer-reviewed journals.

1. Detailed results on biomarker, cognitive, and clinical effects from Study 201 core to OLE (open-label extension): Alzheimer’s Research and Therapy
2. Consistency of efficacy results across various clinical measures and statistical methods in Study 201: Alzheimer’s Research and Therapy
3. ARIA (amyloid-related imaging abnormality) profile in Study 201: Alzheimer’s & Dementia: Translational Research and Clinical Interventions

Study 201 was a multicenter, double-blind, placebo-controlled, Phase 2b trial conducted in 856 patients with early AD. Its core study evaluated key efficacy assessments, including clinical change on the AD Composite Score (ADCOMS) as the primary endpoint at 12 months and as key secondary endpoints, ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14) at 18 months. Following analysis of the 18-month core phase, an intervening off-treatment period (gap period) ranging from 9-59 months (mean 24 months) was taken, which was followed by an OLE with 10 mg/kg IV bi-weekly lecanemab dosing to assess long-term safety and tolerability. The results of the primary analysis in the core study including clinical efficacy and biomarkers have already been published, showing a consistent reduction in clinical decline across several clinical and biomarker endpoints with lecanemab 10 mg/kg bi-weekly dosing.

1. Detailed results on biomarker, cognitive, and clinical effects from Study 201.
“Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open‑label extension of the phase 2 proof‑of‑concept study”
In the core 201 study, lecanemab was shown to reduce brain Aβ accumulation measured by amyloid PET in a dose- and time-dependent manner after 12 and 18 months of treatment, and corresponding changes in plasma biomarkers and reduction in clinical decline. During the gap period, a trend was observed for plasma Aβ42/40 ratio and p-tau181 values to return to the pre-administration levels (re-accumulation) faster than amyloid PET.

In the OLE, lecanemab 10 mg/kg biweekly treatment showed a decrease in brain amyloid beta (Aβ) accumulation measured by amyloid PET, a decrease in the plasma Aβ42/40 ratio, and a decrease in plasma p-tau181.

The potential for disease modification with lecanemab is supported by an increasing difference in clinical measures between the lecanemab group and placebo group in line with time during the core period, differences in clinical progression between subjects who received 10 mg/kg lecanemab and those who received placebo in the core period, which remained persistent throughout the gap period, and an impact on biological measures that reflect key pathophysiological changes in AD. Furthermore, the results showed the potential for monitoring the treatment effects of lecanemab using plasma biomarkers.

2. Consistency of efficacy results across various clinical measures and statistical methods in Study 201.
“Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer’s disease”
In order to assess the robustness of lecanemab’s efficacy in Study 201, sensitivity analyses were performed using several statistical models for three key clinical endpoints (ADCOMS, CDR-SB, ADAS-Cog14). The sensitivity analysis showed that 18 months of lecanemab treatment consistently reduced the clinical decline in all statistical models examined. The results of all sensitivity analyses for three key clinical endpoints at the highest dose (10 mg/kg bi-weekly) at 18 months were consistent, with a 29.1% to 37.4% reduction in clinical deterioration with lecanemab compared to placebo for ADCOMS, 26.5% to 38.4% for CDR-SB and 37.4% to 55.9% for ADAS-Cog14.

3. ARIA profile in Study 201
“ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer’s disease”
In the core study 201, amyloid-related imaging abnormalities-edema (ARIA-E) was dose dependent, with an incidence 9.9% at the highest doses (10 mg/kg bi-weekly) for the overall population and 14.3% for ApoE4 positive subjects. Most ARIA-E occurred within 30 days after the initial dose and had mild to moderate severity in radiographic severity. Symptomatic ARIA-E occurred in 3% of participants in the 10mg/kg bi-weekly treatment group. ARIA cerebral microhemorrhages, intracerebral hemorrhage >1cm, and superficial siderosis (ARIA-H) occurred in 6.2% of subjects who received 10 mg/kg biweekly lecanemab and those events were mostly mild in severity. There were no symptomatic cases of ARIA-H reported in the core study.

Overall ARIA-E events in the OLE phase were generally consistent with the rate seen in the lecanemab 10 mg/kg biweekly group in the core study (four subjects treated with placebo in the core study had ARIA-E in the OLE (4 of 45: 8.9%). As with the core study, most ARIA-E occurred within 3 months after receiving the initial dose in the OLE and had mostly mild to moderate in radiographic severity. ARIA-H events in the OLE were generally consistent with the rate seen in the lecanemab 10 mg/kg biweekly group in the core study. ARIA-H events were mostly mild or moderate in severity. One symptomatic case of ARIA-H, intracerebral hemorrhage > 1cm, was reported in OLE. This subject did not have concurrent ARIA-E, and the adverse event resolved with residual visual field defect.

PK/PD modeling showed that the incidence of ARIA-E was correlated with Cmax at steady state. Based on the fact that lecanemab was generally well tolerated at the highest dose in this study, the Phase 3 Clarity AD study was conducted without dose titration. A subcutaneous formulation that may potentially reduce the Cmax of lecanemab is being developed and evaluated to determine if there is a reduction of the incidence of ARIA-E compared to intravenous formulation.

Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority.

To learn more, visit www.LEQEMBI.com.