Leqembi (lecanemab-irmb)subcutaneous formulation interim study results and clinical improvement in earlier stages of Alzheimer's disease from Clarity AD trials.

1. Subcutaneous Formulation Interim Data; Safety And Effects On Brain Amyloid; 1) Weekly subcutaneous (SC) administration showed 14% greater amyloid plaque removal than biweekly IV administration as suggested in a preliminary analysis using amyloid PET at 6 months of treatment.

• The SC substudy, evaluating the SC formulation in an open-label extension (OLE) of the Clarity AD study, included 72 patients who received Leqembi for the first time as the SC formulation, and 322 patients who received intravenous (IV) Leqembi in the Clarity AD core study followed by SC administration in this substudy. Reduction from baseline of amyloid in the brain by amyloid PET at 6 months in the newly treated SC patients by centiloid reduction was -40.3 ± 2.27 in SC administration compared to -35.4 ± 1.14 in IV administration.

2. SC Pharmacokinetics (AUC) Higher Than IV By 11% :

• Weekly SC administration AUC are 11% higher than the biweekly IV formulation. 90% CI for drug exposure for SC vs. IV is within the bioequivalence limits of 80 to 125%. These datacould allow Eisai to select a dose that achieves AUC that are comparable to the IV dose.

3. Lower Systemic Injection Reaction Rates With SC As Compared To IV :

• Systemic injection/infusion reactions are uncommon and mild with SC administration, and in particular have not been observed in patients who received Leqembi for the first time as the SC formulation. There was a low rate of local injection site reactions (8.1%) in SC treated patients overall. Most were mild and moderate in severity consisting of redness, irritation, or swelling. No skin rash or other hypersensitivity reactions were reported.

4. ARIA Rates Of IV Formulation In Clarity AD Core Study Consistent With Rates In First-Time: Leqembi Patients Entering The SC Sub study In Clarity AD OLE :

• The incidence of ARIA-E with SC was similar to the IV. The incidences of ARIA-E, ARIA-H (cerebral microhemorrhage due to ARIA, cerebral hemorrhage, and brain surface hemosiderin deposition) and ARIA-H alone (ARIA-H without ARIA-E) with IV in the Clarity AD core study (n=898) were 12.6%, 17.3% and 8.9%, respectively. In newly treated patients in the SC substudy of the Clarity AD OLE (n=72), the incidences of ARIA-E, ARIA-H and ARIA-H alone were 16.7%, 22.2% and 8.3%, respectively. However, due to the sample size of newly treated patients in the SC substudy, no exact comparison can be made.

• Based on Phase II and III clinical studies. Cmax (maximum exposure) was the strongest predictor of ARIA-E incidence following IV administration. In the SC substudy, the steady-state exposure (AUCss) appears to be a better predictor of ARIA-E rates in the SC due to a relatively stable exposure profile.

Eisai aims to submit a Leqembi SC formulation Biologics License Application (BLA) with theFDA by March 31, 2024.

Latest Data From Tau Pet Longitudinal Substudy, Including A Post-Hoc Analysis Of The Low And Intermediate + High-Tau Subpopulations In The Clarity AD 18 Month Core Study:1) 76% of patients showed no decline and 60% showed clinical improvement at 18 months in low-tau / earlier stage early AD population.

• The Clarity AD study included an optional Tau PET substudy and used the tau PET probe MK6240 to identify patients with a low accumulation of tau in the brain which represents the earlier stage of early AD. • The low-tau subpopulation, which is in the earlier stages of early AD, is thought to show slow disease progression. In the low-tau subpopulation, 76% of the LEQEMBI group showed no deterioration and 60% showed clinical improvement after 18 months of treatment in the primary endpoint, Clinical Dementia Rating - Sum of Boxes (CDR-SB), compared with 55% and 28% of the placebo group, respectively. 1

• Importantly, in this low-tau subgroup, Leqembi treatment also showed consistent clinical response across multiple endpoints. In this population, Leqembi treatment favored cognition and function in the earlier stage of early AD.

Efficacy Results From Leqembi Clarity AD Open-Label Extension Study: 1) I Patients Continued to Show Benefit at 24 Months of Treatment-

• In the 18-month core study of Clarity AD, there was a statistically significant difference in global cognition and function as measured by CDR-SB between the Leqembi and placebo groups. The separation in CDR-SB between the group that continued to receive Leqembi (early start group) and the group who switched from placebo to Leqembi (delayed start group) was maintained during the 6-month OLE following the core study. This indicates that similar disease trajectory for both early and delayed start groups occurred with Leqembi administration.

• The blood biomarker results (plasma A42/40 ratio, ptau181, GFAP and NfL) showed improvement even after delayed initiation of treatment with Leqembi. These results suggest that Leqembi treatment may affect clinical outcomes through improvement of AD pathology.