BIIB - Eisai Presents New LEQEMBI® (lecanemab-irmb) Investigational Subcutaneous Formulation Interim Study Results and Clinical Improvement Data in Earlier Stages of Early Alzheimer's Disease From Additional Analyses of Clarity AD at The Clinical Trials On Alzhe

Investigational Subcutaneous Formulation Clears 14% More Plaque Than IV, Pharmacokinetics (AUC) 11% Higher, And Similar ARIA Rates To IV

76% Of Patients Showed No Decline And 60% Showed Clinical Improvement At 18 Months in Low-Tau Subpopulation in Additional Analysis of Clarity AD

Dual-Acting LEQEMBI Supports Brain Neuron Function by Removing Highly Toxic Proteins (Protofibrils) That Can Continue to Cause Neuronal Injury and Death Even After Plaque Removal, Offering Early AD Patients the Opportunity for Continued Benefit

TOKYO and CAMBRIDGE, England, Oct. 25, 2023 (GLOBE NEWSWIRE) -- Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") and Biogen Inc. (NASDAQ:BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Christopher A. Viehbacher, ", Biogen", )) announced today that Eisai presented new data for LEQEMBI^® (lecanemab-irmb) 100 mg/mL injection for intravenous (IV) use, in the Late Breaking Symposium 4 "Lecanemab for Early Alzheimer's Disease: Long-Term Outcomes, Predictive Biomarkers and Novel Subcutaneous Administration" at the 16^th annual Clinical Trials on Alzheimer's Disease (CTAD) conference held in Boston, Massachusetts, United States and virtually October 24-27, 2023.

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.¹

   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 data could allow Eisai to select a dose that achieves AUC that are comparable to the IV dose.¹

   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.¹

   4) ARIA Rates Of IV Formulation In Clarity AD Core Study Consistent With Rates In First-Time LEQEMBI Patients Entering The SC Substudy 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.¹
• 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. ¹
  

Eisai aims to submit a LEQEMBI SC formulation Biologics License Application (BLA) with the U.S. Food and Drug Administration by March 31, 2024.

2. 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.¹
• The efficacy results of the Tau PET substudy in the Clarity AD study, which observed tau pathology in the brain by tau PET, were consistent with overall results of the Clarity AD study.¹

   2) Tau PET Substudy Showed LEQEMBI Slows Development Of Tau Tangles In Early AD; Tau Spread In The Brain Is A Hallmark Of Disease Progression.

• In the Clarity AD Tau PET substudy, LEQEMBI treatment slowed the buildup of tau proteins in the temporal lobe (early Braak region), where tau accumulation was observed in the earlier stage of early AD. In the Tau PET substudy, LEQEMBI suppressed the accumulation of tau in the medial temporal brain region in low-tau subpopulations, and in a broader range of brain regions in the intermediate and higher accumulation groups**. This suggests that LEQEMBI treatment may have different effects on brain regions indexed by tau depending on the stage of the disease.¹ The spread of tau in the brain is a hallmark of AD progression.²

3. Efficacy Results From LEQEMBI Clarity AD Open-Label Extension Study

   1) LEQEMBI 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.¹
• The blood biomarker results (plasma A?42/40 ratio, ptau181, GFAP and NfL) showed improvement even after delayed initiation of treatment with LEQEMBI.¹ These results suggest that LEQEMBI treatment may affect clinical outcomes through improvement of AD pathology.¹

4. The Mechanism-Based Rationale Of LEQEMBI Treatment In Early AD

   1) Dual-Acting LEQEMBI³ Continues To Support Brain Neuron Function^3,4,5 By Removing Highly Toxic Proteins (Protofibrils****)^2,4 That Can Cause Neuronal Injury And Death Even After Plaque Removal,^5-8 Offering Patients The Opportunity For Continued Benefit.

• LEQEMBI has a unique dual action^1,3 that binds more selectively to highly toxic protein (protofibrils****) in addition to rapidly clearing plaque,⁷ and continues to support neuronal function^3,4 by removing protofibrils**** that can cause neuronal injury and death after plaque has been cleared.^5-8
  

Eisai is hosting a live webcast of the scientific session featuring the LEQEMBI presentations, which can be viewed on the investors section of the Eisai Co., Ltd. website. The content will be available on demand afterward.

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

This release discusses investigational uses of agents in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such investigational agents will successfully complete clinical development or gain health authority approval.

*Phase III Clarity AD study is a placebo-controlled, double-blind, parallel-group, randomized study to evaluate the efficacy and safety of LEQEMBI 10 mg/kg bi-weekly for 18 months in 1,795 people living with early AD (core study). An OLE is being conducted after the core study. SC dosing is currently being evaluated in the Clarity AD OLE.

**Using the MK6240 tau PET probe, tau accumulation in the brain was defined as low tau accumulation group (MK6240 cutoff value <1.06, 141 subjects), intermediate accumulation group (MK6240 cutoff value between 1.06 and 2.91, 191 subjects), and high accumulation group (MK6240 cutoff value >2.91, 10 subjects).

***Multiple endpoints: CDR-SB, a numeric scale used to quantify the severity of symptoms of dementia; ADAS-Cog14, common cognitive assessment instrument used in AD clinical trials all over the world; and ADCS MCI-ADL, a scale to assess the parties' activities of daily living.

****Protofibrils:

• One of the AD pathological features is the accumulation of clusters (plaques) of amyloid beta (A?) in the brain. The formation of these plaques is the result of a continuous process by which individual A? proteins join together, latching onto each other, one at a time, like adding ...

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