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PharmaShots Interview: In Conversation with Four Prominent Leaders* from Eisai Where they Share Insights on New Alzheimer’s Data Presented at the Alzheimer’s & Parkinson’s Disease Conference

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PharmaShots Interview: In Conversation with Four Prominent Leaders* from Eisai Where they Share Insights on New Alzheimer’s Data Presented at the Alzheimer’s & Parkinson’s Disease Conference

PharmaShots Interview: In Conversation with Four Prominent Leaders* from Eisai Where they Share Insights on New Alzheimer’s Data Presented at the Alzheimer’s & Parkinson’s Disease Conference

Shots:

  • The interview provided an understanding of the data from its Alzheimer’s disease pipeline at the AD/PD Conference
  • The spokespeople also talked about the clinical trial data and key mechanisms of Eisai’s anti-amyloid compound in AD 
  • The discussion showed gave a gist of four key symposium presentations that showed how its lead candidate has the potential to benefit patients with early AD

*Michael Irizarry, Senior Vice President, Deputy Chief Clinical Officer, Neurology Business Group, Eisai Inc.

*Chad Swanson, Executive Director, Clinical Research, Neurology Business Group, Eisai Inc.

*Jin Zhou, Executive Director, Clinical Research, Neurology Business Group, Eisai Inc.

*Larisa Reyderman, Vice President, Clinical Pharmacology & Translational Medicine, Clinical Research, Neurology Business Group, Eisai Inc.

Smriti: Discuss the key points of the data presented at AD/PD.

At the 2022 AD/PD conference, four key symposium presentations explored how investigational lecanemab’s Phase 2 Core and open label extension (OLE) data on treatment-related changes in biomarkers and their relationship to clinical outcomes, the potential for incorporation of maintenance dosing following brain amyloid removal, and overall amyloid-related imaging abnormality (ARIA) rates have the potential to benefit people living with early Alzheimer’s disease.

Eisai provided the latest information from the Phase 2b OLE study of lecanemab in early AD dosing sub-study, Phase 3 study of lecanemab in early AD (Clarity AD), and Phase 3 study of lecanemab in preclinical AD (AHEAD 3-45). In addition, the Mechanism of Action (MOA) of lecanemab was also presented.

The data discussed were hypothesis generating and will be further evaluated in the Phase 3 Clarity AD study. Highlights include:

  1. Of the approximately 12 treatment-naïve patients in the OLE (those who received a placebo in the Core study), more than 40 percent were amyloid negative as early as 3 months and more than 80% were amyloid negative by 12 months as measured by PET image (visual read).
  2. There is potential to use plasma biomarkers to monitor for lecanemab effects, as evidenced by data correlating PET SUVr, plasma AB42:40 ratio & p-tau181, and clinical endpoints and monitoring of treatment effects with plasma biomarkers may allow for simple dose modification following rapid and thorough removal of brain amyloid (for example, in the form of less frequent or lower doses).
  3. The overall ARIA-E rate in the Core study was 9.9% (16/161) of patients treated with lecanemab 10 mg/kg biweekly compared with 0.8% (2/245) of placebo patients. The symptomatic ARIA-E rates were <2% in Core and OLE. 

Smriti: Highlight the critical mechanism of lecanemab.

The amyloid pathway consists of amyloid beta (Aβ) protein that forms soluble aggregated species that are toxic to neurons and implicated in the neurodegenerative process in AD. 

lecanemab is an investigational, humanized IgG1 monoclonal antibody that was designed to preferentially targets soluble aggregated AB species (protofibrils) with activity at insoluble fibrils. Pharmacological studies have indicated that lecanemab selectively binds soluble Aβ aggregated species with >1000-fold selectivity for protofibrils over monomers. lecanemab also has a high affinity for the insoluble fibrils that make up amyloid plaque but with >10-fold preferential activity for protofibrils over these insoluble fibrils. 

Smriti: Can you share the clinical data supporting the efficacy of lecanemab in early AD?

The Phase 2b Core (double-blind phase) identified that lecanemab 10 mg/kg IV biweekly, without titration, was identified as the optimal dose to test in Phase 3 for amyloid clearance, downstream biomarker effects, and clinical efficacy and safety (Alz Res Therapy 13, 80; 2021). The lecanemab Phase 2b study results demonstrated a high degree of Aβ plaque lowering and consistent reduction of clinical decline across several clinical endpoints.

Amyloid clearance correlated with clinical benefit at population and patient level in the Phase 2b Core. The primary analysis conducted at month 12 of treatment for all subjects indicated that the 10mg/kg biweekly effective dose had a 64% probability of being better than placebo with 25% less decline on ADCOMS at 12 months, missing the pre-specified 80% probability threshold for the primary outcome.

Smriti: Why is it essential to monitor and manage ARIA during the treatment?

ARIA is an important adverse event related to amyloid-lowering therapies that are critical to monitor and manage during treatment. It is important to monitor ARIA as part of routine clinical practice.

With lecanemab in the Core study and OLE, the majority of ARIA-E events occurred within the first 3 months of treatment (75% [12/16]) and resolved within 4 months of onset. For the majority of patients, the radiographic severity was mild or moderate; severe radiographic severity was reported in 1.2% (2/161) of patients. The majority of ARIA-E was asymptomatic; with symptomatic ARIA-E reported in 1.9% (3/161) of subjects. Some symptoms reported in association with ARIA-E included headache, visual disturbance, confusion, and aphasia. There has been one case of ARIA-E associated with seizure in the Study 201 Core study and OLE to date.

Smriti: What are the upcoming plans for the update of lecanemab’s clinical development?

Based on exposure-response modeling of the biomarker changes observed over the Core and open-label extension, there is potential to allow for maintenance dosing following robust removal of brain amyloid, and this concept will be tested in the sub-study of Study 201 and Phase 3 Clarity AD open-label extensions.

Eisai is developing a subcutaneous formulation (SC) of lecanemab with the potential to be administered at home by the patient or caregiver via an auto-injector with a more rapid administration than the IV formulation (<15 second SC injection versus ~1h infusion). Exposure-response modeling of Study 201 suggests that the average lecanemab concentration (Cave) predicts amyloid clearance, while the maximal lecanemab concentration (Cmax) predicts the ARIA-E rate. Since subcutaneous administration results in a blunted Cmax, an SC dose with comparable Cave to 10 mg/kg IV is predicted to have a similar amyloid reduction with potentially reduced incidence of ARIA-E relative to IV. Eisai is evaluating the SC formulation in the Clarity AD Open-Label Extension (OLE).

As of March 2022, over 2,900 people were screened resulting in 287 participants enrolled in the AHEAD 3-45 Phase 3 Study in Preclinical AD. AHEAD 3-45 is conducted as a public-private partnership between the Alzheimer’s Clinical Trial Consortium.

In the DIAN-TU Tau NexGen study, lecanemab was selected as the background therapy based on increasing evidence from clinical studies showing that targeting amyloid can reduce biomarkers of AD. This phase II/III study will assess the effect of Eisai’s investigational anti-microtubule binding region tau antibody E2814, in dominantly inherited Alzheimer’s disease. This study was initiated in Dec 2021.

Smriti: How do late-stage anti-amyloid antibodies create changes in the patient journey?

The availability of treatment for early AD will require clinicians to identify cognitive impairment at earlier stages, confirm elevated amyloid in the brain, confirm the patients that are appropriate for treatment, set up the treatment (infusion or SC), and implement appropriate monitoring and management for ARIA-E.  As mentioned in Q5, Eisai is developing an SC formulation of lecanemab.  Eisai is also exploring maintenance dosing regimens after clearing amyloid in the brain.

Smriti: When are you expecting the approval of Lecanemab in the US and other geographies?

lecanemab was granted Breakthrough Therapy and Fast Track designations by the U.S. Food and Drug Administration (FDA) in June and December 2021, respectively. Eisai anticipates completing lecanemab’s rolling submission of a Biologics License Application for the treatment of early AD to the FDA under the accelerated approval pathway. Eisai expects to complete this rolling submission in the first quarter of our fiscal year 2022, which began April 1, 2022. 

Eisai initiated a submission to the Pharmaceuticals and Medical Devices Agency (PMDA) of application data of lecanemab under the prior assessment consultation system in Japan in March 2022. 

Eisai continues to serve as the lead of lecanemab development and regulatory submissions globally. If approved, both companies will be co-commercializing and co-promoting lecanemab, with Eisai having final decision-making authority and booking sales globally.

Smriti: Are you planning to follow Aduhelm’s path to Accelerated Approval for lecanemab?

Eisai anticipates completing lecanemab’s rolling submission of a Biologics License Application for the treatment of early AD to the FDA under the accelerated approval pathway. Eisai expects to complete this rolling submission in the first quarter of our fiscal year 2022, which begins April 1, 2022.

For drugs approved using the accelerated approval pathway, further study is required to verify the expected clinical benefits. The lecanemab Clarity AD Phase 3 clinical trial in early AD is ongoing and completed enrollment in March 2021 with 1,795 patients. The results of the Clarity AD trial will occur in the Fall of 2022 and can serve as the confirmatory study to verify the clinical benefit of lecanemab.

Smriti: Roche’s gantenerumab and Lilly’s donanemab are running in the same race. How is lecanemab superior to those molecules?

There are currently no head-to-head studies comparing the three compounds, therefore direct comparisons cannot be made. lecanemab selectively binds to neutralize and eliminate soluble, toxic amyloid-beta (Aβ) aggregates (protofibrils) that are thought to contribute to the neurodegenerative process in AD. As such, lecanemab may have the potential to have an effect on disease pathology and slow down the progression of the disease.

Smriti: Do you think these molecules are threats to lecanemab?

At Eisai, our focus remains on lecanemab. The investigational compound may have the potential to have an effect on disease pathology and slow down the progression of the disease. 

Source: Canva

About the Authors: 

Michael Irizarry 

Michael Irizarry is the Senior Vice President of Clinical Research and Deputy Chief Clinical Officer of the Neurology Business Group at Eisai. He is responsible for the overall strategy and clinical development of the company’s neurosciences portfolio, including clinical pharmacology and translational medicine. Dr. Irizarry earned undergraduate and medical degrees from Georgetown University, and a Masters of Public Health (M.P.H.) degree from the Harvard School of Public Health

Chad J. Swanson

Chad J. Swanson is the Executive Director of Clinical Research in the Neurology Business Group at Eisai. Dr. Swanson serves as the International Project Team Leader responsible for Lecanemab Clinical Development. He has over 20 years of industry experience. Dr. Swanson received his Ph.D. from the Medical University of South Carolina in Physiology and Neuroscience, and his BS degree from the University of Wisconsin – Madison in Zoology with a neurobiology emphasis

Jin Zhou

Jin Zhou is the Executive Director of Clinical Research in Neurology Business Group at Eisai. She has 15 years of pharmaceutical industry experience and is responsible for developing and executing all clinical aspects of the AHEAD 3-45 (A3/45) study of lecanemab. She earned his Masters's degree in Neurology from the Captial University of Medical Sciences, Beijing, China, and completed a Ph.D. in Neuroscience at the University of Illinois at Chicago, and a postdoc fellowship at Rockefeller University in the US

Larisa Reyderman

Larisa Reyderman is the Vice President and the Global Head of Clinical Pharmacology and Translational Medicine, Neurology Business group at Eisai. She graduated from the University of Pennsylvania and received her Ph.D. in Pharmaceutical Sciences from The University of Texas, at Austin. Prior to joining Eisai. Dr. Reyderman contributed to multiple successful regulatory approvals and co-authored over 100 scientific publications and abstracts

Related Post: PharmaShots Interview: In Conversation with SOTIO’s CMO, Richard Sachse, Where he Shares Insights on New Interim Data presented in an Oral Presentation at AACR 2022 Annual Meetin


Smriti

Smriti is a Senior Editor at PharmaShots. She is curious and very passionate about recent updates and developments in the life sciences industry. She covers Biopharma, MedTech, and Digital health segments along with different reports at PharmaShots. She can be contacted at smriti@pharmashots.com.

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