Michael Irizarry, SVP, Clinical Research, Eisai Shares Insights from the Clinical Data of Lecanemab Presented at AAIC

Shots:

Michael talked about the new data from its Alzheimer’s pipeline at the Alzheimer’s Association International (AAIC)
Michael also highlighted the study design of the P-II & P-III trial evaluating lecanemab
The interview gives an understanding of Eisai’s human health care (hhc) concept which provides innovative products with high unmet medical needs to target diseases including Alzheimer’s

Smriti: Explain the details (MOA, ROA, formulations, etc.) of lecanemab (BAN2401).

Michael Irizarry: Lecanemab is an investigational humanized monoclonal antibody for early Alzheimer's disease (AD). 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 to slow down the progression of the disease.

Study 201 established 10 mg/kg once every two weeks administered intravenously as the most effective dose of lecanemab based on ADCOMS (AD composite score). Lecanemab could potentially be initiated at the 10mg/kg dose without titration.

Smriti: Please highlight the study design of the P-II (Study 201), the P-III confirmatory trial (Clarity AD), and the P-III AHEAD 3-45 clinical trial evaluating lecanemab.

Michael Irizarry: Study 201 (Phase 2): The investigational lecanemab Phase 2 clinical trial (Study 201) of 856 patients with mild cognitive impairment (MCI) due to AD, mild AD, and dementia with confirmed presence of amyloid pathology was published in the peer-reviewed journal Alzheimer’s Research & Therapy. Study 201 was the lecanemab Phase 2b dose-ranging proof-of-concept study which provided a framework for dose selection, sample sizing, and other clinical indices to design the confirmatory Phase 3 study, Clarity AD. The study tested 5 dosing levels of lecanemab versus placebo over 18 months of treatment and evaluated clinical outcomes (ADCOMS, ADAS-cog14, CDR-SB), biomarkers (amyloid in the brain using amyloid PET scans), and safety. The study showed that 10mg/kg was found to be the most effective dose.

Clarity AD (Phase 3): Clarity AD is a global placebo-controlled, double-blind, parallel-group, randomized study in 1,795 (excluding China) patients with mild cognitive impairment (MCI) due to AD or mild Alzheimer's disease dementia. Participants are randomized to lecanemab 10 mg/kg intravenous (IV) biweekly or placebo and treated for 18 months. Clinical Dementia Rating (CDR-SB), cognitive subscale (ADAS-cog14), Alzheimer’s disease composite score (ADCOMS), assesses the competence of patients with Alzheimer's disease in basic and instrumental activities of daily living (ADCS-MCI-ADL), biomarker (imaging, CSF, and plasma), and safety outcomes are assessed. The results of this study will serve as a confirmatory study to verify the clinical benefit of lecanemab.

AHEAD 3-45 (Phase 3): In September 2020, the first patient was dosed in the investigational lecanemab Phase 3 AHEAD 3-45 clinical study for individuals with preclinical AD, meaning they were clinically normal and had intermediate or elevated levels of Aβ in their brains. These individuals are treated with lecanemab for 4 years, with the dosing regimen based on the amount of amyloid in the brain at the beginning of the study. Preclinical Alzheimer's cognitive composite (PACC5), biomarker, and safety outcomes are assessed.

Smriti: As you are currently evaluating lecanemab in the P-III (Clarity AD and AHEAD 3-45) clinical studies, following an accelerated approval under priority review, what plans do you have in mind for pursuing traditional approval for lecanemab in early AD and for the treatment of pre-symptomatic patients?

Michael Irizarry: The Clarity AD Phase 3 clinical trial in early AD is ongoing and completed enrollment in March 2021 with 1,795 patients (excluding China). The FDA has agreed that the results of Clarity AD when completed, can serve as a confirmatory study to verify the clinical benefit of lecanemab. The readout of the primary endpoint data will occur in the fall of 2022.

Eisai utilized the FDA’s Accelerated Approval Pathway in an effort to streamline the submission process for the potential traditional approval of lecanemab in order to expedite patients’ access to lecanemab. Dependent upon the results of the Clarity AD clinical trial, Eisai will submit for traditional approval of lecanemab to the FDA during Eisai’s fiscal year 2022, which ends on March 31, 2023.

AHEAD 3-45 is designed to evaluate the role of lecanemab in individuals with preclinical AD, meaning they are clinically normal and had intermediate or elevated levels of Aβ in their brains. The results of this study will inform future regulatory strategies.

Smriti: Please brief us about the comparative study between the IV administration of lecanemab vs its SC administration. How do you believe that SC formulation of lecanemab will help fulfill Eisai’s human health care mission?

Michael Irizarry: Eisai is developing a subcutaneous (SC) formulation 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).

PK/PD modeling of Study 201 suggests that the average lecanemab concentration (Cave) predicts amyloid clearance while the maximal lecanemab concentration (Cmax) predicts Amyloid-Related Imaging Abnormality (ARIA-E) rate. Since subcutaneous administration results in a blunted Cmax, the SC dose with comparable Cave to 10 mg/kg IV is hypothesized to have a similar amyloid reduction with potentially reduced incidence of ARIA-E relative to IV but less than half the ARIA-E rate as IV.

Eisai is evaluating the SC formulation in the Clarity AD open-label expansion (OLE).

Smriti: Give our readers some insights into Eisai’s extensive partnership with Biogen as well as the benefits that each company has personally reaped from it.

Michael Irizarry: Eisai and Biogen have been collaborating on the joint development and commercialization of AD treatments since 2014. Eisai serves as the lead of lecanemab development and regulatory submissions globally with both companies co-commercializing and co-promoting the product and Eisai having final decision-making authority.

Smriti: Could you please tell us some more about Eisai’s human health care mission? How has, working in close proximity with the patients, helped your company deliver a better therapeutic option?

Michael Irizarry: human health care (hhc) is Eisai’s mission and commitment to addressing the unmet needs of patients and their families. A key component of hhc is the time Eisai employees spend with patients; every employee is intended to spend 1% of their working hours interacting with patients. This commitment helps to identify opportunities to improve the patient journey and experience, both with respect to treatments and beyond.

As we carry out our mission, we continue to advance our robust AD portfolio. Eisai has dedicated four decades to research, development, and commercialization of treatments for AD and dementia. Eisai’s investigational pipeline aims to treat the range of underlying pathophysiology, including amyloid, tau, and neurodegeneration.

Eisai is also committed to increasing the access and representativeness of AD clinical trial participants. Within the Clarity AD trial, 4.5% of participants in the US are black, and 22.5% are Hispanic. This was achieved by selecting investigators and sites with access to diverse populations, outreach activities to the local community, and decentralized clinical trial activities to reduce participant burden (including home infusions and remote safety assessments). The eligibility criteria also allowed patients with a broad range of Comorbidities/Comedications (i.e., hypertension, diabetes, etc.).

Smriti: Human health care is a fantastic endeavor for offering patient support! What other solutions & therapies do you have in mind for addressing unmet medical needs?

Michael Irizarry: At Eisai, we push past the boundaries of science to create life-changing therapies and solutions where we believe by utilizing our skills, expertise, and resources we can have the greatest impact on patients, their loved ones, and those who help them throughout their journey. We bring together science, technology, and real-world expertise to pursue a world free from cancer, Alzheimer’s disease, and other neurodegenerative diseases.

Through our research of candidates for neurodegenerative, sleep/wake, and epilepsy disorders, our pipeline, and brain health initiatives have the potential to change the future of neurology and people’s overall well-being.

Source: Canva

About the Author

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