Michael Irizarry, SVP, Clinical Research, Eisai Shared Insights on P-III Results from Clarity AD Study

Shots:

Michael spoke about the P-III Clarity AD study evaluating Leqembi (lecanemab) for the treatment of mild cognitive impairment due to Alzheimer’s disease presented at CTAD 2022
He also talked about Eisai’s collaboration with Biogen for the co-commercialization and co-promotion of Lecanemab
The interview gives an understanding of how Biogen develops and delivers innovative therapies for people living with serious neurological diseases including Alzheimer’s disease

Smriti: To start with please share your experience of the 2022 Clinical Trials on Alzheimer's Disease (CTAD) conference held in San Francisco.

Michael Irizarry: It was both rewarding and humbling to be at CTAD 2022 and share the progress we have seen with LEQEMBI™(lecanemab-irmb) in our confirmatory Phase 3 Clarity AD study. To be able to share these scientific advancements that have the potential to make a meaningful difference in the treatment of Alzheimer’s disease (AD) is something we have worked towards for decades. The Clarity AD trial was a product of 40 years’ worth of knowledge. Scientists all over the world collaborated in efforts to elucidate the pathology of this complex and devastating disease, and these results mark an achievement for us all.

Along with the presentation of the Phase 3 Clarity AD data at CTAD, the results were published the same day in the New England Journal of Medicine, one of the world's most prestigious peer-reviewed medical journals.

Smriti: Elaborate on the results from the P-III Clarity AD clinical study evaluating Lecanemab (BAN2401) for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease.

Michael Irizarry: The results from the Phase 3 Clarity AD clinical study showed a mean change of Clinical Dementia Rating Sum of Boxes (CDR-SB) from baseline at 18 months as the primary endpoint was 1.21 and 1.66 for LEQEMBI and placebo groups, respectively. LEQEMBI treatment resulted in highly statistically significant results, reducing clinical decline on the global cognitive and functional scale, compared with placebo at 18 months by -0.45 (95% Confidence Interval (CI): -0.67, -0.23; P<0.001), representing a 27% slowing of decline. Starting as early as six months (difference: -0.17 [95% CI: -0.29, -0.05]; P<0.01), and increasing in absolute difference over time across all time points every 3 months, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all p-values are less than 0.01). All key secondary endpoints also showed highly statistically significant results compared with placebo (P<0.001).

The presentation and publication of the positive results from this pivotal study are an important milestone for Eisai in fulfilling our mission to meet the expectations of the AD community. Eisai believes these findings will create new horizons in the diagnosis and treatment of AD as well as further activate innovation for new treatment options.

Smriti: Shed some light on the study design of the Clarity AD clinical trial.

Michael Irizarry: Clarity AD was a global confirmatory Phase 3 placebo-controlled, double-blind, parallel-group, randomized study in 1795 people with early AD. The participants were randomized to receive either placebo or LEQEMBI 10-mg/kg IV biweekly, with participants allocated in a 1:1 ratio to receive either placebo or LEQEMBI.

The randomization was stratified according to clinical subgroup (MCI due to AD or mild AD), presence or absence of concomitant approved AD symptomatic medication at baseline (e.g., acetylcholinesterase inhibitors, memantine, or both), ApoE4 status and geographical region.

The trial allowed people with a broad range of comorbidities/comedications to enroll, including but not limited to hypertension, diabetes, heart disease, obesity, renal disease, and anti-coagulants. The global study was conducted at 235 sites in North America, Europe, and Asia. Eisai’s recruitment strategy for the Clarity AD clinical trial ensured greater inclusion of ethnic and racial populations in the U.S., resulting in approximately 25% of the total U.S. enrollment including Hispanic and African American persons living with early AD. Due to the inclusive eligibility criteria and the successful recruitment of diverse ethnic and racial populations in the U.S., the patient population enrolled in Clarity AD is generally comparable to the portion of Medicare population who may be appropriate candidates for LEQEMBI if approved by the FDA.

Smriti: Highlight the details of the Imaging, Plasma, and CSF Biomarkers Assessments conducted in the Clarity AD study.

Michael Irizarry: In the Clarity AD study, biomarker assessments on amyloid, tau and neurodegeneration with LEQEMBI administration were conducted using imaging, plasma and CSF.

Amyloid biomarkers results showed early and sustained amyloid reversal effects in CSF and plasma Aβ 42/40 ratio with LEQEMBI treatment. Mean amyloid PET was 22.99 Centiloids at 18 months of LEQEMBI treatment which was below threshold for amyloid positivity of 30 Centiloids.

Tau biomarkers showed that removing amyloid improved CSF and plasma p-tau (p-tau181), downstream of amyloid in the AD pathology pathway. Tau PET analysis showed that LEQEMBI treatment slowed tau accumulation in the temporal lobe as well as improved total tau (t-tau) in compared to the placebo.

As for biomarkers of neurodegeneration, LEQEMBI improved glial fibrillary acidic protein (GFAP) in plasma, a marker of astrocyte activation, and neurogranin in CSF, a marker of synaptic dysfunction, improved to normal levels by treatment, while there was no significant difference in neurofilament light chains in CSF or plasma between LEQEMBI and placebo.

Smriti: Tell us about your collaboration with Biogen for co-commercializing and co-promoting of the product.

Michael Irizarry: 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.

Smriti: In which geographical locations do you plan to commercialize Lecanemab? Are you looking forward to another such collaboration(s) for commercialization?

Michael Irizarry: LEQEMBI was granted accelerated approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with mild cognitive impairment or mild dementia stage of Alzheimer’s disease on January 6, 2023, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with LEQEMBI. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.

The U.S. Food and Drug Administration (FDA) accepted Eisai’s Supplemental Biologics License Application (sBLA) for LEQEMBI™ (lecanemab-irmb) 100 mg/mL injection for intravenous use, supporting the conversion of the accelerated approval of LEQEMBI to a traditional approval on March 3, 2023. Eisai’s application has been granted Priority Review, with a Prescription Drug User Fee Act (PDUFA) action date of July 6, 2023.

In the U.S., LEQEMBI became available on January 18, 2023. Commercial efforts will be scaled appropriately in accordance with patient access to LEQEMBI via all payer channels and traditional approval by the FDA. Eisai will do its best to make LEQEMBI available within the allowable coverage by different payers.

On December 22, 2022, Eisai initiated submission of data for Biologics License Application (BLA) to the National Medical Products Administration of China (NMPA). In Europe, Eisai submitted marketing authorization application (MAA) to the European Medicines Agency (EMA) on January 9, 2023 and it was accepted by the EMA on January 27, 2023. In Japan, Eisai submitted an MAA for LEQEMBI to the Pharmaceuticals and Medical Devices Agency (PMDA) on January 15, 2023 and the application was designated for Priority Review by the Japanese Ministry of Health, Labour and Welfare (MHLW) on January 29, 2023.

Smriti: How will Lecanemab stand out from its competitors already available in the market?

Michael Irizarry: Each therapy should be evaluated on its individual efficacy and safety profile. People living with early Alzheimer’s disease and their families need treatment options. While there is a tremendous unmet need, there is also newfound hope with potential therapies in development. LEQEMBI has demonstrated a reduction in amyloid plaque clearance.

The previous drugs indicated for AD were symptomatic therapies, whereas LEQEMBI addresses pathophysiological features of Alzheimer's disease. LEQEMBI is a humanized IgG1 monoclonal antibody directed against aggregated soluble and insoluble forms of Aβ. The accumulation of Aβ plaques in the brain is a defining pathophysiological feature of Alzheimer’s disease. LEQEMBI reduces amyloid beta plaques, as evaluated in Study 201.

Smriti: Lastly, is Eisai planning to present the clinical data at any other Neurological event(s)?

Michael Irizarry: Eisai plans to present additional data findings for LEQEMBI at future medical conferences including the 2023 Alzheimer’s & Parkinson’s Diseases Conference (AD/PD), Alzheimer's Association International Conference (AAIC) and Clinical Trials on Alzheimer's Disease (CTAD) conference. Eisai also plans to publish data in key peer-reviewed journals throughout the year.

Image Source: Canva

About the Author:

Michael Irizarry is the Senior Vice President, Clinical Research at Eisai. Dr. Irizarry joined Eisai in September 2018 as Vice President of Clinical Research, Epilepsy/Sleep, in which he led the clinical development of Eisai’s Epilepsy and Sleep/Wake programs, including regulatory submissions for compounds that received regulatory approvals to treat epilepsy and insomnia. Dr. Irizarry earned undergraduate and medical degrees from Georgetown University and an M.P.H. degree from the Harvard School of Public Health.