Eli Lilly Submits BLA to FDA for Donanemab in Early Alzheimer’s Disease, Demonstrating Slowed Cognitive Decline

October 26, 2021 /BioonBIOON/ -- Eli Lilly recently announced that it has initiated a submission to the U.S. Food and Drug Administration (FDA) rolling submission of a Biologics License Application (BLA), seeking accelerated approvalMonoclonal Antibody DrugsDonanemab, indicated for the treatment of early Alzheimer's disease (AD). In addition, the company also announced plans to initiate a head-to-head Phase 3Clinical Trial(TRAILBLAZER-ALZ 4), conducted in patients with early symptomatic Alzheimer’s disease (AD), to evaluate the superiority of donanemab over the Biogen/Eisai AD drug Aduhelm (aducanumab) in clearing brain amyloid plaques. Patient enrollment for this trial is expected to begin this year. In August this year,Eli Lillystated that Phase 2 trial data indicated that donanemab was more effective than Aduhelm in clearing amyloid plaques.

Donanemab is a monoclonal antibody targeting N3pG (a modified form of β-amyloid).. This June, the United StatesFDAdonanemab was grantedBreakthrough Therapy Designation(BTD). This BLA submission is based on the results of the Phase 2 TRAILBLAZER-ALZ study (NCT03367403). Data released in January this year showed that:In patients with early symptomatic AD, treatment with donanemab significantly slowed the decline in composite measures of cognition and daily function compared with placebo.

This July,Eli LillyAt the 2021 Alzheimer's Association InternationalConferencePresented at (AAIC© 2021) were two new exploratory analyses from the TRAILBLAZER-ALZ study. The first analysis demonstrated that greater amyloid plaque clearance following donanemab treatment was highly correlated with a lower degree of cognitive decline, with patients exhibiting higher plaque clearance rates at 24 weeks of treatment showing less tau progression. The second analysis revealed that donanemab treatment rapidly reduced plasma P-tau217 within 12 weeks, a biomarker reflecting the pathophysiology of AD...Biomarker. These new exploratory analysis results further demonstrate the potential of donanemab to slow disease progression in patients with early symptomatic AD. Importantly, these data link donanemab's mechanism of action and plaque clearance to positive effects on clinical outcomes and brain tau pathology.

TRAILBLAZER-ALZ was a randomized, placebo-controlled, double-blind, multicenter phase 2 study designed to evaluate the safety, tolerability, and efficacy of donanemab in patients with early symptomatic Alzheimer’s disease (AD). The trial enrolled 272 patients, who were selected based on cognitive assessments along with amyloid plaque imaging and tau imaging. The primary endpoint was the change in the integrated Alzheimer’s Disease Rating Scale (iADRS) score from baseline to week 76. The iADRS is a comprehensive clinical tool that combines a cognitive measure, the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13, cognitive function), with a functional measure, the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living (ADCS-iADL, functional capacity). Key secondary endpoints included changes from baseline to week 76 in the ADAS-Cog13, ADCS-iADL, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. Other secondaryBiomarkerEndpoints include changes in brain amyloid deposition and brain tau deposition from baseline to week 76.

Results published this January indicate,The study met its primary endpoint: the change in iADRS score from baseline to week 76, with a 32% slowing of decline in the donanemab group compared with the placebo group. Compared with placebo, donanemab also demonstrated consistent improvement across all prespecified secondary endpoints measuring cognitive and functional abilities., but did not achieve nominal statistical significance for any secondary endpoint.

By targeting N3pGβ-amyloid, donanemab treatment has been shown to rapidly result in high-level clearance of amyloid plaques., as measured by amyloid imaging. In the TRAILBLAZER-ALZ study, at week 76 of treatment, patients in the donanemab group demonstrated a reduction of 84 Centiloid units in amyloid plaques (measured on the Centiloid scale), compared to a baseline of 108 Centiloid units (less than 25 Centiloids is typically indicative of a negative amyloid scan). In this study, donanemab treatment was discontinued and patients were switched to placebo once their plaque levels fell below 25 Centiloids on two consecutive assessments or below 11 Centiloids on any single assessment. The safety profile of donanemab in this study was consistent with observations from Phase I data, with amyloid-related imaging abnormalities (ARIA) observed, which is consistent with amyloid plaque-clearing antibodies. In the donanemab treatment group, 27% of subjects experienced amyloid-related imaging abnormalities-edema (ARIA-E), and 6% experienced symptomatic ARIA-E.

β-amyloid plaques in the brains of AD patients (Image source: hysiciansweekly.com)

The first analysis presented at the AAIC© 2021 conference showed that,During the 24-week treatment period, donanemab induced rapid reduction in amyloid plaques in patients with early symptomatic AD, with the fastest clearance observed in patients with the highest plaque burden at baseline.。At 24 weeks, a subset of patients who achieved complete amyloid plaque clearance (defined as amyloid levels <24.1 CL) could discontinue or reduce the donanemab dose earlier than other patients. Among patients who achieved complete amyloid plaque clearance at 24 weeks and were blindly switched to placebo, exposure-response models demonstrated minimal amyloid reaccumulation over the following year.

Additionally, compared with placebo, fluorodeoxyglucose positron emission tomography (FDG-PET) at week 76 demonstrated a significant reduction in tau spread (a predictive biomarker for AD progression) in the frontal, parietal, and temporal brain regions over the 76-week period among patients who achieved early complete amyloid plaque clearance at week 24.

Greater changes in amyloid plaques at week 24 were also associated with improved integrated Alzheimer's Disease Rating Scale (iADRS) scores, a validated composite measure that combines two established instruments for assessing AD.Clinical Trialcognitive and daily functioning. Furthermore, pharmacokinetic/pharmacodynamic models indicate that the higher the relative clearance rate of amyloid plaques, the greater the clinical benefit.

Second Analysis: This analysis focused on plasma P-tau217 (phosphorylation of tau at threonine 217), which isEli LillyAn investigational blood-based biomarker developed by the company, associated with amyloid and tau pathology and Alzheimer's diseaseDiagnosisRelated. Analysis shows that,Compared with the placebo group, donanemab treatment resulted in an early reduction in P-tau217 (LS mean log10 change, -0.04) and a significant reduction at the 3-month time point (P < 0.01) (LS mean log10 change, 0).. The reduction in P-tau217 was significantly correlated with amyloid changes at all time points: at 24 weeks (R=0.394, P<0.0001) and 76 weeks (R=0.492, P<0.0001).

These data support the amyloid cascade hypothesis and suggest that amyloid-related tauopathy can be modified by donanemab's effect on plaque clearance. Furthermore, the data support that early and profound amyloid clearance may translate into clinical benefits for patients. (Bioon.com)

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