Data show a clinical benefit via a reduction in brain amyloid as early as 3 months in the open-label extension period.
Updates on the phase 2b 201 core study (NCT01767311) and the open label extension (OLE) phase 3 proof-of-concept study of lecanemab (BAN2401) were provided in a late-breaking roundtable discussion at the 14th Clinical Trials on Alzheimer’s Disease Conference (CTAD), November 9-12, 2021. Updates outlined results of new clinical, biomarker, and safety assessments of 5-year clinical status of patients with early Alzheimer disease (AD) and brain amyloid reduction.
The phase 2b trial included 856 patients with early AD who were amyloid positive at the core randomization phase, spanning 18 months. This was followed by an average gap period of 24 months where no treatment was administered, concluding with the OLE, where the maximum dose of 10 mg/kg was administered via intravenous (IV) infusion for up to 10 months.1
Investigators found that lecanemab was able to be initiated without titration at the top dose of 10 mg/kg, administered via biweekly IV, with patients seeing amyloid reduction within 3 months of treatment and clinical efficacy within 6 months of treatment. Over 80% of included participants also went from being amyloid positive to amyloid negative within 12 to 18 months of treatment with lecanemab, according to visual read.
Data from the core study indicated a positive correlation between amyloid reduction and a slowing of clinical decline on ADCOMS. This was measured by PET standardized uptake value ratio (SUVr), with correlations on the group level (correlation coefficients, 0.832; P = .080) and subject level (correlation coefficients, 0.201; slope, 0.199; P = .026).
“What we’ve learned from the gap is that these clinical treatment differences that we see in early AD subjects in the core study—comparing placebo and 10 mg/kg biweekly [doses of lecanemab]—are maintained over the entire 2-year gap period off lecanemab, again suggesting the potential disease-modifying effect from the clinical profile,” Chad J. Swanson, PhD, executive director, Neurology Business Group, Clinical Research, Eisai, said during his presentation at CTAD.2
Also noted was the potential to use plasma biomarkers to monitor for lecanemab treatment effects, as shown via correlations between amyloid measured by PET SUVr, clinical cognition end points, as well as plasma biomarkers, including amyloid-ß 42, amyloid-ß40 ratio (Aß42/40) and phosphotau181 (p-tau181) after lecanemab treatment.
In the core study, the plasma Aß42/40 ratio correlated with PET SUVr (population correlation coefficient, –0.790; P = .112; subject level correlation coefficient, –0.411; P <.017), suggesting that Aß42/40 ratio could be more sensitive as an indicator of amyloid change, compared with PET SUVr. Also in the core study, changes in PET SUVr positively correlated with changes in 181P (correlation coefficient, 0.474; P <.001) at the individual level, and changes in p-tau181 inversely correlated with Aß42/40 ratio (correlation coefficient, –0.359; P = .001), also at the individual level.
“Perhaps this monitoring of treatment effect using plasma biomarkers may allow for us to make simple dosing modifications following the rapid and thorough reduction of amyloid that we’ve seen,” Swanson said.2 “What I mean by this is perhaps we go in with less frequent dosing, or perhaps a lower dose, after amyloid has been removed to the point where a subject becomes amyloid negative by visual read.”
There was less than 10% incidence of amyloid-related imaging abnormality-edema (ARIA-E), less than 15% incidence of apolipoprotein E carrier ARIA-E rate, and less than 2% incidence of symptomatic ARIA rate in both the core and OLE studies. Swanson noted that the data were “hypothesis generating,” and require future evaluation in the ongoing CLARITY AD trial (NCT03887455) and the OLE.
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