Lecanemab Study 201 and OLE
Lecanemab is an investigational humanized monoclonal antibody that preferentially binds to soluble amyloid- beta (Aβ) aggregates (protofibrils). Lecanemab reduced brain Aβ and slowed clinical decline in an 18-month Phase 2b proof of concept study (Study 201, n=856) in early AD (Alz Res Therapy 13; 2021). After analysis of the core study, there was an off-treatment gap period of 9-59 months (period of time between the last dose of lecanemab in the core and the OLE baseline; average of 24 months). After this off-treatment gap, the OLE evaluating the 10 mg/kg IV biweekly lecanemab dosing was implemented (n=180 from core study enrolled). The clinical effect of treatment with lecanemab was assessed via the adjusted mean change of the AD Composite Score (ADCOMS), the primary clinical endpoint of the core study. The ADCOMS scale ranges from a score of 0.00 to 1.97, with higher score indicating greater impairment. Additional clinical endpoints included Clinical Dementia Rating-Sum of Boxes (CDR-SB) and AD Assessment Scale - Cognitive Subscale (ADAS- Cog).
May suggest a potential disease-modifying effect
For subjects with early AD at Study 201 OLE baseline, the dose-dependent clinical treatment effect of lecanemab administration relative to placebo during the core phase was maintained. While off-treatment during the gap period, people who received 10 mg/kg IV in the core continued to perform better than those who received placebo on ADCOMS. While off-treatment during the gap period, subjects declined at the same rate on key clinical measures in all core treatment groups. The increase in adjusted mean change between the three month follow up after the core 18-month and OLE baseline for lecanemab bi-weekly, lecanemab monthly and placebo dosing respectively were 0.11 (0.07 to 0.18 ), 0.10 (0.12 to 0.22) and 0.09 (0.19 to 0.28) for ADCOMS. Similar results were observed for CDR-SB and ADAS-Cog. This may suggest a potential disease-modifying effect of lecanemab.
Potential relationship between the plasma Aβ42/40 ratio, brain amyloid by PET and treatment
Low values of plasma Aβ42/40 ratio is recognized as an indicator of elevated amyloid in the brain, and was assessed in a subset of participants in Study 201.1 The plasma Aβ42/40 ratio increased during the core phase and OLE in those treated with lecanemab and decreased during the gap period, potentially demonstrating the relationship between the plasma Aβ42/40 ratio and treatment with lecanemab. The lecanemab treatment related increases in plasma Aβ42/40 ratio were inversely correlated with treatment related reduction of brain amyloid in the core and OLE (Poster No. 57760).
Assessing the long-term effect of continued treatment with lecanemab
Study participants with early AD at the OLE baseline who received placebo during the core phase and were treated for the first time with lecanemab during OLE, as well as those treated with lecanemab both during the core phase and during OLE, showed reduced clinical decline relative to natural disease progression (reference similar population from ADNI). The adjusted mean change from OLE baseline at the end of the 18-month OLE study period for core 10 mg/kg bi-weekly dosing, 10 mg/kg monthly dosing, and placebo groups respectively were 0.102, 0.165 and 0.07 for ADCOMS, all of which showed a slower rate of progression as compared to ADNI (0.214). Similar results were observed for CDR-SB and ADAS-Cog. The results support the concept of increased long-term benefit of continued treatment with lecanemab when initiated in the early AD stage.
These preliminary findings are based on limited data and are being further evaluated in the ongoing Phase 3 Clarity AD study for early AD.
"The findings from the lecanemab Phase 2b OLE study are encouraging as they supply further insights into outcomes with anti-amyloid therapies and we look forward to learning more in the Phase 3 studies, Clarity AD and AHEAD 3-45, currently underway," said
The enrollment of 1,795 patients with early AD in the Phase 3 Clarity AD clinical study was completed in
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