NEJM Study Finds First-Ever Reduction in Rate of Progression of Alzheimer's... Is Lecanemab a Miracle Drug For AD?
This is the first drug to show a reduction in the rate of progression by 1/4 by attacks amyloid surrounding nerves. Long-term safety is not yet known.
NEJM: van Dyck et al., 2022 Lecanemab in Early Alzheimer’s Disease (Full text available)
Lecanemab is a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils
The study found a massive clearing of amyloid with consequent reduction in the rate of progression of Alzheimer’s diseases symptoms. Only 6.9% of patients had to drop from the trial due to side effects. Side effects included brain bleeds (17% of participants) and brain swelling (13%) (See the adverse events effects section, below) and the full study at NEJM (You have to sign up, but this article is free after that).
From the study:
The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer’s disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer’s disease.
We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer’s disease (mild cognitive impairment or mild dementia due to Alzheimer’s disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).
A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence interval [CI], −0.67 to −0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, −59.1 centiloids; 95% CI, −62.6 to −55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, −1.44 (95% CI, −2.27 to −0.61; P<0.001); for the ADCOMS, −0.050 (95% CI, −0.074 to −0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.
Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455. opens in new tab.)
From the study:
“All panels except Panel B show results in the modified intention-to-treat population. Panel A shows the results for the primary end point, the score on the Clinical Dementia Rating–Sum of Boxes (CDR-SB). Scores for each of six domains range from 0 to 3, with higher scores indicating greater impairment. Total scores range from 0 to 18, with a score of 0.5 to 6 indicating early Alzheimer’s disease. The adjusted mean changes from baseline, standard errors (indicated by 𝙸 bars), and P value were derived with the use of a mixed model for repeated measures, with trial group, visit, trial group–by–visit interaction, clinical subgroup, use of medication for symptoms of Alzheimer’s disease at baseline, ApoE ε4 carrier status, geographic region, and baseline value–by–visit interaction as fixed effects and baseline value as a covariate. Panels B through E show the results for the key secondary end points; values were calculated in the same manner as those for the primary end point. Panel B shows results for the change from baseline in amyloid burden on PET as measured in centiloids (with either florbetaben, florbetapir, or flutemetamol tracers) in a trial substudy. Panel C shows results for the change from baseline in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment). Panel D shows results for the change from baseline in the Alzheimer’s Disease Composite Score (ADCOMS; range, 0 to 1.97, with higher scores indicating greater impairment). Panel E shows results for the change from baseline in the score on the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53, with lower scores indicating greater impairment).”
Adverse Events Section (from the study):
(NB: terms: amyloid-related imaging abnormalities (ARIA) with edema or effusions (ARIA-E))
“Serious adverse events occurred in 14.0% of the participants in the lecanemab group and 11.3% of those in the placebo group. The most commonly reported serious adverse events were infusion-related reactions (in 1.2% of the participants in the lecanemab group and 0 participants in the placebo group), ARIA-E (in 0.8% and 0, respectively), atrial fibrillation (in 0.7% and 0.3%), syncope (in 0.7% and 0.1%), and angina pectoris (in 0.7% and 0). The overall incidence of adverse events was similar in the two groups (Table 3). Adverse events leading to discontinuation of the trial agent occurred in 6.9% of the participants in the lecanemab group and 2.9% of those in the placebo group. The most common adverse events (affecting >10% of the participants) in the lecanemab group were infusion-related reactions (26.4% with lecanemab and 7.4% with placebo); ARIA with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (ARIA-H; 17.3% with lecanemab and 9.0% with placebo); ARIA-E (12.6% with lecanemab and 1.7% with placebo); headache (11.1% with lecanemab and 8.1% with placebo); and falls (10.4% with lecanemab and 9.6% with placebo). Infusion-related reactions were largely mild to moderate (grade 1 or 2, 96%) and occurred with the first dose (75%). A total of 56% of the participants did not take preventative medications (i.e., nonsteroidal antiinflammatory drugs, antihistamines, or glucocorticoids) for infusion-related reactions. Of those who took preventative medications for subsequent doses, 63% did not have additional reactions.
Events of ARIA-E with lecanemab were mostly mild to moderate (91%) on the basis of central reading of imaging with the use of protocol definitions. These events were mostly asymptomatic (78%), occurred during the first 3 months of the treatment period (71%), and resolved within 4 months after detection (81%). A total of 2.8% of the participants in the lecanemab group had symptomatic ARIA-E; commonly reported symptoms were headache, visual disturbance, and confusion. The incidence of isolated ARIA-H (i.e., ARIA-H in participants who did not also have ARIA-E) was 8.9% in the lecanemab group and 7.8% in the placebo group. The incidence of isolated symptomatic ARIA-H was 0.7% in the lecanemab group and 0.2% in the placebo group. The most common symptom associated with isolated symptomatic ARIA-H was dizziness. Macrohemorrhage occurred in 5 of 898 participants (0.6%) in the lecanemab group and 1 of 897 participants (0.1%) in the placebo group. ARIA-H that occurred with ARIA-E tended to occur early (within 6 months). Isolated ARIA-H occurred throughout the trial. ARIA-E and ARIA-H were numerically less common among ApoE ε4 noncarriers than among carriers, with higher frequency among ApoE ε4 homozygotes than among ApoE ε4 heterozygotes (Table 3).”
What do you think? Are we going to turn the table on Alzheimer’s disease with this monoclonal Ab?
Personally, I have to say on the basis of this trial, I might try this if I knew I had a high risk of early onset of Alzheimer’s disease.
Again they are always looking for a drug rather than fight to stop pesticides, vaccine adjutants, GMO's, and other pollutants that are the main drivers of this disease and most others.
Thank you for sharing this! How do think about purported reductions in symptoms, and your own willingness to take this drug, based on the ongoing and more recent data sowing doubt about the direct role of amyloid as a causative agent in AD?