By Lucy Piper, medwireNews reporter
medwireNews: Three-year efficacy and safety data for lecanemab shows continued treatment benefit, particularly in patients who started the drug in the very early stages of the disease.
Christopher van Dyck (Yale University School of Medicine in New Haven, Connecticut, USA) presented the findings at the Alzheimer’s Association International Conference 2024 in Philadelphia, Pennsylvania, USA.
For the open-label extension stage of the core phase 3 CLARITY AD trial , involving nearly 1500 of the original 1795 patients, the participants either continued to receive intravenous infusions of lecanemab 10 mg/kg every 2 weeks having taken it for 18 months or switched to the treatment from placebo.
Data now available at 36 months for these patients show a mean 3.09-point worsening in Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score from baseline. At 18 months, the difference between lecanemab- and placebo-treated patients on the CDR-SB was a mean of 0.45 points and at 36 months when the lecanemab group were compared with matched historical controls from the ADNI study with similar demographics and stage of disease, the difference increased to a mean of 0.95 points.
The patients who continued treatment at 18 months had significantly less decline in CDR-SB than those who switched from placebo at 18 months, but improvement over controls was seen in both groups.
Responder analysis also showed a significant 30% reduction in AD progression through 36 months with lecanemab treatment, so the time for the CDR-SB score to shift from mild cognitive impairment (0.5–4.0 points) to mild AD dementia (4.5–9.0 points) or mild-to-moderate dementia (9.5–15.1 points).
Van Dyck highlighted that the 141 patients who had no or low tau levels (standardized uptake value ratio [SUVR] <1.06) at baseline – 41.2% of the tau PET substudy population – showed “stability or improvement over the 18 to 36 months”.
Among those who continued lecanemab treatment, 59% had no decline in CDR-SB score at 36 months and 51% had improvement, with similar findings on the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog14) and the Activities of Daily Living for Mild Cognitive Impairment scale (ADCS-MCI-ADL).
Given the small sample size of no or low tau patients, van Dyck gave the results for patients with low baseline amyloid levels (<60 Centiloids), representing just over half of the total population, who also continued to show improvement with lecanemab treatment. At 36 months, 46% had no decline on the CDR-SB score, while 33% had improvement. Again, similar results were seen on the ADAS-Cog14 and ADCS-MCI-ADL.
“The real message here is that these low pathology groups do particularly well on lecanemab, and this really underscores the importance of early intervention with lecanemab treatment,” van Dyck commented.
Biomarker results supported continued treatment beyond amyloid clearance at 18 months. At this point (baseline of the open label extension phase) approximately 70% of patients were amyloid negative (<30 Centiloids), yet clinical improvement with ongoing treatment was still evident. There was minimal change in amyloid PET, but the change in the ratio of amyloid-β 42/40 continued to improve.
There was also evidence of a slowing in the rate of tau pathology in the core CLARITY AD trial, as measured by plasma phosphorylated (p)-tau217, but particularly cerebrospinal fluid microtubule binding region-tau243 that tracks tau tangles, which slowed by 44% at 18 months, said van Dyck.
He reported that “there were no new clinically significant adverse events identified with long-term [lecanemab] treatment.” Data were assessed for approximately 3480 person–years of drug exposure, with a mean treatment period of 2.2 years and 3.0 years for more than 450 patients.
“With additional exposure some adverse events go up in the percentage of people who have them, such as serious adverse events and deaths, but when we normalize to person months, there is no increase at all,” said van Dyck.
For instance, the rate of the amyloid-related imaging abnormality edema (ARIA-E) at 36 months was 14.7% in 1616 patients from the CLARITY AD core plus extension studies, compared with 12.6% at 18 months in 898 lecanemab-treated patients and 1.7% in 897 taking placebo. However, after adjusting for months of exposure, it was 6.8 per 100 person–years versus 9.6 and 1.2 person–years, respectively.
The first 6 months of treatment appeared to carry the greatest risk for ARIA-E, van Dyck explained, after which rates were low and comparable to those with placebo.
He added that ARIA was not associated with “accelerated long-term progression,” with the time to worsening on CDR-SB similar when those who did and did not experience ARIA were analyzed separately.
Ideal maintenance dose for lecanemab treatment
These long-term treatment benefits of lecanemab stem from the drug’s dual-action mechanism in targeting neurotoxic oligomers and protofibrils, which continue to be produced after amyloid plaques have been cleared, explained Larisa Reyderman (Eisai Inc).
In one of several presentations looking at the rationale for continuing lecanemab treatment, she explained how biomarker results from the phase 2 Study 201 along with semi-mechanistic pharmacokinetic and pharmacodynamic models created by the lecanemab research team suggest “the ideal maintenance dose for lecanemab beyond amyloid clearance is 10 mg/kg monthly from 18 or 24 months.”
She showed data for 31 patients from Study 201 who were given lecanemab 10 mg/kg every 2 weeks for 18 months and then stopped treatment for a mean of 2 years demonstrating a “detrimental effect of stopping treatment.”
The clinical effect of treatment was maintained during those 2 years, but the rate of cognitive decline reverted to that of the 40 patients given placebo.
Interrupting treatment was associated with a 21% re-accumulation of amyloid positron emission tomography (PET), a 47% worsening in the amyloid-β 42/40 ratio, and re-accumulation rates of 30%, 24%, and 13% for plasma glial fibrillary acidic protein (GFAP), p-tau181, and p-tau217.
The pharmacokinetic and pharmacodynamic models include up to 110 months of data on lecanemab exposure from the Study 201 core and open label extension phases and up to 54 months from the CLARITY AD core and open label extension phases.
These models showed that “changes in fluid biomarkers on treatment discontinuation are more sensitive measures of disease progression,” she noted.
Half of the effect of lecanemab treatment on the amyloid-β 42/40 ratio is lost after 6 months, while half the effect on amyloid PET is lost within 12.1 years. For p-tau181 and GFAP, half the treatment effect is lost in 1.6 and 1.7 years, respectively.
The models predicted that a monthly maintenance dose of lecanemab 10 mg/kg given at either 18 or 24 months was sufficient to prevent the re-accumulation of amyloid and worsening of plasma biomarkers.
The effect of the maintenance dose was also comparable to bi-weekly dosing for 4 years in terms of clinical outcome measured by amyloid PET and CDR-SB.
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