Experimental Alzheimer’s Drug Lecanemab Slows Cognitive Decline in Clinical Trial

A significant development in Alzheimer’s disease research has been announced by the drug company Eisai. In a press release, the company said that their investigational anti-amyloid beta (Aβ) protofibril antibody lecanemab has produced modest but highly statistically significant results in trial. The drug met its primary endpoint of slowing cognitive decline in individuals with mild cognitive impairment (MCI), a clinical presentation thought to be a precursor to Alzheimer’s, and those with mild Alzheimer’s. The compound had been tested in a trial dubbed CLARITY AD.

“Cognitive decline can be slowed”

“The lecanemab CLARITY AD results are exciting, if borne out by the full details of the study, as they are the clearest indicator so far that by lowering amyloid levels in the brain, cognitive decline can be slowed,” said Dr. Catherine Mummery, a consultant neurologist at University College London Hospitals NHS Foundation Trust, in a statement.

CLARITY AD was a Phase III placebo-controlled, double-blind randomized clinical trial involving 1,795 people, where participants received either a placebo or lecanemab. The treatment group received a biweekly dose of the drug. Importantly, said Eisai, the trial’s US enrolment included 25% Hispanic and African American participants, ensuring that the trial population is comparable to Medicare users in the US.

After 18 months, cognitive decline, as measured by the Clinical Dementia Rating-Sum of Boxes (CDR–SB) rating scale, was 27% lower in the treatment group compared to placebo. The reduction in decline, Eisai said, was apparent as early as six months after dosing began. Secondary endpoints related to amyloid levels and other rating scales of day-to-day function were also met with highly statistical performance, although Eisai did not report the numerical change in these measures.

Rob Howard, a professor of old age psychiatry at University College London, who was critical of aducanumab’s approval, commented, “This is an unambiguously statistically positive result and represents something of an historic moment when we see the first convincing modification of Alzheimer’s disease.”

Clinical significance in question

Nevertheless, there were data in the trial that brought the drug’s long-term value into question. While the 27% reduction in cognition was highly statistically significant – with a p-value equal to 0.00005 – the raw clinical change in the CDR–SB in the treatment group was just 0.45 points. “A 0.45-point advantage, on an 18-point scale, where the accepted minimum worthwhile difference ranges from 0.5 to 1.0 points, will mean that there are going to be some very difficult conversations and decisions in the next weeks and months,” Howard commented.

Mummery pointed out that only time will tell whether the difference between control and placebo increases as participants in the trial age.

Side effects

Anti-amyloid therapies are associated with swelling collectively termed amyloid-related imaging abnormalities-edema/effusion (ARIA-E). Eisai said that 2.8% of the lecanemab group showed symptoms of ARIA-E, compared to no incidence in the placebo group. In the treatment group, 0.7% experienced symptoms of ARIA-H, a condition that indicates microhemorrhages in the brain, compared to 0.2% of the placebo group. Howard called for full data to be released to ascertain whether these side effects could have indicated to some patients that they had received lecanemab. This would have the effect of unblinding the study, which can increase the risk of bias in a trial.

A fascinating finding after a false start

The field experienced something of a false start last year with the controversial approval of aducanumab, an antibody developed by Biogen (who are co-commercializing lecanemab with Eisai). Both lecanemab and aducanumab target Aβ, a protein that has been observed to build up in the brains of people with Alzheimer’s and which has been the main target for disease research since the early 1990s.

Aducanumab was able to mop up Aβ in the brain but produced messy data on cognition; in a paired-trial format, one trial showed no effect on cognitive performance, while the other only did at a higher dose level. The drug’s unconvincing efficacy meant it drug failed to gain approval in Europe. With lecanemab, Eisai and Biogen appear to have produced an anti-Alzheimer’s compound that has far more statistically sound effects on cognition, a finding that will go some way towards restoring the tarnished reputation of the “amyloid hypothesis” that had placed Aβ at the center of Alzheimer’s pathology. Nevertheless, researchers and patients will anxiously await the release of Eisai’s full findings.

Regulatory approval

In the statement, Eisai announced its intention to seek regulatory approval for the compound in the US, Japan and Europe by the end of March 2023. The company said it would present full findings from the trial on November 29, 2022, at the Clinical Trials on Alzheimer’s Congress (CTAD). Importantly, it also said results would be published in a peer-reviewed journal.

UCL’s Professor John Hardy, who produced some of the first results that identified Aβ as a Alzheimer’s drug target, called the results “modest but real.”

“It has been a long road for anti-amyloid therapies. This is clearly not a magic bullet. But it looks like a definite “end of the beginning”,” he added.

While questions remain unanswered on the clinical significance of lecanemab, initial reaction to the data looks far more positive than for aducanumab. Howard, who called aducanumab a “treatment without convincing efficacy, with serious associated adverse effects and a high financial cost,” concluded his statement on lecanemab with a comparably effervescent outlook: “God knows, we’ve waited long enough for this.”