With detailed results scheduled to be presented on Nov 29 at the CTAD (Clinical Trials on Alzheimer's Disease) conference, it's likely we will be seeing news articles about the implications discussed below in a 3-minute read from AlzForum on Oct 7: How Will Alzheimer’s Trials, Treatment Change in 2023 and Beyond?
Here are some highlights from the article:
For those wondering how much of a difference 0.45 on the CDR-SB really is, here's a PDF showing a description of scores of 0 (Unimpaired); 0.5 (evidence of MCI); 1.0 (evidence of mild dementia); 2.0 (evidence of moderate dementia).When Eisai and Biogen announced positive top-line results for their anti-amyloid antibody lecanemab, the trial became the first successful, completed Phase 3 Alzheimer's drug study in the Western world in more than 20 years. If lecanemab earns traditional approval from the U.S. Food and Drug Administration based on these results, as is widely expected, the effects could be seismic. For the first time, patients could get a prescription for a disease-modifying treatment along with their Alzheimer’s diagnosis....
Eisai/Biogen reported that lecanemab slowed clinical decline on the CDR-SB, ADAS-Cog14, ADCOMS, and ADCS MCI Activities of Daily Living with robust statistical significance, though the numerical advantage on the CDR-SB was small, amounting to a difference of 0.45 over 18 months [Note: See below for CDR items]. The companies have said they will apply for traditional approval in the U.S., Europe, and Japan, though they have already submitted for accelerated approval in the U.S., with a decision expected by January 6 (May 2022 news; Jul 2022 news). This means lecanemab could be on the U.S. market within three months....
The findings raise a slew of new questions. Chief among them is whether the data will move the Centers for Medicare and Medicaid Services to...[enable] widespread use. Other clinical questions include whether updated Appropriate Use Recommendations are needed, whether lecanemab treatment can be stopped at some point, and how to identify people who respond best...The worldwide Clarity trial posted overall racial and ethnic diversity of 33 percent. Among U.S. participants, 25 percent came from minority groups, reflecting the makeup of the Medicare population...the companies reported...
Researchers Alzforum spoke to were encouraged by Clarity’s top-line results suggesting less ARIA than was seen with aducanumab. Overall, 12 percent more people developed ARIA on lecanemab than on placebo. This took the form of either brain edema alone, or edema with microhemorrhages. AD researchers are anxious to see the data on how ARIA risk varies with APOE genotype. In the Phase 2 lecanemab trial, Eisai reported that the heightened risk clustered in APOE4 homozygotes, with heterozygotes having the same odds as APOE3 carriers (Aug 2022 news). If that holds in Phase 3, it might lead clinicians to use the treatment for a broader range of patients....
Eisai/Biogen are developing a subcutaneous [skin injection] formulation that could be administered at home... The subcutaneous formulation also caused less ARIA-E, due to slower absorption that kept the maximum plasma concentration at one-fourth that of intravenous lecanemab. It is unclear how quickly this formulation could be approved and brought to market...
Researchers...[note] that the availability of lecanemab would facilitate testing of concurrent therapies where each drug hits different aspects of the disease. In the case of other anti-amyloid treatments, trials could test whether they were equivalent to lecanemab in efficacy, while perhaps having advantages in cost, safety, or ease of use,
The Clarity trial enrolled people with mild cognitive impairment or mild dementia, hence lecanemab would be approved only for symptomatic AD. Lecanemab is being tested in a prevention paradigm in the AHEAD 3-45 study of cognitively healthy people with amyloid plaque deposition; that four-year study is recruiting and won't read out any time soon.
Even critics of the amyloid hypothesis told Alzforum they would prescribe lecanemab, or even consider getting a PET scan themselves and trying to get access to the drug in an N-of-1 personal prevention mode. All researchers contacted for this story agree more effective treatments are needed to halt or, better yet, reverse cognitive decline. Most think this will require concurrent therapies that target multiple pathologies. Reiman likened amyloid to a smoldering kindling that lights the fire of neurodegeneration, which then becomes self-sustaining. The fire may take the form of inflammation or aggregated tau, or both.
Clinical Dementia Rating: Sum of Boxes test items
People on lecanemab who stayed at 0.5 (MCI) instead of moving to 0.95 [if 0.5+0.47= average placebo progression with MCI in 18 months] appear to have avoided progression to a diagnosis of dementia for at least a while, and those with mild dementia avoided moving halfway to moderate dementia.
