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The Beta-Amyloid Saga Continues for Biogen

Biogen is at it again. The company along with its collaborator Eisai released preliminary data for the Phase 3 CLARITY study. A potential Alzheimer's disease medication lencanemab met primary and secondary endpoints with acceptable safety profile. This again set the Alzheimer’s world a buzz with optimists and skeptics quickly digging in their heels.

Eisai has a history of developing medications to improve the lives of patients afflicted with Alzheimer’s. Aricept was developed by Eisai in the 1990’s. It is one of the current cornerstones in the management of this disease.

Lecanemab, like aducanumab (Aduhelm), is an antibody targeting beta-amyloid plaque in the brain. The beta-amyloid origination theory continues to be the most recognized mechanism for the onset of Alzheimer’s disease. I’m not going to pretend to understand the nuanced differences between these two antibodies. The idea is to remove the amyloid plaque to improve communication between neurons and ultimately cognition.

Patients were eligible for CLARITY if they had mild cognitive impairment due to Alzheimer’s disease with confirmed presence of amyloid plaque based on PET scan imaging. Participants were over 65 years of age, from various ethnicities, countries, and were included despite the presence of common co-morbid conditions.

According to the press release, the study enrolled 1795 patients. They achieved a reduction of -0.45 points on the CDR-SB dementia scale which was statistically significant. The CDR-SB score ranges from (0-18), with a score of 9 signifying mild dementia. Based on the inclusion criteria this is likely where most of the participants started.

The study showed a significant reduction in amyloid plaque based on PET imaging with a reasonable safety profile. Adverse events were common but more tolerable than Aduhelm. 17.5% of patients experienced cerebral edema and micro-hemorrhages based on imaging, but only 2.8% of these were symptomatic.

From what I could glean from the release, the dosing is by infusion every two weeks and the study ran for 18 months. They plan to release the full study results on Nov 29th at an Alzheimer’s conference.

The significance of a 0.45 point reduction on a difficult to administer dementia scale is up for debate. In my opinion, it’s a “steep climb for a short slide.” At least the safety data was far superior to Aduhelm (30% severe adverse event rate).

It is quite possible this medication will make it through regulatory approval, but I am not optimistic it will be a boon for patients. The beta-amyloid plaque target continues to be a fool’s errand.

It’s true that the presence of amyloid plaque is unique to Alzheimer’s disease. However, the debate on whether it’s a chicken or an egg is quite apparent. Beta-amyloid is the chicken. The hope is the antibody reorganizes the chicken back into the egg, but this is not the case. The antibody just rips the chicken into a bunch of pieces. What’s left is the collateral damage, which is responsible for these adverse events.

Neurons thrive on connection with other neurons. They require constant stimulation to various receptors to strengthen and expand. When these connections are blocked by plaque a neuron will down-regulated, shrivel and enter dormancy.

The researchers in this study appear to have a better understanding of this than the coordinators for Aduhelm. They started further upstream in terms of Alzheimer’s progression by excluding moderate to severe Alzheimer's patients. Targeting early cognitive impairment increased the number of viable neurons/patient in the trial. Despite this they barely eked out a win. The small effect size suggests the difference is due to absence of progression, not clinical improvement. Destruction of newly formed plaque before it interferes with neural communication, not the removal of previously deposited plaque, is the key to longevity. Based on this report, and my logic, lecanemab is equivalent to medicines already available but far more expensive.

Since beta-amyloid is the chicken, you need to prevent the egg from hatching. This would require treating patients well before the plaque ever makes its appearance. The costs for a prevention trial with lencanemab would be immense. The burden on patients would be immense. You would have to start the medication well before there were signs of the disease. The trial alone would cost billions of dollars to conduct. In my opinion, beta amyloid antibodies are destined for the “it doesn’t really work, but it's all we got” category.

The best way to target this disease would be through a vaccine. Train the immune system to remove plaque ahead of time, before neurons go into hibernation. Anyone working on that technology has a chance.

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