My thoughts on the phase 3 results of Alzheimer's drug lecanemab from Biogen and Eisai, presented at #CTAD #CTAD22 and published this evening in the @NEJM. Major takeaway – this is NOT the breakthrough we have been waiting for. Key points: 
1) This trial is much better than the frustrating data associated with Aducanumab. Demographics are well balanced between groups and are (somewhat) more representative, the protocol is coherent and there aren’t major technical problems.
The drug clearly engaged its target, massively lowering β-amyloid levels in the first year of treatment based on amyloid PET scans.
2) The clinical benefit, which seems like a homerun at first glance, is a bit of a mirage. The statistical result is strong, but we need to look beyond p-values. For most individual patients in clinic, the benefits will probably not be detectable.
The primary outcome, the CDR-SB, scores patients' level of function on a 0-3 range in six different areas like memory and problem solving for a total score of 0-18 (smaller numbers are better). The benefit of lecanemab was less than 1/2 of a point. This is tiny.
The much trumpeted "27% slowing" is a relative value - the absolute difference on this test was 2.5%. In this image, I have re-scaled the result from the NEJM paper to include the absolute difference. [Values approximated using a graph extractor.]
3) I am not convinced the treatment is "disease modifying." Almost all of the benefit of treatment occurred in the first year, after which the trajectories were more-or-less parallel. With disease modifying treatments, the differences continue to become bigger over time.
4) Safety is still a huge problem - 44% of patients had treatment-related adverse events, 21% developed brain swelling and/or bleeding, a few of which were severe. Two cases of fatal bleeding occurred when lecanemab was combined with blood thinners. science.org/content/articl…
Severe bleeding occurred in 3.6% of patients taking anticoagulants in the lecanemab trials. This could be higher in the real world with less rigorous screening and monitoring. Patients with cerebral amyloid angiopathy or who require blood thinners should not take this medication.
As with aducanumab, I do not think the benefits seen in this trial clearly outweigh the risks and despite the general excitement around a possible new treatment, I will be advising my patients to keep waiting.
This "positive" result is paradoxically a blow to the amyloid-cascade hypothesis which claims β-amyloid is the major driver of Alzheimer's disease. Twenty+ years of clinical trials showed amyloid-lowering therapy at best produces a barely detectable clinical effect.
We can now say with confidence that β-amyloid is a small part of a complicated disease process, not the singular cause of Alzheimer's disease. It is time to close the book on the amyloid hypothesis.
• • •
Missing some Tweet in this thread? You can try to
force a refresh
