Sharon Cohen, MD, FRCPC, provided an investigator perspective on the use of lecanemab for patients with Alzheimer disease and what the clinician community can take away from the trials.
This is a 2-part interview. To view part 1, click here.
Since the FDA approval of lecanemab (Leqembi, Eisai), an antiamyloid therapy for patients with early Alzheimer disease (AD), the momentum for the AD community has been propelled. Lecanemab became the second approved antiamyloid therapy for the neurodegenerative disease, and showed progressive efficacy and safety not seen in these types of agents. Despite this,prior to the approval, there was a patient death in the phase 3 Clarity AD study (NCT03887455) of lecanemab, where a patient on the drug experienced microhemorrhages after being treated with tissue plasimogen activator for an ischemic stroke. This was the 3rd patient death from the trial.
Sharon Cohen, MD, FRCPC, an investigator from the Clarity AD phase 3 sat down with NeurologyLive® for an exclusive interview to offer her investigator perspective of the lessons learned from the trials and future actions to take for using the therapy in managing the disease. She goes over each of the 3 patient from the trial and the possible reasons for why they occurred. Cohen, a behavioral neurologist and medical director of the Toronto Memory Program at the University of Toronto, also discussed the meaning of the approval for the Alzheimer community and how the clinical community might capitalize on the current research that is being conducted on the treatment.
NeurologyLive®: How do we go from here, in terms of the management of the disease, the use of the therapy and learning lessons from these trials from an investigator perspective?
Sharon Cohen, MD, FRCPC:It's important that the community at large, patients and clinicians who are not researchers, understand that we take mortality and adverse events very seriously within trials. I know that Eisai does as well. Any mortality or serious adverse event are reviewed carefully in terms of attribution. Is it caused by the drug? Is it caused by a variety of factors and something completely unrelated to the drug? What we know from the large phase 3 study is that there were no deaths related to ARIA in people on lecanemab. There was one fatal hemorrhage in a person on placebo, and we do see hemorrhage infrequently, but we do see it as part of Alzheimer's disease. It's important that people understand that in Alzheimer disease, the vessels are leaky. We can have hemorrhage, and that does occur rarely in the disease without any treatment, without any lecanemab or other antiamyloid. We also see microhemorrhage, often asymptomatic, but not infrequently. We see these little spots of bleeding in the brain and patients with Alzheimer just by virtue of having Alzheimer disease.
The question is: is adding lecanemab based on the propensity for bleeding in the brain, does that enhance bleeding? Only a very, very small amount. If you can get benefit and slowing of disease, with only a very slight increase in risk of bleeding, many patients will feel “Hey, this is Alzheimer, I'll take that risk.” Others will say “No, that's not for me.” An informed discussion is very important. With the 3 deaths that were reported, there's been a lot of hype about it and it's really important that clear information comes out. One of the individuals was on an anticoagulant which has its own risk of bleeding, and it was a person who has falls. If you're on an anticoagulant, you hit your head, you'll get more bleeding. Now they were in the open label extension, they were on lecanemab,but it's not clear to me that it was entirely lecanemab they had other reasons for bleeding in the brain.
The second patient reported in a very dramatic way. The patient had a stroke and she was also in the open label lecanemab study. She had a stroke not due to lecanemab, and was given a clot busting drug t-PA, which has a 6% risk of causing bleeding. When you bleed from TPA in the brain, there's about a 45% chance that that bleed will be fatal. To say that lecanemab caused that, to me, is not credible, as she was given a clot busting drug, which itself could have caused the bleeding. Did lecanemab contribute to that? Is that combination of unsafe? We're trying to figure that out and nobody wants to be dismissive here.
The third case, again, somebody in the open label extension on lecanemab. We don't have all the details, I believe they were on anticoagulant as well. Eisai is trying to get the details before we get in this hype about blaming the drug versus blaming something else. We need to lay it out in a scientific matter, and not let it play out in the media. Unfortunately, that's what happens with some of the drama in drug development and that doesn't serve our patients or our community well. But there will be appropriate use of guidelines being developed to guide treating physicians to use lecanemab in the safest possible way. There may be patients, for example, on anticoagulants or who have the genetic genotype of two copies of APOE for who may be at higher risk of bleeding. Therefore, that risk benefit discussion has to happen between clinician and patient, that will ensure that we keep people safe.
What does this approval mean for the momentum of the Alzheimer community and how can the clinical community capitalize on the research that's currently happening?
We have been blessed with a huge boost to momentum now with the approval of lecanemab. It will play out in terms of empowering other drug development programs, not just in the amyloid space, not just within class, but other biologic approaches to treating Alzheimer, of which there are many. It will encourage combination therapies and new trial designs that have been very difficult to implement when you don't have an approved drug available to test against or in combination with, in terms of moving diagnostic technology forward. This is so important because PET scans are expensive and not accessible to everybody. A pet amyloid scan may be the gold standard or spinal tap, which requires a lumbar puncture.
If we can get blood based biomarkers, a blood test, qualified enough to stand alone or at least narrow the funnel so that people can start off with a screening blood test. Then, if they need to go on to a gold standard PET scan or spinal tap, that will be so important. Retinal scans are being developed in other technologies to aid in early diagnosis so that our family physicians and general practitioners can also participate. It's not all about the specialists doing everything, we all have a role to play here. I think that the momentum will be considerable. I know that other companies are very encouraged and the community is encouraged. People will come forward saying “I might have early Alzheimer, is there something you can do for me rather than hiding away?”
Transcript edited for clarity.