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Dr. Isaacson:
Welcome to the Frontline of Alzheimer's Care, where we provide you with quick answers to burning questions from real clinicians about amyloid-targeting therapies in Alzheimer's disease. I'm Dr. Richard Isaacson, and here with me today to help answer these questions, are Drs. Gayatri Devi and Pierre Tariot.
Dr. Grove has a question for us.
Dr. Grove:
What monitoring protocols do you recommend for both improvement and side effects?
Dr. Isaacson:
Great question. I think there's going to be some nuance here. And I think different clinicians may be interested in different data points and use different protocols. Dr. Tariot, maybe you could tell us a little bit about the data and some key points to consider.
Dr. Tariot:
Sure. Those are great questions from Dr. Grove. In terms of monitoring clinical response, you know, I think it would make sense to periodically repeat some objective testing of cognitive performance, as well as functional status. And we actually like to monitor neuropsychiatric features as well with something like the Neuropsychiatric Inventory Questionnaire, which is very brief. And then, of course, just clinical assessments of how they're doing.
In terms of safety of utmost importance, frankly, is monitoring whether or not there are infusion-related reactions and ARIA in particular. Infusion-related reactions usually acute, things like headache, dizziness, fever, muscle aches, nausea, vomiting, flu-like syndrome. In terms of ARIA-E, we're particularly concerned about headache, confusion, visual disturbance, gait disturbance sometimes nausea, rarely seizures, very rarely, but it’s been reported or focal neurological deficits. However, most ARIA is asymptomatic, so you have to have a built in MRI monitoring protocol, slightly different for each drug but basically needed at baseline. And then with aducanumab prior to the 5th, 7th, 9th, and 12th infusions. For the lecanemab, at baseline prior to the 5th, 7th, and 14th. For donanemab, actually this schedule is still being worked out. There was a sort of aggressive MRI monitoring protocol in the phase 3 program, but with subsequent studies, it will be less intensive. So that's still a bit of a moving target.
Dr. Isaacson:
Great. Well, that's very, very helpful.
Dr. Devi you have a lot of clinical experience here what are some approaches are some best practices that you implement in your clinic?
Dr. Devi:
So I have tried to titrate up at a much slower rate for my patients. So with aducanumab, depending on whether they have one or two copies of the APOE4 allele, I titrate up by 1 mg/kg every 2 to 3 months as opposed to the standard protocol, which goes from 1 mg/kg to 10 mg/kg in 8 months. And it's actually obviously during the titration phase when patients are more likely to have ARIA edema and ARIA hemorrhage. But we've titrated up very slowly, especially in our homozygous patients. It takes us as long as 18 to 20 months to get patients up to even 7 or 8 mg/kg.
And in terms of MRI monitoring, I continue to monitor as we continue to titrate a patient. And once a patient gets to the optimal dosage, which is 10 mg/kg for both lecanemab and aducanumab, I then will do a repeat MRI after about 6 months. So it's a little bit different from the protocol that's recommended by the FDA, but that's because my titration schedule is much slower. And we've actually published on us in 20 patients who are homozygous or had at least one copy of the APOE4 allele our risk for ARIA hemorrhage and ARIA edema was zero. And now that was published last year, and this year we have probably about 30 some odd patients on medications. And so far, our risk for ARIA is still quite low. It's about 6% with a slower titration schedule.
Dr. Isaacson:
Great. Well, Dr. Devi, first of all, I want to applaud you for publishing this experience, because it's really hard to gather this kind of date. It really helps clinicians like me, who read that paper very closely, help with answering the question we were asked. So we need more studies just like this, so I'm appreciative of that.
I guess the other question I had is, you know, related to monitoring effectiveness in ways that are maybe less tangible.
Dr. Devi:
Generally speaking, all our patients get a fairly comprehensive neurocognitive battery every year. And when they're on treatment, sometimes even as often as every 8 months. And if I find that the patient is declining rapidly and that they're continuing to show no real slowing of progression, then I have taken patients off the treatments. I have taken them off, discontinued the aducanumab. I sometimes try to switch them to lecanemab, and sometimes not even doing that because the patient is progressing rapidly.
So I do have other metrics. I do ask the family, we have objective testing as well. And we clinically evaluate every patient with a thorough neurological examination every month. But I have to tell you that all four patients who had ARIA, I was not able to detect any changes on their evaluation, they had no symptoms, and two of them had fairly significant edema in multiple lobes of their brain.
Dr. Isaacson:
Well, thank you, Dr. Grove. And thank you Pierre, and Gayatri, for all that perspective. Viewers can listen to our other episodes for more of what clinicians want to know about the clinical use of amyloid-targeting therapies. Thank you all for listening.
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