Dr Atri continues his discussion on aducanumab and AD diagnostic evaluations.
Alireza Atri, MD, PhD: The trick here is that in individuals who have the APOE e4 genotype, a cholesterol plasma protein, it also increases our risk for having Alzheimer disease and experiencing symptoms earlier. They tend to have leakier blood vessels and get more ARIA [amyloid-related imaging abnormalities]. With individuals who didn’t have APOE e4, the rate was about 20%. Individuals who had APOE e4, 1 or more, was about 40%. In the studies, they did genetic testing. In the appropriate use criteria, we don’t say that this has to be done in clinical practice, but there has to be a conversation with individuals about the pros and cons of that. Individuals with APOE e4 can have more risk for this.
The other part of this is the monitoring of the sequences. The FDA label suggested that there be 2 monitoring MRIs. In the clinical trials, they had many. They had 1 every month because they were trying to learn from this. One of the lessons of this is that it was able to be managed. In a controlled setting, in somewhat of a “laboratory” setting of highly selected individuals who were treated and monitored by very proficient staff, ARIA was detectable. It was mostly asymptomatic. When it was symptomatic, it wasn’t usually severe. There were no deaths reported in the phase 3 studies for this. It’s possible to do this. It’s manageable in that setting.
When it comes to real-world practice, one part is getting the right patient. The other part is having the infrastructure of choosing the right patient and being able to have people who are proficient in showing that there’s amyloid positivity, that the right patient is offered this drug, and they understand the counseling and what the expectations are—what it takes, the cost and burdens, and the risks. And then the detection, monitoring, and management of ARIA is important. That requires proficiency.
Let’s go back to the differences between the FDA recommendations and the appropriate use criteria. The FDA suggested 2 monitoring MRIs, one before the seventh infusion and one before the 12th infusion, so right before going up to 10 mg/kg and then being on it for 5 weeks. The appropriate use recommendations suggest an extra MRI before that, at week 5, before going up to the 6 mg/kg dose, and any MRIs before then if there are any suggestions of symptoms that could be attributed to ARIA.
There’s also the question of what should be done if ARIA happens. The appropriate use recommendations suggest that if ARIA occurs and it’s symptomatic, if there are any symptoms related to the ARIA that you can show on the MRI, then the dose should be held, and the patient should be monitored until there’s resolution of the ARIA and the symptoms. If the ARIA is mild and has symptoms, hold. It’s the symptoms part. If there are symptoms, hold. What if the ARIA has no symptoms and is only seen on a monitoring MRI? If it’s mild, then the recommendation in the trials is to continue to dose but to monitor. But if it’s moderate or severe, then withhold the dose and go through the process of monitoring with monthly MRIs to see resolution of the ARIA.
Usually in the clinical trials, the data suggest that ARIA resolves in anywhere from 4 to 12 weeks, on average usually 2 or 3 months. These appropriate use criteria define things like mild ARIA, moderate ARIA, and severe ARIA. It’s the same thing with microhemorrhages and ARIA-E [edema]. Mild ARIA, it’s arbitrary but that’s what’s been used in the studies, was an area that was less than 5 cm and in only 1 area. Anytime we have 2 different areas of ARIA, that would be considered moderate, or if it was 1 area that was between 5 and 10 cm. Larger than 10 cm would be considered severe. In practice, monitoring of ARIA would be very important, in addition to monitoring the patient clinically to see if there are any symptoms, along with having an ongoing discussion about expectations.
This transcript has been edited for clarity.