Celebration Thread! Biogen is going to the FDA with Aducan.

[J11]

This idea is shown in the above PET amyloid scans. What we see in the top middle of each of the figures is bright red regions in the frontal lobe with a large amount of amyloid at the week 6 scan and then in the corresponding middle figuret below removal of most of this red region (the amyloid). The ARIA Flair figure to the right shows how ARIA occurs exactly in these regions of the brain. ARIA occurs where and when there is rapid amyloid removal.

This certainly got me thinking that perhaps radiographic symptomology and symptomatic symptomology might be the wrong way to think about ARIA management. Basically, why not simply target the rate of amyloid removal as the variable of interest? ARIA means that you are doing too much of a good thing. With amyloid monitoring you might be able to calibrate the dose so that ARIA never emerges. This trick could work for Lecanemab. Just titrate up and see how this affects amyloid clearance. Some patients might have strong clearance of amyloid with as little as 3 mg/kg: Go with 3 mg/kg for them; others might need 10 mg/kg and still have weak amyloid clearance. Strangely in mab trials often what happens is that these super responders at the 3 mg/kg dose are treated at 10 kg/kg --> wind up superresponding at 10 mg/kg which can lead to severe and dangerous ARIA and then they can have a serous adverse event or choose to leave the trial due to the side effect (which was actually a superresponse).

Yet, clearing amyloid well is not a bug but a feature! Why don't they ever ask J11? Why not dial back the dose using PET amyloid feedback. Find just the right personal dosage that clears amyloid well but doesn't overdo it? This approach might mean ARIA would never occur. Dosing could be calibrated such that you are always safely below any outward sign of ARIA. The alternative method used on trial of just using standard dosing until ARIA happens does not seem as good an approach. Targeting amyloid might not be perfect, though it possibly could be better than waiting for ARIA symptoms.


The drawback to this approach could be the cost. MRIs can cost as little as $300; PET amyloid closer to $5000. Possibly with economies of scale the PET amyloid price could be reduced.

[J11]

ARIA Slide 4.PNG

ARIA Slide 5.PNG

[J11]

The top slide shows how the amyloid in the brain's blood vessels is thought to relate to ARIA.
The bottom slide shows the effect of dose on ARIA-E rate.

[J11]

ARIA Summary 1.PNG

ARIA Summary 2.PNG

[J11]

These slides give the first round of conclusions about ARIA.

[J11]

ARIA-E 2.PNG

ARIA-E 1.PNG

[J11]

ARIA risk 4.PNG

ARIA-E 3.PNG

[J11]

These are the slides that specifically address ARIA-E.

[J11]

ARIA-H 3.PNG

ARIA-H 2.PNG

ARIA-H 1.PNG

[J11]

These slides consider ARIA-H. The microhemorrhages as the black dots are as we saw them in the third fatality in the Lecanemab extension. The curvilinear MRI features shown in the bottom figure are superficial siderosis.

The top figure is of particular note. Those with Alzheimer's disease are more than half way to having the same level of microhemorrhaging as those with ischaemic stroke. AD is much more intertwinned with stroke than I had realized. It seems possible that amyloid mabs could play an important role in reducing this risk when given early at low dose and low risk.