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

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J11
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

Post by J11 »

Most of my posts to date have been in relation to the general AD population.
What about J11? What does J11 see as the future of Lecanemab personally?

I am extremely positive.

I am in a very low risk subgroup and if I were to start treatment before the onset of CAA and comorbidities
Lecanemab treatment would likely be remarkably safe for me and my immediate family in similar circumstances.
Ensuring that widespread amyloid invasion of the brain never occurred would likely be a powerful anti-dementia strategy.

I also see the extreme power of the unleashing of market forces to move the ball even further upfield. Up till this point there has been very little that AD patients could actually do to potentiate a cure. Without an entre disease modifying treatment the power of the AD economy has largely been absent. The pharma companies have been stuck in a near endless money pit in which it probably seemed there would never be a pay day. Yet, now that we are on the verge of a viable treatment, the money can flow--- there could be a torrential down pour of money. The market system can be allowed to happen and a wide range of products and innovations can then be expected.

I am sure that many are looking forward to easily accessible, affordable AD diagnostics. With approval of a product, this would become highly incentivized. I have already seen urine tests in the research phase that could be affordable and useful. So much innovation could be soon on the way. I have also wondered whether there could be a simple blood test that might be of use in detecting ARIA cheaply and possibly before symptoms emerged. It is always impressive to see what ideas can be imagined when financial incentives are offered.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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There are now a few short term events on the day planner that we should expect.

Of course, PDUFA tomorrow.

Then there could be a Lecanemab pricing decision. I am hoping for a low ball price. With Aducanumab it was mostly: How much does this cost? How much do you have in your wallet? That really is not that helpful. Soon afterwards there were news stories shouting that anti-amyloid treatment could bankrupt the entire government-- that it would cost more than another moon mission. It really would seem for the best if this is going to be launched out of the park to avoid national bankruptcy. We have already seen the problem when there is a maximal price point. Most pharma mabs do not have tens of millions of potential patients.

Next up is the CMS ruling. This will likely be a shocker for most when it is realized that CMS has not clarified their funding decision on Lecanemab as of now. One clearly might expect that some sort of announcement might be near. I am not sure how this could be ignored for much longer. A proactive and preemptive stance might be to quickly announce a large scale (~10,000 patient) ecological clinical study. We have seen how Lecanemab performs in a rigorous clinical trial environment, how might it do in the wild? What choices will patients actually make when they are given more latitude? For example, some might feel more comfortable using uptitration etc.. It will be very interesting to see how this rolls out on main street. CMS could play a leadership role in this research. Of course, the wider funding issue will also need to be addressed soon.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Percentiles 1.PNG
Leca Phase 2.PNG
Leca p2.PNG
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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J11 wrote: Thu Jan 05, 2023 7:11 pm There was a miscommunication problem with the ARIA-H slide. I want to go back to it.
It is startling and bears repeating.

63 placebo patients ( N= 897 7.0%) experienced a Microhemorrhage while in the 18 month Clarity trial.

Sometimes you read something like that and it just rolls over you, you yawn and then continue with your life.

63 microhemorrhages on placebo.

J11 can only do so much to capture the thread readers attention.
Basically, 7.0% of AD patients will typically experience a silent stroke over 18 months.
It is quite startling when you think about that.

At some point the AD stroke nexus will need to be explored more fully.
Of interest is that Lecanemab could play an important part in potentially resolving the problem.
The especially high risk of stroke in AD would seem to be related to the pervasive CAA that is present
in AD patients.
But micro hemorrhages are not equivalent to strokes!! They are not ruptured blood vessels, they are mostly asymptomatic, and seen on MRIs. They do represent silent evidence of likely CAA which has been noted as co-occurring in AD, especially in older groups. They also increase the risk of an actual stroke, but mostly when seen in certain locations (which ones I don’t remember).
Important because it’s something doctors and patients need to discuss, but terminology matters.
4/4 and still an optimist!
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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Thank you NF52. Yes it is important to be clear about the terminology. It is still surprising to me how much
background pathology is occurring in AD patients who are not on treatment.

The figures above are from/derived from a recent Lecanemab article. The percentiles figure was of particular interest to me. We have heard the endless mantra of 0.45 CDR-sb and 27% slowing for Clarity. These are the topline average numbers. What do the numbers look like when you look at the distribution across percentiles? That is what the percentiles figure shows! Surprisingly, the highest dose Lecanemab patients from phase 2 were mostly stable (at most a 0.5 CDR-sb decline) up to the ~75th percentile. This is somewhat better than I would have expected. About 10% of the lecanemab patients and 40% of the placebo did not do so well (~2 CDR-sb decline). So this could be used as a rough heuristic when observing real world AD patients: The patients that are in a clear decline phase, will be 4:1 placebo versus treated. Those asking for clinically meaningful differences with treatment have it. In the middle of the distribution (from the 60th to 90th percentile) there is a ~1.5 CDR-sb separation.

Hopefully, this patient level view will be provided for Clarity. If it could be confirmed in a large trial that patients in some parts of the distribution clearly do quite a bit better, then this would be of considerable interest.

The middle figure shows the CDR-sb response in relation to amyloid clearance in centiloids from the phase 2 trial. We have seen this before from the phase 2 where the individual dosing arms actually have a flat linear regression. The problem I think is that when you span the entire range of amyloid clearance such as for the highest dose you get stuck in this valley. Instead of having a positive slope what happens is that with more dosing you move deeper and deeper into this valley (i.e., better clinical response) while remaining essentially flat. It is only with the middle dosing arms where they are confined mostly to moderate AD removal do you see strong positive slopes. Then as you move to placebo you once again return to this flattish pattern. With the placebo you have a number of patients clustered around 0 amyloid removal who actually improved. Once again there is a patient selection problem. True AD patients do not remain stable over a year and a half.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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The 2:02 pm first figure posted today is a good one. It shows the Lecanemab percentile distribution by dosing arm. I had been unsure about this for quite some time. With Aducanumab there were large numbers of patients who had a 1 CDR-sb point or more benefit on treatment -- this is considered the minimally clinically relevant response. I was not clear why Lecanemab did not seem to also have these responses-- apparently it did. What we see in the figure is that 75% of those on high dose Leca were largely non-progressors (<0.5 CDR-sb over 18 months). We see large separation with placebo over a wide range of the distribution. This speaks to how concentrating on averages can sometimes be highly misleading. We can see that at the 90+th percentile, the highest treatment arm has runaway clinical progression amounting to ~ 5 CDR-sb points. These outlier patients might be skewing the entire readout.

The numbers do not entirely make sense to me as the difference here should only be ~0.3 CDR-sb and from the looks of things the average difference between high and placebo across the entire range appears to be closer to 0.8, though it does give us some feel for the distribution. It also highlights how the placebo still includes patients who really do not have classic AD in terms of at least some progression and also includes some patients who have entered the extreme decline phase of the illness. The donanemab results which are expected over the next several months might be able to more clearly resolve this question for us.
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Re: Celebration Thread! Biogen is going to the FDA with Aducan.

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

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Big news that I have only become aware of now is that Cognito has started their phase 3 for gamma entrainment.
https://clinicaltrials.gov/ct2/show/NCT ... w=2&rank=1 Hope trial
Surprisingly they do not appear to have added PET amyloid imaging.

AD clinical research now feels like it is breaking through.
In the past there would be bad news and then it would be bleak probably for years to come.
Today, there might be some minor disappointment and then the next day we are hitting another all time high.

The gamma phase 3 is set to complete in 2025! Things are moving.
Gamma entrainment could remove amyloid without side effects.
If necessary one could imagine down dosing mabs and adding in gamma to top it up.
This is so fantastic.

Other great news is that Donanemab could be granted accelerted approval in February!
It is not easy to tell because there does not seem to be anywhere online that gives the PDUFA date, though it seems to be some time in February. I am also extremely excited about Trailblazer 2. They added in dual tau selection, so the there could be a complete reset in our understanding of what amyloid reduction can achieve. They also rotted to iADRS which seems like another good call.

Of course, Solanezumab A4 is also on the way.
So much excitement!
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