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

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
User avatar
floramaria
Support Team
Support Team
Posts: 1423
Joined: Tue Jul 04, 2017 11:22 am
Location: Northern New Mexico

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

Post by floramaria »

J11 wrote: June 7, 2021 (Alzheimer Liberation Day) is the start of the journey back to normal life for the global amyloid dementia community. ALD-- the day that changed everything. This is a once in a century day that will redefine the 21st Century.
Immediately after FDA approval of Aduhelm today a new era in Alzheimer's began.
J11, your joy and enthusiasm are wonderful to behold! With all my heart, I hope you are right! :D
Functional Medicine Certified Health Coach
IFM/ Bredesen Training in Reversing Cognitive Decline (March 2017)
ReCODE 2.0 Health Coach with Apollo Health
NF52
Support Team
Support Team
Posts: 2772
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

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

Post by NF52 »

floramaria wrote:This is from the NIA website, from article titled “ NIA Statement on FDA Approval of Aducanumab for Alzheimer’s Disease”.
The FDA also stated that “approval is based on a surrogate or intermediate clinical endpoint (in this case reduction of amyloid plaque in the brain).” Additionally, “drug companies are required to conduct post-approval studies to verify the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial does not verify the drug’s anticipated clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.”

Neither of these say that the Phase 4 trial is limited to safety.
. Hi Floramaria,

You are right, I used a poor example of focusing on safety, since the FDA specifically mentions "clinical benefit" and that's where most of the discussion about the differing results between the two trials centered. (Although with a 40% rate of ARIA-Edema, safety may prove to be an issue also if more cases of severe ARIA emerge.) It seems like the issue will be the difference between "efficacy" and "clinical effectiveness". Here's an explanation of how a drug might seem to "work" in a controlled study with people who tend (in most AD clinical trials) to have high education levels, faithful take the drug or go for infusions, have required study partners to monitor them and far less likely to live in rural, under-served, or under-resourced areas than the diverse populations living with AD: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493021/
The first thing to note about Phase IV studies is that they are more varied in design than the preceding clinical trials [1]. This variety is captured well by Suvan [2] who notes that it can include the research conducted after a drug or device has been approved for marketing. One form of this research is a non-interventional study (NIS) designed to assess a treatment’s safety, tolerability, and effectiveness in clinical practice. Another is the large simple trial (LST), combining aspects of the randomized clinical trial with those of an observational study. Yet another is post-marketing surveillance undertaken to determine safety, tolerability, and effectiveness in a particular population. Then there are retrospective case–control studies to assess what reasonably are thought to be rare side effects. Phase IV can also involve drug utilization studies (DUSS) which tell us how a drug is marketed and actually prescribed within a population...
However, in one very significant regard, they are unalike in that they are more accurately defined as studies to demonstrate effectiveness rather than efficacy. Efficacy refers to “the extent to which a drug has the ability to bring about its intended effect under ideal circumstances, such as a randomized clinical trial” [6]. In contrast, effectiveness refers to “the extent to which a drug achieves its intended effect in the usual clinical setting”.... The distinction is relevant when considering Phase IV studies precisely because they take place under conditions akin to standard care provided in the usual clinical setting. “Essential to Phase IV research is the focus on how drugs work in the real world”. As a consequence, they involve a diversity of clinical settings together with a comparable diversity of patients and clinicians associated with these clinical settings.
I see that some think this requires a placebo group, but I've seen studies who use a control group of people with a diagnosis of AD who did not get a specific treatment used as the "control" group. Time will tell, but Biogen may have to show that those with varying levels of disease stage all showed real clinical benefit compared to other stages (ex. moderate versus mild AD) or compared to those seen in memory clinics with similar demographic/genetic profiles who did not take Aduhelm.

I was struck by the NYT comment of a doctor at a leading memory care center who said they may have 800 patients eligible for Aduhelm, but they only have 6 infusion beds and one PET scan. Not trying to be Debbie Downer--just hoping that research continues on lots of fronts, with lots of people willing to look at options that involve less cost and less risk.
4/4 and still an optimist!
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Thank you NF52 and flora for taking up this concern about the phase 4. These trials might as noted above take on various forms to suit different research questions. There continues to be interest from the FDA and elsewhere in confirming the top line aducan result. One might expect that a confirmatory trial would be best done more in the context of the clinical trial memory setting than in typical community care. When treatment moves to the community a wide range of additional noisy variables probably would be introduced. Yet, any confirmatory trial which withheld the now accepted standard of care (i.e., Aduhelm) from patients would be immoral. Allowing yet more patients to progress through irreparable neurodegenerative illness to provide additional scientific support for the treatment is not ethical.

How then could a no treatment placebo be avoided? Wouldn't a placebo be needed to provide the needed supporting evidence? Perhaps not. The most powerful idea that I have thought of that would not require a placebo is dominant AD trial. What might be tried is to enroll ~200 epsilon 44s (or those with high polygenic risk for AD, etc.) who are ~10 years from expected disease onset. Possibly start off with some microdosing and try to create a dosing schedule which would avoid ARIA (given the time constraint of the time of onset) and then gradually work up to higher dose levels. A moderately sized trial such as this in which those with near Mendelian AD who did not progress into cognitive impairment would offer compelling evidence of aducan's efficacy. Some of the more sensitive psychometric instruments such as PACC etc. could pick up the early decline even before typical tests such as ADAS-cog were able to do so. When you move away from the highly compressed time frame of usual clinical trials and the ever present concerns about cost and let an anti-amyloid trial fit into the natural trajectory of the illness, then you could present near definitive clinical evidence while minimizing safety concerns and expense. It was all the stress of the ticking of the clock and the money involved that caused many of the problems in the phase 3s for aducan. If you take away the clock, then you could report a much stronger result in a much more relaxed environment.

One of my new perceptions that has emerged from the FDA's approval information for Aduhelm is that it appears that in their view "Alzheimer's disease" now encompasses a broader range of the illness spectrum. Considering the lack of a stated need for a positive amyloid scan and the silence on whether even severe dementia might be on label for Aduhelm, the potential treatment population seems fairly inclusive. Even the phase 3 trials were inclusive as a score of 30 MMSE did not disqualify participation in the trials. The move to reimagining Alzheimer's disease as a lifestyle challenge seems inevitable.

I think this is how we should begin to understand AD. Once the patients who are right on the frontier of decline have been treated, AD treatment will move more to a lifestyle illness model. With early enough treatment they would never need to experience side effects and they would completely avoid the cognitive impairment that is currently associated with AD.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

flora, in terms of the question of the business/revenue side of aducan I see a highly plausible workaround to the $56,000 per year price tag problem. Financial analysts are calling for ~ $10 billion per year maximal revenues for aducan. That (in the overall scheme of things) does not seem like that much: $30 per American tax? Many people do not like taxes. OK, if they do not want door A, then how about we try door B? Behind door B is the ~$1,000 per person that AD is already costing society. Should we go back to door A or perhaps some would like to look behind door C? Door A it is. For $30 per capita the risk of AD could be socialized while Biogen still achieved maximal revenue? As other anti-amyloids were approved, patients would have their choice of treatment.

Remarkably as well, the $10 billion per year of revenue only allows for 178,571 patients treated per year at $56,000. Biogen has already indicated that it is committed to providing financial assistance to help those in disadvantaged communities to receive treatment. There will be an enormous unmet need for treatment based upon insufficient financial resources. Offering a population scale buyout of their intellectual property rights in a completely fair and transparent would seem to benefit everyone. There is such an enormous amount of
low lying wealth that could build up our society that it is difficult to believe that such a plan would not happen.

In the Nordics (e.g. Sweden) such communal thinking is a deeply established part of their culture. Creating a dementia free society on the $30 per person budget would offer extreme competitive advantages. While my Swedish needs some practice, I might take up lessons if this obvious solution is only embraced in Nordica. I am highly aware of how dysfunctional life can be in the context of dementing illness and I would gladly pay the $30. My best guess is that life owes me about $1 million for all the misery that AD has caused me; though with life as the defendant there really is no way of collecting on this damage.

I have understood big pharma largely to be in alignment with patient interests for Alzheimer's. Often pharma will invest massive amounts of money into a disease with minimal market potential and then need to charge what might seem to be exorbitant prices for their products.

This logic is not as applicable with AD. The market potential for AD is nearly without limit. The cited AD patient population for anti-amyloids starts off with a core of 1.5 million patients, then the figure of ~5 million with AD is noted; then there are all those millions of amyloid positive elderly who are considered cogniitively "normal", the millions of those before typical age of onset who are accumulating amyloid. The numbers are very very large. As soon as the signal is sent that anti-amyloids are going to main street,
the revenue could be overwhelming.

It could be though that mainstreaming anti-amyloids is being submerged until an oral treatment is approved. The IV infusion of 50 million people could prevent dementia on a population scale, though this might be considered too logistically challenging.


On the issue of aducan approval making it more difficult to enroll patients in AD trials, perhaps the opposite could be true: it might make it easier. What I would like to see now is for the anti-amyloids to offer standard of care (aducan) in place of the placebo. In this context, approval would require superiority to aducan. Funny thing here is that Biogen might then not really have to run phase 4 trials at all; it could simply submit the trials that everyone else conducted with aducan as reference. For the patients, this would be amazing. They would be guaranteed of receiving the FDA standard of care (aducan) or the next generation of anti-amyloid.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

For me one of the highlights of the thread was recognizing the strong correlation between amyloid removal (SUVR) and cognition (CDR-sb). I did admittedly data massage some of the points, though even without aggressive manipulation the points fell along an almost straight line over the full dosing range. It was particularly interesting to see that an entire anti-amyloid class of treatments fit this line. There were thousands and thousands of patients involved; it allowed a view of the totality of the clinical evidence. Everything appeared to fit into place; of course the one obvious outlier was 301 high dose. Almost every point was where it should have been. This was a dramatic revelation to me. The figure clearly suggested to me that anti-amyloids (including aducan) were effective. They became ever more effective the further to the left (more amyloid removal) occurred. In this view of the universe, p-values (i.e., treatment versus placebo) really are no longer relevant. It does not matter so much if the treatment was not "effective" against placebo but what the dose response was. Every single dot in the correlations could have missed statistical significance ( in fact almost every single point did miss statistical significance) and yet that really did not seem to have any importance. What is important is that there was an extremely high correlation between dose and response. This offers you the opportunity of using all the evidence to see the big picture. I think this is an extremely powerful way of seeing the data.

This is also the FDA's position as stated in its approval of aducan. The focus of its approval logic centers on noting strong amyloid clearance and how this clearance is related to cognition. This is the strong correlation that was noted on this thread. A change to thinking less in terms of the p-values and more in terms of the correlations might become a more central feature of trial analysis. This is the expected transition that occurs through time as a biomarker becomes more established.

The one problem that needs to be recognized, though, is that once the correlation becomes the target then it could be gamed. My impression is that the points that I plotted in the regression were derived without awareness of their linear relationship. It was the natural outcome of treating with a single anti-amyloid class with a standardized AD population of MCI/Mild AD. If the linear correlation were a stated trial outcome, then perhaps tactics could be used to force the desired outcome (through patient selection etc.).

Another consideration could be that the 301 high dose problem could possibly be avoided with a correlation orientation. Instead of placing one point to represent all patients in a treatment arm, perhaps dividing the treatment groups into subgroups of ~50 would demonstrate linearity more clearly. The 301 study might then have been seen as much less discordant than the correlation plot suggested. To further highlight the linear dose response relationship, continuous (instead of discrete) dosing could be considered with less of an emphasis on weighting on placebo. The placebo arm provides such minimal information; why not instead reallocate these patients to dosing so they can provide information about the dose effect instead of the information hollow allocation to placebo?

Most of the discussion opposing aducan related to the p-value perspective. Whenever correlation is amyloid to cognition was mentioned it was in the context of their being so minimal a relationship. This was quite confusing as I reported near 100% correlations. The difference there was individually versus group correlation. Perhaps in future anti-amyloid trials with Tau selection etc. even individual level correlation might be moderately strong.
Last edited by J11 on Tue Jun 08, 2021 10:39 pm, edited 3 times in total.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

There are a few other points of interest that I would like to note for future reference.

- Is the long term extension (i.e., Embark) for aducan now still required? Given that aducan is now approved, is there an obligation to continue with this trial? Of even greater interest is, when might results be reported? There is now a great deal of accumulated patient dosing for this trial. It could provide very powerful insights into the longer term effects of treatment. Patients might delay initiation of aducan until such results were divulged.

- Discussing the possibility of an early approval for leca would also be of interest. We have seen recently that a new era of rapid AD clinical trials is feasible. With tau selection, small clinical trials of length ~50 weeks could provide statistically significant results. Given the large scale enrollment in a phase 3 for leca, there could be the potential to use such analytic techniques to possibly establish statistical significance even now. The second generation of anti-amyloids might happen concurrently with the first. While this ordinarily might seem overly optimistic, one should reflect on what happened with COVID approvals. It was quite instructive to see how rapidly regulatory approvals can happen when they have to.

- I have been considering whether aducan treatment might be reasonable for us. It does seem that it could be highly affordable. The game plan might be:

1. Have the C2N AD blood test ~$1,000
2. If amyloid positive, have 5 * $500 (1 mg/kg) infusions per year.

$2,500 of annual treatment expense does not seem unreasonable.
The expected amyloid burden that is likely involved is fairly minimal, so this could be a highly effective way of managing risk.
Not allowing amyloid to accumulate without intervention simply does not seem to be a good strategy, especially when treatment might be as affordable as noted above. I am not clear, though, whether a non a la carte dosing option would be acceptable.

- lack of notable enthusiasm from the scientific community. Regulatory democracy.
Last edited by J11 on Tue Jun 08, 2021 10:56 pm, edited 1 time in total.
User avatar
floramaria
Support Team
Support Team
Posts: 1423
Joined: Tue Jul 04, 2017 11:22 am
Location: Northern New Mexico

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

Post by floramaria »

NF52 wrote:
However, in one very significant regard, they are unalike in that they are more accurately defined as studies to demonstrate effectiveness rather than efficacy. Efficacy refers to “the extent to which a drug has the ability to bring about its intended effect under ideal circumstances, such as a randomized clinical trial” [6]. In contrast, effectiveness refers to “the extent to which a drug achieves its intended effect in the usual clinical setting”.... The distinction is relevant when considering Phase IV studies precisely because they take place under conditions akin to standard care provided in the usual clinical setting. “Essential to Phase IV research is the focus on how drugs work in the real world”. As a consequence, they involve a diversity of clinical settings together with a comparable diversity of patients and clinicians associated with these clinical settings.
Thanks so much, NF52! That is really interesting. I hadn’t ever considered this distinction between the efficacy and effectiveness for a drug and find this fascinating. I had’t occurred to me that clinical trials are conducted in this advantageous environment until reading your post. This provides me with a much better context for understanding what comes next.
Functional Medicine Certified Health Coach
IFM/ Bredesen Training in Reversing Cognitive Decline (March 2017)
ReCODE 2.0 Health Coach with Apollo Health
NF52
Support Team
Support Team
Posts: 2772
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

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

Post by NF52 »

floramaria wrote: That is really interesting. I hadn’t ever considered this distinction between the efficacy and effectiveness for a drug and find this fascinating. I had’t occurred to me that clinical trials are conducted in this advantageous environment until reading your post. This provides me with a much better context for understanding what comes next.
And here's where safety might complicate a Phase IV trial in clinical use:
Screen Shot 2021-05-26 at 3.00.33 PM.png
ARIA-E Severity & resolution.png
ARIA-E risk of ARIA-H.png
https://www.fda.gov/media/143506/download pages: CS10, CS12,CS15
First slide from the FDA report (CS 10): ApoE 4 carriers in the EMERGE and ENGAGE trials had close to a 50% risk of ARIA-E (edema), more than twice the risk of ApoE4 non-carriers.
Second slide (CS12): Good news: 98% of cases of ARIA-E resolve. Troubling: Two-thirds resolve in 12 weeks; 79% resolve in 16 weeks. [The mild-moderate effects can include cognitive changes, headaches, vision disturbances, confusion and gait problems--a long time to suffer those!].
Third slide: About 40% of people with ARIA-E also show ARIA-H micro-hemorrhages, which also resolve. Superficial siderosis is, from my reading, an iron deposit more likely in those with high iron levels (seen with high amyloid). Seems to not be a concern as much?

Other drugs close to Aduhelm in development have an ApoE4 risk of 14.8% (BAN2401) and 0% (Alz-801- an oral drug currently in Phase 2 MCI/Mild AD trials in Europe and moving towards a Phase 2-3 trial in ApoE 4/4s with normal cognition and an MCI/Mild AD trial in the US in 2022 or 2023.

Who is going to manage the ARIA-E? Here's what a team from UCSF wrote in October 2020 after treating Daniel Gibbs, a 66 year old retied neurologist with mild AD who had an unusually severe ARIA-E and ARIA-H episode after only two doses [1 mg/kg and 3 mg/kg] of Aduhelm:
Going forward, if anti-amyloid antibodies become part of future treatment regimens for AD, knowledge of symptoms related to ARIA and an approach to management will be critical for treating clinicians. Risk stratification with APOE ε4 genotyping may help guide treatment decisions. Further studies are needed from larger clinical cohorts to determine the optimal approach to monitoring and treatment. Additional studies including co-localization of ARIA to amyloid and tau on PET and CAA on MRI may clarify the relationship between these entities and provide insights into the pathophysiology of ARIA and related clinical syndromes
Symptomatic amyloid-related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab

Lots of moving parts here.
You do not have the required permissions to view the files attached to this post.
4/4 and still an optimist!
User avatar
Julie G
Mod
Mod
Posts: 9187
Joined: Sat Oct 26, 2013 6:36 pm

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

Post by Julie G »

For me one of the highlights of the thread was recognizing the strong correlation between amyloid removal (SUVR) and cognition (CDR-sb).
I admire your certainty and joy, J11 and pray that the phase 4 trial is successful. If the relationship between amyloid removal and cognitive improvement were that clear cut, it seems like we would have seen evidence in the last 14 trials that targeted that mechanism. Sadly, we have not; see Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis.

Given that the FDA’s approval was predicated upon a false conclusion that “the reduction in these plaques is reasonably likely to predict important benefits to patients,” it’s hard not to lose respect for this organization.
J11
Contributor
Contributor
Posts: 3351
Joined: Sat May 17, 2014 4:04 pm

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

Post by J11 »

Julie G, aducanumab was discovered through Reverse Translational Medicine™. Anti-amyloid antibodies from those people who did not develop AD were screened and aducanumab was found to be the most potent antibody studied. In effect, it was known from the start that aducanumab was safe and effective because it was safe and effective in the healthy cognitive agers studied. This strong logical foundation gives an enormous advantage to pharma companies that are developing products based on this concept. The question becomes: How could aducan actually not have been approved based on this logic? The clinical trials are almost superfluous. The clinical trials merely demonstrated maximal dosing in a minimal time which did not highlight the potentially greater effectiveness that can occur with greater treatment time. Yet, such a dosing plan does not seem plausible for those who are not directly in the line of dementia onset. For those 10-20 years before onset, they could leisurely dose over many many years. It is not easy to imagine that they would even consider the maximal dosing plan.

None of the contrary commentary that I have read about aducanumab's approval broached this topic. I suspect the silence relates to the fact that there is no easy rebuttal. In the mice studies, it was found that aducanumab can lower amyloid with doses ~300 fold lower than used in people without any side effects. Side effects only emerged when treatment included massive doses administered just on the frontier of disease onset. This line of thinking offers a truly compelling argument in favor of aducanumab's efficacy and potential safety.

Using this more gentle (and likely much more effective) approach could produce extremely strong supporting evidence of aducan's anti-dementing effects. Perhaps an "official" phase 4 might not even be entirely necessary to offer such proof. It would not take many epsilon 44s with extreme AD polygenic scores who were treated with aducan before clinical onset and then did not demonstrate cognitive impairment over time to end the discussion. Such treatment could occur in typical medical settings and could then be reported into the medical literature.

Given that there are 10 million epsilon 44s (many of whom find their 44 genotyping as psychologically catastrophic as noted by personal accounts on this forum) and many of them will be highly motivated to seek aducan treatment earlier than later, we might learn that aducan might be highly effective when given in such a preventive manner. It does not seem reasonable to me that such treatment will somehow be stoppable. The FDA's vague reference to "Alzheimer's disease" almost implies that this is the intention. Such "pre-treatment" should not even necessarily be considered outside of such a definition. In our family experience, the early manifestations of cognitive impairment began years (probably decades) before a diagnosis. There was just something not quite right about our loved one for a long time before the dementia.

As people become more aware of the highly sensitive psychometric instruments such as the Logical memory test etc. that can detect these subtle cognitive defects much sooner than the tests used in the aducan trials (MMSE :roll: , etc.) a substantial socio-political force could develop to ensure that patients are offered aducan in order to avoid a devastating neurodegenerative illness (if such a disagreement will even exist at all). Popular discussion about aducan could rapidly become highly favorable as it became widely understood that avoiding AD in those at extreme risk could be possible. The phase 3s had inclusion requirements of aged 50 years or older, MMSE <-30 etc. and many of patients did not progress over the course of the trial. This suggests to me that there were a fair number of preclinical patients in the trials. Thus, it might already be known how such patients fare through time. Of course, since the FDA had data access it would already know these results. Never bet against the dealer who knows all the hands of the players.

In even average e44s, the risk of progression to AD is ~90%. Adding in polygenic selection might move the risk to near 100%. How many e44s with 100% AD risk who did not progress to AD would it take to end all further reasonable objections? Anecdotes as evidence- perhaps- though it could all be prespecified and the p-values would likely be smaller than would seem believable.

Wow! Aduhelm will start shipping within 2 weeks. I thought it could take months!
Post Reply