New FDA-approved drug, Aduhelm,for Alzheimer's

[90sportsfan]

Was just curious what Neurologists thoughts are about this approval. I'm not sure how many Neurologists in academics have a lot of AD patients or actively treat it; especially those who are subspecialists.

I know that in private practice, general Neurologists probably are managing a good number of AD patients; I'm just wondering how this will impact your treatment for this patients, since there tends to be a lot of controversy around it.

Are you planning on incorporating this into treatment for AD patients right away?

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[Thama]

Everything surrounding this drug is a travesty. The FDA scientific committee recommended not to approve the drug because not only were the effects minimally clinically relevant, there was serious concern about the data manipulation that it took to achieve those incredibly uninspiring endpoints. The FDA then showed just how dedicated it really is to fellating the pharmaceutical companies by approving it anyway.

They didn't even pretend that they approved it because it works, as they made an additional post-market efficacy trial a condition of approval! In other words, "yeah you haven't produced anything resembling sufficient data to justify an approval, but we know you need some boost to your stock prices so we'll let you go ahead and extract hundreds of millions of dollars from an already wasteful healthcare system while you get another chance to sufficiently slant your data".

Not only that, but the science surrounding this drug is utter **** to begin with. It's quite literally the principle of repeating an experiment until you get the results you want with this and other beta-amyloid clearing agents. For an AD field that really needed to be cattle-prodded off the beta-amyloid paradigm, this does the exact opposite.

Not only would I never prescribe this drug, I would look at any physician who does with contempt.

 

[neglect]

Everything surrounding this drug is a travesty. The FDA scientific committee recommended not to approve the drug because not only were the effects minimally clinically relevant, there was serious concern about the data manipulation that it took to achieve those incredibly uninspiring endpoints. The FDA then showed just how dedicated it really is to fellating the pharmaceutical companies by approving it anyway.

They didn't even pretend that they approved it because it works, as they made an additional post-market efficacy trial a condition of approval! In other words, "yeah you haven't produced anything resembling sufficient data to justify an approval, but we know you need some boost to your stock prices so we'll let you go ahead and extract hundreds of millions of dollars from an already wasteful healthcare system while you get another chance to sufficiently slant your data".

Not only that, but the science surrounding this drug is utter **** to begin with. It's quite literally the principle of repeating an experiment until you get the results you want with this and other beta-amyloid clearing agents. For an AD field that really needed to be cattle-prodded off the beta-amyloid paradigm, this does the exact opposite.

Not only would I never prescribe this drug, I would look at any physician who does with contempt.

Well, that's one take.

So actually it is way more complicated than that. The FDA is not full of people who are ready to "fellate" pharma companies. They take these things seriously, but not Biogen's stock price. They've looked at the data, more data than we have, and have granted accelerated approval. This does NOT mean that they're saying it doesn't work. They are saying that data is very complicated, which it is. They conducted an early phase 1b trial which was robust enough to be a 2b, it was markedly positive, went right into phase 3, without doing a dose-finding traditional phase 2 trial (thinking the 1b trial was good enough). They found that they needed to adjust doses along the way, did so, then the trial got halted by the DSMC for futility.

THEN their data-set showed one positive trial, one negative trial. The positive trial showed good effect, which is clinically meaningful. While the negative trial was negative, those who got the highest dose did better than placebo.

So look at me with contempt. I'm fine with it. You're being overly shrill and only make me want to give more of it!

 

[Thama]

Well, that's one take.

So actually it is way more complicated than that. The FDA is not full of people who are ready to "fellate" pharma companies. They take these things seriously, but not Biogen's stock price. They've looked at the data, more data than we have, and have granted accelerated approval. This does NOT mean that they're saying it doesn't work. They are saying that data is very complicated, which it is. They conducted an early phase 1b trial which was robust enough to be a 2b, it was markedly positive, went right into phase 3, without doing a dose-finding traditional phase 2 trial (thinking the 1b trial was good enough). They found that they needed to adjust doses along the way, did so, then the trial got halted by the DSMC for futility.

THEN their data-set showed one positive trial, one negative trial. The positive trial showed good effect, which is clinically meaningful. While the negative trial was negative, those who got the highest dose did better than placebo.

So look at me with contempt. I'm fine with it. You're being overly shrill and only make me want to give more of it!

The people on the FDA that are responsible for looking at the data are the scientific advisory committee. Those people saw all the data that we haven't seen and recommended against approval. The administrators then went back and acted against the scientific recommendation.

 

[neglect]

The people on the FDA that are responsible for looking at the data are the scientific advisory committee. Those people saw all the data that we haven't seen and recommended against approval. The administrators then went back and acted against the scientific recommendation.

I'm not sure this is true. I'm not serving in a regulatory capacity in any way, nor have I sat on one of the ad panels for the FDA. That said, the FDA people are 100% responsible for looking at the data. The advisors are precisely that: advisors. They advise the FDA and are not responsible for approval or denial of the drug.

And who do you think these "administrators" are? They are all doctors. Billy Dunn, M.D., right?

Clearly the data was complex. But it is possible for someone to look at that data and think this is a win. Do you have contempt for Steven Salloway?

 

[VA Hopeful Dr]

I'm not sure this is true. I'm not serving in a regulatory capacity in any way, nor have I sat on one of the ad panels for the FDA. That said, the FDA people are 100% responsible for looking at the data. The advisors are precisely that: advisors. They advise the FDA and are not responsible for approval or denial of the drug.

And who do you think these "administrators" are? They are all doctors. Billy Dunn, M.D., right?

Clearly the data was complex. But it is possible for someone to look at that data and think this is a win. Do you have contempt for Steven Salloway?

I dunno man, I'm not a neurologist or anything approaching a researcher but lots of this seems fishy to me:

F.D.A. Approves Alzheimer’s Drug Despite Fierce Debate Over Whether It Works (Published 2021)

Aducanumab, or Aduhelm, is the first new Alzheimer’s treatment in 18 years and the first to attack the disease process. But some experts say there’s not enough evidence it can address cognitive symptoms.

www.nytimes.com

A Highly Controversial Alzheimer’s Treatment Won FDA Approval. Scientists Say We Don’t Know If It Actually Works.

In one sense, aducanumab is a historic drug — but many scientists say its approval is a triumph of business interests over public health.

www.buzzfeednews.com

 

[Thama]

I'm not sure this is true. I'm not serving in a regulatory capacity in any way, nor have I sat on one of the ad panels for the FDA. That said, the FDA people are 100% responsible for looking at the data. The advisors are precisely that: advisors. They advise the FDA and are not responsible for approval or denial of the drug.

And who do you think these "administrators" are? They are all doctors. Billy Dunn, M.D., right?

Clearly the data was complex. But it is possible for someone to look at that data and think this is a win. Do you have contempt for Steven Salloway?

It's possible to look at this data and think it's promising and worthy of funding an additional trial to find out if it works. I don't think it's possible to look at it and think that it meets approval criteria, and the scientific advisory counsel agrees with me.

FDA administration runs the gamut from physicians to PhDs to faceless government bureaucrats to assistant to the regional nursing manager types. Who knows who made this call, and who knows what influence they are under. Part of the point of having an advisory committee is to make the process less insular, and thus more difficult to corrupt. It's the same principle that NIH review and advisory committees operate under.

edit to add: This is why the FDA follows their advisory committee recommendations in the overwhelming majority of instances. When they don't, they are usually clear about why. When they aren't, especially when this much pharma money is on the line, it's not a stretch to cry foul.

 

[robellis]

A lot of the government is corrupt nothing to see here

 

[deathmerchant]

And Biogen is charging $56000 a pop for this medicine! For a medicine that most likely doesn't work or at BEST slightly slows/reverses cognition. Most patient population with AD is >80 and it won't make a meaningful difference in their life other than to thin their pockets and give false hope. Plus side effects.
Until we have a more promising study, Its a no from me dawg!

 

[xenotype]

I'm not sure this is true. I'm not serving in a regulatory capacity in any way, nor have I sat on one of the ad panels for the FDA. That said, the FDA people are 100% responsible for looking at the data. The advisors are precisely that: advisors. They advise the FDA and are not responsible for approval or denial of the drug.

And who do you think these "administrators" are? They are all doctors. Billy Dunn, M.D., right?

Clearly the data was complex. But it is possible for someone to look at that data and think this is a win. Do you have contempt for Steven Salloway?

The drug is crap. The only way they had positive data at all was excluding 'rapid progressors' which they have no reliable way to identify prospectively. 30-40% get cerebral edema with symptoms. 20% microhemorrhages. Serial MRIs required due to safety problems. All for a very questionable benefit because patient advocacy groups bullied the FDA. This is a worthless drug, the amyloid hypothesis it is based on is not even clinically proven (look at all the other failed drugs in the same class with the same target), and CMS should not cover it. I expect medicare to deny coverage for it outside of very specific circumstances, and private insurers will follow whatever medicare decides. They may even decide to deny coverage entirely which I would be in favor of.

 

[neglect]

The drug is crap. The only way they had positive data at all was excluding 'rapid progressors' which they have no reliable way to identify prospectively. 30-40% get cerebral edema with symptoms. 20% microhemorrhages. Serial MRIs required due to safety problems. All for a very questionable benefit because patient advocacy groups bullied the FDA. This is a worthless drug, the amyloid hypothesis it is based on is not even clinically proven (look at all the other failed drugs in the same class with the same target), and CMS should not cover it. I expect medicare to deny coverage for it outside of very specific circumstances, and private insurers will follow whatever medicare decides. They may even decide to deny coverage entirely which I would be in favor of.

There are three positive trials in amyloid. The amyloid hypothesis is the best supported and never falsified one we have. Show me an upregulated amyloid formation to 150% of normal, I'll show you AD in 4-5 decades. Many anti-amyloid drugs are coming down the pike and you'll use them if they generate positive data.

You are also incorrect. One of their trials was positive. The other was negative and they speculate this was due to more rapid progressors being randomized into the drug arm. This does not offset their positive trial.

You are not correct in calling this a worthless drug. While it is impossible to know if the drug works, it is also impossible to know it doesn't. The trials were not completed, so we don't know.

You are even incorrect on the rates of symptomatic ARIA (9%). Please stop pretending to know things!

By trying to sound smart and iconoclastic, you end up sounding - not smart. By tearing down the people who are actually trying to do work, you end up looking - a bit small.

I happen to agree that what the FDA did was deplorable. I happen to agree that the drug is a win with an *. I'm likely to only give it in very discrete circumstances, perhaps not even at all outside clinical trials. But I find all the critiques above to be specious, biased with anti-pharma sentiments (move to England you commie!), and not correct.

The reason to not give the drug is because: 1. Amyloid is complex and getting rid of fibullar amyloid (that we measure on PET) is NOT known to be a good surrogate for therapy. 2. One trial was positive, one negative, so we don't know if it works. 3. ARIA at 35% (more if APOE4 carrier) with 9% symptomatic rates should give anyone pause. Please stick with these reasons.

 

[neglect]

It's possible to look at this data and think it's promising and worthy of funding an additional trial to find out if it works. I don't think it's possible to look at it and think that it meets approval criteria, and the scientific advisory counsel agrees with me.

FDA administration runs the gamut from physicians to PhDs to faceless government bureaucrats to assistant to the regional nursing manager types. Who knows who made this call, and who knows what influence they are under. Part of the point of having an advisory committee is to make the process less insular, and thus more difficult to corrupt. It's the same principle that NIH review and advisory committees operate under.

edit to add: This is why the FDA follows their advisory committee recommendations in the overwhelming majority of instances. When they don't, they are usually clear about why. When they aren't, especially when this much pharma money is on the line, it's not a stretch to cry foul.

Dunn was clear about why in his letter. https://www.fda.gov/media/149903/download

He didn't give a sh1t what they thought. He only cared about biomarkers and wants patients, families, and doctors to make a choice. He basically abandoned his leadership and regulatory responsibilities and outsourced the decision to you and me. You can make your decision, but holding good people like Salloway in contempt for not thinking like you isn't a good look.

 

[Thama]

Dunn was clear about why in his letter. https://www.fda.gov/media/149903/download

He didn't give a sh1t what they thought. He only cared about biomarkers and wants patients, families, and doctors to make a choice. He basically abandoned his leadership and regulatory responsibilities and outsourced the decision to you and me. You can make your decision, but holding good people like Salloway in contempt for not thinking like you isn't a good look.

I don't think he was clear at all there - he totally copped out of constructing a valid argument for his decision. Biomarkers ain't it, or we would have had an approved drug a long time ago. As you said, abdicating his basic regulatory responsibility, and I don't think that happens without a ton of pressure one way or another.

Regarding Dr. Salloway, not only is he not at all an unbiased commentator here as a study PI, a quick search for his comments on this reveals that while he's excited about the impetus that this drug will provide for testing and further funding for AD drug advances, even he thinks that there's a lot of issues with the data and was particularly concerned about the overly broad labelling for advanced AD. You're right that contempt is a strong word here, but I do think he and some like him are blinded by proximity.

 

[xenotype]

You are not correct in calling this a worthless drug. While it is impossible to know if the drug works, it is also impossible to know it doesn't. The trials were not completed, so we don't know.

They will never do the postmarketing trials like most drugs that are approved under these circumstances. Thanks for calling me small minded. Three positive trials on amyloid amongst a graveyard of phase 2 and 3 trials. Spending >$56,000 a year on this drug with this level of evidence is absolute insanity. You will be fleecing desperate people of their money with not much if any medical benefit to show for it by even offering it.

 

[Thama]

There are three positive trials in amyloid. The amyloid hypothesis is the best supported and never falsified one we have. Show me an upregulated amyloid formation to 150% of normal, I'll show you AD in 4-5 decades. Many anti-amyloid drugs are coming down the pike and you'll use them if they generate positive data.

Also, this is kind of wrong. The amyloid hypothesis rests not on beta-amyloid being *associated* with or *predictive* of AD, but essential to the pathogenesis of the clinical symptoms of AD. The way that one would falsify this is running a trial or several that shows that A-beta is cleared without consequences to clinical symptoms, something which had been shown repeatedly now.

It's the same story as most of our neurodegenerative diseases, whether synuclein in PD or tau in a bunch of others - just because an abnormality exists doesn't mean it is the root cause of the problem. It may just as well be a reactive or even protective response to an as yet unknown disease process, or have any number of other relationships. Stridency from dementia researchers regarding the amyloid hypothesis has even infected the PD field I know much more about - since A-beta is found in advanced PD and PD dementia, there's a push to claim that AD pathology is responsible for PD dementia. Of course this is nonsense, as these patients have cortical synuclein, no tau pathology, and very different patterns of cognitive impairment compared to AD. But to some, the presence of plaques is enough to call it AD, details be damned.

 

[90sportsfan]

How often do most academic neurologists treat Alzheimer’s Disease patients?

Are they usually treated by geriatric neurologists or are they mostly treated by general neurologists in private practice settings?

 

[Thama]

How often do most academic neurologists treat Alzheimer’s Disease patients?

Are they usually treated by geriatric neurologists or are they mostly treated by general neurologists in private practice settings?

In academic centers they are usually treated by behavioral/dementia subspecialists. In private practice/small centers, they are treated by general neurologists or even primary care physicians, as behavioral neurologists tend to concentrate themselves disproportionately in the large research centers.

 

[neglect]

They will never do the postmarketing trials like most drugs that are approved under these circumstances. Thanks for calling me small minded. Three positive trials on amyloid amongst a graveyard of phase 2 and 3 trials. Spending >$56,000 a year on this drug with this level of evidence is absolute insanity. You will be fleecing desperate people of their money with not much if any medical benefit to show for it by even offering it.

The FDA obligated them to do a trial. It must be completed by 2030.

I agree, the price is an outrage. But that's only the opening negotiation. Payers will buy for FAR less than that.

Also, this is kind of wrong. The amyloid hypothesis rests not on beta-amyloid being *associated* with or *predictive* of AD, but essential to the pathogenesis of the clinical symptoms of AD. The way that one would falsify this is running a trial or several that shows that A-beta is cleared without consequences to clinical symptoms, something which had been shown repeatedly now.

It's the same story as most of our neurodegenerative diseases, whether synuclein in PD or tau in a bunch of others - just because an abnormality exists doesn't mean it is the root cause of the problem. It may just as well be a reactive or even protective response to an as yet unknown disease process, or have any number of other relationships. Stridency from dementia researchers regarding the amyloid hypothesis has even infected the PD field I know much more about - since A-beta is found in advanced PD and PD dementia, there's a push to claim that AD pathology is responsible for PD dementia. Of course this is nonsense, as these patients have cortical synuclein, no tau pathology, and very different patterns of cognitive impairment compared to AD. But to some, the presence of plaques is enough to call it AD, details be damned.

You don't live and breath AD biomarkers. Lilly: + trial, cleared amyloid. BAN2401, same.

 

[Thama]

You don't live and breath AD biomarkers. Lilly: + trial, cleared amyloid. BAN2401, same.

Given the history of the field, I'll wait for properly powered phase 3 trials before I believe this.

 

[xenotype]

The FDA obligated them to do a trial. It must be completed by 2030.

I agree, the price is an outrage. But that's only the opening negotiation. Payers will buy for FAR less than that.



You don't live and breath AD biomarkers. Lilly: + trial, cleared amyloid. BAN2401, same.

Tell me the percentage of drugs that actually complete FDA mandated postmarketing approval clinical trials. Especially the percentage that complete mandated trials prior to patent expiration.

 

[neglect]

Tell me the percentage of drugs that actually complete FDA mandated postmarketing approval clinical trials. Especially the percentage that complete mandated trials prior to patent expiration.

Those who do not trust cannot be trusted. Why assume the worst?

Even Serapta started doing a DMD confirmatory trial.

 

[xenotype]

Those who do not trust cannot be trusted. Why assume the worst?

Even Serapta started doing a DMD confirmatory trial.

You answered with an anecdote, not a fact. If I knew someone that told the truth less than 40% of the time, that is not a trustworthy person.

 

[neglect]

How often do most academic neurologists treat Alzheimer’s Disease patients?

Are they usually treated by geriatric neurologists or are they mostly treated by general neurologists in private practice settings?

They see VIP families who think that a doctor who spends 1 day a week in clinic and 95% of her mental energy on academic advancement (papers, perhaps a lab, teaching, admin/committees) is the best. They also tend to see more AD variants, other dementias, and young people with AD.

AD is very common, so most diagnoses are made in primary care settings.

You answered with an anecdote, not a fact. If I knew someone that told the truth less than 40% of the time, that is not a trustworthy person.

I'm confused, Serapta is the anecdote?

 

[xenotype]

I'm confused, Serapta is the anecdote?

Yes. Here is the actual, dismal, non-anecdotal evidence on how flawed relying on postmarketing trials is. 1 2 3 4 5

Many not done, not done on time, or not published even when they are completed. Of the trials that are completed and published- very often indications are narrowed and black box warnings are added. Despite the poor record- no drugs withdrawn from the market or companies penalized for not completing the trials on time.

 

[sloh]

"The FDA poses a series of hurdles to get a drug to market, but none of those hurdles are an assurance a drug works or has net benefit to people. Then the agency stamps drugs with their imprimatur. Ironically, this system is ideal for medium and large pharmaceutical firms. Small firms are kept off the market, and larger firms specialize in jumping through the hoops."

Great editorial by Vinay Prasad

Opinion | The FDA Is Failing the American People

The agency's recent decision to approve aducanumab offers more evidence of a broken system

www.medpagetoday.com

 

[neglect]

"The FDA poses a series of hurdles to get a drug to market, but none of those hurdles are an assurance a drug works or has net benefit to people. Then the agency stamps drugs with their imprimatur. Ironically, this system is ideal for medium and large pharmaceutical firms. Small firms are kept off the market, and larger firms specialize in jumping through the hoops."

Great editorial by Vinay Prasad

Opinion | The FDA Is Failing the American People

The agency's recent decision to approve aducanumab offers more evidence of a broken system

www.medpagetoday.com

Oh please, he’s an anti-pharma ideologue who is funded by the Arnold foundation to reduce pharma market share. Arnold himself is an ex-Enron crook who worked for Enron, then started a hedge fund. Prasad has zero experience running a trial at any level, in any role. He has no experience in regulatory matters. He has only vitriol for pharma and recently is dabbling with anti-vax ideology, especially with kids (despite also having zero experience in vaccines or ID).

His op/ed follows from his biases. He allows the reader to imagine a conspiracy, that the FDA sets drug prices, that the FDA is in bed with pharma, and that drug development is easy. He literally says it has no barriers. Biogen invested something that’s probably around a billion, but no matter.

Prasad’s other interest is COI. I normally don’t care for that low level dialogue, but in his case I’ll make an exception. He’s funded by a foundation that aims to reduce pharma prices. He should say so, anything less is a character deficit. And that’s what we see.

 

[xenotype]

I think it's important to note for this garbage fire of a thread the updates including the OIG investigation (would be an interesting turn if criminal charges are filed), the quitting of a significant fraction of the advisory committee that did not vote to approve the medication, the walked back-narrowed clinical indication, and the mounting political pressure to dump the FDA acting commisioner.

Well, that's one take.

So actually it is way more complicated than that. The FDA is not full of people who are ready to "fellate" pharma companies. They take these things seriously, but not Biogen's stock price. They've looked at the data, more data than we have, and have granted accelerated approval. This does NOT mean that they're saying it doesn't work. They are saying that data is very complicated, which it is. They conducted an early phase 1b trial which was robust enough to be a 2b, it was markedly positive, went right into phase 3, without doing a dose-finding traditional phase 2 trial (thinking the 1b trial was good enough). They found that they needed to adjust doses along the way, did so, then the trial got halted by the DSMC for futility.

THEN their data-set showed one positive trial, one negative trial. The positive trial showed good effect, which is clinically meaningful. While the negative trial was negative, those who got the highest dose did better than placebo.

So look at me with contempt. I'm fine with it. You're being overly shrill and only make me want to give more of it!

To go back to your first comment OIG will figure out exactly how much "fellate" happened between FDA officials and Biogen. Woodcock's time at the FDA is likely limited at this point.

The main negative here is that every dementia consult for every neurologist will turn into an extra hour of explaining why this drug won't help them, and why they shouldn't bankrupt themselves to get it.

 

[neglect]

I think it's important to note for this garbage fire of a thread the updates including the OIG investigation (would be an interesting turn if criminal charges are filed), the quitting of a significant fraction of the advisory committee that did not vote to approve the medication, the walked back-narrowed clinical indication, and the mounting political pressure to dump the FDA acting commisioner.


To go back to your first comment OIG will figure out exactly how much "fellate" happened between FDA officials and Biogen. Woodcock's time at the FDA is likely limited at this point.

The main negative here is that every dementia consult for every neurologist will turn into an extra hour of explaining why this drug won't help them, and why they shouldn't bankrupt themselves to get it.

Criminal charges? You’re seriously accusing Dunn of criminal action here? That’s pretty far from anything the current evidence suggests. Given the drama here, it is impossible to say this couldn’t happen, but when it doesn’t, will you come out and say you were wrong?

And you know Biogen requested the changes on the label, just terribly sloppy by the FDA.

Manchin is exactly right. The FDA needs a real commisioner. You know that Manchin’s daughter is the one fluffing the Epipen’s price point, which is something the FDA could put an end to by allowing a Chinese generic to enter the US market. Injectable epi, not brain surgery, just costs the same.

Woodcock is smart enough, and made a brilliant move here, so will be around for years. In one request, she protected the FDA and herself. THere will be no public hearing and questions from *****ic senators about drug development.

Extra hour? I live in this space. Try a 15 second “no, this is not suitable for them, they’d get all the side effects and no benefit.” Or “yeah, this might be a good fit, I’ll put you on a list.” Mostly, ”Yes, this is a good marker that we’re making progress, let’s talk about other clinical trials.”

 

[xenotype]

Criminal charges? You’re seriously accusing Dunn of criminal action here? That’s pretty far from anything the current evidence suggests. Given the drama here, it is impossible to say this couldn’t happen, but when it doesn’t, will you come out and say you were wrong?

And you know Biogen requested the changes on the label, just terribly sloppy by the FDA.

Manchin is exactly right. The FDA needs a real commisioner. You know that Manchin’s daughter is the one fluffing the Epipen’s price point, which is something the FDA could put an end to by allowing a Chinese generic to enter the US market. Injectable epi, not brain surgery, just costs the same.

Woodcock is smart enough, and made a brilliant move here, so will be around for years. In one request, she protected the FDA and herself. THere will be no public hearing and questions from *****ic senators about drug development.

Extra hour? I live in this space. Try a 15 second “no, this is not suitable for them, they’d get all the side effects and no benefit.” Or “yeah, this might be a good fit, I’ll put you on a list.” Mostly, ”Yes, this is a good marker that we’re making progress, let’s talk about other clinical trials.”

I said criminal charges would be an interesting turn and the OIG has the capability to pursue them. I did not guarantee there would be charges. I also highly doubt your patients are convinced with a 15 second statement about this drug.

How much stock do you have in Biogen? Are you a consultant or speaker for them? When you say you 'live in this space'- what is your financial disclosure in regards to the excessive cheerleading here for this drug? How much clinical trial funding do you receive for drugs based on the same mechanism? As of today Cleveland Clinic has banned administration of the drug on any of its campuses, as has Mount Sinai.

 

[Thama]

As of today Cleveland Clinic has banned administration of the drug on any of its campuses

If CCF is going to refrain from building another wing for foreign royalty to receive bespoke Aduhelm infusions, then that's really saying something.

 

[neglect]

I said criminal charges would be an interesting turn and the OIG has the capability to pursue them. I did not guarantee there would be charges. I also highly doubt your patients are convinced with a 15 second statement about this drug.

How much stock do you have in Biogen? Are you a consultant or speaker for them? When you say you 'live in this space'- what is your financial disclosure in regards to the excessive cheerleading here for this drug? How much clinical trial funding do you receive for drugs based on the same mechanism? As of today Cleveland Clinic has banned administration of the drug on any of its campuses, as has Mount Sinai.

15 second no. Easy. 15 sec to put on waiting list for further discussion as it is not available yet. Easy. Does it take you longer?

I’ve done many others with same possible mechanism.

Is that a prohibition on having an opinion? COI is the lowest form of discourse.

The Cleveland clinic has egg on its face. Guess Biogen has to be Theranos for them to adopt such a top down prohibition.

 

[xenotype]

Is that a prohibition on having an opinion? COI is the lowest form of discourse.

So you directly financially benefit from this medication then. That makes all of your comments make a lot more sense.

 

[neglect]

So you directly financially benefit from this medication then. That makes all of your comments make a lot more sense.

Hilariously revealing comment. I haven’t benefitted at all from its approval. I will, of course. So will you, especially if you are an employed doctor.

If you actually want to discuss the merits, and the problems of the approval, happy to do so.

for everyone else, watch this space. In a few years we will have DMTs for AD that we know work, not just have glimmers. Those who took a polarized stance against will be strangely silent.

 

[JerryMouse]

Hilariously revealing comment. I haven’t benefitted at all from its approval. I will, of course. So will you, especially if you are an employed doctor.

If you actually want to discuss the merits, and the problems of the approval, happy to do so.

for everyone else, watch this space. In a few years we will have DMTs for AD that we know work, not just have glimmers. Those who took a polarized stance against will be strangely silent.

What are these potential new DMTs? I haven’t seen anything in clinical trials that look very promising.
Very interesting thread. Thanks to all those with expertise who have posted.

 

[Thama]

In a few years we will have DMTs for AD that we know work, not just have glimmers. Those who took a polarized stance against will be strangely silent.

I hope so, but this has been said constantly for the last 2 decades or so. History suggests it won't be that easy.

The most revealing part of this, however, is that you seem to think that those of us against Aduhelm's approval have taken that stance because we are against an effective DMT for AD, not because the data for this particular DMT is unambiguously inadequate for FDA approval and the approval process appears to have been brazenly circumvented. Should a DMT, this one or otherwise, show clear benefit in a well-conducted RCT, I would be thrilled and happy to recommend it to my patients. I suspect everyone here would feel the same.

 

[neglect]

What are these potential new DMTs? I haven’t seen anything in clinical trials that look very promising.
Very interesting thread. Thanks to all those with expertise who have posted.

There are currently two other drugs that are very much like aducanumab: BAN2401 and gante. Both are in late stage trials, have less ARIA (brain swelling) risk. BAN, or lecanemab, had a positive phase2b trial, showing for the first time that removing amyloid was possible, and tied to better outcomes. Lilly‘s donanemab hits a different amyloid target and racked up a phase II win, now in a phase III which is enrolling.

This is actually the reason why the FDA folks think removing amyloid works: BAN and donanemab. But there have to be thresholds. BACE-inhibitors move amyloid (that we measure on PET, there are likely many different species of amyloid), but only about 5% and no clinical effect. BAN turned PET scans from visually positive to visually negative, so it is a much greater effect.

I hope so, but this has been said constantly for the last 2 decades or so. History suggests it won't be that easy.

The most revealing part of this, however, is that you seem to think that those of us against Aduhelm's approval have taken that stance because we are against an effective DMT for AD, not because the data for this particular DMT is unambiguously inadequate for FDA approval and the approval process appears to have been brazenly circumvented. Should a DMT, this one or otherwise, show clear benefit in a well-conducted RCT, I would be thrilled and happy to recommend it to my patients. I suspect everyone here would feel the same.

Seem to think you are against an effective AD med? When and where did I say that? I realize the data is complex. What I object to is saying that one has contempt for people like Salloway, who’s already used the drug. I also object to dismissing one entire trial, which was positive but stopped early. This showled a clear benefit. The trial was not conducted well due to fear of ARIA In APOE4 people and lack of understanding that the titration won’t do anything to bend the slope (see above about threshold effect), but despite it all, we have one positive trials and we can’t go back. This is thrilling and a cause for celebration, despite the mixed data.

What I object to is seeing this with biased, simplistic eyes. Anti-pharma bias exists in large part here. There’s a ton of anti-amyloid bias, with many researchers saying there are other targets, which is true but useless (and many saying these other targets should be at the exclusion of amyloid, which is stupid but dogmatic). And simply dismissing the data because it is complex and the FDA made a decision one disagrees with is objectionable.

‘It won’t be easy’: understatement of the year.

 

[JerryMouse]

There are currently two other drugs that are very much like aducanumab: BAN2401 and gante. Both are in late stage trials, have less ARIA (brain swelling) risk. BAN, or lecanemab, had a positive phase2b trial, showing for the first time that removing amyloid was possible, and tied to better outcomes. Lilly‘s donanemab hits a different amyloid target and racked up a phase II win, now in a phase III which is enrolling.

This is actually the reason why the FDA folks think removing amyloid works: BAN and donanemab. But there have to be thresholds. BACE-inhibitors move amyloid (that we measure on PET, there are likely many different species of amyloid), but only about 5% and no clinical effect. BAN turned PET scans from visually positive to visually negative, so it is a much greater effect.

Yes, I remember reading the lecanemab and donanemab results. The amyloid clearance results are definitely very good, but the cognitive results are modest, about a 30% slowing of decline. For example, in the donanemab study, the group given donanemab declined by 6.8 points and the placebo group declined by 10 points on the 144 point iADRS (a combined cognitive and ADL scale). If these findings are repeated in the phase 3 trials, then it would be a positive, though I wonder how much real life benefit will be seen, since the effect sizes are similar to that of cholinesterase inhibitors, which slowed decline by about 2 points on the MMSE in the 6 month study period.

Maybe secondary prevention trials (treating amyloid PET positive people who are cognitively normal) will show better results.

 

[Dusn]

Dunn was clear about why in his letter. https://www.fda.gov/media/149903/download

He didn't give a sh1t what they thought. He only cared about biomarkers and wants patients, families, and doctors to make a choice. He basically abandoned his leadership and regulatory responsibilities and outsourced the decision to you and me. You can make your decision, but holding good people like Salloway in contempt for not thinking like you isn't a good look.

Dunn’s letter tells you everything about the FDA leadership.
1) the FDA leadership is and has been systematically creating pathways for drug and device companies to get approval despite a lack of evidence for safety or efficacy. The leadership created a very weak pathway to approval leading to this inevitable consequence.
2) ultimately politics and legal arguments made by the company/sponsor take precedence over medical/scientific concerns
3) the FDA leadership’s ultimate goal is to take all of the medical officer’s concerns, put them in the small print in the drug/device label, and shift all responsibility to the physician.
Unfortunately when the FDA makes a bad decision or mistake it weakens them forever. From this point forward, any company can say, “you accepted this for biogen, what makes us different?” The FDA has to act similarly to all companies and the law does not allow them to say that they want to make their standard more strict, they can only make their standards weaker.
This is now their new standard.

 

[neglect]

Yes, I remember reading the lecanemab and donanemab results. The amyloid clearance results are definitely very good, but the cognitive results are modest, about a 30% slowing of decline. For example, in the donanemab study, the group given donanemab declined by 6.8 points and the placebo group declined by 10 points on the 144 point iADRS (a combined cognitive and ADL scale). If these findings are repeated in the phase 3 trials, then it would be a positive, though I wonder how much real life benefit will be seen, since the effect sizes are similar to that of cholinesterase inhibitors, which slowed decline by about 2 points on the MMSE in the 6 month study period.

Maybe secondary prevention trials (treating amyloid PET positive people who are cognitively normal) will show better results.

The very fact there’s evidence that we can bend the slope of Alzheimer’s disease is a miracle. The iADRS is a made up combo of two other metrics: ADAS-COG and ADCS-ADL. The trials show that the drugs affect cognitive metrics more than functional ones.

ACHE-I do NOT slow decline. They result in symptomatic improvement. Bending the curve is the goal. This medication is a good start, just like Copaxone, AZT, or early chemotherapy.

Prodromal trials are very difficult, but we’re getting there.

Dunn’s letter tells you everything about the FDA leadership.
1) the FDA leadership is and has been systematically creating pathways for drug and device companies to get approval despite a lack of evidence for safety or efficacy. The leadership created a very weak pathway to approval leading to this inevitable consequence.
2) ultimately politics and legal arguments made by the company/sponsor take precedence over medical/scientific concerns
3) the FDA leadership’s ultimate goal is to take all of the medical officer’s concerns, put them in the small print in the drug/device label, and shift all responsibility to the physician.
Unfortunately when the FDA makes a bad decision or mistake it weakens them forever. From this point forward, any company can say, “you accepted this for biogen, what makes us different?” The FDA has to act similarly to all companies and the law does not allow them to say that they want to make their standard more strict, they can only make their standards weaker.
This is now their new standard.

I agree, which is why they shouldn’t have gone this route. But they did and they have their reasons. It is out of our hands. We have to deal with the consequences.

 

[neglect]

Lecanemab clears amyloid and works, increasing the likelihood that aducanumab works.

 

[sharkbaitwhohaha]

Lecanemab clears amyloid and works, increasing the likelihood that aducanumab works.

Do you think it will be covered by CMS? Or adopted by neurologists as a whole? OrAduhelm x2

 

[neglect]

Do you think it will be covered by CMS? Or adopted by neurologists as a whole? OrAduhelm x2

As I tried to show above, I think adu likely works. And I think lec works as well. Lec is actually a bit older than adu, entering SAD/MAD phase 1 in 2010. But they did a phase 2b, so they got a good answer about dosing and safety. Biogen rushed into two identical phase 3 trials, and fortune disfavored the bold. Regardless, they are in the same drug class, but have different targets, and fascinatingly different and brilliant origin stories. So the question is really tricky. Small differences can have markedly different outcomes. I don’t think either one should be called X2.

Yes, I think lec will be covered by CMS. Given the data that was released, it is non-controversial for full approval, using their 2b trial and this one.

Yes, I think it will be adopted. You saw the uncaring vitriol above, in which neurologists tried to control others judgement through shaming. But science always wins. Lec will be a winner.

The interesting thing, that no-one wants to talk about, are the people who were totally, loudly, and even nastily wrong about adu. I said that they are different, but I think that when you see both drugs with similar biomarkers in the same field, what you really see is confirmation that adu’s accelerated approval was correct. You saw some of this mindset above. The people who were loudly wrong about adu and amyloid will not, even for a moment, stop and reflect. This is maddening. Being wrong is fine, but be professional about it. When you’re wrong, explain why you messed up. THat’s as important as recognizing the error: recognizing the process.

Thing is that patients do hear the controversy, which actually drives them out of trials or prevents screening.

 

[Thama]

As I tried to show above, I think adu likely works. And I think lec works as well. Lec is actually a bit older than adu, entering SAD/MAD phase 1 in 2010. But they did a phase 2b, so they got a good answer about dosing and safety. Biogen rushed into two identical phase 3 trials, and fortune disfavored the bold. Regardless, they are in the same drug class, but have different targets, and fascinatingly different and brilliant origin stories. So the question is really tricky. Small differences can have markedly different outcomes. I don’t think either one should be called X2.

Yes, I think lec will be covered by CMS. Given the data that was released, it is non-controversial for full approval, using their 2b trial and this one.

Yes, I think it will be adopted. You saw the uncaring vitriol above, in which neurologists tried to control others judgement through shaming. But science always wins. Lec will be a winner.

The interesting thing, that no-one wants to talk about, are the people who were totally, loudly, and even nastily wrong about adu. I said that they are different, but I think that when you see both drugs with similar biomarkers in the same field, what you really see is confirmation that adu’s accelerated approval was correct. You saw some of this mindset above. The people who were loudly wrong about adu and amyloid will not, even for a moment, stop and reflect. This is maddening. Being wrong is fine, but be professional about it. When you’re wrong, explain why you messed up. THat’s as important as recognizing the error: recognizing the process.

Thing is that patients do hear the controversy, which actually drives them out of trials or prevents screening.

This is a whole lot of chest thumping for a drug that reduced change in CDR by less than half a point over 18 months, or less than you'd expect to get from donepezil (which I basically consider a glorified placebo anyway). I'm a whole lot more comfortable with this one being approved given the clear significant benefit without resorting to post-hoc statistical scumbaggery like we saw last round (as far as we know), but given the relatively small clinical benefit with a still significant risk of ARIA, this looks to me like an incremental step rather than a massive win. Medicare will also have a difficult decision ahead of it as the financial cost here is likely to be very high relative to the impact on QOL.

There is still a whole lot left to be explained for amyloid enthusiasts regarding why amyloid clearance can be so robust but clinical change be so limited, if amyloid is really the alpha and omega of AD pathogenesis.

 

[neglect]

This is a whole lot of chest thumping for a drug that reduced change in CDR by less than half a point over 18 months, or less than you'd expect to get from donepezil (which I basically consider a glorified placebo anyway). I'm a whole lot more comfortable with this one being approved given the clear significant benefit without resorting to post-hoc statistical scumbaggery like we saw last round (as far as we know), but given the relatively small clinical benefit with a still significant risk of ARIA, this looks to me like an incremental step rather than a massive win. Medicare will also have a difficult decision ahead of it as the financial cost here is likely to be very high relative to the impact on QOL.

There is still a whole lot left to be explained for amyloid enthusiasts regarding why amyloid clearance can be so robust but clinical change be so limited, if amyloid is really the alpha and omega of AD pathogenesis.

Perfectly on cue. "The people who were loudly wrong about adu and amyloid will not, even for a moment, stop and reflect." - Me, three posts ago.

Now it is positive, but it isn't positive enough. What you don't know is that half a point on CDR-SB is amazing because placebo declines an average of 1.5 points over 1.5 years.

 

[Thama]

Perfectly on cue. "The people who were loudly wrong about adu and amyloid will not, even for a moment, stop and reflect." - Me, three posts ago.

Now it is positive, but it isn't positive enough. What you don't know is that half a point on CDR-SB is amazing because placebo declines an average of 1.5 points over 1.5 years.

a) Lecanemab hitting its endpoints doesn't make the aducanumab data any stronger. Their being in the same class of drugs means very little, a lesson that any properly trained neurologist should immediately remember from the history of stroke trials at the very least. The criticisms of aducanumab above were not "loudly wrong", and I would continue to think poorly of the clinical reasoning of any neurologist who ignored the issues raised by the FDA committee and decided to regularly prescribe it. I would not think the same way about a neurologist prescribing lecanemab from what we currently know, though there's a note of rearranging the chairs on the deck of the Titanic to its clinical efficacy versus cost, effort, and risk analysis here.

b) Lecanemab hitting its endpoints is a win for the amyloid hypothesis, but still leaves a lot of questions. Why would there be any continued decline after robust amyloid clearance if amyloid is the central mechanism here? Given the robust clearance here with what seems to be very strong patient selection criteria, I wonder whether there is even anywhere else for this therapeutic mechanism to go to improve outcomes further in clinically manifest cases (prodromal cases are a different matter). In statistical terms, our model is significant but explains a low proportion of the total variance.

c) You and I have very different ideas of what constitutes "amazing". You've benefited a patient by less than a third of the magnitude of effect of normal aging over the same time period? Putting it the way you just did only highlights how small the effect really is.

 

[deathmerchant]

Cant believe we are still talking about this and there are physicians thinking about prescribing these meds. This is not a win for amyloid hypothesis. Everyone except the "sunken cost" people are highly skeptical of it. Esp after the recent findings that the pivotal amyloid trials was fabricated. People need to be in jail for this fraud. For anyone who is not keeping up-

Science | AAAS

www.science.org

Science | AAAS

www.science.org

Please don't prescribe this medicine at this time!

 

[Thama]

Cant believe we are still talking about this and there are physicians thinking about prescribing these meds. This is not a win for amyloid hypothesis. Everyone except the "sunken cost" people are highly skeptical of it. Esp after the recent findings that the pivotal amyloid trials was fabricated. People need to be in jail for this fraud. For anyone who is not keeping up-

Science | AAAS

www.science.org

Science | AAAS

www.science.org

Please don't prescribe this medicine at this time!

Let's be clear - the allegations of fraud do not undermine the entire AD field or even the core of the amyloid hypothesis. This was a single researcher that focused on one subtype of A-beta. While this finding may have contributed to the field, it would not be fair to say that without this finding the whole field falls apart - it's one brick in a fairly large structure. I know a lot of AD researchers and have collaborated closely with some of them. They are good and honest people and not the types to pull this kind of stunt. Lumping in studies like DIAN with this crap really isn't fair.

The repetitive failures of anti-amyloid trials, and the discrepancy between magnitude of clinical benefit and amyloid clearance even in those touted as successes, are far more problematic for the A-beta hypothesis than any academic fraud committed by Lesne.

 

[deathmerchant]

Let's be clear - the allegations of fraud do not undermine the entire AD field or even the core of the amyloid hypothesis. This was a single researcher that focused on one subtype of A-beta. While this finding may have contributed to the field, it would not be fair to say that without this finding the whole field falls apart - it's one brick in a fairly large structure. I know a lot of AD researchers and have collaborated closely with some of them. They are good and honest people and not the types to pull this kind of stunt. Lumping in studies like DIAN with this crap really isn't fair.

The repetitive failures of anti-amyloid trials, and the discrepancy between magnitude of clinical benefit and amyloid clearance even in those touted as successes, are far more problematic for the A-beta hypothesis than any academic fraud committed by Lesne.

Im not saying any current amyloid/AD researchers are fraudulent or dishonest. I believe they followed what we all thought (including me) to be the most likely pathogenesis and rightly so. Just pointing out that one of the first/landmark trial on which most "amyloid as a cause and not just a residue" theories are based on was totally fabricated. This basically causes massive confirmation and other biases in all future studies. I have personally worked with AD experts for a good while. It is not one brick, it is the foundation. Thats also why, not surprisingly most amyloid drug trials have turned out to be basically duds.
Amyloid people need to stop being so confident/defensive and promoting Pharma's dismal attempts at making money; and start looking into alternative theories. I believe the amyloid hypothesis will totally fall apart in the next 5 years.

 

[neglect]

a) Lecanemab hitting its endpoints doesn't make the aducanumab data any stronger.

Please. Given the lecanemab data, obviously the adu data didn't change, but please tell me it didn't change your perspective. Then your belief is dogmatic and we can be done. The issues raised by the FDA advisory(!) committee were listened to. An FDA stats guy gave a talk at AAIC and explained their rational for accelerated approval. The bottom line was that they took the advice, went back and double checked. There was reasonable likelihood that it worked, they gave it accelerated approval.

Think what happened next: donanemab had a positive phase 2 trial. Tau plasma biomarkers showed reductions in adu (and lec and don). And now lec has a positive phase 3. Every bit of data is coming down on to support the FDA decision.

This med will likely delay time to CDR=3/institutionalization by many years. Small effects over a decade or two build up. Catch it early.

Cant believe we are still talking about this and there are physicians thinking about prescribing these meds. This is not a win for amyloid hypothesis. Everyone except the "sunken cost" people are highly skeptical of it. Esp after the recent findings that the pivotal amyloid trials was fabricated. People need to be in jail for this fraud. For anyone who is not keeping up-

Science | AAAS

www.science.org

Science | AAAS

www.science.org

Please don't prescribe this medicine at this time!

As was pointed out, A*56 has nothing to do with any amyloid drug, ever. Sadly this was puffery from those involved in uncovering this misconduct and actually rises to journalistic malpractice. This did as much damage to the field as comparing aducanumab to drugs we knew failed.

This was the first oligomer to be discovered. It might have been faked. Either way, other oligomers have now been identified.

This was NOT "one of the first/landmark trial on which most "amyloid as a cause and not just a residue" theories are based." For that, try Downs and the presenilin mutations.

 

[Thama]

Please. Given the lecanemab data, obviously the adu data didn't change, but please tell me it didn't change your perspective.

It didn't change my perspective all that much. My perspective on adu was that it probably did have an effect, but given a) the small magnitude of effect, b) the very significant adverse events in a non-trivial fraction of participants, and c) the messiness of the way the trials were conducted, we needed another study at minimum with unambiguous results before it would be worthy of approval. While lec isn't the same drug, it also had more robust patient selection criteria, and so I'm guessing that this is why the outcomes data is cleaner. Had Biogen run this study with adu instead and gotten the same result as they did with lec, I'd be fine with adu being approved right now. I still don't think lec is a particularly good option for use across the board given the low magnitude of benefit and still significant ARIA incidence, but it may be reasonable to use with careful patient selection.

There was reasonable likelihood that it worked, they gave it accelerated approval.

"reasonable likelihood" should never be the basis of drug approval outside of something like a humanitarian device exemption. The last minute shifting of approval standards to seemingly whatever Biogen wanted them to be is exactly the problem here.

This med will likely delay time to CDR=3/institutionalization by many years. Small effects over a decade or two build up. Catch it early.

Maybe, maybe not - RCT with this as the endpoint or GTFO. If you haven't yet learned to replace blind enthusiasm with healthy skepticism regarding assumptions like this when it comes to the effects of AD trials, then you truly are a lost cause.