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The FDA fails again - Aduhelm - Treatment for Alzheimers (1 Viewer)

MTskibum

MTskibum

Footballguy
The FDA approved a drug that costs ~56,000 dollars per year that does not work. It is snake oil, yet desperate people will pay tons of money for this snake oil. The FDA is failing at its most important job, first it did not approve the vaccines fast enough, now it is approving expensive drugs that do not even work.

https://www.statnews.com/2021/06/07/fda-grants-historic-approval-to-alzheimers-drug-designed-to-slow-cognitive-decline/

The drug — which just two years ago was declared a stunning failure — is now expected to generate billions of dollars in revenue for its maker, Biogen.

https://arstechnica.com/science/2021/06/a-disgraceful-decision-researchers-blast-fda-for-approving-alzheimers-drug/

Even the FDA's own advisers and statisticians didn't think the drug should be approved.

Critics of the decision note that Aduhelm has little data indicating it is effective at treating Alzheimer’s, and it comes with a hefty risk of painful brain swelling. In fact, Aduhelm initially flunked out of two randomized, double-blind, placebo-controlled Phase III clinical trials in 2019. An early analysis dubbed the drug “futile,” and Biogen ended the trials early.

 
Thanks for posting this, I had heard of the new treatment via some news headlines and I chalked it up to good news without looking into it yet.

Looks like wall street was able to cash in on the approval. 

 
MTskibum said:
The FDA approved a drug that costs ~56,000 dollars per year that does not work. It is snake oil, yet desperate people will pay tons of money for this snake oil. The FDA is failing at its most important job, first it did not approve the vaccines fast enough, now it is approving expensive drugs that do not even work.

https://www.statnews.com/2021/06/07/fda-grants-historic-approval-to-alzheimers-drug-designed-to-slow-cognitive-decline/

The drug — which just two years ago was declared a stunning failure — is now expected to generate billions of dollars in revenue for its maker, Biogen.

https://arstechnica.com/science/2021/06/a-disgraceful-decision-researchers-blast-fda-for-approving-alzheimers-drug/

Even the FDA's own advisers and statisticians didn't think the drug should be approved.

Critics of the decision note that Aduhelm has little data indicating it is effective at treating Alzheimer’s, and it comes with a hefty risk of painful brain swelling. In fact, Aduhelm initially flunked out of two randomized, double-blind, placebo-controlled Phase III clinical trials in 2019. An early analysis dubbed the drug “futile,” and Biogen ended the trials early.
Click to expand...


Why do you think the FDA approved Aduhelm?

 
whoknew said:
Why do you think the FDA approved Aduhelm?
Click to expand...


The quote from the FDA director of drug evaluation is below. Pretty much they approved it not because it worked, but because there was nothing else to treat Alzheimers with, ie snake oil.

We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit…

 
MTskibum said:
The quote from the FDA director of drug evaluation is below. Pretty much they approved it not because it worked, but because there was nothing else to treat Alzheimers with, ie snake oil.

We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit…
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“Expectation of clinical benefit” doesn’t sound like snake oil. 

 
Not sure why they pushed this one through, but all the approved dementia drugs suck.

At least the new obesity drug looks promising.

 
yea they truly appear to have buckled under the pressure from corporations. This time next year they will be selling a million of these bills a month

 
The FDA buckled under pressure from big pharma and advocacy groups like the Alzheimer's Association.  Aducanumab (AduhelmTM) is not quite snake oil, as it does actually remove an Alzheimer's protein known as amyloid from the  brain. But its clinical benefit is in doubt  - one study showed no benefit and another study showed a possibly small benefit to slowing down the decline of memory and thinking associated with Alzheimer's Disease.

The next step is for CMS (Medicare) to determine (1) which patients would be covered (requires an amyloid PET scan or a lumbar puncture to prove that a person has amyloid in the brain, and memory testing to show only mild impairment, as advanced dementia subjects will likely not benefit - treatment is too late)  and (2) how much to reimburse for monthly infusions of the drug ($50,000+ per year), and (3) how frequently to pay for MRI scans to check for a common side effect in the brain associated with removal of amyloid, which is usually asymptomatic, but sometimes associated with mild symptoms such as headaches. When these imaging abnormalities appear in the brain, the next dose of aducanumab may have to be reduced or stopped. It's not an easy drug to administer.

Here is a lay write-up and commentary from experts in the field, including predictions that this approval will both increase and decrease drug discovery. In the short-term, it will make it more difficult to enroll participants into clinical drugs trials - "Would one of your loved ones agree to participate in a long-shot clinical trial for a new AD drug given aducanumab’s availability? Mine wouldn’t. They would skip the trial and take the approved drug ... it’s backed by science, right?".

https://www.alzforum.org/news/research-news/aducanumab-approved-treat-alzheimers-disease

 
The Z Machine said:
Yeah, I dunno if this approval was a good idea.  Was it EUA or full approval?  
Click to expand...
Accelerated approval "which provides patients suffering from a serious disease earlier access to drugs when there is an expectation of clinical benefit despite some uncertainty about the clinical benefit of the drug." The company also has to do a Phase IV trial to show clinical benefit. But: "While the FDA has required a Phase 4 study, Biogen’s announcement that this study will take nine years to complete makes it clear that this requirement will not fill gaps in our understanding of drug utility."

https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information

https://www.alzforum.org/news/research-news/aducanumab-approved-treat-alzheimers-disease

 
Its not necessarily snake oil, but in my opinion it's similar to Remdesivir for covid, in that its an expensive drug that may not be an effective treatment for its intended purpose, especially for people in advanced stages, which are the people that need a treatment the most. 

It clearly does reduce amyloid in the brain but I wish the required phase 4 trial could be completed sooner. 9 years to perform the trial? And it seems like for advanced stages, this drug just takes away the gun after the bullet has already been fired. I worry that desperate people will place false hope in this treatment, spend a lot of money, and not see any results. 

 
TwinTurbo said:
Its not necessarily snake oil, but in my opinion it's similar to Remdesivir for covid, in that its an expensive drug that may not be an effective treatment for its intended purpose, especially for people in advanced stages, which are the people that need a treatment the most. 

It clearly does reduce amyloid in the brain but I wish the required phase 4 trial could be completed sooner. 9 years to perform the trial? And it seems like for advanced stages, this drug just takes away the gun after the bullet has already been fired. I worry that desperate people will place false hope in this treatment, spend a lot of money, and not see any results. 
Click to expand...
Most of the money on the drug will be spent by us taxpayers through Medicare. A few desperate people (and their families) who don't qualify because they fail to meet eligibility criteria for insurance to pay, will spend their own money. In theory, it's not a lifetime drug since treatment could be stopped once enough amyloid is removed from the brain, as shown by followup spinal taps or PET scans. Very soon, detection of amyloid in the brain will be replaced by blood biomarkers tests, which could open the floodgates for this drug even more.

 
TwinTurbo said:
Its not necessarily snake oil, but in my opinion it's similar to Remdesivir for covid, in that its an expensive drug that may not be an effective treatment for its intended purpose, especially for people in advanced stages, which are the people that need a treatment the most. 

It clearly does reduce amyloid in the brain but I wish the required phase 4 trial could be completed sooner. 9 years to perform the trial? And it seems like for advanced stages, this drug just takes away the gun after the bullet has already been fired. I worry that desperate people will place false hope in this treatment, spend a lot of money, and not see any results. 
Click to expand...


SoBeDad said:
Most of the money on the drug will be spent by us taxpayers through Medicare. A few desperate people (and their families) who don't qualify because they fail to meet eligibility criteria for insurance to pay, will spend their own money. In theory, it's not a lifetime drug since treatment could be stopped once enough amyloid is removed from the brain, as shown by followup spinal taps or PET scans. Very soon, detection of amyloid in the brain will be replaced by blood biomarkers tests, which could open the floodgates for this drug even more.
Click to expand...


The drug is not proven to remove amyloid plaques in the brain, even at the highest dose it could be a statistical blip.  Furthermore, there are quite a few researchers who do not believe that the amyloid plaques cause Alzheimers. So even if the drug worked at its purpose, there is a strong chance that it would not help with Alzheimers anyways.

Below is one such study, however there are other independent studies as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208728/

However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.

 
MTskibum said:
The drug is not proven to remove amyloid plaques in the brain, even at the highest dose it could be a statistical blip.  Furthermore, there are quite a few researchers who do not believe that the amyloid plaques cause Alzheimers. So even if the drug worked at its purpose, there is a strong chance that it would not help with Alzheimers anyways.

Below is one such study, however there are other independent studies as well.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208728/

However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.
Click to expand...
This drug and others do remove some form of amyloid from the brain. For example, in the Lilly Trailblazer1 study, 40% of participants on donanemab, a similar anti-body,  became amyloid negative on PET scans at 24 weeks. 

The issue is whether to rely on a biomarker outcome, that may only be modestly related (or not related) to a clinical outcome for Alzheimer's patients, such as memory scores or activities of daily living. The same issue of relying on a biomarker outcome occurred with a muscular dystrophy drug (Sarepta's Exondys) and 5 years later there is still no proven clinical benefit for this FFA-approved drug.

Yes, this could slow down investigations into non-amyloid treatments for Alzheimers.

 
I have a friend that works for a similar company and does regulatory affairs.   I've referenced her before.  She's a PhD neuroscientist and a close friend.  

She said, "I 10000% understand the concerns but I think they're misrepresenting the trial data and the overall conduct of clinical trials

The drug failed 1 study based on the clinical endpoint (which is the most important thing) but it did show good results on affecting the pharmacodynamic effect (meaning affecting the pathological biological underpinnings of the disease). The "futile" wording comes from a statistical consideration called "futility analysis", which takes into account not only the clinical benefit but other considerations on why you would stop a trial (magnitude of the effect, only working on a subpopulation, safety concerns, etc, which are all incorporated into a massive statistical analysis plan). So the "futile" attribution is a bit misguided since it isn't intended to mean the layperson definition.

The safety data on brain swelling sounds awful, but my understanding is that it was the same as placebo and can be considered part of disease progression. But as a disclaimer, I haven't looked at it closely.

[I interject here to talk about why approve a drug that doesn't actually affect the true endpoints.]

And this is why the drug was granted Accelerated Approval. This is a regulatory mechanism by which the Agency approved a drug based on a reasonable expectation of clinical efficacy based on biomarker data and what are called "surrogate endpoints".  So biogen HAS to do a phase 4 study to confirm the effects. With this patient population, in a slow disease, this can take a decade.  If it confirms the efficacy, they're good. If not, the approval is revoked.

But the fda decision was "accelerated approval", which i think represents the agency's compromise.

Take for example a lot of genetic metabolic diseases- eg where you're born without or with little Enzyme X.  Several products have been approved based on the data showing the product replaced Enzyme X. Now, the full clinical benefit you wouldn't see for YEARS. Meaning, whether the patients live longer, feel better, and do things they couldn't do before but the biological hypothesis is sound.  So the agency has approved multiple drugs based on the reasonable expectation of clinical benefit based on plausible scientific rationales. Then the companies confirm later.

NOW- the downside.  It's challenging for a drug like this, for which there is a HUGE need, to not become the standard of care. So patients may be less likely to join a trial for a drug that may ultimately be better, because they have the "best" thing at hand. It's a low precedent that other companies shouldn't strive for, but likely will.  And it offers hope to a lot of people who likely won't benefit from it. But also won't benefit from anything else we can offer.  Lastly, just for some context- since the last AD drug was approved, to now, about 20 years and $900B have been spent in R&D. Yet here we are.

This #### is hard."

 
The Z Machine said:
I have a friend that works for a similar company and does regulatory affairs.   I've referenced her before.  She's a PhD neuroscientist and a close friend.  

She said, "I 10000% understand the concerns but I think they're misrepresenting the trial data and the overall conduct of clinical trials

The drug failed 1 study based on the clinical endpoint (which is the most important thing) but it did show good results on affecting the pharmacodynamic effect (meaning affecting the pathological biological underpinnings of the disease). The "futile" wording comes from a statistical consideration called "futility analysis", which takes into account not only the clinical benefit but other considerations on why you would stop a trial (magnitude of the effect, only working on a subpopulation, safety concerns, etc, which are all incorporated into a massive statistical analysis plan). So the "futile" attribution is a bit misguided since it isn't intended to mean the layperson definition.

The safety data on brain swelling sounds awful, but my understanding is that it was the same as placebo and can be considered part of disease progression. But as a disclaimer, I haven't looked at it closely.

[I interject here to talk about why approve a drug that doesn't actually affect the true endpoints.]

And this is why the drug was granted Accelerated Approval. This is a regulatory mechanism by which the Agency approved a drug based on a reasonable expectation of clinical efficacy based on biomarker data and what are called "surrogate endpoints".  So biogen HAS to do a phase 4 study to confirm the effects. With this patient population, in a slow disease, this can take a decade.  If it confirms the efficacy, they're good. If not, the approval is revoked.

But the fda decision was "accelerated approval", which i think represents the agency's compromise.

Take for example a lot of genetic metabolic diseases- eg where you're born without or with little Enzyme X.  Several products have been approved based on the data showing the product replaced Enzyme X. Now, the full clinical benefit you wouldn't see for YEARS. Meaning, whether the patients live longer, feel better, and do things they couldn't do before but the biological hypothesis is sound.  So the agency has approved multiple drugs based on the reasonable expectation of clinical benefit based on plausible scientific rationales. Then the companies confirm later.

NOW- the downside.  It's challenging for a drug like this, for which there is a HUGE need, to not become the standard of care. So patients may be less likely to join a trial for a drug that may ultimately be better, because they have the "best" thing at hand. It's a low precedent that other companies shouldn't strive for, but likely will.  And it offers hope to a lot of people who likely won't benefit from it. But also won't benefit from anything else we can offer.  Lastly, just for some context- since the last AD drug was approved, to now, about 20 years and $900B have been spent in R&D. Yet here we are.

This #### is hard."
Click to expand...
Very good points. 

Aducanumab does cause more ARIA (Amyloid-related imaging abnormalities) than placebo as seen on MRI, both edema-type and hemorrhage-type, especially among those with an APOE 4 allele. Most (~70%) are asymptomatic, and the symptoms tend to be mild and resolve. But some cases of ARIA are associated with more rapid progression of disease symptoms. So, MRI scans will be required before treatment and during treatment, about 6 months after the first infusion. The next dose might have to be reduced or stopped altogether. It's a known issue for this class of medications. 

https://www.alzforum.org/news/research-news/aducanumab-approved-treat-alzheimers-disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693547/

 
https://arstechnica.com/science/2021/06/three-experts-resign-as-fda-advisors-over-approval-of-alzheimers-drug/

Three experts resign as FDA advisors over approval of Alzheimer’s drug

Fallout continues from the Food and Drug Administration’s contentious decision this week to approve Biogen’s Alzheimer’s drug Aduhelm (aducanumab) despite a lack of efficacy data.

Three experts who sat on an advisory committee for the FDA have now resigned over the decision.

The advisory committee reviewed the data behind Aduhelm last November and voted overwhelmingly against approval. Of the 11 advisors on the committee, 10 voted “no” on the question of whether Biogen had collected enough evidence to indicate that the drug is effective. The remaining advisor voted “uncertain.”

Nevertheless, the FDA approved the drug on Monday. Though the regulator acknowledged that there are “residual uncertainties regarding [the] clinical benefit” of Aduhelm, the FDA said it decided to lower the requirements for approval after the advisory committee voted.

 
Max Power said:
https://arstechnica.com/science/2021/06/three-experts-resign-as-fda-advisors-over-approval-of-alzheimers-drug/

Three experts resign as FDA advisors over approval of Alzheimer’s drug

Fallout continues from the Food and Drug Administration’s contentious decision this week to approve Biogen’s Alzheimer’s drug Aduhelm (aducanumab) despite a lack of efficacy data.

Three experts who sat on an advisory committee for the FDA have now resigned over the decision.

The advisory committee reviewed the data behind Aduhelm last November and voted overwhelmingly against approval. Of the 11 advisors on the committee, 10 voted “no” on the question of whether Biogen had collected enough evidence to indicate that the drug is effective. The remaining advisor voted “uncertain.”

Nevertheless, the FDA approved the drug on Monday. Though the regulator acknowledged that there are “residual uncertainties regarding [the] clinical benefit” of Aduhelm, the FDA said it decided to lower the requirements for approval after the advisory committee voted.
Click to expand...
Well this isn't good news.  Now what is Biden going to take?  I'm guessing it was approved because he's fading fast but this news certainly is concerning.

 
BladeRunner said:
Well this isn't good news.  Now what is Biden going to take?  I'm guessing it was approved because he's fading fast but this news certainly is concerning.
Click to expand...
Wait, you think that the FDA approved this drug because of the President's opinion polls?  Is that really how you think the federal government works?

This drug was likely approved due to pressure from patient advocate groups in combination with a plausible biological theory that it will help on actual outcomes and a Phase 4 trial that seeks to prove those outcomes.

 
Max Power said:
https://arstechnica.com/science/2021/06/three-experts-resign-as-fda-advisors-over-approval-of-alzheimers-drug/

Three experts resign as FDA advisors over approval of Alzheimer’s drug

Fallout continues from the Food and Drug Administration’s contentious decision this week to approve Biogen’s Alzheimer’s drug Aduhelm (aducanumab) despite a lack of efficacy data.

Three experts who sat on an advisory committee for the FDA have now resigned over the decision.

The advisory committee reviewed the data behind Aduhelm last November and voted overwhelmingly against approval. Of the 11 advisors on the committee, 10 voted “no” on the question of whether Biogen had collected enough evidence to indicate that the drug is effective. The remaining advisor voted “uncertain.”

Nevertheless, the FDA approved the drug on Monday. Though the regulator acknowledged that there are “residual uncertainties regarding [the] clinical benefit” of Aduhelm, the FDA said it decided to lower the requirements for approval after the advisory committee voted.
Click to expand...
unsettling feeling with the lowering of credibility of the FDA.

 
WSJ Editorial Board’s Contrarian Take:

The Food and Drug Administration gave hope to millions of Americans suffering from Alzheimer’s disease on Monday by approving Biogen’saducanumab, the first treatment shown to slow cognitive decline. Credit to Acting Commissioner Janet Woodcock for resisting pressure from the public-health left who campaigned against the drug…

…The FDA’s approval offers much-needed reassurance to U.S. drug makers that it won’t bow to political pressure and let biotech breakthroughs go to waste.
Click to expand...

 
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Anyone watching Dopesick in Hulu?  It pretty much follows the way OxyContin was approved and rolled out.  Sickening. 

 
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