"Most worryingly, it turns out that there was a clear difference between the placebo group and the treatment group in APOE4 status."
I would turn to Derek Lowe as he is an expert in the field who has been looking forward to this release... he holds out hope, but is not positive on "the field is in the state it’s in today."
"APOE4, a lipoprotein, has been recognized as a risk factor for Alzheimer’s since back in the 1990s, although the mechanism behind that has been the subject of debate. But there was a regulatory-mandated change in enrollment of APOE4 patients during the (Bayesian) trial, for fear of a brain-swelling side effect that these patients are also prone to, and there ended up being far more APOE4-positive patients in the placebo group compared to the high-dose group (70% versus 30%)."
Should also note that the study missed its primary endpoint, but the companies decided to wait for the 18 month analysis anyway, and one dose seemed promising at this 18 month timepiint. Other doses did worse than placebo
Other analysts who have been looking forward to the data and have digested it in detail have similar takes, others more positive:
APOE4 status was an issue. Also the fact that two doses did worse than placebo was odd. And one of the measures of cognitive decline was a metric developed by the company, which could be concerning or could be valid, idk
>"Although the results are promising, this trial was fairly small, and as Vox points out, it’s frowned upon in the research community to change your end results midway through a trial. At the moment, the FDA requires new drugs targeting Alzheimer’s to go through two phase III trials, showing a reduction of both a biological marker for the disease and cognitive decline. In March of this year, the organization published a draft report that said in the future they would accept only a reduction of biomarkers, without a reduction in cognitive decline, a decision has been supported by the research community. This is because in early cases of Alzheimer’s, patients may have the biological indicators of the disease without actually showing symptoms."
I wouldn't consider this promising at all. It looks like it was "too hard" so standards are being lowered.
At this point, reading headlines like this, I'm just going into the comment thread expecting the top comment to tell me, why the headline is BS. And again, I was right.
yeah, i got this feeling too. the drug companies are desperate to make money off of alzheimer's, but the disease is too obstinate to go along with their wishes unless they juke the stats.
improving cognitive function is very difficult under any circumstance. making a drug that alters a biomarker reliably is, in comparison, very easy.
of course, if the biomarker doesn't have a strong correlate to health, it won't help the patient. but they would prefer to sell drugs that "work" without improving the patient's quality of life if it is between that and not selling any drugs.
the other reason that these interventions are always so focused on "early" or "preclinical" alzheimer's is because that's when the patient's brain is still more neurotypical than not. as the disease progresses, i get the feeling that many of the normal rules of thumb regarding brain function and drug action in the brain start to fall through, which makes therapy development far harder.
> It looks like it was "too hard" so standards are being lowered.
Not at all. It turns out one of the standards was not relevant to the target population. As you quoted: "This is because in early cases of Alzheimer’s, patients may have the biological indicators of the disease without actually showing symptoms."
There's no point in trying to alleviate symptoms where there are no symptoms. If I develop a drug that removes tumors that eventually caused headaches, is it somehow lowering standards if it removes tumors before a headache appears?
>"This is because in early cases of Alzheimer’s, patients may have the biological indicators of the disease without actually showing symptoms."
This is called a "degenerating research programme". The theory always lags the facts, this is just another ad hoc adjustment to keep it going for some reason. Why? I really cant understand. Whats the last interesting prediction that has come out of the amyloid hypothesis?
Here is an interesting prediction: Amyloid accumulation will be found to be associated with every single disease state where it is investigated. Every single one. This is because amyloid formation is very thermodynamically favorable for polypeptide chains and a cell must be healthy to prevent it.
Well pretty much everyone does have some amyloid plaques in their brain but I mean that there is a higher level of amyloid in your kidney now than before you had the infection.
>"Amyloidosis is a group of diseases in which abnormal protein, known as amyloid fibrils, builds up in tissue.
[...]
The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved.
[...]
AA is suspected on clinical grounds in individuals with longstanding infections or inflammatory diseases."
https://en.wikipedia.org/wiki/Amyloidosis
but arent the biological markers of Alzheimer's still theoretical? i thought that is part of why a cure is so hard to come by -- we don't know if it's the plaques or something else. so if you measure a drug that reduces plaques but you don't measure its affects on cognition how do you know you are making progress?
Well if you have a drug to catch someone early and they have no measurable decline in cognitive ability how would you ever have a drug that prevents the disease get passed?
originally i was going to write this entire trial off as a pharma industry snow job with heavily contrived data -- and it still might be -- but i think there's probably at least something worth talking about here.
the drug slows progression, allegedly by clearing amyloid plaques. in one sense, that is not enough. alzheimer's still wins in the long run. in another sense, it's a big improvement in the state of the science and clinical practice. the stuff we were using to try to slow the progression of alzheimer's before was largely ineffective. trials like this shed light on fundamental research questions while hopefully helping patients at the same time.
on the other hand, if the progression is slowed at the cost of a large drop in patient quality of life, it may not be worth it clinically in the present state. there's no indication that this is the case, but i wouldn't rule it out until we have more data. there seem to be allergic reactions and potential brain swelling as side effects of the therapy. personally, i would predict that these effects are far more common than is being currently reported. that doesn't mean the therapy is useless, just that it has consequences like any other therapy does.
finally, the amyloid hypothesis has come under a lot of scrutiny recently. as the article points out, removing most plaques does not lead to a cured patient, merely an improvement -- but not an improvement which brings the patient back to normal function. if this trial ends up falling through, it might be the end of the amyloid hypothesis in clinical practice and drug development. that would be a step forward towards a greater understanding... but also very discouraging because we'd need to discard a lot of what we were assuming was the canon up to this point.
It's hard to evaluate this because there is nothing published yet. There have been grumblings on twitter of imbalance in important genetically-driven predictors of Alzheimer's[1]. This might make it very hard to understand whether the effect is due to this imbalance, or truly due to the drug. I can't really evaluate for myself since I don't see the data anywhere.
Disclaimer: I am a lay person that does not know a lot about this subject, but have read a few things on it and have people in my family this could potentially affect.
I think the Herpes research is much more promising than trying to fight Alzheimer's by removing plaques. Catching it earlier in the process seems potentially better?
Especially since the plaques are thought to be a protective immune response to invaders, like viruses, because the plaques encapsulate them to prevent them from affecting the brain.
Plaques may still potentially be a cause of issues- but is enough known that reducing their quantity will significantly help without destroying the beneficial nature of the immune response that causes the plaques? and do we know for sure that the plaques themselves cause the decline, or are they just a by-product that seemed like a potential candidate that got latched onto?
Herpes viruses are implicated in so many illnesses, cancer, auto immune diseases, now Alzheimers, we need a lot more effort going into producing HHV6/7 and EBV vaccines. (Probably HSV1/2 also but I don't know enough about those two.)
"Most worryingly, it turns out that there was a clear difference between the placebo group and the treatment group in APOE4 status."
I would turn to Derek Lowe as he is an expert in the field who has been looking forward to this release... he holds out hope, but is not positive on "the field is in the state it’s in today."
http://blogs.sciencemag.org/pipeline/archives/2018/07/26/bio...
"APOE4, a lipoprotein, has been recognized as a risk factor for Alzheimer’s since back in the 1990s, although the mechanism behind that has been the subject of debate. But there was a regulatory-mandated change in enrollment of APOE4 patients during the (Bayesian) trial, for fear of a brain-swelling side effect that these patients are also prone to, and there ended up being far more APOE4-positive patients in the placebo group compared to the high-dose group (70% versus 30%)."
Should also note that the study missed its primary endpoint, but the companies decided to wait for the 18 month analysis anyway, and one dose seemed promising at this 18 month timepiint. Other doses did worse than placebo
Other analysts who have been looking forward to the data and have digested it in detail have similar takes, others more positive:
https://www.fiercebiotech.com/biotech/biogen-and-eisai-s-ant...
APOE4 status was an issue. Also the fact that two doses did worse than placebo was odd. And one of the measures of cognitive decline was a metric developed by the company, which could be concerning or could be valid, idk
>"Although the results are promising, this trial was fairly small, and as Vox points out, it’s frowned upon in the research community to change your end results midway through a trial. At the moment, the FDA requires new drugs targeting Alzheimer’s to go through two phase III trials, showing a reduction of both a biological marker for the disease and cognitive decline. In March of this year, the organization published a draft report that said in the future they would accept only a reduction of biomarkers, without a reduction in cognitive decline, a decision has been supported by the research community. This is because in early cases of Alzheimer’s, patients may have the biological indicators of the disease without actually showing symptoms."
I wouldn't consider this promising at all. It looks like it was "too hard" so standards are being lowered.
At this point, reading headlines like this, I'm just going into the comment thread expecting the top comment to tell me, why the headline is BS. And again, I was right.
yeah, i got this feeling too. the drug companies are desperate to make money off of alzheimer's, but the disease is too obstinate to go along with their wishes unless they juke the stats.
improving cognitive function is very difficult under any circumstance. making a drug that alters a biomarker reliably is, in comparison, very easy.
of course, if the biomarker doesn't have a strong correlate to health, it won't help the patient. but they would prefer to sell drugs that "work" without improving the patient's quality of life if it is between that and not selling any drugs.
the other reason that these interventions are always so focused on "early" or "preclinical" alzheimer's is because that's when the patient's brain is still more neurotypical than not. as the disease progresses, i get the feeling that many of the normal rules of thumb regarding brain function and drug action in the brain start to fall through, which makes therapy development far harder.
> It looks like it was "too hard" so standards are being lowered.
Not at all. It turns out one of the standards was not relevant to the target population. As you quoted: "This is because in early cases of Alzheimer’s, patients may have the biological indicators of the disease without actually showing symptoms."
There's no point in trying to alleviate symptoms where there are no symptoms. If I develop a drug that removes tumors that eventually caused headaches, is it somehow lowering standards if it removes tumors before a headache appears?
>"This is because in early cases of Alzheimer’s, patients may have the biological indicators of the disease without actually showing symptoms."
This is called a "degenerating research programme". The theory always lags the facts, this is just another ad hoc adjustment to keep it going for some reason. Why? I really cant understand. Whats the last interesting prediction that has come out of the amyloid hypothesis?
Here is an interesting prediction: Amyloid accumulation will be found to be associated with every single disease state where it is investigated. Every single one. This is because amyloid formation is very thermodynamically favorable for polypeptide chains and a cell must be healthy to prevent it.
That's interesting. I've got a kidney infection at the moment, are you suggesting that I have amyloid plaques in my brain?
Well pretty much everyone does have some amyloid plaques in their brain but I mean that there is a higher level of amyloid in your kidney now than before you had the infection.
Wikipedia has a bit on it:
>"Amyloidosis is a group of diseases in which abnormal protein, known as amyloid fibrils, builds up in tissue. [...] The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved. [...] AA is suspected on clinical grounds in individuals with longstanding infections or inflammatory diseases." https://en.wikipedia.org/wiki/Amyloidosis
but arent the biological markers of Alzheimer's still theoretical? i thought that is part of why a cure is so hard to come by -- we don't know if it's the plaques or something else. so if you measure a drug that reduces plaques but you don't measure its affects on cognition how do you know you are making progress?
They've defined it circularly so that the same symptoms without extensive plaques is a different disease.
Well if you have a drug to catch someone early and they have no measurable decline in cognitive ability how would you ever have a drug that prevents the disease get passed?
You compare them to a control group and check which group has had more decline after five or ten years?
originally i was going to write this entire trial off as a pharma industry snow job with heavily contrived data -- and it still might be -- but i think there's probably at least something worth talking about here.
the drug slows progression, allegedly by clearing amyloid plaques. in one sense, that is not enough. alzheimer's still wins in the long run. in another sense, it's a big improvement in the state of the science and clinical practice. the stuff we were using to try to slow the progression of alzheimer's before was largely ineffective. trials like this shed light on fundamental research questions while hopefully helping patients at the same time.
on the other hand, if the progression is slowed at the cost of a large drop in patient quality of life, it may not be worth it clinically in the present state. there's no indication that this is the case, but i wouldn't rule it out until we have more data. there seem to be allergic reactions and potential brain swelling as side effects of the therapy. personally, i would predict that these effects are far more common than is being currently reported. that doesn't mean the therapy is useless, just that it has consequences like any other therapy does.
finally, the amyloid hypothesis has come under a lot of scrutiny recently. as the article points out, removing most plaques does not lead to a cured patient, merely an improvement -- but not an improvement which brings the patient back to normal function. if this trial ends up falling through, it might be the end of the amyloid hypothesis in clinical practice and drug development. that would be a step forward towards a greater understanding... but also very discouraging because we'd need to discard a lot of what we were assuming was the canon up to this point.
It's hard to evaluate this because there is nothing published yet. There have been grumblings on twitter of imbalance in important genetically-driven predictors of Alzheimer's[1]. This might make it very hard to understand whether the effect is due to this imbalance, or truly due to the drug. I can't really evaluate for myself since I don't see the data anywhere.
1 = https://twitter.com/sciencescanner/status/102246964947947520...
Disclaimer: I am a lay person that does not know a lot about this subject, but have read a few things on it and have people in my family this could potentially affect.
I think the Herpes research is much more promising than trying to fight Alzheimer's by removing plaques. Catching it earlier in the process seems potentially better?
Especially since the plaques are thought to be a protective immune response to invaders, like viruses, because the plaques encapsulate them to prevent them from affecting the brain.
Plaques may still potentially be a cause of issues- but is enough known that reducing their quantity will significantly help without destroying the beneficial nature of the immune response that causes the plaques? and do we know for sure that the plaques themselves cause the decline, or are they just a by-product that seemed like a potential candidate that got latched onto?
Herpes viruses are implicated in so many illnesses, cancer, auto immune diseases, now Alzheimers, we need a lot more effort going into producing HHV6/7 and EBV vaccines. (Probably HSV1/2 also but I don't know enough about those two.)
Just a few links above this article was this:
https://www.nature.com/articles/d41586-018-05719-4
Which seems, like many studies ("Coffee is great! Coffee gives you cancer!"), to show contradictory information.
It's not a cure, it only slows the progression and has no positive effect at all on the mental symptoms.
Wouldn't performing better on two different cognitive tests over placebo be a positive effect on symptoms?
Just yesterday there was this opinion piece in Nature, suggesting that reducing amyloids might not help.
The amyloid hypothesis on trial https://www.nature.com/articles/d41586-018-05719-4