Congratulations to Al Sandrock, from Biogen, for never giving up on science and for being a risk-taker extraordinaire.
In a NY Times article Dr Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California and one of the aducanumab site investigators said “This should not be approved, because substantial evidence of effectiveness hasn’t been shown and there’s very little potential that this will address the needs of patients.”
What the FDA has done is use the so-called Accelerated Approval Pathway, which allows them to approve a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug’s clinical benefit.
What the FDA is implying is that Alzheimer’s Disease (AD) is caused by amyloid deposition, i.e. amyloid is the disease. I personally think the jury is still out on this issue. I still need to be convinced that amyloid is causal, i.e. amyloid deposition may be downstream of causal events. Therefore clearing amyloid or preventing its deposition may not reverse or prevent dementia.
Other reasons for the shitstorm is the proposed cost of the treatment, $56,000 per annum before infusion costs, and the marginal benefits in relation to the potential risks of the therapy, in particular the amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain and often resolves over time.
From a scientific perspective, how will the FDA's decision impact future drug development? For example, will placebo-controlled trials be ethical? These same debates happened when interferon-beta-1b was licensed for the treatment of MS and the MS community sorted them out, i.e. equitable access and the issue around future trial design. Therefore, I am less concerned about these issues.
Finally, the FDA decision also has major implications for other neurodegenerative diseases, in particular, the definition of these diseases using biomarkers. This changes the way disease-modifying trials will be done in Parkinson’s disease, Progressive Supranuclear palsy (PSP), frontotemporal dementia (FTD) and other diseases. Is this good or bad news? I would say good news because we are getting away from the clinical definition of diseases and moving towards biological definitions.
The aducanumab shitstorm will be long and winding and reminds me of the Chinese curse "May you live in interesting times". Whatever your perspective on the FDA's decision to license aducanumab we should celebrate the science and technology behind aducanumab. For this reason, I would like to personally congratulate Al Sandrock, from Biogen, for never giving up on science and for being a risk-taker extraordinaire.
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MS Research
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.
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The FDA’s controversial approval of aducanumab for the treatment of Alzheimer’s disease on Monday has caused a shitstorm. The main reason is that in November the FDA’s independent advisory committee voted against recommending approval; they said the data failed to demonstrate persuasively that aducanumab slowed cognitive decline.
In a NY Times article Dr Lon Schneider, director of the California Alzheimer’s Disease Center at the University of Southern California and one of the aducanumab site investigators said “This should not be approved, because substantial evidence of effectiveness hasn’t been shown and there’s very little potential that this will address the needs of patients.”
What the FDA has done is use the so-called Accelerated Approval Pathway, which allows them to approve a drug for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug’s clinical benefit.
What the FDA is implying is that Alzheimer’s Disease (AD) is caused by amyloid deposition, i.e. amyloid is the disease. I personally think the jury is still out on this issue. I still need to be convinced that amyloid is causal, i.e. amyloid deposition may be downstream of causal events. Therefore clearing amyloid or preventing its deposition may not reverse or prevent dementia.
Other reasons for the shitstorm is the proposed cost of the treatment, $56,000 per annum before infusion costs, and the marginal benefits in relation to the potential risks of the therapy, in particular the amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain and often resolves over time.
The shitstorm for me wearing my preventive neurology hat are the implications aducanumab will have on healthcare and science. Let’s assume brain amyloid deposition is the cause of Alzheimer’s disease, as implied by the FDA license, then Biogen, the neurological community and the general population won’t want the use of aducanumab to be limited to patients who are symptomatic, i.e. have MCI (minimal cognitive impairment), but to target people who are asymptomatic or in the prodromal stage of AD. This means population screening for the 'amyloid brain'. Are we ready for this?
I suspect we will start off with an age-related AD risk calculator, which will include genomic screening, that will identify high-risk individuals who will then have biomarker screening for early amyloid deposition in the brain, for example, amyloid PET imaging or body fluid correlates of amyloid deposition (peripheral blood or CSF Aβ42 to Aβ40 ratios). Subjects who are identified as having asymptomatic or prodromal AZD will then want to be started on aducanumab. If there is no socialised healthcare system approval of aducanumab for asymptomatic AD then it will only be the rich who will be able to afford aducanumab. This will create the haves (aducanumab) and have-nots (no treatment) or the have-nots (no-AD) or haves (AD). The moral, ethical and political fall-out from this scenario will be enormous.
I suspect we will start off with an age-related AD risk calculator, which will include genomic screening, that will identify high-risk individuals who will then have biomarker screening for early amyloid deposition in the brain, for example, amyloid PET imaging or body fluid correlates of amyloid deposition (peripheral blood or CSF Aβ42 to Aβ40 ratios). Subjects who are identified as having asymptomatic or prodromal AZD will then want to be started on aducanumab. If there is no socialised healthcare system approval of aducanumab for asymptomatic AD then it will only be the rich who will be able to afford aducanumab. This will create the haves (aducanumab) and have-nots (no treatment) or the have-nots (no-AD) or haves (AD). The moral, ethical and political fall-out from this scenario will be enormous.
From a scientific perspective, how will the FDA's decision impact future drug development? For example, will placebo-controlled trials be ethical? These same debates happened when interferon-beta-1b was licensed for the treatment of MS and the MS community sorted them out, i.e. equitable access and the issue around future trial design. Therefore, I am less concerned about these issues.
Finally, the FDA decision also has major implications for other neurodegenerative diseases, in particular, the definition of these diseases using biomarkers. This changes the way disease-modifying trials will be done in Parkinson’s disease, Progressive Supranuclear palsy (PSP), frontotemporal dementia (FTD) and other diseases. Is this good or bad news? I would say good news because we are getting away from the clinical definition of diseases and moving towards biological definitions.
The aducanumab shitstorm will be long and winding and reminds me of the Chinese curse "May you live in interesting times". Whatever your perspective on the FDA's decision to license aducanumab we should celebrate the science and technology behind aducanumab. For this reason, I would like to personally congratulate Al Sandrock, from Biogen, for never giving up on science and for being a risk-taker extraordinaire.
Conflicts of Interest
MS Research
Medium
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.
Incredible story, couldn't believe what I was hearing on Monday's news. Didn't think it would take you long to post on it!
ReplyDeleteNo argument that this monoclonal antibody gets into the brain and amyloid depleted.. extension study and long term follow up will be really interesting.