European Drug Regulation Advisors Recommend Against Approving Aduhelm in E.U.

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Julie G
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Re: European Drug Regulation Advisors Recommend Against Approving Aduhelm in E.U.

Post by Julie G »

It's surprising that they only reference cost as their rationale for not recommending. Given the recent death associated with Aduhelm side effects, it seems like patient safety would have also played a part in their decision making.
One patient death after treatment with Aduhelm was reported to the FDA Adverse Event Reporting System (FAERS), according to the agency’s latest update rounding up cases it had received through the end of September. The fatal case came from a 75-year-old female in Canada after she was diagnosed with brain swelling and bleeding, or amyloid-related imaging abnormality (ARIA).
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Re: European Drug Regulation Advisors Recommend Against Approving Aduhelm in E.U.

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Julie G wrote:It's surprising that they only reference cost as their rationale for not recommending. Given the recent death associated with Aduhelm side effects, it seems like patient safety would have also played a part in their decision making.
One patient death after treatment with Aduhelm was reported to the FDA Adverse Event Reporting System (FAERS), according to the agency’s latest update rounding up cases it had received through the end of September. The fatal case came from a 75-year-old female in Canada after she was diagnosed with brain swelling and bleeding, or amyloid-related imaging abnormality (ARIA).
Read more: https://www.fiercepharma.com/pharma/bio ... g-to-blame
I'm not a big fan of Aduhelm, which showed both less reduction of amyloid, much higher incidence of ARIA-E and equivocal cognitive benefits compared to newer, more oligomer-focused drugs like Donanemab and lecanemab (BAN2401). But it's still fair to say that "association" doesn't prove causation until more is known of about this case. I did see a presentation at the CTAD conference this month modeling a "Quality of Life benefit" for aduhelm based on the age of the people in the trials (late 70's) and the limited response (about 3 months less progression) that suggested the reasonable cost based on QOL benefit might be as as $3000/yr for Aduhelm. His conclusion was that future drug approvals will likely depend on both safety and on clinical benefits that justify their proposed cost.
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Re: European Drug Regulation Advisors Recommend Against Approving Aduhelm in E.U.

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Also the American Academy of Neurology (AAN) just issued a new position statement for ethical guidelines regarding how to advise patients inquiring about aducanumab (aduhelm).

"This is a high-cost drug that was approved by the FDA without convincing evidence of benefits and with known harms, so the purpose of this position statement is to offer ethical guidance on how neurologists can help patients make informed decisions about this treatment."

The statement says neurologists must make sure Alzheimer's patients and their families understand that the controversial drug aducanumab does not restore mental function. The statement also noted that while aducanumab reduces the beta-amyloid plaques in the brain that are markers of Alzheimer's, it's unclear whether that provides any meaningful benefits to patients.

https://www.upi.com/Health_News/2021/11 ... 6QYvm26STo
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Re: European Drug Regulation Advisors Recommend Against Approving Aduhelm in E.U.

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You can read a bit more about the Aduhelm associated death here: https://endpts.com/rbc-analyst-reports- ... ent-death/
The FDA tells Endpoints News today that it’s aware of the death of a patient taking Biogen’s controversial Alzheimer’s drug Aduhelm (aducanumab) and is “actively investigating” the case.

Their statement follows the latest comments from RBC analyst Brian Abrahams, who is back with an update on the death, and this time he says that there are solid reasons to believe that the event was likely drug related and may have been preventable.

A spokesperson for the agency tells Endpoints: “FDA is aware of this case and is actively investigating it.”

Abrahams, a physician, notes that he obtained new information using FOIA, getting the “detailed case report” about the aducanumab patient he was first to report on.

After reviewing the sequence of events, it appears likely to us that progressively severe cerebral edema/ARIA, which led to status epilepticus, was the inciting factor for the pt’s deterioration and ultimate demise, and that this is likely to have been caused by aducanumab.

That’s not likely by itself to cause the drug to be yanked out of the market, he adds, but it may well call for more stringent monitoring of patients, something that will add to the already considerable cost of the therapy — as well as the mounting skepticism over its use.

The pt’s specific reaction to this usually benign AE may have been atypical, and there look to have been multiple points at which increased risk could have been recognized and adu either not started or discontinued. These included several findings of asymptomatic ARIA-E and ARIA-H observed in prior years (when the pt was receiving an investigational therapy, perhaps adu) as well as moderate ARIA-E primarily on the left side (the side that worsened) found upon re-examination of an MRI taken a few months prior. We note that according to the present label, ARIA is not necessarily a reason for discontinuation, and “treatment may be continued with caution.”

Biogen, which acknowledged earlier that it is investigating the death, issued a statement Thursday afternoon saying that Abrahams only has part of the information needed to draw a conclusion, and that they’re continuing their own probe to assess the cause. The company states:

The RBC report only provides a partial view of the case. As we previously stated, the cause of death is unknown at this time. We know the 75-year-old clinical trial patient was admitted to the hospital with a seizure and diagnosed with cerebral edema thought to be ARIA-E. Following a prolonged hospitalization, the patient was being prepared for discharge when she deteriorated and was transferred to another facility. We have requested missing information, including brain imaging, from the critical last nine days of hospitalization.

If the death is definitively linked to the drug, it will raise fresh fears that the FDA approved a therapeutic that presents a clear threat to patients, without any solid evidence that it could help soften the onset of the memory-wasting disease. So far, the drug has proven an embarrassment to Biogen, which saw sales sputter to a ragged start after the FDA’s approval triggered a storm of controversy as experts denounced the move.

It’s also bad news for the other manufacturers in the space — like Eli Lilly and Roche — angling to leapfrog Biogen into the market with their own rival drugs, which also are linked to high rates of ARIA. The developers maintain that the bulk of these cases involving brain swelling and bleeds are relatively mild and are easily controlled. Critics, though, wonder how well severe cases can be managed with a drug aimed at a huge population of patients.

This has been a miserable week for Biogen CEO Michel Vounatsos, who first accepted the resignation of the company’s chief scientist — and primary aducanumab advocate — Al Sandrock, then soon after reported that European regulators had turned thumbs down on an approval, likely wiping out what could have been 40% of their global market.
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Re: European Drug Regulation Advisors Recommend Against Approving Aduhelm in E.U.

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Julie G wrote:You can read a bit more about the Aduhelm associated death here: https://endpts.com/rbc-analyst-reports- ... ent-death/
there look to have been multiple points at which increased risk could have been recognized and adu either not started or discontinued. These included several findings of asymptomatic ARIA-E and ARIA-H observed in prior year… [and] moderate ARIA-E primarily on the left side (the side that worsened) found upon re-examination of an MRI taken a few months prior….
We have requested missing information, including brain imaging, from the critical last nine days of hospitalization.
Thanks for the additional information, Julie. Presentations I have heard from researchers and study organizers for other drugs have emphasized that while “dosing” appears to be safe with asymptomatic cases found on MRI and those with very mild symptoms, it has been paused or suspended in those with moderate/severe cases. That may prove to be a key decision failure in this case.

Most ARIA cases happen in the first 6 months of treatment, so her continued episodes may be evidence of other pathology, including cerebral amyloid angiopathy CAA)
Cerebral amyloid angiopathy (CAA) is a condition in which proteins called amyloid build up on the walls of the arteries in the brain. CAA increases the risk for stroke caused by bleeding and dementia.which is not classic AD but has amyloid build up in the arteries of the brain and can cause strokes.
https://medlineplus.gov/ency/article/000719.htm

Given this poor woman's repeated history of ARIA, it may be that evidence from her MRIs should have led to a decision not to prescribe by her clinician.
Or not.. I’m looking forward to more info on this case.
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Re: European Drug Regulation Advisors Recommend Against Approving Aduhelm in E.U.

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The reports on this drug seem to get worse and worse, now this from MedpageToday:

Brain Inflammation Seen in Four of 10 Alzheimer's Aducanumab Patients
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