Aducanumab Approved by FDA to Treat Alzheimer's Disease

The underside of the approval of aducanumab, an immunotherapy that clears amyloid-β from the brain, is very much a textbook case of regulatory capture. While the treatment does clear amyloid-β, it doesn't help patients all that much. Benefits observed in trials were marginal to the point of non-existence. The arm-wrestling under the hood has nothing to do with the welfare of patients and everything to do with maintenance of bureaucracy and control for the sake of bureaucracy and control on one side versus rent seeking on the other. An ugly business.

The silver lining is that now it will be easier to work on combination therapies that remove amyloid-β and address other issues. Amyloid-β is either a side-effect of the development of Alzheimer's disease, or one of several important mechanisms, most or all of which must be meaningfully addressed in order to help patients. It is hard to make progress in the latter scenario if regulators insist on only testing one thing at a time, and also have an efficacy bar for approval.

The regulatory system is dramatically broken. Absent regulators, it would cost a tenth as much as it does now, or less, to prove out new therapies in human volunteers. For most medicines, there really isn't a sizable practical difference between the over the top rigor of GMP manufacture and ordinary, sensible quality control on a batch by batch basis. The enormous cost imposed by the the FDA process really isn't essential to producing safe medicines, or to testing efficacy. Yet here we are, in a world in which progress is glacial because the powers that be have decided that pursuing the unattainable goal of zero risk is worth any cost in lives and funding, and the population at large never sees the medical progress that would have taken place absent the regulators.

FDA's Decision to Approve New Treatment for Alzheimer's Disease

Today FDA approved Aduhelm (aducanumab) to treat patients with Alzheimer's disease using the Accelerated Approval pathway, under which the FDA approves 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.

We are well-aware of the attention surrounding this approval. We understand that Aduhelm has garnered the attention of the press, the Alzheimer's patient community, our elected officials, and other interested stakeholders. The late-stage development program for Aduhelm consisted of two phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, Aduhelm consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.

We know that the Peripheral and Central Nervous System Drugs Advisory Committee, which convened in November 2020 to review the clinical trial data and discuss the evidence supporting the Aduhelm application, did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval. As mentioned above, treatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit. After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the Aduhelm application met the standard for Accelerated Approval.

The need for treatments is urgent: right now, more than 6 million Americans are living with Alzheimer's disease and this number is expected to grow as the population ages. Alzheimer's is the sixth leading cause of death in the United States. Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients.


I would say that a drug which can target a specific condition, here it is amyloid plaque and not AD , can and should be approved. Reducing β Amyloid might have other benefits for unrelated conditions.

But yeah, the approval process is too damn slow and expensive.

Posted by: Cuberat at June 8th, 2021 2:54 PM

Contrary to the general tone of Reason's commentary, I think this is proof of the medical regulations becoming more lax, particularly the first paragraph in the article.

Posted by: Antonio at June 8th, 2021 4:39 PM

Don't misunderstand my question, I do find the 'regulations are deterring innovation' narrative persuasive. But why haven't some deep pockets set up a large drug research lab in a country with more flexible testing regulations?

Posted by: JohnD at June 8th, 2021 4:59 PM

Probably they could setup a screening lab but if you want to get certified and approved you need to follow the rules. Probably they could do human studies but publish them as "simian", for example. It would still take many years, though

Posted by: Cuberat at June 8th, 2021 6:45 PM

A "disgraceful decision:" Researchers blast FDA for approving Alzheimer's drug

'Critics of the decision note that 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.

But, later that same year, Biogen shockingly resurrected the drug, saying that residual data from one of the trials indicated a modest, statistically-significant benefit. According to Biogen, later analyses showed that people who received a high dose of the drug (which was the dosage approved by the FDA Monday) saw a small reduction in beta-amyloid plaques over 78 weeks. And participants in one of the trials saw a small improvement on a cognitive test. Participants in the other trial still saw no benefit, though. Meanwhile, around 40 percent of people who got the approved dosage developed brain swelling.'
'A statistical evaluation by FDA reviewers (page 247) thoroughly dismantled Biogen's analysis, concluding that "there is no compelling substantial evidence of treatment effect or disease slowing" and "another study is needed to confirm or deny the positive study and the negative study."

Likewise, in November of 2020, an independent advisory committee for the FDA roundly rejected the drug and Biogen's data. Ten of the 11 committee members voted "no" to the question of whether it was "reasonable" to consider the limited data Biogen collected as "primary evidence of effectiveness of aducanumab for the treatment of Alzheimer's disease." The 11th member voted "uncertain."

One no-voting committee member later remarked on the "incongruity" of Biogen's rosy take on the drug and the actual data behind it. "It just feels to me like the audio and the video on the TV are out of sync, and there are literally a dozen red threads that suggests concerns about the consistency of evidence-a dozen," member, Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, said at the meeting. "For every point that you can find suggesting support, there's another point or two that raises concerns."

Still, the FDA approved the drug Monday based on that same data. The agency justified the decision saying it didn't approve Aduhelm based on efficacy, but rather a "surrogate endpoint," which in this case was the potential for the drug to clear out the beta-amyloid clumps-that may or may not be the root cause of the disease.'

Posted by: Jones at June 9th, 2021 4:31 AM

What a waste of time. A perfect example of targeting a biomarker, not a disease.

Posted by: Mark at June 9th, 2021 6:10 AM

At > US $50,000 a year and close to a decade of "Phase 4" development to see if it works, this is a text book case of the little guy being indirectly forced to pay a potentially very big R&D bill

Posted by: jim petrov at June 9th, 2021 10:05 AM

At 50k per year it's all of us little guys paying the R&D cost…or funding big profits …with ever increasing health insurance costs. I'd like to think that we are entering into the dawn of much faster approval rates but that may be only for the highest profit drugs.
Meanwhile in Japan where high dose vitamin K is approved to treat osteoporosis you'd think they would have advanced other alzheimer's treatments as well. But they too are considering approval.

It seems that most of the world follows in US footsteps quite a bit on drugs.
Not on everything though. They and Europe have had far more effective sunscreens than us for over 20 years now with likely safer ingredients - that the FDA won't allow here. It probably costs too much to go through US regulatory approval for just one country.

Yes, it's all very frustrating. You can do all the offshore R&D you want but the limiting biggest cost is still the regulatory demands not the meaningful research.

Posted by: August33 at June 9th, 2021 9:12 PM

Thank you Reason! I can trust the information you present here is not funded, guided, and constrained by the FDA/Big Pharma conglomeration that started forming in the early 20th century under the Rockefellers. You have a great and heroic voice. I really can't thank you enough.

Posted by: Thomas Mark Schaefer at June 10th, 2021 8:05 AM

The fightaging article that Reason posted just prior to this one was: A Mechanism by which Amyloid-β can Reduce Capillary Density in the Alzheimer's Brain
It is quite possible that removing the Amyloids, which this drug is proven to do, didn't improve Alzheimer's because by the time you develop them it's simply too late. Perhaps the oxygen deprivation they cause or the reduction in capillary density caused the disease and once that damage is done simply removing the amyloids doesn't reverse it.

Posted by: august33 at June 10th, 2021 9:12 PM
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