Inside the FDA’s fateful Alzheimer’s decision

March 19, 2021

If Biogen’s controversial aducanumab is approved, it could become the best-selling drug of all time — and it’s a drug that has only shown modest efficacy. Here’s more on why the Alzheimer’s pipeline is primed for such a remarkable situation.


Karen Langhauser: It’s no secret that the last year has been major for the FDA. With the world grappling with the pandemic, the agency has been hustling to clear a path to approve a number of very badly needed COVID-19 vaccines and therapeutics.

But the FDA has also been staring down a major decision related to another disease — Alzheimer’s. And it’s a fateful decision with massive ramifications all of its own.

I’m Karen Langhauser, chief content director of Pharma Manufacturing magazine and you’re listening to Off Script, Pharma Manufacturing’s podcast that goes beyond the pages of our magazine to discuss the issues that matter most to the industry.

This month, our cover story sets the stage for what promises to be one of the FDA’s most consequential approval decisions of the decade — aducanumab, Biogen’s controversial treatment for Alzheimer’s disease.

So, what makes this situation such a big deal for the agency? And what will it mean for the industry?

To help us understand the impact of the aducanumab decision, I’m joined today by Meagan Parrish, our senior editor, who wrote this month’s cover story: The Alzheimer’s Maze.

Thanks so much for joining me.

Meagan Parrish: Hey, Karen. Thanks for having me.

Karen: So, why don’t we start by talking about how you developed this story and why you decided to focus the entire article on this one drug.

Meagan: So, it’s March. Typically, in March, we say we’re going to tackle the “State of Pharma” but we sort of have a tradition now — at least, it’s a new one I just started last year — where we look at big pharma pipelines in March.

Last year, I wrote about the pipeline for cancer treatments, which is immense and complicated. And this year, I wanted to follow it up with a deep dive into the Alzheimer’s pipeline.

To be honest, I’ve been dying to do this story on the Alzheimer’s pipeline for months because it’s a treatment area that is begging for a big win. For starters, there are currently no disease-modifying drugs on the market yet. So, patients with Alzheimer’s — and there are about 6 million in the U.S. and 50 million globally — only have a handful of drugs at their disposal to potentially alleviate symptoms. Even more vexing is the fact that the number of patients with Alzheimer’s is expected to climb, of course, as the population ages and people stay alive for longer.

So, a disease-modifying treatment for Alzheimer’s is like the holy grail for pharma. If a company could manage to develop a treatment that actually slowed or halted the progression of the disease, it would basically be an instant blockbuster and would have the market all to itself.

But so far, every disease-modifying drug that has made it to clinical trials has failed. Historically, this a pipeline filled with nothing more than the tombstones of discarded drugs and billions in lost R&D dollars. 

Karen: So, there are over 100 drugs in clinical development for Alzheimer’s. So, why not focus on the entire pipeline? Why is aducanumab alone such a big deal?

 Meagan: Well, you won’t get far into research on Alzheimer’s drugs before coming across the aducanumab story because it has been such big news in the last few years. Basically, aducanumab has been on a roller coaster ride since 2019. First, Biogen, which is developing the drug, halted two late-stage studies of the drug in March 2019 — an announcement that was not met with an enormous amount of surprise. Like I said, nearly every drug trialed for Alzheimer’s ultimately falters — the common estimation is that 99 percent of Alzheimer’s drugs end in failure.

But a few months later, Biogen pulled a surprise about-face and announced that it was wrong to halt the March trials. According to the company, the decision to pull the plug came down to a futility analysis that concluded that the drug was not going to meet its primary endpoints. But Biogen then said that in the months following the end of the trials, it had reanalyzed the data and determined that the futility analysis had been wrong, and in fact, one of the trials had shown some benefits to patients.

Then, in a move that truly shocked the pharma world, Biogen announced in October 2019 that it was going to file for approval for aducanumab with the FDA. And that’s where the drama really began.

As of right now, the FDA has not rendered a final verdict on aducanumab. But if you start digging into what’s happening in the Alzheimer’s pipeline, the subject of aducanumab comes up repeatedly because the implications of what the FDA ultimately decides are going to be huge for the industry in a number of ways.

And this is what I find really remarkable about the aducanumab situation right now. If you believe Biogen’s analysis of the drug, then it, at best, provides modest efficacy. Yet, if it’s approved, some analysts believe that it will become the best-selling drug of all time — far outpacing Humira, which has long held that throne, and even potentially breezing past Keytruda which is on track to best Humira within the next few years. And I find it amazing that because there is such an enormous need for something to treat Alzheimer’s patients, that a drug that doesn’t even cure the disease — it may just slow it down for a few months — could become the best-selling drug of all time.

On top of that, the success or failure of aducanumab will also have a major impact on Biogen’s financial futures, and because of the science related to this drug, it could impact the entire R&D focus of other Alzheimer’s treatments for an untold number years to come.

And I mean, in Alzheimer’s drug development, it doesn’t allcome down to aducanumab. Regardless of what happens with the drug, other companies will continue developing their own treatments — some will fail but maybe one will succeed. But it’s fair to say that, aside from COVID-related treatments, this is going to be the most closely-watched drug approval decision of the year and just an enormous amount is riding on which way the FDA goes.

Karen: Wow, yeah that is pretty remarkable. Let’s talk about how aducanumab works and why the science behind the drug is so critical.

Meagan: Aducanumab is a monoclonal antibody that was developed to target beta-amyloid, which is a sticky protein that can build up in plaques on the brain. Underneath amyloid, another protein call tau can also build up in tangles in patients with Alzheimer’s.

Many years ago, before imaging was developed that allowed researchers to see amyloid and tau on living patients, the only way Alzheimer’s was diagnosed was through autopsies, when scientists studied the brains of patients with Alzheimer’s who had died and took note of these plaques.

So unsurprisingly, amyloid and tau were thought to potentially be the cause of Alzheimer’s and thus drug development for well over a decade focused on clearing these plaques. And this became what is now known as the “amyloid hypothesis.”

But there was a surprise and disappointing twist to this story — researchers ultimately found out that even if you were successful at clearing amyloid and tau from the brain, patients still had clinical dementia symptoms. So, then it became understood that by the time amyloid and tau clump up, it’s too late. One scientist notoriously quipped that removing amyloid is like taking tombstones out of a graveyard — it doesn’t make the people there “any less dead.”

So, when we look at the long list of Alzheimer’s drugs that have failed, these are mostly amyloid targeting drugs. And although those drugs did end in defeat, they also did help inform a better understanding of the biology of how Alzheimer’s progresses.

But drugmakers haven’t abandoned amyloid all together — although plenty of scientists think they should. Like I said, aducanumab is an amyloid clearing drug. So, if it turns out that the FDA deems it effective enough to be on the market, it will, in a sense, be a confirmation that clearing amyloid — if done in the right way at the right time — is a viable way to treat Alzheimer’s — or treat it modestly at least.

But, if aducanumab fails, I think that will be a signal to the industry that maybe it is in fact time to throw in the towel on amyloid and instead invest in other types of treatments.

Karen: OK, but you said that aducanumab has been shown to be at least modestly effective. Can you explain that more?

Meagan: So, this is where we start getting into what’s really controversial about aducanumab.

So, Biogen conducted two late-stage studies of the drug. They were identically designed studies that involved about 3,300 patients around the world. One is called 301 and the other is called 302.

When Biogen came back in October and said one of the studies had shown some efficacy, it was referring to study 302. But the improvement Biogen said it provided was about 22 percent using something called a CDR score, which is a globally recognized scale with six domains for measuring a number of dementia-related symptoms such as memory, orientation, judgement and more.

What does a 22 percent improvement look like in real-world terms? It’s a little tough to say right now — and the lack of understanding about the drug is a criticism that has been raised. But to get some insights on this I talked to Dr. Alireza Atri, who is a neurologist and the director of Banner Sun Health Research Institute, who was also a site investigator on one of the aducanumab trials and has consulted Biogen about the drug.

According to Dr. Atri, over an 18-month period, a 22 percent improvement on the CDR scale could translate into a few months of the disease progression slowing down — but not stopping. And it’s important to distinguish that aducanumab does not stop the progression of the disease. It only slows it down. But if aducanumab was given earlier — like if a patient was diagnosed with Alzheimer’s before they started showing symptoms and they still had 10-15 years of life left, a 22 percent improvement could translate into two to three years of potential benefit for the patient.

But the reality is that we don’t really know for sure what this benefit means for patients in real-world terms and it could take years of additional study to better understand that better. And that’s just one of the many muddy issues surrounding aducanumab.

Karen: Certainly some unanswered questions there.Are there other sticking points associated with the drug?

Meagan: Well, like I said, Biogen had two late-stage studies, which were identically designed, and one of them — study 302 — trended in a positive direction. That means, of course, that the other one — study 301— was negative. How is that possible?

Biogen has explained this by saying that the two studies were launched at different times and along the way, Biogen made a program amendment to give some patients a higher dose. Ultimately this meant that some of the patients in 301 did not have the opportunity to experience the higher dose for the same duration as patients in 302. And it was on this higher dose, 10 mg, that patients received the most benefit. So, Biogen says this dosing discrepancy is what led to the diverging outcomes. They’ve also said that a handful of patients with a rapidly progressing form of the disease skewed the result.

Karen: Ok. This all seems pretty logical. So, where’s the controversy?

Meagan: Alright, the real controversy started when one of the FDA’s advisory committees reviewed the drug. Their response to the data and to Biogen’s explanation of the data was pretty close to outrage.

I listened in to the public hearing of the advisory committee, which met virtually on Nov. 6, 2020, and right out of the gate, many of these 11 scientists on the committee were tearing apart these explanations. Many didn’t think that Biogen’s explanations for the diverging results added up, and some thought that the efficacy data was not nearly robust enough.

But as far as I can tell, a lot of the issues were less about Biogen’s data, and more about how Biogen presented that data.

For example, one of the biggest complaints was related to a pre-briefing document that the FDA issued right before the advisory committee meeting. Typically, the FDA submits its own pre-briefing document and then the sponsor — or company — submits a separate document. But for the aducanumab meeting, the pre-briefing document was merged.

So, just about everyone I spoke to in the industry said that this kind of merged pre-briefing document was “unprecedented.” But I also spoke to one of the members of the committee reviewing aducanumab — a guy named Dr. Scott Emerson — and he’s been serving on FDA advisory committees for nearly 20 years and he said he has seen this before. But he hasn’t seen it much and typically it’s only been in oncology. And even though this wasn’t the first time he’d seen this kind of merged pre-briefing document, he said he doesn’t like it. It puts a bad taste in everyone’s mouth and raises questions about whether or not the agency is being biased.

Why did the FDA collaborate with Biogen on this pre-briefing document? I don’t know. Biogen did not respond to my repeated requests for an interview, so I couldn’t ask them unfortunately. And I haven’t seen any interviews with anyone from Biogen or the FDA on this particular point.

But, whatever the case, it has triggered a cascade of criticisms from watchdogs in the industry who think that it clearly shows that the FDA is being biased towards Biogen.

Dr. Emerson also said that the presentation the FDA gave to the advisory committee was “abnormally imbalanced” in its tone and seemed to indicate that the FDA had already decided it wants to approve aducanumab.

Ultimately, the committee shot down aducanumab, voting overwhelmingly against its approval. But it’s important to note, the committee’s vote is non-binding, and the FDA is not required to follow its advice.

Karen: Why do you think the FDA would want to approve aducanumab given the questions about its efficacy?

Meagan: There is overwhelming patient demand for this drug. Even if the efficacy is modest, patients have no other options right now. There is no hope, at least in the immediate future. There are other drugs in the works, but as of right now, no other drug has been shown to have any kind of positive outcome from a phase 3 trial. This is it for the moment.

I know when we think about pandemics now, we think about viruses. But Alzheimer’s has also been characterized as a pandemic — a slow moving one that is currently impacting just about everyone, either because they have the disease or because they know or are caring for someone with the disease.

And to think that we’ve known about Alzheimer’s for a century but have yet to come up with any kind of solution…it’s pretty heartbreaking.  

Karen: Yeah absolutely. The FDA recently moved its decision date on aducanumab from March to June 7. So, when the agency finally makes its decision, what is the fallout going to be?

Meagan: Clearly Biogen has a lot on the line here. The company’s revenues slid by about 6 percent between 2019 and 2020, largely due to several of its top-selling drugs facing new generics and biosimilar competition.

I’m sure they’re not going to go bankrupt without aducanumab — but it will be a major blow to the company. And they’ve reported that they’re already dedicating manufacturing capacity to aducanumab and preparing for a rollout this year, so they are laying all their chips on the table with this drug.

An FDA approval could also serve as a sort of confirmation of the amyloid hypothesis, which we talked about before. If the FDA is willing to accept an amyloid-clearing drug with modest efficacy, I think drugmakers are going to see that as a good signal that it’s still worth investing in this type of treatment. And there are still dozens of amyloid drugs in clinical trials.

But if it’s not approved? R&D dollars might be more readily placed in other types of treatments instead.

And of course, patients have a lot to potentially gain or lose here.

Karen: Given what we know, which way does it look like the FDA might go?

Meagan: There are some pretty clear signals that the FDA is likely going to approve aducanumab. Moving the action date to June is one, because the agency could have denied it by now but instead they asked Biogen for more data and have given themselves more time to review everything. This little delay also allows them to say that they are looking at data that the advisory committee did not review in November, so that could give them some justification for an approval, despite the committee’s reservations.

The looming question of who the permanent FDA commissioner is going to be could also impact this decision. Since former Commissioner Stephen Hahn left, Janet Woodcock, the director of CDER, has been serving as the interim commissioner. And I think many consider her the front-runner for the job. And in the past, Janet Woodcock has been willing to support approval for drugs that have modest efficacy but a large unmet need. So, if it comes down to her — the chances for aducanumab succeeding are likely higher.

But since the Biden administration is taking so long to name a permanent commissioner, it’s leaving the door open for lots of speculation and criticisms and lately, some Senate Democrats have been signaling that they may not support Janet Woodcock because they’re unhappy with how the agency handled the opioid epidemic while she was in a leadership position there.

Karen: It sounds like the industry is really divided on what should happen in this situation.

Meagan: I conducted about 10 interviews with various stakeholders in pharma and it’s safe to say that the industry is sharply divided on this issue. Some think Biogen did a great job designing these studies and should be applauded for their efforts with advancing aducanumab.

Others are extremely critical of Biogen and the FDA and think they are working too closely together on this.

Karen: So, what do you think this decision is going to come down to?

Meagan: I think ultimately, this is going to be a risk/benefit calculation, which is typically the case with most drug approvals.

With this drug, the risk here is that you could approve it, but doesn’t offer much help but costs patients and the health care economy an enormous amount of money — the estimates are that aducanumab could be priced as high as $50k a year

And there’s the risk that the FDA could steer the industry in the direction of amyloid for some untold period of time by waving this drug through. Yet, even with an approval, there are lots of other drugs in the works, many that target amyloid and tau and many that don’t, so I also think that R&D is going to chug along in those directions either way.

But the potential benefit here is that, if given early enough, this drug could offer patients some level of help for months or maybe years.

So which issues do you prioritize here? I think that’s what the FDA is going to have to decide. And I’ll tell you this much — I wouldn’t want to be the one that has to make that call. Either way, this decision is going to be heavily scrutinized by the industry and by patients for many years to come, whichever way the FDA goes.

Karen: Are you a betting person?

Meagan: Yeah, maybe.

Karen: What would you bet the FDA does in June?

Meagan: Honestly, I think based on what we know today about the drug, I think there’s a good chance the FDA is going to compromise. Meaning that they’ll give aducanumab a conditional approval that mandates a post-market late-stage trial. That way patients who want access to the drug can get it. But Biogen will have to continue to study how well this drug works so that we understand its efficacy better and its impact long-term on patient care.

Karen: Well, fortunately, I think the FDA is pretty used to being in the hot seat, but this seems like a particularly complicated situation, and I guess, at this point, all we can do is wait and see. Something tells me that we’ll be hearing a lot more about this as we near the June decision.

Please be sure to visit our website, and read Meagan’s most-recent cover story, “The Alzheimer’s Approval Maze.”

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