FDA OKs aducanumab for Alzheimer's, turning controversial Biogen drug into a megablockbuster

Monday, June 7, 2021

Source: Endpoints News

The FDA has approved the Biogen drug aducanumab for Alzheimer’s, a stunning decision that caps nearly two years of controversy and hands the large biotech a mega-blockbuster that could earn more than $10 billion per year.

The decision makes aducanumab — now marketed as Aduhelm — the first drug specifically approved to slow the progression of the devastating memory-wasting disease, a milestone that patient advocacy groups and some leading neurologists hailed for months leading up to the FDA’s deadline. Prior to aducanumab, nearly every effort to treat Alzheimer’s had failed, even as the number of Americans living with the disorder swelled past 6 million. The last approved drug came in 2003 and only temporarily boosts memory.

The approval, however, will do little to quell criticisms from the swath of Alzheimer’s researchers, biostatisticians, and clinicians who have argued that Biogen cherry-picked data and failed to show convincing evidence that the drug can slow patients’ cognitive decline. In green-lighting aducanumab, the FDA overruled the near-unanimous recommendation of its advisory committee, who excoriated both Biogen and the agency in a withering marathon session last fall.


“I almost fell out of my chair,” said Caleb Alexander, an epidemiologist at Johns Hopkins and one of the members of that committee. “I think it’s possible but unlikely that there’s new data that hasn’t been shared, but barring that it’s simply hard to see. At best I can tell, the magnitude of unmet need has driven this product forward in spite of the paucity of persuasive evidence.”

Biogen said they would charge $56,000 for the drug — the upper bound of the $20,000 to $50,000 range analysts predicted prior the FDA’s decision. ICER, the drug-pricing watchdog, had recommended a price between $2,500 and $8,300 because they concluded there was flimsy evidence suggesting it could benefit patients.

In light of the controversy and conflicting data, the FDA opted to grant the drug an accelerated approval, making it available while requiring the company to conduct a confirmatory study. The pathway is intended to give patients early access to therapies but the FDA has been criticized in the past for rarely enforcing the requirement that companies run follow-up studies in a speedy manner.

Biogen CEO Michel Vounatsos told CNBC Monday afternoon the company will have 9 years to complete the confirmatory trial.

Biogen’s shares $BIIB, stuck in a holding pattern since 2019, skyrocketed on the news, from $286 to $406 — the payoff of a gutsy strategy Biogen R&D chief Al Sandrock and CEO Michel Vounatsos charted in the fall of 2019, choosing to apply for approval despite missing the bar the FDA had set for Alzheimer’s drugs and, at times, seemingly daring the agency not to approve it. “Lots more people” would get Alzheimer’s without treatment options if the FDA rejects it, Sandrock said at a STAT conference in 2019. “It’s in their hands now.” (A spokesperson later walked back the remarks.)

Opinion remained as divided after the announcement as it had before. Alzheimer’s Association’s President Harry John, having advocated for months for approval, declared Monday “a new day” and a “victory for people living with Alzheimer’s and their families.” The clutch of neurologists and experts who saw potential similarly welcomed the news, looking forward to offering patients new options.

“I think it’s fantastic, I think it’s a great day for the field,” Jeffrey Cummings, a neurologist at the University of Nevada-Las Vegas, told Endpoints. “We’ve been waiting for this day since 2003 and it’s controversial but I think the data are enough for approval.”

Yet aspects of the approval surprised even those who believed aducanumab has benefits. After a series of similar drugs failed in patients with advanced or moderate disease, Biogen studied theirs only in the earliest stage patients, some of whom had yet to develop symptoms at all. It was widely expected that if an approval came, it would come for that subset; instead they approved it for all Alzheimer’s patients, including those with advanced disease and those who don’t have amyloid — the sticky protein aducanumab targets — in their brain.

Peter Stein, director of the FDA’s Office of New Drugs, defended the label on a conference call. He argued that because amyloid is a hallmark of the disease, there’s no reason to think the drug shouldn’t also benefit later-stage patients. But Cummings said he and other neurologists would be reluctant to prescribe it beyond the early-stage patients where it was studied, particularly given that the drug can come with significant side effects, including brain swelling and bleeds.

“I was a little surprised they didn’t put more guardrails,” Cummings said. “We’ll have to do that ourselves.”

Biogen licensed aducanumab from the small Swiss biotech Neurimmune in 2007, a time when the idea that clearing sticky plaques, called beta-amyloid, that accumulate in patients’ brains was widely considered the best path toward slowing or even curing the disease. Even as other amyloid-clearing antibodies from major drugmakers failed, aducanumab emerged as the leading hope, particularly after a 2015 study found that it cleared amyloid and improved cognition in a small group of patients.

In March 2019, though, Biogen announced they were aborting the two Phase III trials the FDA mandates for Alzheimer’s drugs after an interim analysis found it had no chance of beating placebo. It was a stunning and devastating announcement for a field that had already faced three decades of failure — albeit less stunning than the announcement Biogen made seven months later, when they claimed that, after analyzing a larger data set, they believed the drug actually worked and that would apply for approval.

The quality of that analysis has now been the subject of 19 months of debate. Biogen said that although one trial failed entirely, the high dose group in the second trial saw their disease decline more slowly than patients who received placebo. It was enough, they argued, to apply for approval in a disease with no other options. They pointed to a series of post hoc analyses to explain the conflicting results, at one point arguing that there was only a 1 in 10,000 chance that the benefit the high-dose group saw was a false-positive.

The data won over some longtime experts, who believed the drug could provide benefits, even if they didn’t buy Biogen’s enthusiasm.

“I am pleased,” John Hardy, a geneticist at the UK Dementia Research Institute at University College London, told Endpoints. “But I can certainly understand people who take the opposing view, this is not something where this drug is a slam dunk.”

The FDA’s head of neuroscience, Billy Dunn, appeared to agree, writing an enthusiastic endorsement prior to an advisory hearing last November. But the FDA’s statisticians offered the opposite view and the advisors appeared unconvinced. “There are at least a dozen red threads that raise concern about the data,” Alexander said at the hearing.

Both the short- and long-term implications of the FDA decision remain unclear. Although the agency has indicated the drug for all Alzheimer’s patients, how many actually receive it will be determined by both physicians and payers, and it remains unclear whether insurers will agree to cover a costly drug for a massive patient population, where the benefit is contested. Biogen is now required to run a confirmatory study to prove aducanumab can slow cognitive development, but historically the agency has been reluctant to enforce that requirement: Sarepta waited more than 3 years after their controversial accelerated approval for Exondys 51 before launching a confirmatory study.

Speaking to reporters, CDER director Patrizia Cavazzoni defended the decision, saying they believed Biogen could run a timely study and that the agency had the authority and the willingness to pull the drug if they did not do so or if the study came back negative.

“Do some of these [post-approval requirements] get done? Yes. Do many not get done? Yes. Do they get on time? Not always,” Alexander told Endpoints. “It’s a mess, it’s a mess.”

Others worry about the precedent the FDA has set by approving aducanumab in the manner they did. The accelerated approval process requires that a company show its drug had an impact on a “surrogate endpoint” — a biomarker that’s likely to correlate with a more direct measure of clinical benefit. Cavazzoni said Biogen showed the drug had a large impact on amyloid clearance and demonstrated that was “reasonably likely” to mean the drug will also slow patients’ mental decline.

But prior to Biogen’s conflicting studies, numerous trials for other amyloid-clearing drugs from major drugmakers showed no effect on cognition, despite the fact that they cleared amyloid. And some scientists — pointing to those trials, among other pieces of evidence — have argued for years that amyloid is merely a symptom of the disease, rather than the root cause, and clearing it will never make a substantial impact on disease.

“That’s against the data,” Nikos Robakis, a neuroscientist at Mt. Sinai Medical Center, said of the FDA’s conclusion. “There was never any doubt about clearing amyloid. All the amyloid drugs do that. The problem is they do not improve cognition.”

Robakis chalked up the decision in part to Big Pharma growing more assertive with regulators. He now fears companies will spend billions trying to get similar amyloid-clearing antibodies through clinical trials and past regulators, which he views as a senseless waste of capital scientists believe could be put to better use funding basic research and alternative pathways.

A few such treatments are already in mid-to-late stage development, most notably a Phase III drug from Eli Lilly that, in earlier studies, appeared even better at clearing amyloid. Investors largely agreed with Robakis’s prediction, even if they had a rosier gloss.

Lilly $LLY was up 13% on the news, from $201.99 to $229.99 — an increase of $27 billion in market cap.

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