Biogen stunned investors and Alzheimer's researchers on Tuesday with news it will ask the Food and Drug Administration to approve its experimental drug aducanumab.
Just seven months ago, Biogen shut down two large Phase 3 studies after a first look at the data signaled the trials were unlikely to prove positive.
Yet the biotech kept collecting and analyzing results, leading to disclosure that aducanumab, in fact, succeeded in one of the two trials. While the other still missed its goal, Biogen says the fuller dataset provides compelling evidence aducanumab can lessen the functional and cognitive decline brought on by Alzheimer's.
Executives tried to defend that claim to skeptical Wall Street analysts on a Tuesday conference call. Much remains uncertain, foremost of which is whether the FDA will agree with Biogen's analysis.
Here are seven of the most pressing questions facing Biogen and its Alzheimer's hopes, some of which could be cleared up when the drugmaker presents fuller data at the Clinical Trials on Alzheimer's Disease conference in December. Others, however, will linger until the FDA weighs in.
What changed from Biogen's earlier analysis?
Biogen's explanation centers on the length of time patients were exposed to the higher dose of aducanumab tested in the two studies, called ENGAGE and EMERGE.
In March, when the company decided to discontinue the trials, there wasn't sufficient data to reveal the benefit of high-dose aducanumab over time, executives said.
That call was based on what's known as a futility analysis. In brief, company statisticians calculated the probability the studies would succeed based on data through Dec. 26, 2018. At that time, Biogen had results from 1,748 patients who had the opportunity to complete a full 18-month study period in either trial.
Running the numbers, the drugmaker concluded both dose arms in both trials had less than a 20% probability to meet the primary endpoint at a final analysis.
"In retrospect, the result of our futility analysis was incorrect," CEO Michel Vounatsos said on Tuesday's conference call. "Based on what we know now, it is clear that the prespecified futility criteria did not adequately anticipate the effect of all the variability in these trials."
Biogen now has results from 2,066 patients who had the opportunity to complete 18 months of study, as well as from all 3,285 enrolled into ENGAGE and EMERGE. Data also cover three more months of treatment, through March 20, 2019.
Two changes in study protocol made in July 2016 and March 2017 allowed more patients to reach the high 10 mg/kg dose that Biogen believes to be most effective. And because those study changes came, respectively, 10 months and 18 months after the trials began, patients enrolled early on and included in the futility analysis had less average exposure to aducanumab.
"These two protocol amendments were put in place precisely to enable more patients to reach high dose aducanumab and for a longer duration," said Al Sandrock, Biogen's chief medical officer and new head of R&D. "As a consequence, the larger data set available after trial cessation included more patients with sufficient exposure to high dose aducanumab."
One study failed. Could the success be a false positive?
In EMERGE, Biogen said treatment with high-dose aducanumab resulted in a 23% reduction in clinical decline versus placebo on a function and cognition test known as CDR-SB, the study's primary endpoint.
This both cleared the bar for statistical significance and surpassed the 20% mark executives argued is sufficient to be clinically meaningful to patients.
But in ENGAGE, a supposedly identical trial, patients on high-dose aducanumab saw no benefit as measured by CDR-SB.
For some analysts, that raised the question of whether EMERGE's success represents a false positive.
"When anybody says a p-value is <0.05, this means that there's less than a 5% chance the data is a fluke," wrote Mizuho's Salim Syed.
EMERGE had a p-value equal to 0.01 on CDR-SB, according to Biogen, "which is great and it means the odds of that trial having fluke data are really low," Syed added. "But again, ENGAGE did not have this same result … This is why the FDA typically requires two trials, to rule out a fluke."
As Biogen explains it, the discrepancy between ENGAGE and EMERGE comes down to the same reason why a second analysis resulted in a different outcome than in March.
"Differences between EMERGE and ENGAGE can mostly be accounted for by a greater level of exposure to high dose aducanumab in EMERGE due to multiple factors, including the fact that ENGAGE started earlier and enrolled earlier than EMERGE," said Sandrock.
However, ENGAGE only started one month before EMERGE and, in a comparison Biogen made among a subset of patients who had sufficient exposure to high-dose aducanumab, the difference in patient numbers between the two studies was only 30 participants.
"The EMERGE data are clearly positive but the ENGAGE data look definitively negative, and based on what we've seen (somewhat limited details) we feel unconfident that the ENGAGE subgroup salvages the overall narrative," wrote Paul Matteis of Stifel, an investment bank, in an Oct. 22 note to investors.
Steven Seedhouse of Raymond James went even further.
"We don't think this plan is going to work and assign 0% probability of success to aducanumab in Alzheimer's," he wrote.
Will the FDA agree with Biogen's interpretation?
For Biogen, this is a multibillion-dollar question. No disease-modifying treatments for Alzheimer's are approved, meaning the first drug cleared would have an easy path to blockbuster sales.
Generally, the FDA requires two positive, well-controlled studies to approve a new therapy, although the regulator has shown greater flexibility on this standard in recent years.
Biogen appears to have one clear success in EMERGE, with ENGAGE delivering results some saw as confounding. The company will also submit to the FDA data from PRIME, the Phase 1b study that led to Phase 3 testing of aducanumab.
On Tuesday's call, Biogen executives emphasized they made the decision to file aducanumab following meetings with the FDA in June and again on Oct. 21. But it's not clear what kind of feedback regulators gave, and the agency could agree to have a look but still take issue with Biogen's findings.
Analysts doubted, though, whether Biogen would have pushed forward without some positive signal from the agency.
"We would doubt that a company of Biogen's stature would misread filing feedback from the agency," wrote Stifel's Matteis.
Were the FDA to accept Biogen's application, it could convene an advisory panel to help vet aducanumab's data. But ultimately, what regulators think won't be known until they decide whether to approve or reject the drug — an event that could come as early as the end of next year if Biogen submits in January and all standard regulatory timelines hold.
The FDA could also decide that Biogen's data show promise, but that more study is needed to confirm the drug's benefit.
"I'd want to see a third trial before I'd approve this thing," said Howard Fillit, a neuroscientist and chief science officer of the Alzheimer's Drug Discovery Foundation, in an interview. "This is going to be a very expensive drug a that a lot of people are going to want."
Why would aducanumab work when all other amyloid-targeting agents have failed?
The failure of so many experimental anti-amyloid drugs has caused many to challenge the prevailing notion that amyloid beta is the main culprit in neurodegenerative decline.
"We believe this data will be heavily scrutinized by the scientific community, as it conflicts with the broader set of data about the amyloid mechanism so far," noted Berstein analyst Ronny Gal.
Proponents of the amyloid hypothesis have focused on giving patients higher doses and at earlier stages of disease, as Biogen's ENGAGE and EMERGE did, along with trials to prevent Alzheimer's in high-risk people.
In addition, aducanumab is touted as perhaps being more effective in modifying the course of Alzheimer's because it binds with and removes amyloid beta aggregates, as found in brain plaques. Other agents, like Eli Lilly's solanezumab, bind with smaller molecules called monomers that may, in fact, help to protect brain cells.
Didn't Biogen's head of research just leave?
Yes. Michael Ehlers, who joined Biogen in 2016, stepped down at the beginning of October, leaving the company to become a venture partner at life science fund Apple Tree Partners.
Al Sandrock, a 20-year Biogen veteran, took over Ehler's duties in addition to his current responsibilities as chief medical officer.
It's not clear whether Ehler's departure is related to Biogen's new plans for aducanumab. Still, several Wall Street analysts wondered if there might have been disagreement among company leadership regarding the drug that factored into his exit.
As head of R&D, Ehlers oversaw ENGAGE and EMERGE, which began about 8 months prior to his arrival at Biogen. The decision to halt the two studies came in March, and the company met with the FDA to discuss results in June and on Oct. 21, ten days after Ehlers' official last day.
Does this kind of thing happen often?
In short, no. Failing an interim analysis, as aducanumab did in its Phase 3 program, is usually the end of the drug development road.
But there is precedent for the FDA to overlook mixed trial results and approve a drug in a disease with no effective treatments, or for what looks like a clinical failure to turn out more successful with additional analysis.
One example is Dendreon's ill-fated Provenge, an early immuno-oncology agent that failed to prevent prostate cancer patients from progressing at a slower rate than placebo but inexplicably helped patients live longer.
Another example is Lynparza, on which AstraZeneca had all but given up until a retrospective analysis showed it could keep BRCA-mutated ovarian cancer patients from dying or having their cancer relapse longer than placebo.
The lack of effective Alzheimer's disease treatments certainly might make regulators more friendly toward aducanumab as they were with Provenge and Lynparza, but it will be difficult to get a read on the FDA's actual view for months, with a potential FDA advisory committee as one milestone when internal staff thinking could be revealed.
How would payers respond if aducanumab were to win approval?
Since Alzheimer's affects mainly elderly people, Medicare would be the chief payer. In 2017, its Part D plans were billed for nearly $2 billion worth — at list price — of small-molecule Alzheimer's drugs like Aricept, most of which are now generic.
These drugs have shown such limited effectiveness in altering the disease course that the National Health Service in Great Britain refused to pay for them at their initial prices.
An expensive new infused biologic would be covered primarily by Part B of Medicare, which has fewer cost-control mechanisms in place, and might cost tens of thousands of dollars a year per patient.
In the event of aducanumab's approval, Medicare would likely require strict adherence to the label. Based on the EMERGE and ENGAGE trials, the label could include only patients who have mild cognitive impairment with elevated brain amyloid confirmed by PET imaging.
Payers may also restrict the drug to the higher-risk patients, called APOE4 carriers, who comprised two-thirds of the patients in EMERGE and ENGAGE.