The scientific community let out a collective sigh in March 2019 that was more akin to defeat than disappointment. The Cambridge-based biotech company Biogen announced that it was ending two large-scale Phase 3 clinical trials for aducanumab, an experimental antibody medication that targets the protein accumulation thought to be the cause of Alzheimer’s disease.
After reviewing the data, the independent monitoring board rendered a decision that the researchers had feared: the trials were unlikely to be successful. This felt like another door closing after decades of fruitless attempts to treat Alzheimer’s by some of the biggest pharmaceutical companies in the world. Biogen then held another press conference seven months later. Furthermore, very little of it made the most sense.
| Category | Details |
|---|---|
| Drug Name | Aducanumab (Brand: Aduhelm) |
| Developer | Biogen Inc. |
| Drug Type | Monoclonal antibody targeting beta-amyloid protein |
| Target Disease | Alzheimer’s Disease (Early Stage) |
| FDA Status | Accelerated Approval Granted (2021) |
| Clinical Trials | ENGAGE & EMERGE (Phase 3); PRIME (Phase 1b) |
| Trial Halt Date | March 2019 (reinstated for analysis, Oct 2019) |
| CEO (at announcement) | Michel Vounatsos |
| Chief Medical Officer | Al Sandrock |
| Headquartered | Cambridge, Massachusetts, USA |
| Stock Impact | Biogen shares soared on announcement day |
| Patients Affected | ~5.7 million Americans 65+ with Alzheimer’s |
| Reference Website | Biogen Official – Aduhelm |
The business had not just moved on. Its statisticians had continued gathering information, conducting analyses, and gazing at figures that now told a different tale. One of the two trials, known as EMERGE, had actually achieved its main objective when the larger dataset—which included 2,066 patients who had finished the 18-month study, as opposed to the 1,748 used in the previous futility analysis—came in.
When compared to a placebo, patients receiving the maximum dosage of aducanumab demonstrated a 23% decrease in clinical decline as determined by a test that monitors daily functioning and cognition. Recall. Language. orientation. the capacity to travel independently and handle personal finances. actual things. measurable items.
It’s difficult to ignore the odd, almost unsettling tension in what Biogen was saying: according to their CEO, the analysis they had used to kill the drug had been “incorrect.”
During a conference call with Wall Street analysts who were clearly skeptical, Michel Vounatsos clarified that the initial futility analysis had not sufficiently taken into consideration the amount of time patients had spent on the higher dose. The purpose of two protocol modifications, one in July 2016 and another in March 2017, was to increase the number of patients receiving the 10 mg/kg dose that was thought to be the most beneficial.
However, by the time the monitoring board examined the data, patients who were enrolled in the trial’s early months had naturally received less cumulative exposure to that higher dose. With more time and more patients receiving the higher dosage, the situation abruptly changed. Sitting with this explanation, it seems more like the trial design was catching up to itself than the drug was failing.
However, there were still issues with the second trial, ENGAGE. On the same primary endpoint, a nearly identical parallel study found no benefit for high-dose aducanumab. This wasn’t a technicality to analysts like Raymond James’ Steven Seedhouse, who gave the drug a flat 0% chance of succeeding. It was a basic warning sign.
For good reason, the FDA has long required two successful trials before approving a request. Even though Biogen’s team proudly cited a p-value of 0.01, one success in two attempts raises the unsettling possibility that EMERGE’s numbers were a statistical anomaly.
Investment bank Stifel’s Paul Matteis put it bluntly: the ENGAGE data appeared unmistakably negative, while the EMERGE data were obviously positive. Some observers thought it was a stretch to try to explain that away with a subset analysis involving just 30 additional patients at high dose. Nevertheless, research on Alzheimer’s has been a graveyard of uncertainties. A case that appears to be closed frequently reopens.
The Alzheimer’s Association’s Rebecca Edelmayer described it as possibly “a game-changer for the field.” After so many setbacks, Ronald Petersen, director of the Mayo Clinic Alzheimer’s Disease Research Center, who had advised Biogen on the medication, called the news “a bright light” but cautioned that persuading the FDA would still be a difficult task. Actually, both responses feel correct. The field has every reason to be both extremely cautious and cautiously optimistic at the same time.
It’s important to take a step back and consider how Alzheimer’s research has changed over the last 20 years. The amyloid hypothesis, which holds that removing beta-amyloid plaques from the brain could slow or stop the disease, has been attacked by company after company with funds, time, and scientific credibility. Pfizer made an attempt. Janssen made an effort. Eli Lilly witnessed the failure of promising medications in the final stages of testing.
Not only did each failure cost money, but it also cost momentum, undermined confidence, and forced patients and their families to wait again. Today, 5.7 million Americans over 65 are thought to have Alzheimer’s. That figure might be close to 14 million by 2050. Nothing that has been approved in the past 16 years has slowed the disease itself, although there are medications that manage some symptoms. If authorized, aducanumab would be the first.
That is not a minor issue. The FDA might need more information before making a commitment. Following the approval decision, three members of the agency’s own advisory committee resigned, indicating that Wall Street wasn’t the only place where scientists were uncomfortable with the trial data.
However, in 2021, accelerated approval was finally given, signifying a cautious, conditional yes from regulators who understood that sometimes waiting for perfect evidence means millions of people also have to wait.
There’s a sense that Alzheimer’s research has been a slow, grinding negotiation between science and biology as you watch this develop over time, from the early animal studies in 1999 that demonstrated dramatic plaque-clearing to the unsuccessful human immunization trial in 2003 to Biogen’s own stumble and reversal. The illness refuses to cooperate. The data is not delivered in a clean manner. When victories do occur, they do so in an untidy manner with asterisks.
There is still no cure for aducanumab. Whether lowering amyloid levels consistently results in memory and function preservation for the majority of patients is still unknown. The pharmaceutical industry must carefully consider whether to stick with the amyloid hypothesis or shift its focus to other targets, such as inflammation, the immune system, or synaptic health, in light of the upcoming trials and increased scrutiny. More and more experts are stating that any anti-Alzheimer’s medication will likely work in concert rather than alone.
For the time being, however, a medication that was deemed dead returned with data. And that messy, contentious, incredibly uncertain comeback is, against all odds, something in a field that has seen so many clean losses.