The story of Biogen’s new Alzheimer’s drug can be linked back to a nearly forgotten experimental compound developed by two companies that no longer exist.

In 2006, drugmakers Elan and Wyeth began a Phase 1 study of an antibody drug called bapineuzumab that worked similarly to Biogen’s. Both bind to and remove a protein called amyloid beta that piles up into toxic plaques in the brains of patients with Alzheimer’s disease.

Within six years, bapineuzumab advanced far enough to be tested in a large, placebo-controlled clinical trial, which found the drug didn’t slow disease progression, ending research on the drug. Researchers did report, however, that bapineuzumab reduced amyloid plaques in a group of patients, the same justification the Food and Drug Administration on Monday gave for approving Biogen’s drug, now called Aduhelm.

Unexpectedly, the FDA chose to clear Aduhelm conditionally, based on the drug’s ability to reduce amyloid, rather than for the clinical benefit Biogen claimed to show in one late-stage trial. The agency’s decision sets a precedent, signaling acceptance of amyloid lowering as a predictive measure of effectiveness and potentially opening the door for other developers to take a similar approach.

Aduhelm’s approval also offers regulatory validation of the so-called amyloid hypothesis, which points to the sticky plaques as the main culprit behind the cognitive and functional declines in Alzheimer’s. Before Aduhelm, the failures of a long line of drugs like bapineuzumab and Eli Lilly’s solanezumab in late-stage testing had cast substantial doubt on the theory.

FDA officials, however, believe Aduhelm is different, taking the view that each anti-amyloid drug is distinct based on which the form of the protein it targets.

“It’s difficult to extrapolate conclusions from one to another,” Peter Stein, director of FDA’s Office of New Drugs, told reporters Monday. “Many of the earlier studied antibodies really had only slight or no reductions seen in amyloid plaque and the reason these trials may have failed is because the amyloid reduction may have been too small to yield clinical benefit.”

But with Aduhelm now on the market, and billions of dollars of revenue in reach for Biogen, other drugmakers are likely to ask whether they could also pursue accelerated approval, too. The FDA even seems to be urging them on.

“The agency is very encouraged by the incredible progress being made in the Alzheimer’s drug development space,” said Patrizia Cavazzoni, head of the FDA’s Center for Drug Evaluation and Review, on Monday’s call. “It is our hope that in the years to come we will have the opportunity to approve additional treatment options.”

Most notably, Lilly recently released promising Phase 2 trial results for a drug called donanemab that binds to a similar region of the amyloid as aducanumab. In that mid-stage trial, treatment lowered brain plaque levels and slowed decline, as measured by a cognitive and functional scale, by 32% versus placebo.

“In some way, the donanemab trial may have given us the cleanest view for what the prospects of amyloid therapy might be. It actually did move the needle a tiny bit in the context of dramatically clearing amyloid.” said David Knopman, a neurologist and Alzheimer’s specialist at the Mayo Clinic, in an April interview. “But the effect size in the donanemab trial was very small. Is that the best we can do?”

Despite the promising data, Lilly said in April it would not seek accelerated approval. The company did not respond to phone and email inquiries from BioPharma Dive about whether it might reconsider in the wake of Aduhelm’s OK.

Shares in the Indianapolis drugmaker rose by 10% Monday, adding nearly $20 billion to the company’s market value, as investors drew confidence from Aduhelm’s approval.

In addition to Aduhelm, Biogen is also partnered on a second amyloid-binding drug that’s far along in testing. Together with Japanese pharma Eisai, Biogen is studying a drug called lecanemab — formerly known BAN2401 — in a Phase 3 trial that completed enrollment in March. Results could come sometime in the second half of 2022. Lecanemab has also been shown to reduce brain amyloid.

Other companies may also consider whether data from past failures might be mined to support renewed regulatory discussions, or at least reviewed again.

“I think maybe some prior failed products would be taken off the shelf and dusted off,” Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, in a recent interview with BioPharma Dive before Aduhelm’s approval.

In the case of bapineuzumab, researchers did find signs treatment helped to clear amyloid from brain plaques. Solanezumab, which binds to an different form of amyloid, helped slow cognitive decline in some pre-specified groups in two of the clinical trials Lilly ran, although the studies clearly missed their main goals.

One of the explanations for bapineuzumab’s failure is that the drug’s side effects, most notably brain swelling, required keeping the dose low. Solanezumab was more benign, so much so that subsequent trials in the preventive setting, like an ongoing trial called A4, are testing a dose four times higher than Lilly used in its clinical program.

Solanezumab, however, wasn’t associated with the plaque clearance the FDA cited when approving Aduhelm. Even in the preventive setting and with higher doses, the drug has struggled to show any effect on Alzheimer’s progression.

Roche, meanwhile, hasn’t completely written off its drugs gantenerumab and crenezumab despite negative Phase 3 results. The latter is still being studied in a large family group in Colombia that carries a mutation linked to increased risk of early onset Alzheimer’s. Crenezumab binds to a similar section of the amyloid protein as solanezumab.

The Swiss drugmaker has also persisted with gantenerumab, which is thought to bind to the same region of amyloid beta as Aduhelm and donanemab. But at least two trials have been terminated early because analyses showed no sign the drug would slow progression.

The latest gantenerumab trial is enrolling patients early in disease progression. Results are due to read out in 2022. Roche is also testing a version of the drug that uses a “brain shuttle” technology that’s designed to help gantenerumab cross into the brain more easily.