There’s a morose metaphor that seasoned drug developers often use to sum up decades of failed efforts to find treatments for Alzheimer’s disease: They call the mind-robbing condition “the graveyard of drug development.”
But lately, sentiments have started to shift, with the arrival of Leqembi, a new drug approved by federal regulators in January.
The medicine’s benefits are modest — it slowed cognitive decline by 27 percent in an 18-month clinical study run by the Japanese drug firm Eisai and its Cambridge partner Biogen — but hopes are high that it could mark a turning point in Alzheimer’s research.
“It will open up the whole field,” said Dr. Philip Scheltens, head of the Dementia Fund at the health care investment firm EQT Life Sciences. “The graveyard, and the grave mood, has been lifted.”
Those sentiments were echoed by dozens of biotech executives, investors, and scientists interviewed by the Globe. Because Leqembi is far from a cure, doctors and drug developers are already thinking about how still-experimental therapies could compete with the new drug or potentially be paired with it for greater effect.
Glimpses of that potential sea change emerged at the health care industry’s biggest annual business conference in San Francisco last month. Companies working on Alzheimer’s therapies credited Leqembi — which was approved days before the event — for a busy schedule of meetings with prospective investors, and with lifting the tenor of those discussions.
“It’s night and day,” said Dr. Martin Tolar, who has been chief executive of Alzheon for 10 years. The Framingham-based company is in the advanced stages of testing a drug in people whose genes increase their risk of developing Alzheimer’s. “Even a couple years ago it was like the stupidest idea to do something in Alzheimer’s because everything has been failing.”
Those failures largely centered on a sticky protein called amyloid beta, which forms plaques in the brains of many people with the disease and was hypothesized to be its root cause. But as the graveyard of Alzheimer’s drugs grew, some scientists wondered if the whole field was being held back by a dogged belief in the amyloid hypothesis.
Leqembi, which targets a specific form of amyloid that some scientists think is especially toxic, is poised to play out differently. There are still concerns about the safety of the drug, which ― in a minority of cases — can cause brain bleeding and swelling. And debate will surely swirl around how meaningful its effects will be. But even scientists whose work has moved beyond the amyloid hypothesis have applauded the clinical trial’s unequivocally positive results.
“You would have to be extremely grumpy to not be excited about this,” said Frédéric Calon, a professor of pharmacy who is investigating links between insulin and Alzheimer’s at Québec-Laval University in Canada. “The Alzheimer’s field is kind of like a sports team losing every game, and then suddenly it wins.”
With analyst forecasts for sales of Leqembi rising to $8 billion annually, some biotech leaders say big pharma firms that previously dropped out of the Alzheimer’s race may want back in. “No one’s going to leave a market of this magnitude to a single competitor,” said Daniel O’Connell, chief executive of Acumen Pharmaceuticals.
There are already dozens of Alzheimer’s drug development programs underway. Some, like Acumen’s early-phase drug, are antibodies that take aim at amyloid. The one closest to the finish line is Eli Lilly and Company’s donanemab, which targets a slightly different form of amyloid than Leqembi. Results from an advanced study are expected this spring.
Dr. Mark Mintun, vice president of neuroscience research and development at Lilly, said the company has “a lot of confidence” that donanemab will work, but no matter what the trial data show, the firm isn’t giving up on amyloid. Lilly has an earlier-stage antibody called remternetug that it believes could be even better.
“We’re in this and we’re in it to stay,” Mintun said. “And now that it looks like these [amyloid drugs] are going to be with us for a long time, we want to make sure that we’re making the drug as good as possible.”
It’s possible that renewed excitement for amyloid could come at the expense of newer ideas for tackling the disease, but most researchers aren’t worried about that happening. Disagreements over the amyloid hypothesis simply being right or wrong oversimplify the science, they say. While Leqembi may prove that amyloid is partly responsible for the disease, it may not be the only culprit.
“It’s not like the Red Sox versus the Yankees. We embrace the complexity,” said Tracy Young-Pearse, an associate professor of neurology at Harvard Medical School and associate chair of neuroscience research at Brigham and Women’s Hospital. “There’s still a very strong appetite to do better than that 27 percent slowing of cognitive decline.”
The next big approach in the field centers around a different problematic protein called tau. It can damage brain cells, especially in more advanced forms of the disease. Biogen, Eisai, and Lilly all have experimental drugs that aim to remove tau in slightly different ways. There’s optimism that combining amyloid and tau drugs, or even giving them to people before they develop memory problems, could lead to more effective treatments. But the work won’t stop there.
“We have to look beyond amyloid and tau because we know for a fact there are other drivers and hallmarks of Alzheimer’s disease,” said Ivan Cheung, chairman and chief executive of Eisai’s US operation.
The company is in the early stage of work on drugs intended to preserve or regenerate connections between brain cells that are damaged during Alzheimer’s, according to Dr. Michael Irizarry, Eisai’s senior vice president of clinical research. The firm’s genetics and dementia research center in Cambridge is also working on drugs aimed at microglia — the immune cells in the brain that genetic studies are increasingly linking to Alzheimer’s and other forms of dementia.
Arnon Rosenthal, chief executive of Alector in South San Francisco, said that microglia are like “trash collectors” that help clean up cellular debris, including amyloid, that accumulates in the brain with age. They also help repair damaged connections between brain cells, he added. The company is testing one of its microglia-targeting drugs with the pharma giant Abbvie. Results from an intermediate-stage study are expected next year.
Rosenthal believes that Alzheimer’s research could start to resemble investments in cancer immunotherapy. In that field, some companies rushed to develop copycat medicines of the so-called checkpoint inhibitors that make Bristol Myers Squibb and Merck billions annually, while other companies sought to develop new drugs that can be paired with checkpoint inhibitors to make them more effective for more people.
Dr. Al Sandrock, the former research head of Biogen who now leads the neuroscience and gene therapy company Voyager Therapeutics, said the Alzheimer’s field reminds him of the first drug approvals for multiple sclerosis in the mid-1990s. “They were only about 30 percent effective,” he said, “but 30 percent compared to zero was quite a step forward.”
Those drugs attracted investors and other companies to make better medicines, of which there are now more than a dozen, Sandrock said. “Success breeds success,” he said. “And I think that the same thing is happening for Alzheimer’s disease.”
A couple of major details may need to be ironed out before more funding materializes, including Medicare coverage of Leqembi. “That is the huge thing that everyone is focused on,” said Myles Minter, a biotech analyst at the investment bank William Blair.
Leqembi only received accelerated approval from the Food and Drug Administration in January, and a prior Medicare ruling suggests that its $26,500 annual price tag won’t be covered for most patients until the medicine gets full approval from the FDA, which could come late this year or in early 2024.
So far, the excitement around accelerated Alzheimer’s investment has amounted to little more than talk, but that may soon change.
“There is a curiosity,” Rosenthal said. “It will be interesting to see how far it translates into actual action.”