Everyone needs a backup plan, including one of the biggest biotech companies in town. So when Biogen earlier this year gave up on turning a profit from its beleaguered Alzheimer’s drug, Aduhelm, the Cambridge company moved its chips to another experimental Alzheimer’s treatment.
The new drug, called lecanemab, could be safer and provide more obvious benefits than its controversial predecessor, and Biogen expects results from an advanced clinical trial this fall. And, as was once said of Aduhelm, the outcome of the lecanemab trial will be crucial for Biogen’s future.
“It is very important to the company,” said Brian Abrahams, an analyst at RBC Capital Markets who has followed the drug closely. If lecanemab works and is well received, it could easily earn Biogen billions. If it fails, Biogen will need to drop the “swing for the fences” approach it took with Alzheimer’s and focus on less risky, and potentially less lucrative, drugs to bolster the company’s pipeline, Abrahams said.
Lecanemab is the latest in a long line of experimental drugs focused on one theory of Alzheimer’s: that the buildup of a sticky protein called amyloid in the brains of patients contributes to its debilitating conditions, including memory loss and dementia. For years, neuroscientists have hoped that removing large clumps of amyloid, called plaques, would halt the disease. So far that hypothesis hasn’t panned out.
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Although Aduhelm did reduce plaques, scientists and doctors fiercely debated whether it slowed memory loss and cognitive decline in patients. The US Food and Drug Administration skirted that question entirely by granting Aduhelm a so-called accelerated approval based on its ability to reduce amyloid.
Investors initially expected Biogen to cash in on Aduhelm, but many hospitals refused to offer the drug, and private insurers balked at its initial price of $56,000, which was later cut in half. The final blow came in April when Medicare said it would only pay for Aduhelm used by patients in clinical studies. Soon after, Biogen said it would dismantle its Aduhelm sales division.
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Biogen declined interview requests for this story.
Neurologists are split over whether lecanemab will be different, but many are cautiously optimistic. “I put it in the bucket of drugs that are promising, but we need to see more data,” said Dr. Brian Silver, interim chair of the Department of Neurology at the University of Massachusetts Memorial Health.
Those data are coming soon, as Biogen and its Japanese partner, Eisai, wrap up the Phase 3 study, called Clarity AD. One patient with mild cognitive impairment who signed up for the trial is 59-year-old Hugh Courtney of Concord. Every two weeks he commutes to McLean Hospital in Belmont for an infusion — he won’t know if it is lecanemab or a placebo until the testing is done.
Alzheimer’s runs in Courtney’s family, so he always knew there was a chance of getting the disease. As a former professor and dean of the D’Amore-McKim School of Business at Northeastern University, he understands the value of research. Joining the study was an easy decision for him.
“How could I not do this?” Courtney said while getting his 36th infusion at McClean last month. “Given my family’s history and my own, it just made a lot of sense.” He had several more infusions to go before the 18-month study wraps up.
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Decades of failed attempts to cure or better treat Alzheimer’s have tempered expectations for new drugs. No one expects lecanemab to reverse the disease or even completely halt memory loss. In Eisai’s intermediate clinical trial of lecanemab, which was published last year, the highest dose slowed one measure of cognitive decline by about 33 percent over 18 months, compared with 22 percent in one of two Phase 3 trials of Aduhelm.
“It is possible that there could be a bigger clinical effect with lecanemab,” but it might not be enough for clinicians or families to notice, said Dr. Brent P. Forester, chief of geriatric psychiatry at McLean, who is leading the hospital’s Clarity AD study and previously led studies there on Aduhelm. “It is hard to imagine that it will be dramatically better, especially based on what I’ve seen with people that I’ve treated in these trials.”
That’s been Courtney’s experience so far. “I suspect that there is a little bit of a change, but not much,” he said. But since there’s nothing else available to slow memory loss, he added, even a modestly effective therapy would “absolutely” be meaningful to him.
Aduhelm’s meager benefit in one trial was undercut by a second Biogen study that suggested the drug was no better than a placebo. And potentially dangerous side effects made Aduhelm a hard sell. Now, many experts are hoping the Clarity AD trial will paint a clearer picture of the drug’s possible benefits.
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In an earlier study of lecanemab, about 80 percent of patients who got a high dosage became “amyloid negative” on their brain scans after 18 months of treatment. “That is pretty remarkable because it probably takes 10 to 15 years for amyloid to accumulate, and this drug can clear it in a year-and-a-half,” said Dr. Michael Irizarry, Eisai’s senior vice president of clinical research and deputy chief clinical officer.
In a move that baffled doctors, Eisai and Biogen have requested the FDA grant an accelerated approval for lecanemab, based on its ability to reduce amyloid — the same pathway that caused Medicare to spurn Aduhelm.
“If lecanemab is given an accelerated approval” for that reason, Forester said, “no one will pay for it.”
But if the Clarity AD trial proves that lecanemab slows cognitive decline, Forester expects it would get a full FDA approval, and Medicare coverage.
Aduhelm’s questionable benefits were further threatened by serious side effects, including brain swelling and bleeding in some patients, leading to at least a few deaths. In the earlier lecanemab trial, regular MRI scans found that about 10 percent of participants developed brain swelling, compared with about 35 percent of those on Aduhelm.
Irizarry said that Aduhelm may be more likely to cause collateral damage to the brain’s blood vessels because the amyloid plaques it targets accumulate there. Lecanemab, in contrast, primarily targets a form of amyloid that is a precursor to plaques, which isn’t found in blood vessels as often.
Roche and Eli Lilly and Company are testing their own therapies to reduce amyloid, gantenerumab and donanemab, with results expected later this year and in the first half of 2023, respectively.
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If all three have positive results, “that would really bolster the amyloid hypothesis, and would make people more likely to believe that the positive trial of Aduhelm was the correct trial,” rather than a fluke, said Dr. David Rind, chief medical officer for the Institute for Clinical and Economic Review, a drug-pricing watchdog in Boston.
But even if the drugs fail, the amyloid hypothesis is unlikely to die. Companies may test using amyloid drugs earlier in life to prevent disease, or combine them with other therapies. For instance, Biogen and Eisai are developing drugs to reduce a protein called tau, which forms toxic tangles inside brain cells of people with Alzheimer’s.
Dr. Randall J. Bateman, a neurologist at Washington University School of Medicine in St. Louis, is leading a large study that will be the first to test both amyloid-lowering and tau-lowering drugs at the same time. “We think that’s going to be more effective,” he said.
That combination study, which is just beginning, will take years to get answers. But the more advanced studies testing amyloid-lowering therapies by themselves involve 18-month trials, which some doctors say may not be long enough to tell how well they will work over the long term.
“I want to see something that is not just improvement for six months; I want to see something over years,” said Dr. Richard Dupee, chief of geriatric services at Tufts Medical Center.
Courtney has been told that in August he is guaranteed to start getting lecanemab, but he’s not expecting a miracle.
“It’s not the sort of thing where you take a shot and don’t have to worry about it again,” he said. “I hope that what the medication can do is give me more clarity, and more time.”
Ryan Cross can be reached at ryan.cross@globe.com. Follow him on Twitter @RLCscienceboss.