At last: a glimmer of hope on the horizon.
After decades of frustration and failure, including a spectacular misfire by one of the state’s biotech pillars, the first medicines to slow cognitive decline in Alzheimer’s patients are starting to arrive.
The drugs ― which provide modest but measurable benefit for people in early stages of the memory-ravaging disease ― are being hailed by patients as the dawn of a new era in its treatment.
And Cambridge biotech Biogen, not long ago reeling from its disastrous rollout of an earlier Alzheimer’s therapy, has re-emerged as a leader in the push to vanquish the long intractable illness.
The long-delayed progress comes as the scourge of Alzheimer’s spreads across an aging population. More than 6 million mostly older Americans suffer from the disease. By 2050, that number is projected to more than double, to 13 million.
“We’re seeing some real breakthroughs, and I’m ecstatic,” said Cambridge resident Betsy Groves, 73, a retired social worker and teacher who was diagnosed with early-stage Alzheimer’s more than a year ago and is tracking new therapies that might help her and others in the future. “I’m doing well now, but I know there’ll come a time when I’m not.”
Biogen, one of the last remaining independent players from the first Cambridge biotech cluster in the 1980s, won conditional Food and Drug Administration approval in January for Leqembi, a drug it developed with Japanese business partner Eisai. They hope to win full US approval this summer.
But Biogen won’t have the market to itself. Promising clinical findings this month from an Eli Lilly medicine, called donanemab, could help propel it to market by year-end and set up competition for tens of billions of dollars in projected sales.
And that’s just the opening round in the fight to subdue Alzheimer’s. Scientists around the globe are working on a pipeline of more than 100 other potential treatments, said Dr. Howard Fillit, executive director of the Alzheimer’s Drug Discovery Foundation in New York, which funds dozens of research programs.
Nineteen are in late-stage clinical trials, far enough along that some could be launched within three to five years, Fillit predicted.
The first drugs coming to patients, including Leqembi and donanemab, break up beta amyloid deposits, or plaques, that have accumulated in the brain. Researchers working on many drugs under development are experimenting with other approaches, such as reducing inflammation thought to boost plaque production, and switching off genes that appear to increase Alzheimer’s risks. Other efforts seek to repurpose existing medicines, such as the diabetes drug Metformin, for use against Alzheimer’s.
“I’ve been in research and care of Alzheimer’s patients for over 40 years,” Fillit said, “and I’ve never been more optimistic about our ability to slow this disease down and perhaps even stop it in its tracks.”
The goal of many scientists is to tailor Alzheimer’s drugs to subsets of patients, depending on their genetic makeup. New diagnostic tests will help neurologists identify ”the dominant processes contributing to neurodegeneration and ultimately get to a world of precision medicine with combination therapies,” Fillit said.
Some liken the first Alzheimer’s drugs to the debut of medications for AIDS, which once seemed to defy treatment, 35 years ago.
Until now, “there was literally nothing” in the medical arsenal to deploy against Alzheimer’s, said Biogen chief executive Chris Viehbacher. “This is the first breach of the wall.”
The new therapies won’t be cheap. Biogen has given Leqembi a price tag of $26,500 a year per patient. But its ability to deliver the drug on a large scale will hinge on several factors. For one, most patients are over 65 and insured by Medicare. If Biogen wins full approval this summer, as the company expects, the agency must still rule on whether to pay for it, a costly proposition.
A study released Thursday, led by researchers from the University of California, Los Angeles, said Leqembi could boost Medicare’s annual spending by $2 billion to $5 billion.
“We will see pressure on Medicare’s budget,” said Rena Conti, health economist at Boston University’s Questrom School of Business. But if a price competition emerges between Biogen and Eli Lilly, she said, that could ease the agency’s financial strains.
Viehbacher cautioned that it will take time for the Alzheimer’s drug market to develop. He estimated that 100,000 patients will receive Leqembi ― administered through a series of infusions ― over the next three years, with the patient population growing from there. In the short term, however, neurologists will need to be educated on who can benefit and how to administer treatments.
That will require an infrastructure of diagnosis and infusion centers across the nation, something that doesn’t now exist. Getting Alzheimer’s drugs to patients in rural settings, and to those who lack access to health resources in cities, will be another hurdle.
Even in a medical hub like the Boston area, “There’s a significant shortage of neurologists, and finding one was a challenge,” said Groves, the ex-social worker, who shared her experience during a visit with Biogen researchers in Kendall Square last September. Without testing, it’s often hard for doctors to distinguish Alzheimer’s from the short-term memory loss that comes with normal aging, she said.
Groves still walks and swims, sings in two choral groups, and baby-sits her granddaughter. After a career at Boston Medical Center, she began teaching courses in early childhood mental health at Harvard’s Graduate School of Education about seven years ago. A few years later, however, she began experiencing memory lapses.
“I was having trouble with students’ names,” Groves said. “And I felt that my capacity to manage classroom exchanges and discussions were not as sharp as they used to be.”
She was initially diagnosed through neuropsychological testing about 16 months ago. But it took a lumbar puncture and analysis of biomarkers in her spinal fluid to confirm the diagnosis. Groves said she’s grappled with anxiety since then, but has become more hopeful as she’s learned about the new drugs. She’s hoping to enroll in a clinical trial soon.
Other patients can be diagnosed through a PET scan that detects plaque deposits in the brain. As diagnostics and medicines improve, doctors hope they’ll eventually be able to begin treatments for patients even before they exhibit symptoms.
The need for such intervention is crucial. More than 55 million people are thought to have Alzheimer’s worldwide. In the United States alone, between 1.7 million and 2 million Americans over 65 are estimated to be in the first stages of the disease.
Less than two years ago, prospects for new treatments looked dim after a high-profile Biogen setback that still echoes throughout the industry.
US regulators approved the company’s first Alzheimer’s drug, Aduhelm, in 2021 over the objections of a panel of outside scientific advisers to the FDA who questioned its benefits. That prompted three advisers to quit the panel in protest. An 18-month congressional investigation concluded the approval process was “rife with irregularities,’’ including dozens of undocumented or poorly documented meetings between regulators and Biogen representatives. Critics said the meetings smacked of inappropriate coziness.
In the final blow, Medicare refused to cover Aduhelm for patients outside clinical trials, effectively dooming the drug program.
The chain of events left Biogen’s reputation in tatters. It also seemed to discredit the so-called “amyloid hypothesis” — a hotly debated theory that beta amyloid plaque buildup in the brain is the primary cause of Alzheimer’s — that long underpinned research in the field.
“If you went back even six months ago, there was still a lot of doubt about whether reducing the plaque had a benefit,” said Viehbacher, a veteran biopharma executive who was tapped for the top job at Biogen last November after Michel Vounatsos stepped down in the aftermath of the Aduhelm controversy.
Since then, Leqembi became the first amyloid-clearing drug to unequivocally show it helped patients. Leqembi, like Aduhelm, is a monoclonal antibody that targets and attacks clumps of plaques like biological intruders. Both drugs are administered intravenously.
In a late-stage trial, the Biogen-Eisai drug slowed the pace of disease progression by 27 percent over an 18-month trial involving nearly 1,800 people. FDA regulators granted it conditional, or “accelerated,” approval in January, and the drug is on the docket for full approval by July 6. But until it’s covered by Medicare, a decision that should come later in the year, only a limited number of seniors will be able to afford the bill.
Donanemab, the Eli Lilly drug candidate, meanwhile, slowed patients’ rate of cognitive and functional decline by 35 percent over 18 months compared with a placebo in a study that enrolled 1,182 early-stage patients. Lilly plans to file for full FDA approval of its amyloid-busting therapy next month.
“This is the best result we’ve had yet,” said Dr. Stephen Salloway, director of neurology at Butler Hospital in Providence, who managed the hospital’s clinical trials of Aduhelm, Leqembi, and donanemab.
Donanemab has another apparent advantage over Leqembi. While both are administered intravenously, donanemab only needed to be given monthly, while Leqembi is infused every two weeks. Lilly will price its drug only after it wins US regulatory approval.
Biogen executives see Leqembi as key to the company’s rebound, along with an experimental drug developed with another Cambridge biotech, Sage Therapeutics, that treats postpartum depression. Biogen still markets multiple sclerosis drugs, but it slashed spending and eliminated hundreds of jobs globally after the Aduhelm episode. Its workforce in Massachusetts has fallen to about 2,300, from 2,800 in 2021.
Leqembi will have a headstart in the marketplace, and, possibly, other advantages. In clinical trials, donanemab appeared to cause more potentially serious side effects. About 24 percent of patients who received donanemab experienced brain swelling, and an overlapping 31.4 percent had bleeding in the brain. Those are known risks for anti-amyloid drugs, but were higher than the rates for Leqembi.
Although most brain swelling and bleeding cases were manageable, there were several deaths linked to side effects in clinical trials for both drugs.
Biotech analysts said the market for a safe and effective treatment for early-stage Alzheimer’s is huge — so big that both companies could share it and still profit from a “blockbuster,” the industry term for a drug that generates more than $1 billion in sales annually.
“There’s a lot of room in this new market for multiple entrants,” said Brian Abrahams, an analyst with RBC Capital Markets. He estimated Leqembi’s annual sales could approach $10 billion worldwide by 2031 even if Biogen shares the market with Lilly.
In a note to investors, Brian Skorney, an analyst with Baird Equity Research, said he believes donanemab’s clinical results will boost the prospects for a successful launch of Leqembi.
That’s because, even after the FDA granted Leqembi conditional approval in January, many doctors and patients remained skeptical of Biogen’s drug, Skorney said. Those misgivings were “greatly diminished by these [donanemab] results,” he wrote.
Analysts also predicted the latest trial results will likely prod Medicare to reimburse patients for the new class of medicines.
Salloway said patients who begin treatments with the new drugs will have to be monitored carefully by their doctors. But ultimately, he said, both medicines could be a boon to patients.
Groves, the Cambridge retiree with early-stage Alzheimer’s, is excited about the drug rollouts even while acknowledging it’s too soon to know how much she might benefit.
“Based on everything I’ve heard,” she said, “it looks really promising.”
An earlier version of this story incorrectly described how Aduhelm is administered.