By 2029, more than 20 percent of people in the United States will be over the age of 65. That’s why the race to find effective treatments for Alzheimer’s disease feels urgent. A few drugs, approved well over a decade ago, can slow patients’ mental decline for some time. But everything else that has reached large-scale clinical trials, often with hopes of treating the underlying cause of the disease and halting its progress, has failed to show benefit, sometimes after hundreds of millions of dollars of investment.
With that track record—a nearly complete failure rate from 2002 to 2012—it’s hard to be optimistic.
Yet the late stage pipeline of potential new Alzheimer’s drugs is crowded, according to this recent analysis by the advocacy group USAgainstAlzheimers.
There is an outside chance a significant treatment could be available by the end of this decade, unlocking pent-up demand from possibly hundreds of thousands of people. Planning has to start now. A lot of resources, from imaging equipment to special clinics to trained staff, will have to be in place.
For example, three high-profile drugs now in Phase 3 studies would need to be taken intravenously once a month in an infusion clinic, a more complicated scenario than exists with current Alzheimer’s treatments, which are taken as pills. Biogen (NASDAQ: BIIB) CEO George Scangos, whose company is testing one of those drugs, called aducanumab, worried during a speech earlier this year that there wouldn’t be enough infusion centers to accommodate “millions of people.”
“Millions” is a stretch, at least in the short term, for reasons we’ll see in a moment. (Asked to clarify Scangos’s comment, Biogen spokeswoman Christine Falcetti said it was “an observation of the current situation” with Alzheimer’s, not a projection for aducanumab.)
But the worries about preparedness are real. I asked several dementia specialists across the country if the healthcare system is ready for the new wave of Alzheimer’s treatments, should they make it to market. What they had to say revealed a complex interplay between drug companies, health providers, regulators, and insurance companies, often with one group waiting for another to make progress before moving ahead.
Looming above it all, of course, is the ever-present debate over healthcare costs. Alzheimer’s is exacting a social, medical, and financial toll on aging societies like ours. Caring for people with dementia costs three times as much, on average, as caring for people of the same age and health profile minus the dementia, according to a 2010 report by the Alzheimer Study Group.
But can we afford to treat Alzheimer’s if and when a next-generation drug or drugs come to market? The Alzheimer’s Association says one in nine Americans over 65 have the disease. That’s 5.1 million total, more than 90 percent of all Alzheimer’s cases. And as noted above, we’re aging fast, with 10,000 Americans turning 65 every day.
If a new drug is approved, no matter what kind or what the label says about the patient profile it’s meant for, doctors are bracing for the visits. “A lot of these people will be the ‘worried well,'” says Zaldy Tan, medical director of the Alzheimer’s and Dementia Care Program at the University of California, Los Angeles, which sees people with all manner of memory complaints.
“If there’s a blockbuster we’ll probably have to change our system to accommodate it,” says Tan. It’s too early to make concrete changes such as hiring more staff, he says, but he worries about the impact to his center, which is already managing the care of about 1,300 patients. “It could be overwhelming. What happens to those who don’t have dementia but still have the need for specialists?”
At the Banner Alzheimer’s Institute of Phoenix, director Pierre Tariot says it will be hard to game-plan until one of the big drugs produces Phase 3 trial results. “That will give us a little time to model what volumes of people we’re talking about, although it could be several hundreds of thousands in the U.S. if it’s a biologic.”
About those volumes: Arguably the most promising drugs in the late-stage pipeline—the “biologics” that Tariot refers to—are being tested on people with mild Alzheimer’s, who could account for anywhere from 25 percent to 40 percent of total cases, according to various estimates. If one or more of those drugs is approved for those patients, not all of them would show up at the doctor’s office at once, of course, or even be diagnosed in time to take advantage of the new drugs. But the surge could be significant.
Those drugs—all monoclonal antibodies—work by clearing the protein amyloid beta, which forms clumps or “plaques” in the brains of people with Alzheimer’s. But anti-amyloid antibodies have not worked in people with more advanced disease—as demonstrated by some of the big clinical trial failures of the past decade.
The working theory is that they’re being administered too late, the pharmaceutical equivalent of putting a Band-Aid on a person who has nearly bled to death. So researchers have moved their trials into patients who don’t yet have full-blown symptoms.
Eli Lilly (NYSE: LLY) of Indianapolis took solanezumab, which failed to improve people with mild to moderate disease, and tried again in a trial focused only on mild disease, which should produce results later this year. If all goes well Lilly could ask the FDA for approval of the drug in 2017. Cambridge, MA-based Biogen, jumped its aducanumab last year into twin 1,350-person Phase 3 trials in early Alzheimer’s, after a 166-person Phase 1 trial produced promising results.
And despite a failed Phase 2 trial with its anti-amyloid antibody gantenerumab, Roche saw hopeful signals in a sliver of patients with mild disease and is pressing ahead with a Phase 3 trial. (Both solanezumab and gantenerumab are also being evaluated as a preventative measure in a trial for people at risk for or starting to show symptoms of an inherited form of Alzheimer’s.)
People running these trials have taken great care selecting the patients for the experiments. If one of these drugs is approved for patients with mild Alzheimer’s, doctors will have to be just as careful. Assessing who’s in that window is no easy feat. Patients with mild Alzheimer’s have symptoms that have begun to affect their daily lives—like getting lost in their own neighborhood—but those can be due to other causes. Specialists wrongly diagnose Alzheimer’s in those who don’t have it about 30 percent of the time, and the false positive rate is even higher in non-specialists, says Peter Snyder, chief research officer of Rhode Island’s Lifespan Hospital System and a neurology professor at Brown University.
“Insurance companies will insist on scans,” says Snyder, to show that a patient really has a buildup of amyloid in his brain before agreeing to pay for an anti-amyloid drug. Such scans cost about $5,000 a pop, he says, raising the question whether everyone who needs one will be able to get one, either due to their location, their insurance coverage, or both.
One scan used to detect amyloid employs a tracer agent called florbetapir F 18 (Amyvid) that’s made by Avid Radiopharmaceuticals, which Lilly bought for $300 million upfront in 2010. The agent is approved by the FDA but not covered by Medicare.
And such scans aren’t foolproof. A percentage of people—one study says 20 percent—who have discernible amyloid in their brains never lapse into dementia.
Several clinicians told me they hope a less expensive test or set of tests will eventually make the scans irrelevant. (In this story, I delved into some of the technologies, like retinal scans, that one day could help diagnose Alzheimer’s.)
There’s a separate question about brain scans. Some drugs, such as Biogen’s aducanumab and Roche’s gantenerumab, can cause edema, or swelling, in the brain. Regulators might insist that patients who take those drugs be monitored with MRI scans for side effects, further straining the health system’s infrastructure. (Side note: Lilly’s solanezumab to date hasn’t produced edema problems, probably because it prevents amyloid plaques from forming instead of busting them up. Its approval might not require follow-up scans.)
Doctors’ role in sorting out who will benefit from a drug will remain important. But if an approved drug suddenly offers hope, specialists will be stretched thin. Primary care doctors will have to shoulder much of the load, which leads to a second point that several in the field raised with me: Training.
Thanks to the Affordable Care Act, the annual checkup for Medicare patients now includes a memory evaluation. But David Morgan, CEO and director of the University of South Florida’s Byrd Alzheimer Institute in Tampa, says because it takes extra time without separate reimbursement, doctors often do a perfunctory exam. “Most physicians check the box by asking if you’ve had memory problems lately,” Morgan says. “We need greater training.”
There are programs underway, such as this one run by the U.S. Department of Health and Human Services. Morgan’s group has received one of its grants. The Byrd Institute is recruiting retired healthcare workers to set up free memory testing sites in retirement communities, which could add a layer of screening to find people in the early stages of Alzheimer’s. (Morgan and George Vradenburg of USAgainstAlzheimer’s penned an op-ed for The Hill recently to make a plea for more preparation to Washington insiders.)
Out west, the Banner Institute’s parent group, Banner Health, is rolling out training to its healthcare workers to help with the influx of patients with dementia (whether new Alzheimer’s drugs are available or not). “The rest of the system has to become ‘dementia capable,'” says Tariot.
That includes specialty centers that do nothing but imaging or infusions. There are plenty of infusion centers for chemotherapy or multiple sclerosis drugs. If new antibody drugs become available for a huge population of patients with cognition problems, those patients could require monthly infusions for the rest of their lives. That could put a strain on capacity, not to mention the skills of the people running the front desk and putting in IV lines.
While Biogen’s Scangos has publicly worried about infusion capacity, others say a big Alzheimer’s market will provide incentive to build more or convert existing centers. “I don’t expect infusions will be a problem for those who want them,” says Phyllis Ferrell, vice president and global development leader for Alzheimer’s disease at Lilly, although she says the “experience” will need to be tailored to Alzheimer’s patients and the caregivers who bring them and wait—typically 30 to 60 minutes for the infusion process.
The big elephant in the room is cost. “Antibodies are going to be expensive,” says Morgan of the University of South Florida. Biogen’s Scangos has said publicly that, all told, Biogen will end up spending $2.5 billion on aducanumab development. After backing Biogen’s big bets in Alzheimer’s and other neurology indications, shareholders will likely push for ample reward.
While assessing those prices, payers will be pulled by the emotional appeal of a new Alzheimer’s drug, on one hand, and the calculus of how much benefit the drug provides. Because of the large over-65 population who would be taking the drugs, Medicare’s decisions will be key. But private insurers will be involved, as well, with younger patients showing tell-tale signs. “There are days we don’t see a person over 60,” says Rachelle Doody, director of the Alzheimer’s Disease and Memory Disorders Center at the Baylor College of Medicine in Houston, which has about 2,500 people in its care.
“If any treatment shows incremental value, people will be clamoring for it,” says Andy Behm, vice president, office of clinical evaluation and policy, at Express Scripts (NYSE: ESRX), the nation’s largest drug-buying middleman. “But if those benefits are in fact modest or incremental, you’ll probably see payers put guardrails around access.”
The pressures could be huge. “If Lilly blows the doors off” with fantastic data for solanezumab later this year, the temptation for doctors and patients “will be to think about it from a preventative standpoint,” says Behm, which would mean giving the drug to younger people with, say, a family history of the disease but not showing symptoms yet. “Ethically it’s going to be a challenging area.”
Medicare’s outlook is hard to parse. “Speculating is not in our best interest,” says Lilly’s Ferrell, noting Medicare’s decision not to cover the PET scan technology Lilly bought in 2010. “That surprised us,” she says. (A spokesperson for the Center for Medicare and Medicaid Services did not respond to my questions by press time.)
Morgan says that in the drug-price debate, the biggest factors should be whether a drug works well enough to keep people out of costly residential care facilities and boosts patients’ and family members’ work productivity.
Alzheimer’s is notoriously slow to develop. Clinical trials to measure a drug’s effectiveness over many years would be prohibitively expensive, so it’s possible regulators could approve a drug conditionally, then monitor it. Insurers could do the same. “Sometimes you’ve got to get the product on the market to understand its full benefit,” says Behm of Express Scripts. It’s a hint that flexibility and creativity will be necessary if and when an Alzheimer’s drug approval unlocks demand. But getting the drug to the right patients within the right window of time won’t be possible without a ton of preparation.