Studies are ‘muddy,’ reviews are mixed
If someone you love is suffering from Alzheimer’s, the most common form of dementia, wouldn’t you do everything possible to help them? What about if the medicine you give them has questionable usefulness or potentially dangerous side effects and costs a fortune?
That’s a question millions of people may face soon. The Food and Drug Administration (FDA) recently approved Aduhelm, also called aducanumab, in June, in one of its most contentious decisions. This came eight months after a harsh rejection of the treatment by an FDA advisory committee, which warned its supposed benefit relied on flimsy data and hasn’t been shown to help slow the brain-destroying disease.
Soon after, the FDA announced it is limiting the recommended use of Aduhelm to patients with mild cognitive impairment or early dementia, a change from the original label that included everyone. The revised label will mean that about two million people will be offered the drug, versus the six million suggested previously. They did this because the original announcement led to “negative attention and confusion.”
The new drug, which Biogen developed with Japan’s Eisai Co., is for mild cognitive impairment or early-stage dementia caused by Alzheimer’s. It is the first new Alzheimer’s treatment since 2003 and the first treatment ever sold to slow the deterioration in brain function caused by the disease, not just to ease symptoms. Other drugs for the disease only temporarily ease symptoms like memory problems, insomnia and depression.
Inside the agency, there were disagreements about how to handle the drug, which was designed to slow cognitive decline but had confusing data on effectiveness. Eventually, the FDA decided against “full approval.” One of the main clinical trials did not show a benefit to patients, but another late-stage trial and an early-stage trial showed the drug helped, agency officials concluded. But that study was marred by hard-to-interpret results. The data were so murky that the FDA ultimately granted the drug conditional approval based on a different measure: its ability to get rid of harmful clumps of plaque in the brains of patients with early forms of the disease.
The FDA gave “accelerated approval” for the drug, saying it was “reasonably likely” the treatment would slow cognitive decline in patients. Critics assailed the decision, arguing that the FDA approval represents a dangerous lowering of standards in response to pressure from patients and advocacy groups.
Understanding Alzheimer’s
Alzheimer’s is a type of brain disease, the same way coronary artery disease is a type of heart disease. Alzheimer’s gets worse over time and is thought to begin 20 years or more before symptoms arise. It usually starts with changes in the brain that are unnoticeable to the person affected. A toxic protein called beta-amyloid slowly accumulates and eventually disrupts another protein that is critical to brain function. Over time, people suffer memory loss and language problems because nerve cells or neurons in the brain involved in cognitive functions like thinking, learning and memory have been damaged or destroyed. As the disease progresses, other parts of the brain are also damaged. Over time, the parts of the brain that allow a person to carry out basic functions like walking and swallowing are affected. People become bed-bound, requiring around-the-clock care. Alzheimer’s is ultimately fatal.
Aducanumab, the new medication, is a monoclonal antibody, a protein made in the laboratory that can bind to substances — in this case, clumps of amyloid beta, a sticky plaque compound that many scientists think causes the brain damage. The treatment is designed to trigger an immune response that removes the plaques.
There have been controversy and questions since the 1990s about the “amyloid hypothesis,” a theory that amyloid plaques are the cause or at least an important hallmark of Alzheimer’s and should be targeted. Detractors say this approach has yielded a string of failed drugs – including ones that clear amyloid but don’t improve cognition – and that has squeezed out other approaches. But supporters say using higher doses of anti-amyloid treatments and administering them much earlier will make them effective. What both sides agree on is that other approaches need to be explored and it will probably require a combination of drugs to find an effective treatment.
More than six million Americans have Alzheimer’s currently, a number expected to jump to 14 million by 2060 in the U.S. It is the sixth-leading cause of death in the U.S. and quickly moving up on that list. With deaths due to Alzheimer’s rising 145 percent over the past 20 years, the disease not only robs individuals of their autonomy but also places a huge burden on family members. Caring for people with Alzheimer’s in the U.S. cost $355 billion last year, and that number is skyrocketing.
Mixed reviews
Supporters, including some doctors who treat Alzheimer’s, and advocacy groups such as the Alzheimer’s Association and UsAgainstAlzheimer’s, acknowledge the drug’s clinical trial data is far from perfect. They argue it would help some patients and will result in increased research and investment into therapies. But Harvard’s Kesselheim, who quit the committee after the approval, said it’s cruel to people with Alzheimer’s to “put out a product that doesn’t work,” which will be sold at an extremely high price and waste resources that could go to other potential solutions.
While the medication could potentially slow down the disease, giving patients more valuable time with their families, critics point out that the studies so far have had potentially dangerous side effects so there are risks involved. In two of the largest Biogen clinical trials, brain swelling and hemorrhages or tiny bleeds occurred in about 40 percent of participants. While the side effects usually resolved, in rare cases they led to more severe bleeding that could potentially cause brain injury or other dangerous complications. And about 6 percent of patients had to quit the trials because of the brain swelling or brain bleeding.
Where this all gets even more controversial – for the patients and their families – is the cost. Aduhelm is expected to carry a price tag of $56,000 a year per patient and it has the potential to be used by millions of patients, adding multi-billions of dollars to the nation’s health tab – with Medicare and Medicaid picking up the bulk of that, depending how FDA writes the rules.
Moving forward, Medicare, Medicaid and other entities are expected to require brain MRIs to monitor anyone taking the drug, which could easily approach $10,000 the first year, according to physicians. One study proponent, who favors the FDA decision, estimated that one out of 200 or 300 individuals could have serious side effects that might require hospitalization.
Insurers will likely require prior approval of those scans, which could delay care for many. They will likely cover the scan costs as well as other medical costs, but depending on coverage, patients still might be liable for thousands of dollars annually from the scans and treatments due to deductibles and other out-of-pocket costs.
One carefully calculated budget projection of the costs suggested that spending on the drug for Medicare patients could end up being higher than the entire budgets for the Environmental Protection Agency or NASA. An estimated six million Medicare enrollees do not purchase supplemental drug coverage, so they would have to pay 20 percent of the drug’s cost, which would be $11,200 this year. It is also impossible to predict the costs for people covered under Medicare Advantage.
Many other practical questions remain including how long do patients benefit? How do physicians determine when to discontinue the drug? Does the drug have any benefit in patients with more advanced dementia?
Dr. Stephen Salloway, a Brown University professor of neurology and psychiatry, who directs the Memory and Aging Program at Butler Hospital and has been researching Alzheimer’s disease for 30 years, has been closely involved with the clinical development of the drug. He understands the desperation situation of patients and families facing no treatments for the disease. If he told patients there was a new Alzheimer’s drug with mixed data on effectiveness and asked whether they would like to try it “they’d say, ‘Are you nuts? Of course I would,’” Salloway told the Washington Post.
The controversy over the drug has focused on whether or not the drug works. But another major issue has received less attention: which patients should receive the drug and what doctors should do to prescribe it responsibly and safely.
While the only patients who received the drug during clinical trials were those with very mild Alzheimer’s or an even milder pre-Alzheimer’s impairment, the FDA’s label for the drug says simply it is “for the treatment of Alzheimer’s disease.” Under “contraindications,” the term for health conditions or other characteristics that should prevent patients from taking a drug, the label says “None.”
The broadness of the label has surprised and concerned even the biggest champions of the drug. Even advocates for the drug like Salloway suggest limits. He suggests doctors should only try the drug on those in early stages of the disease whose brains contain high levels of amyloid, the group that the drug has been tested on, instead of people with later stages of Alzheimer’s.
Congress, budget experts and many Democratic and Republican White House administrations have spent many years suggesting ways to trim spending in Medicare, a large and growing share of the federal budget. Sens. Elizabeth Warren, D.-Mass., and Bill Cassidy, R.-La. recently called for hearings, concerned that spending billions on Aduhelm could undermine Medicare and Medicaid. The House Committee on Oversight and Reform has already announced an investigation into the drug’s approval and pricing.
Medicare, which covers 61 million Americans 65 and over, does have some tools to contain costs, but it cannot negotiate a bulk price purchase for the drug. It could decide to cover the drug in a way that is more limited than the FDA approval, a break from its normal practice.
Or it could do something even more unusual: try putting the drug into a randomized experiment to evaluate how well it works — paying to cover the drug in some parts of the country, but not others. Such policy experiments were authorized under the Affordable Care Act, but one has never been used to limit coverage of a drug in this way.
The companies now have nine years to complete an additional clinical trial demonstrating that the drug can reduce the onset of Alzheimer’s disease, although revoking approval for a drug is rare.
Critics suggest that Biogen should conduct a third trial, but Johns, of the Alzheimer’s Association, said a third trial would simply take too long — four to six years — during which more and more patients would slide deeper into dementia. But it also means that patients will be using the drug without actually being certain that it has the ability to help them.
A useful resource for families dealing with potential Alzheimer’s cases:
https://www.alzheimersnavigator.org
Also contributing to this column: Washington Post, New York Times, Forbes; Roll Call; and NBC.
