A Prescription for Frustration

Alzheimer’s sufferers and their caregivers no doubt cheered the June 9 decision by a Food and Drug Administration advisory panel that will likely lead to the agency’s full approval this week of a drug that may slow the progress of the disease. A number of factors, however, may dampen their enthusiasm as the long slog toward a cure continues.

The panel examined a late-stage clinical study showing lecanemab, which Big Pharma giant Eisai will sell under the brand name Leqembi, slightly slowed the rate of cognitive decline among patients — essentially outperforming a placebo. That moderate benefit, panelists agreed, outweighed the risks of brain swelling some study participants experienced.

As Alice Park reports in Time, one of the study’s researchers, Sharon Cohen, MD, medical director of the Toronto Memory Program, argued that any treatment that extends a patient’s ability to live independently is worth the risk. “The ability to remain at an earlier stage of disease for a longer period of time is incredibly important,” she noted.

While that argument won the day at the FDA, it seemed to land with a thud at the Centers for Medicare and Medicaid Services (CMS). Officials there had already stated the agency would only cover the costs of the treatment ($26,500 per year) for patients who agreed to enroll in a national registry designed to collect “evidence about how these drugs work in the real world,” and they showed no signs of changing their position after the advisory panel’s unanimous ruling.

It’s essentially the same stipulation CMS placed on its coverage of Aduhelm, Biogen’s Alzheimer’s drug that received accelerated approval from the FDA last year despite similarly tepid clinical trial results. And, as in the Aduhelm case, those limitations are guaranteed to suppress demand — and frustrate patient-advocacy groups and Big Pharma. “The question becomes what CMS means by ‘registry,’” Eisai CEO Ivan Cheung tells Time. “No one knows the answer — only CMS does. Until CMS puts out an operational manual about how it’s going to work, we are all guessing.”

That’s not the only guesswork that’s obstructing access to Alzheimer’s treatments. As Jason Karlawish, MD, writes in STAT News, “The problem isn’t the drugs. It’s the drugs in the [healthcare] system.”

Karlawish, a professor at the University of Pennsylvania’s Perelman School of Medicine and codirector of the Penn Memory Center, argues that the various challenges inherent in evaluating and prescribing Alzheimer’s drugs dampens any hope of a breakthrough. “If we’re going to have the better drugs,” he writes, “we need a better system.”

Because these drugs are designed to treat patients who display signs of mild cognitive impairment or early-stage dementia — or those who carry certain disease biomarkers — diagnosis is extremely tricky, he explains. Physicians need to compile a reliable history from the patient and a close friend or relative, review and interpret the results of cognitive tests and PET scans, and then weigh the risks of a brain bleed against the benefit of a few extra months of lucidity.

“These new drugs mean more real harms from mis- or missed diagnosis,” Karlawish warns. “A missed diagnosis (‘It’s normal aging . . .’) sends away a person who might benefit from an effective treatment. A false positive will unnecessarily expose a person to the drugs’ risks.”

Not surprisingly, few general practitioners feel comfortable making an Alzheimer’s diagnosis, he adds. They are seldom prepared to care for these patients and there are few specialists available to assist them in the treatment. Even most neurologists, geriatricians, and geriatric psychiatrists lack the skills to diagnose the disease at its early stages and prescribe the appropriate drugs.

Plus, even trying to calculate the benefits of the treatment remains difficult. “The benefit of cancer treatments such as CAR-T is measured with a simple language: Patients live longer.

That’s easy to measure and to understand,” he explains. “In dementia treatment, survival has never been measured as a benefit. Instead, we speak of living longer in a certain state of mind. The measures we use — cognition and day-to-day function — and the significance of changes in them aren’t readily understandable.”

Unable to clearly grasp the benefits, experts tend to focus primarily on the risks — a perspective that may be fueling CMS’s reluctance to cover the costs of these drugs without gathering substantially more data on their effectiveness. Hence the registry gambit.

While CMS officials work out the details on that particular data-collection system, Karlawish argues that a similar process has already proven effective in keeping promising, but controversial, drugs available to patients. The FDA has employed more than 300 Risk Evaluation and Mitigation Strategies (REMS) since 2007 to set education and monitoring requirements designed to mitigate a medication’s risk.

He points to a REMS initiative that collected sufficient risk/benefit information to keep Tysabri, a promising drug to treat multiple sclerosis, available despite clinical results showing a rare brain infection among some study participants. A similar process has been used to gain approval of politically controversial drugs, including mifepristone.

REMS is a proven tool that could be used to evaluate Alzheimer’s drugs, as well. Providers would be required to compile various patient characteristics, such as genetic biomarkers, disease histories, and current medication use, while also sharing MRI results showing any signs of microhemorrhages or other symptoms. “This would likely satisfy Medicare’s coverage with evidence development requirement for a registry,” he writes. “In fact, Medicare and the FDA might actually design it together.”

That might qualify as wishful thinking, given the divergent priorities of the two agencies. The FDA, under immense pressure from patient-advocacy groups and Big Pharma, is all about expanding access to promising treatments. CMS, on the other hand, no doubt views with some trepidation the potential costs of covering millions of Alzheimer’s patients in the years ahead.

That equation alone, never mind the limited capabilities of our current healthcare system, suggests Alzheimer’s patients and their caregivers still have a long way to go — no matter what miracle drug comes down the pipeline next.

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