Show us the data

Collecting good information on patient outcomes can prove if those new Alzheimer's drugs are worth their hefty price. Will CMS get it right?

Last month, the Food and Drug Administration approved Eisai Inc.’s lecanemab (Leqembi), the first of a new class of drugs for treating Alzheimer’s disease. FDA approval of a second drug in this class, Eli Lilly’s donanemab, is anticipated by the end of the year.

These drugs could wind up costing taxpayers and seniors tens of billions of dollars a year. The extent to which these new drugs, which clear amyloid plaque from the brain, slow a person’s descent into dementia and at what risk to their health remain open questions.

I am as desperate as anyone for medical science to come up with something that is truly effective at halting or substantially delaying dementia. My grandfather, my father, my paternal uncle, and my older brother each became mentally absent following a half decade of decline. I have seen the family heartache and caretaker grief caused by the slow-motion destruction of a human personality.

The APOE ε4 genetic mutation, which heightens one’s risk of developing Alzheimer’s and is more prevalent among Ashkenazi Jews than the general population, may run in my family. I have never been tested. Why bother when there is nothing you can do about it other than what I already do, which is to stay mentally engaged (by continuing to write this column, for instance) along with all the other things one does in pursuit of a long and healthy life.

But what if I have it, and I begin showing signs of cognitive decline? What I will want to know before taking any dementia drug, including the two in this new class, is whether there was accurate measurement of patient outcomes from their use in the general population – not just in the controlled setting of an industry-run clinical trial. And I want greater insight not just into their known side effects, but any other negative consequences that may not have shown up in trials where fewer than 2,000 people took the drugs. And I want to know how different sub-populations responded to the drugs once they are widely deployed.

Minimal benefit, big risks

What we know so far is that the results in the industry-run approval trials for both drugs showed a remarkable ability to clear plaque. But both trials yielded only a modest slowing in patients’ decline from mild cognitive impairment or mild dementia due to Alzheimer’s – about four to seven months. The trials also revealed substantial risks, including cerebral bleeding and a few deaths. Patients with the APOE ε4 genetic mutation were at greater risk of experiencing those side effects.

Importantly, this was not four to seven months with no decline. Both groups – those given monthly infusions of the drug and those infused with a placebo – continued their descent into dementia through the 18 months of the trials. The only benefit to the group getting the plaque-clearing drug was that it took a little longer to get to the same level of dementia.  

Numerous medical commentators have referred to the results as having “minimal clinical relevance.” The independent evaluation committee at the Institute for Clinical and Economic Review, which evaluates the cost-effectiveness of new medical technologies, recommended slashing lecanemab’s planned price of $26,000 a year by as much as two-thirds. Its scientific panel voted 12-3 that “the evidence is not adequate to demonstrate that the net health benefit of lecanemab added to supportive care is superior to supportive care alone.”

An editorial in JAMA, where the results of donanemab’s trial appeared last month, noted the obvious. “The exceptional ability of drugs such as donanemab and lecanemab to remove amyloid, paired with their rather subtle effect on the rate of decline in cognitive and functional measures, suggests that amyloid is likely not the only factor that contributes to Alzheimer disease progression.”

Registries to the rescue?

Given the minimal clinical benefits and the disturbingly high level of risk (about one in five patients experienced cerebral bleeding), the Centers for Medicare and Medicaid Services set one condition before it will pay for the drugs, tests and physician fees, which will bring the total cost of treatment to about $85,000 per patient per year. (There are an estimated 6 to 7 million people living with Alzheimer’s, with about a half million to 1 million new diagnoses of its beginning phase, and thus eligible to start on the drugs, each year.) CMS will require prescribing physicians to deposit data about their patients’ use, outcomes and side effects in a publicly-available registry open for analysis by outside and independent researchers – properly de-identified, of course.

Will CMS administrator Chiquita Brooks-LaSure stand up a rock-solid registry for Alzheimer drugs?

The drug industry is already balking at the registry requirement and may be working to undermine its effectiveness. Eli Lilly CEO David Ricks told CNBC last month that the data registry requirement appears to be a “pretty light touch,” won’t “take a lot of effort,” and will wind up being “pretty low value.” Ricks expressed hope the registry requirement will be “rescinded in time.” PhRMA, the industry trade group, also blasted the registry requirement, claiming it will “severely restrict” patient access by erecting a barrier to “potentially life-changing” treatments.

There is one private registry already in operation called ALZ-NET, which is run by the Alzheimer’s Association. In late July, about two dozen independent researchers, including a former head of the Medicare Payment Advisory Commission and a former chair of CMS’ Medicare Evidence Development and Coverage Advisory Committee, wrote HHS Secretary Xavier Becerra and CMS administrator Chiquita Brooks-LaSure to express concern that a proliferation of private registries may undermine the government’s goals for having a registry in the first place.

“We are very concerned that Leqembi registries developed by medical societies, medical centers, nonprofit organizations, or other non-governmental entities may limit access to their respective population-level data, potentially making it difficult for CMS and other researchers to conduct independent analysis of the data,” the letter said. “As a condition of coverage, CMS should require that population-level data from any and all registries be made available to CMS (and preferably other researchers as well) to be independently statistically analyzed, and that all registries, whether government-sponsored or privately maintained, obtain a baseline level of information.”

They also called for all registries to use a common set of measured variables, including a single standard for measuring cognitive impairment. “If different measures are used by different registries, and those registries also vary in terms of the diversity of patients or other variables studied, it will be difficult if not impossible to draw conclusions,” they wrote.

I asked the Alzheimer’s Association about plans for its registry. A spokeswoman replied that its de-identified data will be “shared quickly and transparently with a variety of stakeholders, including researchers, regulators, such as the FDA, and payers, such as CMS.” She added “ALZ-NET is gathering significantly more data than is required by the CMS registry,” including “demographic, medical history, neurologic, cognitive, functional, genetics, imaging, biomarker, treatment and safety data.”

Will it be adequate? Will CMS have high standards for its own registry?

I’m in no position to judge since I’m not a researcher. That is something the scientists at CMS and the FDA must decide, since they are responsible for determining whether these drugs are providing significant benefits with acceptable harms, and are worth the tens of billions of dollars this country is about to spend on them – money that otherwise might go to supporting caregivers and improving the quality of life of seniors enduring the living hell of dementia.