The press release issued by pharmaceutical companies Eisai and Biogen on Sept. 27 might someday be remembered as the beginning of a revolution in Alzheimer’s diagnosis and treatment.
Years and years of failed Alzheimer’s trials created, and then fortified, doubts about whether drugs that attacked amyloid, a brain protein linked to Alzheimer’s disease, were a valid approach to its treatment. Those doubts may have been quelled.
The companies reported so-called top-line results of CLARITY-AD, a study of their drug lecanemab, among individuals with either mild cognitive impairment (MCI) or mild-stage dementia and evidence of accumulation of amyloid in their brain. “Top line” describes overall summaries of the results of the primary and secondary endpoints.
The drug slowed declines in both cognitive and day-to-day functions, and reduced the amount of amyloid in the brain. If these data hold up to scrutiny, lecanemab sounds like a drug I might prescribe.
Or maybe not.
The development of Alzheimer’s drugs has borne incredibly gifted and talented children but, like childhood actors, they suffer rough and often disastrous transitions into adulthood. The poster child is the FDA’s breathtaking decision to approve Biogen’s drug aducanumab (Aduhelm) based on conditional approval that relied only on the drug’s well-documented ability to reduce amyloid biomarkers. Aducanumab didn’t effectively slow declines in cognition or function. Based on data made public before the FDA’s ruling, I did not intend to prescribe the drug if the FDA approved it.
A trustworthy process is needed to review the lecanemab data and, if they hold up, I’ll have to decide whether to bring it into my clinical practice or accept that it’s not ready for me to prescribe.
This process should learn from history.
Present the data expeditiously
Drug development is a business. I entirely respect the requirement for a company to expeditiously release material information, like the CLARITY-AD results. Lecanemab may be a breakthrough, the proof that amyloid is among the causes of Alzheimer’s disease, but the data were presented in a press release, not a peer-reviewed scientific paper or a presentation at a scientific meeting.
Memories of aducanumab linger. Presentations about it at scientific conferences were a frustrating series of highly curated talks with little time for questions and debate. Publication of the results in the medical literature suffered a bad case of writer’s block — it came months after the FDA’s decision.
This November, CLARITY-AD’s results will be presented at the Clinical Trials on Alzheimer’s Disease meeting in San Francisco. I hope ample time is afforded for questions, discussion, and, yes, debate. Quite soon, before FDA’s decision, I look forward to reading the paper that presents the results, from top to bottom.
Clearly describe the disease and the patients
If lecanemab is approved, its label will be read with great care. Clinicians, as well as insurers such as Medicare, will scrutinize the text to decide for whom this drug is reasonable and necessary. There will be no room for ambiguity or second-guessing language. The label has to speak to clinical practice.
And therein is the grand irony that everyone will confront as they decide how to use lecanemab to tackle Alzheimer’s disease. To participate in the trial, people had to have had evidence of elevated amyloid, a biomarker of Alzheimer’s disease. Yet there’s no widely accepted clinical practice that integrates assessments of cognition, function, and biomarkers. Their use is largely limited to research settings. CLARITY-AD could change this.
Again, we can learn from aducanumab.
Aduhelm’s label originally read “for the treatment of Alzheimer’s disease.” This invited the wild idea that aducanumab might work in persons who are cognitively unimpaired but have elevated amyloid or with moderate-to-severe-stage dementia. The label was also silent on what biomarkers, if any, should guide prescribers.
A defense of the text was that FDA doesn’t instruct clinicians about how to diagnose a disease. That is true, but FDA did revise the label in the weeks following its approval to specify patients with mild cognitive impairment or mild dementia.
The Biogen/Eisai press release suggests the lessons of aducanumab haven’t been fully learned. It describes participants in CLARITY-AD as having “early Alzheimer’s disease.” Honestly, I’m not sure what this novel term means. I expect it will be confused with “early onset Alzheimer’s” signifying AD that begins before age 65. The press release explains the participants had either “mild cognitive impairment (MCI) due to Alzheimer’s disease (AD)” or “mild AD.”
The problem here isn’t simply the lack of parallel structure; it is that the two groups of patients who were studied were labeled using two different conceptual models of Alzheimer’s disease.
One group is described with a clinical stage — mild cognitive impairment — and a cause of it — Alzheimer’s disease, the disease of amyloid accumulation (another protein that may be involved in Alzheimer’s, tau, was not an eligibility requirement for CLARITY). The second group, however, isn’t described with a clinical stage. “Mild AD” could refer to some sort of mild stage of pathology or a mild stage of clinical Alzheimer’s, such as dementia.
“Mild AD” sounds like the pre-biomarker era of Alzheimer’s nomenclature, when Alzheimer’s disease was synonymous with dementia. In fact, the term is shorthand for “mild stage dementia due to Alzheimer’s disease,” the more precise nomenclature used on the trial’s listing on clinicaltrials.gov. Mild cognitive impairment and mild-stage dementia due to Alzheimer’s disease together with a clear statement about biomarker positivity are starting points for a coherent label.
Making sense of lecanemab’s benefits
Lecanemab’s benefits were measured using the Clinical Dementia Rating, or CDR, a scale that blends assessments of cognition and function. It’s essentially unknown to clinicians.
Researchers use the CDR to stage Alzheimer’s into one of five categories, ranging from normal to severely impaired. It also can be turned into a score ranging from 0 to 18, with higher scores indicating greater impairment. This is called the “sum of boxes.” A great debate is beginning over the reported 0.45 difference between the drug and placebo groups on this score.
Is a half-point difference on this 18-point scale clinically significant? It is worth lecanemab’s well-quantified risks of brain swelling and bleeding?
What’s notable to me is that the participants’ scores were all clustered at the low end of the scale. The CDR isn’t a measure of the mind but, in this range, one-half a point may well be a notable preservation of a mind that is experiencing progressive damage and transformed feelings of identity and sense of self.
The Clinical Dementia Rating and measures of cognition and function may be sufficient for the FDA to approve the drug (I’m assuming full approval here, not accelerated approval). But unlike cancer or heart disease where measures of benefit are reduction in deaths, strokes, and heart attacks, the language of benefit for an Alzheimer’s therapy is neither clear nor simple.
As Medicare scrutinizes these benefits, it will decide whether to stick with the “coverage with evidence development” requirements it issued in the aftermath of aducanumab’s approval. The insurer of the majority of people living with Alzheimer’s will only cover a prescription for an anti-amyloid therapy provided data are also being gathered to better understand the drug’s benefits and harms.
A national registry that captures the health and well-being of patients prescribed and those not prescribed make sense. Lecanemab is a notably innovative drug. Its endpoints are not routinely measured in clinical practice.
This registry must be as pragmatic as possible. To expect clinicians to conduct the Clinical Dementia Rating for each patient, complete consent forms, and go to websites to enter data will introduce hassles — as well as underreporting and sloppy data. Ideally, the registry would be linked to the use of long-term care services and supports. But the U.S. doesn’t have such a system.
A revolution in diagnosis and treatment and perhaps also creating a long overdue learning and caring health care system: this promising young drug has some great expectations to live up to.
Jason Karlawish is a professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine; co-director of the Penn Memory Center; and author of “The Problem of Alzheimer’s: How Science, Culture and Politics Turned a Rare Disease Into a Crisis and What We Can Do About It” (MacMillan, 2021). He is also a site investigator on clinical trials sponsored by Biogen, Eisai, and Eli Lilly.