Alzheimer's Press Release Heard ‘round the World
In a press release last week with perhaps the longest headline in history, Eisai Co., Ltd., a Japanese firm, and Biogen Inc., the Cambridge company behind last year’s ill-fated launch of the Alzheimer’s drug, Aduhelm, announced dramatic results from a clinical trial of a new Alzheimer’s medication called lecanemab.
Medical experts cautioned against reading too much into a press release and said they awaited more details. Many then added, however, that lecanemab appears to be an impressive development in treating early Alzheimer’s patients. Of equal importance, perhaps, is the trial’s claimed confirmation of the connection between the disease and the accumulation of amyloid proteins in the brains of people with Alzheimer’s.
First, though, that headline, in bold-face capital letters:
LECANEMAB CONFIRMATORY PHASE 3 CLARITY AD STUDY MET PRIMARY ENDPOINT, SHOWING HIGHLY STATISTICALLY SIGNIFICANT REDUCTION OF CLINICAL DECLINE IN LARGE GLOBAL CLINICAL STUDY OF 1,795 PARTICIPANTS WITH EARLY ALZHEIMER’S DISEASE
“Lecanemab treatment met the primary endpoint and reduced clinical decline on the global cognitive and functional scale, CDR-SB, compared with placebo at 18 months by 27 percent,” the press release said, “which represents a treatment difference in the score change of -0.45 (p=0.00005) in the analysis of Intent-to-treat (ITT) population. Starting as early as six months, across all time points, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all p-values are less than 0.01).”
With apologies for clinical details that likely will send you to a medical dictionary (see below for more on CDR-SB), these results were encouraging enough to prompt the companies (with Eisai as the lead firm) to seek accelerated approvals for needed government reviews that would lead to commercialization of the drug. In the clinical trial, participants received lecanemab infusions every two weeks.
From my grandstand seat, Biogen’s willingness to trumpet these findings so aggressively is certainly an attempt to recover from Aduhelm (see that story here). But the fact that the bruised company supported such a positive spin is noteworthy in its own right.
“The lecanemab Clarity AD study results prove the amyloid hypothesis, in which the abnormal accumulation of Aβ in the brain is one of the main causes of Alzheimer’s disease, when targeted with a protofibril-binding therapy, Eisai CEO Haruo Naito said in the release. “Eisai believes these findings will create new horizons in the diagnosis and treatment of Alzheimer’s disease as well as further activate innovation for new treatment options.”
If lecanemab is ultimately cleared by the U.S. Food and Drug Administration, Medicare will be under pressure to cover the drug. Health experts noted that unlike the Adulhelm fiasco, the Eisai clinical trial was skillfully crafted as part of a long-term strategy to commercialize the drug. Eisai said in its release that participants in its trial, which was called Clarity AD, matched the profile of the U.S. Medicare population.
Here are selected excerpts from news stories about the announcement. The medical news site STAT did a particularly thorough job.
The company said on Tuesday night that it would first continue with the accelerated approval process, with an F.D.A. decision expected by early January, and then use the newer data to seek full approval. (Accelerated approval requires companies to do further trials and prove that their drug works.)
Some experts said the drug’s ability to slow cognitive decline — by 0.45 on an 18-point scale — was modest at best and might not be a difference that patients in the mild early stages of the disease would notice.
The drug reduced cognitive and functional decline by 27 percent, compared with a placebo. The data, which haven’t yet been published in a peer-reviewed medical journal, hit all of the trial’s primary and secondary endpoints, with many analysts calling it a best-case scenario. Importantly, while the drug did show safety concerns such as brain swelling, it looked safer than other candidates now making their way through clinical trials
The positive data make it likely that the Food and Drug Administration will grant Biogen accelerated approval in January, with full approval coming later next year. The bigger question for investors, patients and society is what the Centers for Medicare and Medicaid Services will do. Biogen’s last approved drug for the disease, Aduhelm, received the FDA nod, but CMS effectively killed its commercial prospects by restricting it due to lack of meaningful improvement in health outcomes.
From a statistical point of view, the results are strong, and likely enough to get full approval in the US, experts said, while cautioning the magnitude of benefits is hardly enormous.
“For the field of Alzheimer’s disease research, this is a sort of a triumph,” said Marsel Mesulam, a neurologist at Northwestern University’s Feinberg School of Medicine. “The not-so-good news is that this is very cumbersome, it has side effects, it is likely to be very expensive, and the clinical effect is very, very small.”
Eisai’s success might also be due to the fact it took its time to perform the clinical trials right. It conducted an unusually large phase-2 trial, involving more than 800 people, helping it select the most effective dose, which turned out to be the highest one. Then it ran a massive phase-3 trial involving almost 1,800 patients -- big enough to spot even small benefits from the drug. Eisai let the trial run to the end instead of halting it early, as Biogen did with Aduhelm.
The benefit seen in the Eisai trial “is below what is generally considered clinically significant,” said Rob Howard, a professor of old age psychiatry at University College London. “This will be a problem” in places like the UK where cost effectiveness is a key determinant of coverage, he said.
The CDR-SB scale used in the trial incorporates six cognitive metrics, including memory, problem solving, and personal care. Higher scores on the 18-point scale indicate more advanced dementia.
Mia Yang, a geriatrician at Wake Forest, noted that the impact of a .45-point difference on the scale depended on where someone was. Someone with a CDR score of 0.5, for example, might have some memory problems but could still keep up with daily activities. Someone with a score of 1, however, might start encountering some functional losses.
A half-point difference wouldn’t mean much for someone with more advanced Alzheimer’s, Yang said.
“I’m cautiously optimistic that it could be potentially meaningful for those folks who are in the mild stage,” Yang said about lecanemab. Indeed, the trial focused on people with early-stage Alzheimer’s.
STAT (STAT stories are normally behind a pay wall.)
Here’s the thing about randomized controlled clinical trials, the type of studies used to test most new drugs: They are medicine’s mic drop. By randomly assigning patients to get one treatment or another, they reduce the risk that a result is due to bias. But even more than that, they are the closest things that science has to a definitive experiment. If one medicine shows a benefit over another, or over placebo, in a perfectly constructed randomized controlled trial, there is simply no debate over which to use.
We can’t be 100 percent sure of the lecanemab results because they were presented via a press release that leaves key questions unanswered. (Full results will be presented at a medical meeting in November.) One big question is whether patients did better or worse on these questionnaires depending whether they had a side effect called ARIA, for “amyloid related imaging abnormality,” which can indicate swelling in the brain. ARIA is a side effect of amyloid drugs, and if patients were aware whether they received drug or placebo that could affect how they or their doctors answered questions.
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CLARITY-AD was the first domino in what could be a transformational nine months for Alzheimer’s research and the decades-long debate over the amyloid hypothesis. Later this year, Roche will have data from a pair of two-year studies on gantenerumab, a competing amyloid treatment. And in the first half of next year, Eli Lilly will disclose Phase 3 results for donanemab, another medicine aimed at the same target.
But amyloid comes in many forms, and success for one treatment doesn’t necessarily make the case for the rest. Lecanemab specifically targets what are called amyloid protofibrils, free-flowing proteins that eventually twist together and become plaques. Gantenerumab, by contrast, targets one species of amyloid that has already aggregated into plaque, while donanemab is aimed at another. Each has demonstrated substantial reductions in amyloid measure by PET scans in earlier studies.
Eisai won’t announce lecanemab’s price until it has the approval in hand, but $28,000 per year is a reasonable estimate — and one that some sell-side [investment] analysts are using in their financial models. Recall, Biogen initially priced Aduhelm at $56,000 per year, but then cut the price in half in an attempt to assuage critics and smooth reimbursement. (It didn’t work.)
Philip Moeller is the principal author of the Get What’s Yours series of books about Social Security, Medicare, and health care. @PhilMoeller