Last month, the FDA fully approved lecanemab (brand name Leqembi) for the treatment of Alzheimer’s Disease. This drug targets beta-amyloid, one of the proteins believed to be responsible for the progression of Alzheimer’s. Unlike its predecessor drug aducanumab, lecanemab actually showed a statistically significant difference in slowing cognitive decline in its clinical trial. But can the drug improve patients’ quality of life?
Statistical vs clinical significance
Dr. Susan Molchan and Dr. Adriane Fugh-Berman, researchers from the PharmedOut project at Georgetown University Medical Center, explain why they’re skeptical of the new crop of Alzheimer’s drugs, in a recent Viewpoint in JAMA Internal Medicine. They write, “A statistically significant change on a test or scale does not mean that the change is clinically significant, such that patients or their families would see a benefit in their daily lives.”
According to the clinical trial of Leqembi published in the New England Journal of Medicine, the drug actually shows a statistically significant impact on measures of cognitive decline (not just a reduction of beta amyloid like Aduhelm). However, we don’t yet know whether the result is clinically significant (a big enough difference to improve patients’ quality of life), given that the differences in cognitive decline between the two groups was small. Leqembi users showed a 0.45 point difference on the Clinical Dementia Rating compared to the placebo group, which previous research has not found enough to be a “meaningful” clinical change.
If the patient or their families don’t see an improvement in their daily lives, if there is no meaningful change in retaining cognitive function or how they interact with loved ones, are they really doing “better”?
“A statistically significant change on a test or scale does not mean that the change is clinically significant, such that patients or their families would see a benefit in their daily lives.”
-Susan Molchan, MD and Adriane Fugh-Berman, MD, of PharmedOut at Georgetown University Medical Center
This isn’t the first time a class of drugs for Alzheimer’s produced promising results but failed to deliver on clinical significance. While the beta-amyloid hypothesis remains dominant today, the cholinergic hypothesis ruled up until the 90s. Molchan and Fugh-Berman remind readers that drugs cholinesterase inhibitors like donepezil, which were approved to treat Alzheimer’s in 1996, had similar results in clinical trials as this new class of drugs that target beta-amyloid. They showed a reduced decline in cognitive function that passed the test for statistical significance, but did not meet the threshold for clinical significance. Cholinesterase inhibitors are rarely prescribed for Alzheimer’s today, and yet lecanemab, with similar results, is being hailed as something revolutionary. Is this real innovation, or just history repeating?
New drugs aren’t risk-free
There are other reasons to be cautious about lecanemab and other new Alzheimer’s medications. Some physicians and patient advocates have remained wary of the newly-approved drugs due to their concerning side effects ranging from brain atrophy to death, especially given the dearth of evidence showing clinical significance.
These treatments are also expensive. A recent report by UCLA estimated that lecanemab could cause a $2-5 billion increase in annual Medicare spending. Out-of-pocket costs for patients lacking coverage could reach up to $6,600 per year, or about 20% of the median income of Medicare beneficiaries. As the report notes, additional costs likely lead to increased premiums, and many Americans are already living close to the edge financially as is.
Molchan and Fugh-Berman point out that the resources directed towards biochemical interventions might have more impact if applied towards preventative measures. “Focusing on drugs for Alzheimer disease with at best marginal efficacy distracts from the use of drugs with clear benefits for diabetes, hypertension, and depression. The treatment of these diseases is associated with a substantially decreased risk of developing Alzheimer disease and other dementias (as well as many other diseases).”
“At present, drugs for Alzheimer disease have unproven clinical benefits and proven harms. Billions of dollars spent on hearing aids, smoking cessation, encouragement of healthy lifestyles, and treatment of hypertension, diabetes, and other modifiable risk factors may benefit patients more than spending on these drugs.”
-Susan Molchan, MD and Adriane Fugh-Berman, MD, of PharmedOut at Georgetown University Medical Center
Given the haziness around whether lecanemab can meaningfully improve quality of life – the ultimate goal of any health intervention – it may be time to invest more into other interventions with proven, positive, tangible results.