The US Food and Drug Administration’s (FDA) recent approval of lecanemab for the treatment of Alzheimer disease (AD) in patients with mild cognitive impairment or mild dementia has been met with optimism and skepticism by experts in a field with a limited range of treatment options.1
In the phase 2 study that led to its approval via the FDA’s accelerated pathway, patients with early AD who were treated with lecanemab 10 mg/kg biweekly showed significant dose-dependent reductions in amyloid plaques compared with patients who received lower doses of lecanemab or placebo.2 Although modest, these findings were viewed as more conclusive than the mixed results of the 2 phase 3 trials that led to the FDA’s accelerated approval of the anti-amyloid drug, aducanumab, in 2021.3,4 Lecanemab also demonstrated promising results across primary and secondary endpoints, including measures of cognitive decline, in the subsequent phase 3 Clarity AD trial (ClinicalTrials.gov Identifier: NCT03887455).5
Following the trial, concerns soon arose that the potential benefits of lecanemab may not be worth the associated risks. Of particular concern are reports of 3 patient deaths that have occurred in the extension phase of Clarity AD. Two of the deaths reportedly resulted from brain hemorrhage, and the third death occurred after the patient experienced extensive cerebral edema, microhemorrhages, and seizures.6
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To gauge clinician perspectives on the risks, benefits, and anticipated real-world usage of lecanemab following FDA approval, we spoke with the following experts:
- Peter V. Rabins, MD, MPH, the Richman Family Professor of Alzheimer’s and Related Dementias, Emeritus, and founding director of the division of geriatric psychiatry and neuropsychiatry at Johns Hopkins School of Medicine in Baltimore, Maryland
- Matthew S. Schrag, MD, PhD, assistant professor of neurology and director of the Cerebral Amyloid Angiopathy Clinic at the Vanderbilt University School of Medicine in Nashville, Tennessee
- B. Joy Snider, MD, PhD, professor of neurology and director of the Knight Alzheimer’s Disease Research Center Clinical Trials Unit at Washington University School of Medicine in Saint Louis, Missouri, where she has served as the site principal investigator for the Clarity AD study as well as other studies using lecanemab
- Lon S. Schneider, MD, the Della Martin Chair of Psychiatry and Neuroscience and professor of psychiatry, neurology, and gerontology at the Keck School of Medicine at the University of Southern California in Los Angeles
Given that the accelerated approval of lecanemab by the FDA is based on the phase 2 proof-of-concept study, do the results from the phase 3 trial strengthen your perception of lecanemab’s place in practice?
Three patient deaths were recorded in the extended phase of the phase 3 trial – how do you weigh this risk in relation to the general benefits of the drug?
Dr Rabins: I think of anti-amyloid beta drugs as similar in concept to the first chemotherapeutic anti-cancer drugs introduced in the early 1950s. Minimal efficacy but an important first step.
Dr Schrag: We are always looking to balance benefits against risks. In the case of lecanemab, the benefits are quite small — the difference between the treatment group and the placebo group was so subtle that I doubt most patients or families would notice it. The risks, on the other hand, are significant. More than 20% of patients developed some degree of swelling or bleeding in their brains, and while most cases were fortunately mild, a few were very serious and at least 3 patients died from complications likely linked to the treatment.
Dr Snider: The results from the phase 3 study are critical, as they demonstrate the clinical effectiveness of the drug. These results showed that the drug measurably slowed the worsening of cognitive symptoms in people with very mild symptoms of AD.
The deaths of participants in the study are a concern and, as with all drugs, clinicians and patients and their families will need to weigh the potential risks and benefits of this medication for each patient. I look forward to learning more about the safety profile of this medication and to learning whether the beneficial effects of the medication increase or wane with longer-term use as more information from the ongoing open-label studies becomes available.
Dr Schneider: [Additional research of] the phase 3 study still has to be reviewed by the FDA. Assuming the results are as presented, then they still show the very small effects that aducanumab showed. A difference of -0.45 on CDR-SB (Clinical Dementia Rating–Sum of Boxes) scores is very small and of questionable clinical meaning. It’s no different than the difference of -.39 on CDDR-SB scores observed with aducanumab. Lecanemab’s place in clinical practice will remain uncertain until many more people receive it, and there is some evidence for long-term positive effects.
As there is the potential for the 3 deaths to be associated with lecanemab, and the deaths could foreshadow what would be seen under real-world circumstances, they suggest that the rate could be 3 per less than 1,700 exposed to lecanemab. If in fact we were to see this in clinical practice — i.e., a rate of 1 to 2 per 1,000 — then that would be too high. It would mean that if 100,000 people were treated, there would be 100-200 deaths.
Lecanemab is the second drug approved in a new class of drugs for the treatment of AD. Where do you see lecanemab and other amyloid beta-directed antibodies in our current first-, second-, and subsequent lines of treatment?
Dr Rabins: While these drugs are first in class, their limited efficacy, high cost, and challenging characteristics — not oral, repeated MRIs, amyloid-related imaging abnormalities (ARIAs) — will limit their widespread use.
Dr Snider: Lecanemab is the first truly “disease-modifying” medication shown to slow progression of the memory and thinking symptoms in AD. It could be a “first-line” therapy in appropriately selected patients with very mild symptoms of AD. There are similar drugs as well as drugs targeting other aspects of AD for example, those targeting tau, inflammation, and other disease pathways — that are being studied now. We hope that the next few years will give us more options to treat AD.
Dr Schneider: If lecanemab should get regular approval towards the end of this year, then it would be seen as the first anti-amyloid antibody, as aducanumab would not be used. A first-line treatment would imply that nearly everyone with the condition should be receiving treatment. I doubt that lecanemab will be considered in that sense, as a standard of care.
Families will weigh the potentially small benefit, if any, against the considerable time, effort, costs, and potential risks involved with the indefinitely long infusions every 2 weeks, as well as the effects on lifestyle. This will not be a treatment for everyone. Moreover, even if Medicare would cover it, the copays would still be approximately $20,000 per year, way beyond affordability for the vast majority of older people.
In the US, lecanemab will be launched at a price point of $26,500 per year if administered biweekly.7 It is not yet known whether this will be covered by private or commercial insurances or by the US Center for Medicare and Medicaid Services (CMS). How do you measure the drug’s value for individual patients given the price point?
Dr Rabins: This is an individual decision. Some people want to do “everything possible,” while others take a much more measured approach.
Dr Schrag: To me, the combination of minimal benefits and moderate risks associated with this extremely expensive drug, compounded by the practical difficulty of taking an infusion every 2 weeks and needing frequent magnetic resonance imaging (MRI) scans to monitor for side effects, add up to a clear conclusion: Lecanemab is not likely to help most of our patients.
Dr Snider:This is a great question and one that CMS is likely considering. The value to an individual patient and family will depend on many factors, including how rapidly memory loss is progressing. We hope that CMS and other payors will come up with an approach that provides equitable access to these medications for all of our patients.
Dr Schneider: The price is much more than $26,500 a year. There are costs for the infusion centers, MRIs, positron emission tomography (PET) scan, other safety procedures, and physician visits. Not only that, but with infusions every 2 weeks, there is a substantial transportation cost and the need to have the patient’s family involved.
The uptake of anti-amyloid antibodies in practice is expected to be slow and insurance coverage will be a barrier to patients. How do you think this will affect future research and development for these types of therapies?
Dr Rabins: Since the clinical benefit is so modest and not clinically significant, combination therapies such as combined anti-amyloid/anti-tau therapies and other combination strategies are a reasonable next step.
Dr Snider:The high price point could well be a limiting factor in how widely this medication is used, but the positive results of the lecanemab trial, showing that this medication can slow cognitive decline by a variety of measures, should have a very positive effect on development of other therapies. We hope there will be efforts to develop safer and more easily administered medications, such as subcutaneous forms of these drugs or oral drugs that have similar benefits.
Lecanemab and aducanumab are the first medications approved for AD in nearly 2 decades. In clinical trials, both drugs were compared with placebo. How do these therapies measure against other treatment options such as acetylcholinesterase inhibitors and N-methyl-D-aspartate receptor (NMDA) receptor antagonists?
Dr Rabins: Cholinesterase inhibitors and NMDA receptor antagonists do not target the disease’s pathobiology, while lecanemab and aducanumab do. This is a major advance.
Dr Snider:A little over one-half of the participants in the phase 3 clinical trial for lecanemab were taking currently approved treatments — acetylcholinesterase inhibitors and NMDA receptor antagonists — so overall, the beneficial results of lecanemab were in addition to any benefit from acetylcholinesterase inhibitors and NMDA receptor antagonists.
The key difference between medications like lecanemab and aducanumab and acetylcholinesterase inhibitors and NMDA receptor antagonists is that the amyloid antibodies alter the underlying disease process, while acetylcholinesterase inhibitors and NMDA receptor antagonists provide some benefit for disease symptoms but do not change the underlying disease process. This means that, over time, it is possible that the effects of lecanemab and aducanumab will be more sustained and could, perhaps in combination with other medications being developed, stop the worsening of cognitive symptoms.
Dr Schneider: Here’s the irony: The anti-amyloid antibodies are being presented as disease-modifying medications that might change the course of illness. On average, people in the lecanemab trial scored about 0.5 points better on the CDR-SB and about 1 point better on the ADAS-Cog (Alzheimer’s Disease Assessment Scale-Cognitive Subscale) after about 1.5 years of treatment in the trial. We might hope that the treatment effect increases with longer treatment, but we haven’t done those studies. It might be helpful to compare this effect with the effect of the acetylcholinesterase inhibitors currently marketed for AD, such as donepezil, for example. With these therapies, the increase in ADAS-Cog scores is about 2.5 points after 3-6 months. So, this is something else to consider. 8
Disclosures: Dr Snider has served as the site principal investigator at Washington University for the Clarity AD study and other studies using lecanemab. She has also served on advisory boards for Eisai in the past year. She reports that she does not own any stock or equity in Eisai or any other pharmaceutical company.
Dr Schneider is part of a team that oversees the DIAN-TU trial of Eisai’s anti-tau antibody in dominantly inherited AD (ClinicalTrials.gov Identifier: NCT01760005), which all participants receive lecanemab as background or concomitant treatment. USC has conducted trials with lecanemab, donanemab, solanezumab, and aducanumab, sponsored by NIA, Eisai, Eli Lilly, and Biogen, and has served as a consultant and DSMB member for Eli Lilly, Baxter, Biogen, Eisai, Hoffman-LaRoche, and Genentech, all manufacturers of anti-amyloid antbodies.
Dr Schrag has done paid consulting for Raymond James and Associates and Labaton Sucharow.
References
- FDA grants accelerated approval for Alzheimer’s disease treatment. US Food and Drug Administration. Published January 6, 2023. Accessed February 5, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
- Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. Published online April 17, 2021. doi:10.1186/s13195-021-00813-8
- FDA grants accelerated approval for Alzheimer’s drug. US Food and Drug Administration. Published June 7, 2021. Accessed February 5, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
- Vaz M, Silva V, Monteiro C, Silvestre S. Role of aducanumab in the treatment of Alzheimer’s disease: Challenges and opportunities. Clin Interv Aging. Published online May 18, 2022. doi:10.2147/CIA.S325026
- van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. Published online January 5, 2023. doi:10.1056/NEJMoa2212948
- Piller C. Scientists tie third clinical trial death to experimental Alzheimer’s drug. Science. Published December 21, 2022. Accessed February 5, 2023.
- Eisai Co, Ltd. Eisai’s approach to U.S. pricing for Leqembi™ (lecanemab), a treatment for early Alzheimer’s disease, sets forth our concept of “societal value of medicine” in relation to “price of medicine.” Published January 7, 2023. Accessed February 5, 2023. https://www.eisai.com/news/2023/news202302.html
- Takeda A, Loveman E, Clegg A, et al. A systematic review of the clinical effectiveness of donepezil, rivastigmine and galantamine on cognition, quality of life and adverse events in Alzheimer’s disease. Int J Geriatr Psychiatry. Published online December 2, 2005. doi:10.1002/gps.1402
This article originally appeared on Neurology Advisor
