Given the aducanumab (Aduhelm)/FDA investigation by Congress, the timing of the lecanemab (Leqembi) approval last week through the accelerated approval pathway is awkward to say the least. While lecanemab may seem like a solid choice for the treatment of Alzheimer’s disease compared to aducanumab, there are still the risks of side effects, significant burden of treatment, and a lack of healthcare infrastructure that can deliver the infusion.
In my previous op-ed on lecanemab from October, I shared my insights on the incomplete results of the lecanemab phase III clinical trial. More recently, the full results of the placebo-controlled, randomized clinical trial (Clarity AD) were published in the New England Journal of Medicine. The trial investigated how well lecanemab, a monoclonal antibody, slowed progression on cognitive test (Clinical Dementia Rating-Sum of Boxes [CDR-SB) compared to placebo, along with amyloid reduction and other secondary outcomes over 18 months. However, FDA’s recent approval was based on a phase II study since the accelerated approval pathway considers biomarkers, not clinical benefit. The phase III trial results will be important as the company pursues traditional approval.
With the news of the accelerated approval, I’d like to take a closer look at the latest evidence for lecanemab’s safety and efficacy, and explore potential barriers to treatment.
Clarity AD had an extensive list of exclusions for participants including:
- History of transient ischemic attacks, stroke, or seizures within 12 months of screening
- Any psychiatric diagnoses including major depression that could interfere with study procedures
- Contraindications to MRI such as pacemakers/defibrillators and other MRI-incompatible devices
- More than four microhemorrhages or a single macro hemorrhage (>10 mm)
- Multiple lacunar strokes
- Severe small white matter disease
- Any autoimmune conditions that requires treatment with immunoglobulins or systemic immunosuppressants
- International normalized ratio (INR) >1.5
- And any other medical conditions that are not stably controlled during the study assessments
To be eligible, patients needed at least a recent (within 1 year) MRI of the brain confirming no vascular or hemorrhagic findings as well as confirmation of presence of amyloid prior to initiating treatment. Very few patients, except those within existing clinical trials, have knowledge of their amyloid status. Very few patients outside of research studies are aware of their apolipoprotein E (APOE) ɛ4 carrier status, as the risk of amyloid-related imaging abnormalities (ARIAs) are higher in APOE ɛ4 homozygotes. Take for example the fact that if 100 represents the total number of Americans with a clinical diagnosis of Alzheimer’s disease, less than one would be eligible for aducanumab; the same analysis applies to lecanemab. Although the Clarity AD trial included participants up to age 90 — which is higher than the 85-year-old age limit for the aducanumab trials (EMERGE and ENGAGE) — the actual number of eligible patients remains very small. Furthermore, of 1,795 enrolled participants internationally, 12.5% were Hispanic but only 2.5% of participants were Black.
Clarity AD trial showed a mean change from 1.66 down to 1.21 on the CDR-SB, which was statistically significant. However, there has been debate about whether this amount of change is clinically significant. Because the trial was exclusively among those participants with mild cognitive impairment or mild Alzheimer’s disease, the average CDR-SB was around 3 at baseline, with standard deviation of 1.34.
For those early in the disease course, I do believe that a change of -0.45 could bring a realistic slowing of disease progression as a disease modifying therapy. Interestingly, the activities of daily living (ADL) score also improved for those on lecanemab, with a mean difference of 2 (ADL ranges from 0 to 53 with a lower score indicating greater impairment, with participants scores at baseline ranging from 12 to 53).
Monitoring for Side Effects
The FDA offered suggested frequency of monitoring of lecanemab via MRI: one scan within 12 months of infusion initiation, then before the fifth, seventh, and fourteenth infusions, or before months 3, 4, and 8. If there are symptomatic ARIAs, infusion should be stopped. Symptoms of ARIAs could be non-specific headaches, dizziness, and confusion, all very common in older adults, but difficult to correlate without a brain MRI, interpreted by skilled radiologists.
Unfortunately, we do not know the frequency of side effects in those under age 65 or over 80 due to the few numbers of participants within these categories. Symptomatic ARIA in the Clarity AD trial occurred in 3% of participants, and most resolved once infusion was stopped. Asymptomatic ARIA was observed in 12% of the treatment group compared to 5% in the placebo group. Both symptomatic and asymptomatic ARIAs were more likely to occur in APOE ɛ4 carriers, especially if homozygotes. Total ARIAs, whether symptomatic or asymptomatic, were reported in 21.5% of the treated group compared to 9.5% in the placebo group. There were also several highly public deaths among trial participants possibly linked to lecanemab.
Although there is controversy over whether the deaths were truly related to lecanemab, it’s important that a related condition called cerebral amyloid angiopathy (CAA) should be part of the clinical discussion of risk. In CAA patients, amyloid is deposited in the walls of the blood vessels in the brain, while in amyloid-positive Alzheimer’s disease, amyloid is deposited in the parenchyma of the brain. Diagnosis of CAA is based on prior microhemorrhages on brain imaging or symptomatic intracranial bleed. The exact prevalence of CAA is unknown, but could be up to 48% coexistence in patients with Alzheimer’s disease. It is possible that those highly public deaths had amyloid deposited in both the parenchyma and in the blood vessels, but we can only distinguish CAA from Alzheimer’s disease via autopsy pathology (not via CSF, blood, nor amyloid PET scan).
At this time, health professionals should discuss with interested and eligible patients the small risk of death due to intracranial hemorrhage. Some patients may accept this risk of sudden death in the face of a drawn-out decline over many years due to Alzheimer’s disease. But to their families, that would potentially mean significantly fewer years together with their loved one, while their impairments from Alzheimer’s are still mild. Patients and their families should be aware of all possible benefits and risks so they can make an informed decision.
Other Barriers to Access
Even if patients were part of a CMS-approved clinical trial where their drug costs were covered, we still need a healthcare infrastructure that can:
- Identify patients with cognitive impairment early in their disease course
- Confirm amyloid status with biomarkers (however, amyloid PET scans are still not covered by insurance such as Medicare or private insurers)
- Train clinicians and radiologists in delivering and monitoring for side effects
- Locate space in infusion clinics, commonly associated with neurology practices, to be able to deliver lecanemab infusions every 2 weeks for possibly 18 months
While we wait until further data is gathered from ongoing longer-term studies on lecanemab, we should take this opportunity to discuss other less risky interventions for patients who present with mild memory problems: screen and treat for anxiety and depression; stop anticholinergic medications including any over-the-counter medications and sleep aids; evaluate for hearing impairment (masks revealed many patients who relied on reading lips); evaluate and treat for obstructive sleep apnea; check orthostatic blood pressure from lying to standing and consider intensive blood pressure control to systolic blood pressure ≤120 mmHg based on SPRINT MIND data.
In short, I would be open to prescribing lecanemab for a very limited number of patients who fit the clinical trial eligibility criteria after informed consent for risks, benefits, burden of infusions, and MRI monitoring. However, I do not expect many patients with early signs of Alzheimer’s disease will sign up for lecanemab at this time due to the barriers discussed above.
Mia Yang, MD, MS, is a geriatrician/clinician-researcher at Atrium Health Wake Forest Baptist in Winston-Salem, North Carolina. She hosts a podcast called “Ask Dr. Mia: Conversations on Aging Well.” The opinions expressed are the author’s and do not represent those of any institution or company with which she is affiliated.