JAMA. Published online July 17, 2023. doi:10.1001/jama.2023.11701
A two year review of Alzheimer's clinical trials of antibodies like aducanumab, lecanemab, and donanemab and setbacks, encouragements, and adverse effects.
In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval of aducanumab, a monoclonal antibody against β-amyloid for treatment of early Alzheimer disease. The approval generated significant backlash due to unclear evidence of the drug’s clinical efficacy, risk of severe adverse effects, absence of diversity in trial populations, high costs, and an opaque approval process that, per one congressional inquiry, was “rife with irregularities.
Two years later, aducanumab is rarely used. Many insurers, including the Centers for Medicare & Medicaid Services (CMS), have significantly restricted coverage, limiting not only whatever enthusiasm was left to prescribe this medication but also any drive to develop the substantial infrastructure needed for its appropriate and safe administration. However, the prospects for amyloid antibodies are likely to improve in the immediate future. In January 2023, the FDA gave accelerated approval to another amyloid antibody, lecanemab, which was followed by approval through the standard pathway in July 2023. It is anticipated that the FDA will grant a similar standard approval for a third antibody, donanemab, based on the findings of the TRAILBLAZER-ALZ 2 study published in this issue of JAMA.
The TRAILBLAZER-ALZ 2 study of donanemab was an 18-month double-blind, placebo-controlled trial of individuals with mild cognitive impairment (MCI) and mild-stage dementia due to Alzheimer disease with evidence of amyloid and tau pathology on positron emission tomography (PET) scans. Unlike lecanemab’s every-other-week infusions, donanemab was only given every 4 weeks, with a planned switch to placebo at 24 weeks or 52 weeks if PET scans showed sufficient amyloid clearance (which occurred in about half of the patients at 12 months). This is a welcome difference for patients and payers, limiting infusion-related burdens as well as longer-term costs, with the caveat that it remains unclear whether future maintenance doses will be needed with donanemab.
As with lecanemab, donanemab showed an impressive ability to remove amyloid from the brain, leading to what will eventually either be categorized as an extraordinary feat of science or a statistically significant but minimally clinically relevant result: less worsening in patients receiving donanemab compared with those receiving placebo in both the primary end point and a host of secondary end points of cognition and function at 18 months. For example, when looking at the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB), dementia severity in patients receiving donanemab worsened by 1.72 points over 18 months compared with a worsening of 2.42 points for those receiving placebo, for a difference of 0.7 points on this 18-point scale. A similar finding was seen with lecanemab’s CLARITY-AD study, with the CDR-SB score declining by 1.21 points with lecanemab vs 1.66 points with placebo (comparisons should be taken with caution though because CLARITY-AD did not require individuals to have tau pathology).
This slightly less worsening is small when looked at in absolute values. However, slowing progression by a quarter to a half a year as seen with donanemab allows for someone to remain in MCI or mild-stage dementia for just that much longer. In addition, 47% of participants in the low/medium tau group receiving donanemab were considered stable based on the CDR-SB at 1 year compared with 29% of participants receiving placebo. For some, this can be considered clinically and personally meaningful.
These results serve to highlight the complexity of Alzheimer disease itself. The exceptional ability of drugs such as donanemab and lecanemab to remove amyloid, paired with their rather subtle effect on the rate of decline in cognitive and functional measures, suggests that amyloid is likely not the only factor that contributes to Alzheimer disease progression.
From a more practical standpoint, the modest benefits would likely not be questioned by patients, clinicians, or payers if amyloid antibodies were low risk, inexpensive, and simple to administer. However, they are none of these. The harms include infusion reactions and amyloid-related imaging abnormalities (ARIA). Although ARIA may often be asymptomatic to mild in nature, they can lead to life-threatening events including what was likely 3 treatment-related deaths in each of the donanemab and lecanemab studies. These deaths may be an adverse effect of the removal of amyloid plaques, which may weaken cerebral blood vessels, a risk heightened in people who are homozygotes of an allele producing the ε4 type of apolipoprotein E (APOE ε4), those who have cerebral amyloid angiopathy, and those taking anticoagulant drugs. The costs will be substantial, not just for the medication itself, but also for the biomarker and imaging workup, the likely addition of determining APOE status to risk stratify patients, baseline magnetic resonance imaging (MRI) with frequent follow-up MRI to assess for ARIA, and additional PET scans to determine when amyloid has been cleared enough to stop treatment.
Whether the harms of these drugs are balanced by their modest clinical benefits will ultimately require more data, including that from open-label extension studies, to determine whether the differences between intervention and placebo groups will continue to increase beyond 18 months. This extended period of study will allow for better understanding of the impact of slowing decline on a person’s disease stage, cognitive and functional abilities, quality of life, and caregiver burden. Furthermore, data on treatment beyond 18 months will be critical to determine other unanticipated harms, including whether the accelerated whole brain atrophy seen in individuals receiving antiamyloid therapy will have a negative impact later in the clinical course.
Debates about safety and efficacy aside, 2023 will see amyloid antibodies moving from the tightly controlled world of clinical trials to the real world. What matters now is taking data, however imperfect, and implementing in a population that may look very different than the population studied.
Two populations deserve particular attention in this regard.
First, TRAILBLAZER-ALZ 2 had an age limit of 85 years with no stated justification for this exclusion. For an age-related illness such as Alzheimer disease, this is a disappointing but sadly not uncommon issue that contributes to inadequate representation of older adults in clinical studies.
Second, although representation from non-White participants was improved in the TRAILBLAZER-ALZ 2 study compared with previous studies, it remains inadequate given that Alzheimer disease impacts Black and Latinx patients at rates that are 2 times and 1.5 times higher, respectively, than in White patients. Generalizing the results of this clinical trial to these patients will be a challenge, but this is unfortunately not a new or uncommon experience for clinicians when they are selecting appropriate therapy for their patients. One way to improve understanding of the clinical outcomes of these drugs across broad patient populations is for clinicians to participate in patient registries to collect real-world information on patients receiving antiamyloid therapy, a requirement currently set by CMS for reimbursement.
Although participating in a registry could be an additional barrier to access these medications, it pales in comparison to the numerous other barriers that health care systems will need to overcome to deliver antiamyloid drugs in an effective, safe, and equitable manner. Primary care clinics will need to create systems and incorporate validated tools to aid in the early detection of Alzheimer disease. Specialty dementia clinics staffed by neurologists, geriatricians, and geropsychiatrists will need to develop the necessary expertise to diagnose different types of dementia with the aid of biomarkers. They will need to create policies and workflows to guide referring clinicians and patients through the eligibility, infusion, and monitoring requirements that will undoubtedly be different for the various amyloid antibodies available. Clinical partnerships will be needed with emergency departments and radiologists as care for individuals extends beyond the clinics and after office hours. Raising awareness and providing education on adverse events will be critical to avoid catastrophic neurological sequela yet minimize unnecessary health care use.
Beyond knowledge of the medications, adverse effects, and monitoring schedules, health care systems will need to create time for clinic staff to accurately diagnose the disease, ethically and compassionately disclose results and obtain consent, and use shared decision-making to initiate treatment. Once treatment starts, clinics will be needed to shepherd patients through the time-intensive treatment regimen. Fortunately, the field can learn from its colleagues in fields such as oncology and transplant medicine. Electronic medical record tools and nurse navigators can be utilized to coordinate complex visit schedules, follow patient safety protocols, suggest treatment plan changes based on clinical data, integrate with pharmacy, and reduce clinician documentation time.
Ultimately, new treatments such as donanemab will not only change the Alzheimer research landscape but also the clinical one. Accurate and timely diagnosis, thoughtful discussion on individualized risks and benefits, and an emphasis on chronic care management have never been more important.