Dear Administrator Brooks-LaSure:
On behalf of the undersigned physicians and research leaders who care for individuals with cognitive decline and dementia, thank you for the opportunity to address the Centers for Medicare & Medicaid Services on the National Coverage Determination of for the anti-amyloid monoclonal antibody class of therapeutics. We strongly urge you to issue a favorable National Coverage Determination starting with coverage for aducanumab, and make this and future Alzheimer's therapies available to all individuals who will benefit.
Through our work, we see firsthand every day the devastating toll Alzheimer’s disease takes on individuals, their caregivers, and families. To date, the therapeutic options for patients with Alzheimer’s have been limited to neurotransmitter-based symptomatic therapies that are approved only for patients with dementia and do not modify amyloid plaques and tau tangles, the neuropathological features that define the disease. There are currently no approved treatments for Mild Cognitive Impairment (MCI), a pre-dementia stage of the disease, during which patients have objectively confirmed cognitive impairment but are still able to maintain independent function.
Aducanumab, a monoclonal antibody that targets amyloid-beta, is the first treatment approved for Alzheimer’s disease since 2003 and the first to directly address the underlying biology of the disease. The drug was granted accelerated approval based on clear evidence that it leads to ~60% reduction in amyloid plaques as measured by PET scans, a surrogate endpoint that the FDA deemed “reasonably likely” to predict a clinical benefit. High dose drug treatment was associated with slowing of clinical decline as measured by primary and secondary cognitive and functional endpoints in one of two phase 3 randomized controlled trials. Similar results of amyloid lowering and slowing of clinical decline have also been reported in Phase 2 studies of two other antibodies in this class, lecanemab and donanemab. Amyloid reduction by all three antibodies was also accompanied by modification of tau biomarkers in subsets of study participants who underwent cerebrospinal fluid analysis or tau PET. This additional biomarker signal is consistent with modification of disease pathophysiology. Tau biomarkers are strongly associated with clinical outcomes in longitudinal observational studies, and staging of tau pathology at autopsy correlates with clinical stage and cognition prior to death. Collectively, these data support the premise that reducing amyloid in patients who are at an early clinical stage can modify the pathophysiology of Alzheimer’s and are likely to yield a clinical benefit. Importantly, earlier trials of amyloid-targeting monoclonal antibodies that did not show a clinical benefit included clinically more advanced patients treated with substantially lower doses of antibodies that were less effective at removing amyloid.
We strongly believe that use of aducanumab in clinical practice should closely follow the Appropriate Use Recommendations recently published by Cummings et al. (J Prevent Alz Dis, July 2021). These recommendations adapted the inclusion and exclusion criteria of the aducanumab clinical trials for “real-world” clinical use. As stated in the FDA label, drug use should be restricted to patients with MCI or mild dementia due to AD. Proof of brain amyloid (via PET or CSF) should be required to establish eligibility for treatment, and these diagnostic tests should also be covered by CMS in patients who are candidates for treatment. Patients who are at increased risk for adverse drug effects, most notably amyloid related imaging abnormalities (ARIA), based on co-morbidities, anticoagulation therapy or microbleeds on baseline brain MRI should not receive the drug. MRI scans should be performed during dose titration or in anyone with clinically suspected ARIA to maximize patient safety. The decision to treat should be based on shared decision making between patients and their treating clinicians. The goal of treatment in this setting is to slow progression and preserve function at this early clinical stage of disease. While the slowing of clinical progression is expected to be modest and certainly not a cure, maintaining function in the MCI or early dementia stages for months or longer is clinically meaningful and something that anyone who has experienced this devastating disease would want for their loved one. Additionally, the first step to receiving appropriate care involves receiving a timely and accurate diagnosis, and appropriate disclosure, education and counseling; we believe that coverage will also improve the evaluation, diagnostic and care process for patients and families, whether or not they ultimately qualify or choose to undergo treatment with aducanumab.
As you consider coverage and access, CMS must consider the racial and ethnic populations that are disproportionately impacted by Alzheimer's and other dementias and who have been historically underserved in health care and underrepresented in research populations. Older Blacks are about twice as likely to have Alzheimer’s or other dementias as older Whites and older Hispanics are about one and one-half times as likely to have the disease as older Whites. We refer CMS and the CAG to the Alzheimer’s Association’s 2021 special report, Race, Ethnicity and Alzheimer's in America, a key finding of which is that discrimination remains a barrier to Alzheimer’s and dementia care.
This is the first of a number of new treatments to come. History has shown us that approvals of the first drug in a new category will invigorate the field, increase investments in new treatments, and generate greater innovation, helping to diversify the treatment pipeline to address this devastating disease at all stages through multiple pathways and for all communities, as we have with other major diseases
This group of undersigned leaders in the field of dementia are grateful for the CAG’s careful consideration of all evidence and information. Thank you for the opportunity to comment.