Aducanumab (AduhelmTM), a medication designed to treat Alzheimer's disease, recently received approval by the U.S. Food and Drug Administration (FDA). Why does this matter?
Aducanumab is not only the first new therapy approved for Alzheimer’s disease since 2003, it is also the first Alzheimer’s medication approved as a disease-modifying therapy, meaning that it is intended to treat the underlying pathophysiology of the disease. The approval of the medication has been met with considerable controversy as the clinical effectiveness of the medication remains unclear.
How does the medication work?
Aducanumab is a monoclonal antibody directed against amyloid beta (Aβ), the key component of amyloid plaques, implicated in the development of Alzheimer’s disease. Amyloid beta occurs normally in the brain as a single protein (monomer). In Alzheimer’s disease, however, there is an abnormal aggregation of these monomers into clumps. Aducanumab and other monoclonal antibodies under investigation preferentially target these aggregated forms of amyloid-beta.
Why was FDA approval of the medication controversial?
Aducanumab was approved by the FDA under an accelerated approval pathway on June 7, 2021. It was approved on the basis that review of three separate double-blinded studies (totaling 3,482 patients) demonstrated reduction in amyloid beta plaque burden as measured by positron emission tomography (PET) imaging.
However, several independent investigators have questioned the actual clinical benefit of the medication. Two of the previous Phase III trials were actually halted given the absence of apparent improvement in treatment subjects. The pharmaceutical company responsible for development of Aducanumab has reported cognitive improvement in a subset of individuals after re-analysis of all available clinical data. As a part of the accelerated pathway program, the FDA has required a larger follow-up clinical trial to demonstrate cognitive improvement.
Investigators have also raised concern that the medication has the potential for serious side effects. Some patients under treatment with monoclonal antibody treatment for amyloid beta have shown both radiographic and clinical evidence of brain edema (swelling) and micro-hemorrhages. Thus, MRI imaging is recommended prior to the seventh and twelfth doses of the medication to identify these amyloid-related imaging abnormalities (ARIA).
For whom is the medication approved?
In the original announcement, the FDA did not specify in its approval which patients with Alzheimer’s disease should receive the medication. It later clarified that indicated patient population should mirror the clinical trials of Aducanumab, which have targeted patients with mild cognitive impairment (MCI) or mild forms of the disease as it is generally believed that patients at severe stages are unlikely to benefit. The annual cost of the medication is expected to be $56,000 annually. Medicare is expected to announce a National Coverage Determination (NCD) process for Aducanumab.
What does this mean for insurance?
In the short and intermediate term, we may see an increase in diagnostic testing for Alzheimer’s both due to improved reimbursement patterns (now that a disease-modifying treatment is available), as well as public interest in the therapy. Given that the predictive window of these diagnostic tests can even be 10-plus years in advance of clinical symptoms, insurers will need to be wary of anti-selective pressures both for long-term care and life product lines. The potential impact for healthcare expenditures has already been discussed.In the longer term, the hope is approval of Aducanumab will renew interest and prospects in Alzheimer’s therapy. After the failure of several large and expensive clinical trials between 2016 and 2019, several drug makers pulled back on Alzheimer’s research. There are currently 126 medications in the Alzheimer’s drug pipeline, 28 of which are in Phase III testing, with the great majority of these also targeting the underlying pathophysiology of this devastating disease.