On June 7, the U.S. Food and Drug Administration granted accelerated approval to Biogen and Eisai’s Aduhelm (aducanumab), the first new treatment for Alzheimer’s disease (AD) in nearly 20 years, the first biologic in the space, and the first therapy targeting amyloid beta plaques in the brain, a key pathophysiological feature of the disease. The accumulation of such plaques and their resulting toxicity to the brain is a prominent, long-promoted hypothesis on the origins of AD.
Aduhelm was not approved on the basis of functional outcomes, which would take many years to materialize (and are therefore incompatible with an accelerated approval). Rather, the approval was based on the surrogate endpoint of amyloid plaque clearance. By reducing this plaque burden, the new antibody therapeutic aims to slow the cognitive decline in affected patients. As a condition of the accelerated approval, Biogen is required to conduct a Phase 4 clinical study to verify that Aduhelm provides the expected therapeutic benefit. Biogen estimates that it may take as much as nine years before results of such trials are known.
While Aduhelm’s approval may be a long-awaited milestone for AD patients and caregivers, and for the field of AD research and treatment generally, it also poses several questions.
Among them is how to best identify patients who are most suitable for treatment. Aduhelm was originally approved with a broad label, which would have allowed, in theory, prescription for any of the more than 6 million people affected by AD. However, the drug was mostly studied in and is expected to provide the greatest benefit to patients with early-stage AD. On July 7, the labeling for Aduhelm was narrowed to more closely represent the patient population participating in the clinical trials: those patients “with mild cognitive impairment or mild dementia stage of disease.”
Those patients were confirmed via PET scan prior to treatment as having significant amyloid brain deposits, thus making them suitable candidates for treatment with Aduhelm. However, PET scans are costly, not currently reimbursed for AD patients outside of clinical trials, and remain primarily limited to academic medical centers, which are not the main care setting for AD patients – especially early-stage. These factors may limit accessibility and potentially create bottlenecks in the diagnostic process. Indeed, the vast majority of Alzheimer’s patients are under the care of primary care practitioners (PCPs), which poses additional barriers for timely actions with early AD. A survey conducted by the American Alzheimer’s Association found that more than a third of those physicians have little or no residency training in Alzheimer’s diagnosis and care, and about 40% have limited confidence in their ability to care for patients with AD or other dementias. While one-third of the surveyed PCPs said that they refer dementia patients to specialists at least once a month, more than half said there are not enough dementia care specialists in their area to meet patient demand.
Thus, identifying patients suitable for treatment with Aduhelm in an affordable and widely accessible way, especially when cognitive symptoms are mild or perhaps not yet clearly manifested, will be a critical challenge.
We’ve written in the past about newer, less costly diagnostic methods including digital technologies that could help identify those with early stage disease or higher risk as early as 10 years before symptoms emerge, or that could help monitor cognitive changes over time. Indeed, Biogen has made a serious investment in digital technologies for CNS-related conditions, including Alzheimer’s disease. The company is conducting an observational study using Apple Watch and iPhone apps to develop digital biomarkers based on psychological and behavioral changes that could be used to monitor cognitive performance and identify early signs of mild cognitive impairment. In addition, a number of other digital tools are in development from companies including Cogstate and NeuroTrack Technologies. Such low cost, non-invasive technologies could provide much wider access for screening patients at heightened risk, due to familial AD associations, or who are showing early signs of cognitive problems.
Other new diagnostic approaches aimed at earlier identification and monitoring patients with AD include methods based on changes in blood flow, brain metabolism, or blood tests, such as the one from C2N Diagnostics approved in November 2020. The C2N Diagnostics test measures blood levels of biomarkers that reflect the presence of amyloid (and/or tau) pathologies in the brain and detects genetic mutations that increase the risk of developing the disease.
Another important question relates to physicians’ overall willingness to prescribe Aduhelm. The FDA’s decision to approve the antibody therapeutic has been a controversial one. It went against the decision of the advisory panel’s review of Aduhelm, and disappointed many of the academic experts on Alzheimer’s disease, who believe that the clinical data did not yet support the finding of a clear benefit for the new treatment. Supporting evidence may yet be coming, however, even before Biogen’s Phase 4 trial with Aduhelm is completed. Three further amyloid-clearing antibodies from Eli Lilly, Roche, and Biogen/Eisai, already in advanced clinical testing, have shown a clearer benefit in treated patients on the rate of cognitive decline and effect on daily living activities.
In addition, Aduhelm’s side-effect profile and the risks of brain swelling and hypersensitive reactions are an important consideration for physicians’ willingness to prescribe the new treatment. Aduhelm was associated with serious potential side-effects that occurred in about a third of the clinical trial participants; as a result, patients will also need ongoing safety monitoring via MRI brain scans, which further complicates the management of these patients. Availability of treatment is also likely to be impacted by several key bottlenecks. Gaining access to Aduhelm will likely require referral to Alzheimer’s disease specialists, who we’ve already mentioned are in short supply. Aduhelm is administered by infusion and currently only about 900 U.S. medical centers are set to treat patients at launch. In addition, many of the physicians asked to prescribe the drug are likely to be neurologists who are not AD specialists with specialized training in dementia and who will need education and guidance on patient identification and eligibility.
Lastly, the price that Biogen has set for Aduhelm, at about $56,000 per year, may cause insurers to further restrict access, for example by requiring evidence of patient suitability based on PET imaging, other prior authorization, or potentially, the use of step therapy. Medicare will also need to make a national determination on which procedures, which patients, and how much they will reimburse. An estimated 80% of the potential patient population for Aduhelm are Medicare beneficiaries, making this a significant need.