***** On April 7, 2022, the Centers for Medicare & Medicaid Services (CMS) released its final national coverage decision regarding the anti-amyloid immunotherapy drug Aduhelm. The language of the coverage determination is complex and legal and regulatory experts are still working to understand all of its implications. On May 3, 2022, Biogen announced that it is shutting down the commercialization unit supporting Aduhelm, effectively removing it from the market, and will be revamping its drug development pipeline. United Healthcare, the nation’s largest provider of Medicare Advantage plans, announced it would follow the lead of CMS and severely restrict coverage of Aduhelm; Blue Cross Blue Shield had already made a similar announcement, closing the door on the last possibility of widespread payor coverage. However, Biogen, in partnership with Eisai, will continue to pursue the commercialization of anti-amyloid immunotherapy lecanemab.*****
On June 7, 2021, the FDA announced the accelerated approval for Aduhelm for the treatment of Alzheimer’s disease. On July 8, following controversy and upon application by Biogen, the FDA revised the label to indicate that Aduhelm should be prescribed only for patients with mild cognitive impairment or mild dementia. Although currently hard to obtain, Aduhelm is now legally available to patients.
Aduhelm is the brand name for aducanumab, a monoclonal antibody developed by Biogen that is designed to bind to aggregated forms of beta amyloid in the brain to trigger their degradation and removal by the brain’s immune system. Plaques of aggregated beta amyloid are one of three widely recognized elements of Alzheimer’s pathology; the other two are neurofibrillary tau tangles and neuroinflammation. Together, these lead to neurodegeneration, the loss of brain cells and structures, that initially manifests as cognitive and memory dysfunction and eventually leads to physical decline as well.
Patients receive Aduhelm via a roughly hour-long intravenous infusion once a month in specialized medical settings. Dosage starts low to reduce the incidence of side effects and over a number of months is increased until the patient reaches the maintenance dose. It is as-yet unknown how long a patient should keep taking Aduhelm or how to determine, other than for safety concerns, that they can or should cease treatment on the basis of the drug’s biological or cognitive effects.
The approval of Aduhelm marks the first new drug for AD to reach the market in 18 years, and the first ever that is intended to change the course of the disease, not just treat symptoms. A number of other anti-amyloid monoclonal antibodies have previously failed to achieve cognitive benefit endpoints in phase 2 and 3 clinical trials and so have not been submitted to the FDA for possible approval. Although there is no evidence to date that Aduhelm can stop or reverse clinical symptoms of Alzheimer’s disease, it is the first drug with FDA-accepted phase 3 clinical trial evidence showing slowing of cognitive decline.
Aduhelm was tested in two large phase 3 clinical trials designed to determine whether treatment provided cognitive benefits to patients with mild cognitive symptoms and elevated levels of beta amyloid plaques in their brains. In both trials it was very effective at every dose in reducing brain beta amyloid accumulation.
Across the two trials, about 40% of patients treated with the highest dose of Aduhelm experienced amyloid-related imaging abnormalities (ARIA). ARIA is a recognized side effect of all of the anti-amyloid antibodies that have been tested in late-stage clinical trials. Among those who experienced it, ARIA was asymptomatic for approximately 75% of the highest-dose trial participants but symptomatic for the others in this treatment arm. While symptoms can be mild, such as headaches and nausea, more serious symptoms like brain swelling and microbleeds can require hospitalization and cause significant damage. Carriers of the APOE4 gene variant, who are at increased risk of Alzheimer’s disease and are disproportionately represented in the Alzheimer’s patient population, are at significantly higher risk of ARIA. However, the risk of serious ARIA can be mitigated if patients start with a low dose of Aduhelm and increase to the effective dose over repeated treatments.
The two Aduhelm trials had identical protocols that defined primary success as better outcomes on a standardized cognitive assessment tool, CDR-SB, for treated than for trial participants on placebo. The trial protocols included a planned interim checkpoint at which the data collected to that point would be analyzed to see if the trials were statistically likely to be successful. At that checkpoint, because the combined data from the two trials indicated that treated participants were not likely to benefit, both trials were terminated.
Biogen later analyzed all of the data collected up to the date of termination for each trial separately. In both trials, treated and placebo participants worsened on the CDR-SB scale over the 18-month treatment period. However, in one of the two trials, participants who received the highest dose of Aduhelm for the longest period of time worsened on the CDR-SB 22% more slowly than did participants on placebo. CDR-SB scores are out of 18 and high-dose participants in this trial had .39 less worsening on the scale than did participants on placebo. The same highest dose/longest treatment group in the other trial did not achieve statistically significant cognitive benefit compared to the group on placebo.
The FDA announced that it gave accelerated approval to Aduhelm because it expects that the drug’s well-demonstrated ability to reduce levels of aggregated amyloid in the brain will yield cognitive clinical benefit to patients. Because Aduhelm’s phase 3 clinical trials did not achieve these benefits for participants under their original design, the drug did not meet the FDA’s usual standards for unconditional approval.
The accelerated approval program is designed to allow drugs to reach the market quickly that have demonstrated that they affect a surrogate biomarker in a way that scientific evidence strongly suggests will lead to clinical benefit to patients, even if the benefit was not achieved during the course of the trials. As an example, in cancer, tumor size reduction may be a surrogate biomarker for improving a cancer patient’s prognosis. Under accelerated approval, a drug’s sponsor, like Biogen for Aducanumab, must run a confirmatory post-approval study demonstrating that patients benefit cognitively from the drug or the FDA can act to remove it from the market. The FDA gave Biogen until 2030 to complete this trial; Biogen has announced its intention to act faster but has not provided a timeline.
Biogen and the FDA have released some but not all of the Aduhelm clinical trial data. FDA officials and publicly released internal documents describe using data from other anti-amyloid antibody trials and from the broader scientific context to inform the decision to endorse amyloid as a surrogate biomarker for Alzheimer’s disease and to thus provide accelerated approval to Aduhelm, but the FDA has not specified what these inputs were. Without more information, understanding the decision-making process is challenging.
The value to a patient and their loved ones of more time with more independence is vitally important yet incalculable. For patients in the early stages of AD like those in the Aduhelm clinical trials, slowing the loss of cognitive function could mean being able to work, drive, and/or manage their life themselves for a few extra months, delaying some of the need for paid and unpaid caregiving. Experts are divided on whether the 22% slower rate of decline seen in the one positive Aduhelm study would be noticeable to patients and families, and there is no evidence yet regarding whether taking Aduhelm for longer than the trial period might increase its benefits. People with Alzheimer’s also progress in their disease at different rates, further complicating the analysis. The intangible value and financial savings from the possible delay in decline are very challenging to estimate and will differ from person to person.
The list price of Aduhelm at the maintenance dose was set by Biogen at $56,000 per year; the costs of associated medical tests and professional services are likely to push the per patient costs, whether paid by patients, Medicare, or private insurance, to over $100,000 per year. PET imaging and cerebrospinal fluid biomarker testing can confirm the presence of accumulated beta amyloid in a patient’s brain but are not currently covered by Medicare under most circumstances. A blood test that accurately predicts amyloid burden in the brain is clinically available, but it has not yet been approved by the FDA or accepted for coverage by Medicare.
Approximately six million people in the United States have an Alzheimer’s diagnosis that would make them eligible for Aduhelm under the label originally approved by the FDA to guide doctors in determining patient eligibility. The estimate of the eligible patient population under the revised label is approximately one to two million. Most researchers expect that many more people have mild memory concerns and would be amyloid positive if tested but have not yet sought or received a diagnosis.
Since most Alzheimer’s patients are over age 65, in the United States most obtain health care coverage through Medicare; younger Alzheimer’s patients are in some cases covered by Medicaid. On July 12, the Centers for Medicare & Medicaid Services (CMS) announced the start of a National Coverage Determination (NCD) process that within nine months will yield its decision on whether and under what circumstances it will cover monoclonal antibodies targeting amyloid for the treatment of Alzheimer’s disease, including Aduhelm. In the meantime, coverage determinations are being made by Medicare contractors in each of their 12 jurisdictions, but they have not announced their local policies. The NCD will decide first if a national policy is appropriate and, if so, whether the clinical and other evidence for Aduhelm meets Medicare’s legally mandated standard that a medical intervention be “reasonable and necessary for the diagnosis or treatment of illness or injury…”.
To make this determination, CMS uses a formal process established by statute. Professional society guidelines are a named input to this process. The American Neurological Association, which represents academic neurologists and neuroscientists, has announced its position that Aduhelm should not have been approved based on the clinical evidence provided by Biogen. The American Academy of Neurology, which represents practicing neurologists, will publish a guide to Aduhelm this spring which, in its words, “will not include recommendation statements.”
Because Aduhelm is an infusion therapy, if covered by Medicare, it would fall under Medicare Part B. Physicians and hospitals acquire and pay for drugs like Aduhelm and then are reimbursed by Medicare and patients when they administer the drugs. Patients could face significant copays and could need private supplemental insurance for costs associated with taking the drug. A number of private insurance payers in some of the largest markets, including Blue Cross Blue Shield affiliates, have announced that they will not cover Aduhelm because there is insufficient evidence that it yields clinical benefit to patients. As of July 21, at least three medical systems, including Mt. Sanai and The Cleveland Clinic, have announced their facilities will not administer Aduhelm, although their physicians can still prescribe it. However, other major medical centers began administering it immediately after approval.
Aduhelm’s list price point has been highly controversial. Under Medicare Part B rules, outpatient clinics administering infusion drugs may be eligible for discounted pricing but do not have to pass along these discounts to payers or patients. Payers, like insurance companies, often but not always are able to negotiate lower net prices for the people they cover, which can lead to lower costs for their customers, but Medicare is not legally allowed to negotiate what it pays providers for Part B drugs. Biogen has announced that it is going to work with specific coverage and provider entities to provide screening and open access to traditionally underserved groups.
Before the FDA announced its decision, the Alzheimer’s world, from researchers to clinicians to patients and caregivers, was divided regarding whether what was publicly known about the clinical trial data justified approval. Many advocacy and disease organizations in Alzheimer’s, dementia, and geriatrics lobbied the FDA for or against approval. Cure Alzheimer’s Fund did not lobby the FDA because our affiliated scientists were divided and we believe the FDA’s decisions should be driven by rigorous scientific assessment rather than by the loudest voices in the debate.
During its decision-making process, the FDA tasked a standing external advisory group of experts to discuss and assess data presented by Biogen and FDA officials. Some members of this group, scientists and clinicians, have significant experience with Alzheimer’s disease while others specialize in other neurological areas and scientific disciplines. None of them voted that the data they were given to review was sufficient evidence of clinical efficacy to justify approval of Aduhelm. They were not asked to vote on whether the data demonstrating that treatment with Aduhelm reduced brain amyloid levels justified accelerated approval. The FDA is not required to follow the guidance of its external advisors.
The FDA and its acting Commissioner, Dr. Janet Woodcock, have stated that the agency stands by its decision. There are at least two Congressional investigations and an internal FDA investigation regarding the process and outcome of the FDA’s Aduhelm approval and whether the FDA’s scientific standards and independence from external influence were compromised. Members of Congress have also said publicly that they want to question Biogen about how it determined the price for Aduhelm.
The CureAlz Research Leadership Group (RLG) discussed the publicly available Aduhelm data several times between the end of the trials and the FDA’s decision. Some members believed it should be approved, and even more believed it would be approved given the clinical trial data, the enormity of the unmet need, and the prognosis for untreated AD. The majority of the CureAlz RLG believes that the amyloid cascade hypothesis is solidly supported by data from genetics, animal studies, human studies, and epidemiology and that reducing amyloid sufficiently early in AD will yield clinical benefits. However, they also believe that no drug should be approved that has not met scientific standards for efficacy. In the case of Aduhelm, although few RLG members expressed strongly positive support for approval, some RLG members were highly negative against it.
Given the inconsistency of the data from the clinical trials and the common and potentially serious side effects, nearly everyone across the Alzheimer’s world expected that any approval would be limited to patients and use patterns matching those in the successful clinical trial subgroup. Instead, the FDA’s original Aduhelm label, which doctors will use to guide their prescription decisions, was very broad. The revised label does state that efficacy and safety data is only available for patients in early stages of AD and thus that Aduhelm is indicated only for that population, but it does not require evidence that a person has excess amyloid in their brain. The three MRIs (magnetic resonance imaging tests) required are to check for the ARIA side effect as dosing is gradually increased.
Irrespective of the FDA’s Aduhelm label, the consensus among leading Alzheimer’s clinicians is that Aduhelm should be prescribed only to patients meeting the original criteria for the clinical trial and that treatment should be accompanied by ongoing monitoring for efficacy and safety. These requirements maximize the likelihood a patient will benefit from taking the drug and ensure any ARIA is detected and addressed. In their view, few medical practices or centers currently have the necessary infrastructure and expertise to appropriately screen and treat patients with this drug.
Among other parameters, the clinical trial limited participation to those with mild cognitive symptoms, confirmed brain amyloid accumulation, and no significant or recent history of heart, liver, or neurovascular disease. Although Black Americans are at significantly higher risk of Alzheimer’s and of neurovascular disease, less than 1% of trial participants were Black. Identifying patients who match the profile that benefited in the trial will require extensive neurocognitive testing, amyloid PET imaging scans or CSF/blood tests, MRls, clinical histories, genotyping and experienced clinical judgment. Assessment of whether ongoing treatment is safe or beneficial will also require regular amyloid tests, neurocognitive testing, and MRls.
Patients, families, and clinicians will need to talk frankly about how to balance the possibility of more time at a higher level of cognitive functioning with the weakness of the evidence for cognitive benefit, the small magnitude of the slowing of decline in the one positive trial subgroup, and the logistical and financial burdens of treatment.
With this decision, the FDA for the first time officially endorsed the amyloid cascade hypothesis, which holds that the accumulation of beta amyloid in the brain triggers a range of changes and pathologies that together drive neurodegeneration that eventually manifests as clinical cognitive symptoms. Amyloid accumulation starts and triggers most of its consequences before clinical symptoms of Alzheimer’s disease develop. Using amyloid as a surrogate biomarker will allow drugs to be assessed for their ability to stop amyloid accumulation before any cognitive damage is done, meaning true prevention can be pursued.
The FDA has also already acted on this principle by giving Breakthrough status to two other anti-amyloid antibodies that demonstrated significant ability to reduce brain amyloid levels in late clinical trials, potentially accelerating their path to patients. Eli Lilly has announced that it will seek approval for one of them based on an already-completed Phase 2 trial that showed both amyloid reduction and cognitive benefit in its relatively small cohort. If successful, these drugs would bring both clinical and financial competition to the marketplace. Other anti-amyloid therapies that are not antibodies and may avoid some of the safety and cost issues these present may also see increased financial investment and FDA support that could accelerate their availability to patients.
The availability of an approved disease-modifying drug may make enrolling clinical trials of new drug candidates, and even of the FDA-required post-marketing study of Aduhelm, harder and more expensive. Patients may prefer to take Aduhelm under their physician’s care rather than participating in a trial in which they might receive a placebo, for example. Alternatively, if Aduhelm becomes the standard of care for early AD, trials may have to compare any new drug’s performance to that of Aduhelm; since Aduhelm is very expensive, that will increase trial sponsors’ costs. However, this scenario is common in other diseases in which new drug candidates must compete with already available drugs to demonstrate superior efficacy.