Several agents from a packed pipeline of anti-amyloid therapies for the treatment of Alzheimer's disease may come to market within the next year, prompting experts in the field to ask: Are the systems of care within neurology and health care in general ready for the changes to dementia care delivery that will come with more widespread use of these medications?
For at least one of the new drugs in the class, the point has been mainly moot. Aducanumab (Aduhelm), the first of the anti-amyloid class to be approved, had a rocky launch, as findings from the EMERGE and ENGAGE clinical trials were not clear-cut, and there were significant risks of adverse events, particularly amyloid-related imaging abnormalities-edema/effusion (ARIA-E), which affected 40 percent of trial participants and was symptomatic in about one-quarter of those patients.
The Food and Drug Administration's (FDA) decision to approve aducanumab was controversial, and the Centers for Medicare and Medicaid Services (CMS) elected to cover aducanumab only in the setting of FDA- or National Institutes of Health (NIH)-approved trials. As a result, it has not been widely adopted; Biogen reported just $2.9 million in aducanumab sales through the first six months of 2022.
But at least three other drugs in the class—lecanemab, donanemab, and gantenerumab—are nearing FDA review, and positive top-line results for lecanemab in the Clarity-AD trial released by manufacturers Eisai/Biogen in September renewed flagging hopes for these agents.
Peer-reviewed data have not yet been published, but according to a news release from the manufacturer, lecanemab reduced clinical decline on the 18-point global cognitive and functional scale, the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), compared with placebo at 18 months by 27 percent, representing a treatment difference in the score change of -0.45 (p=0.00005) in the analysis of intent-to-treat population.
“Starting as early as six months, across all time points, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo," noted the company release. The incidence of ARIA-E was also generally lower in this trial.
“This data is very encouraging to me, providing more credence to the anti-amyloid hypothesis," said Jeff Gelblum, MD, a senior neurologist with Florida-based First Choice Neurology, the largest single-specialty neurology group in the country with 81 offices and over 100 neurologists. “It reinforces what we had thought to be true with aducanumab, which is if you select the right patients, the drug should be effective."
Coming to Market in 2023?
If these data bear out under FDA scrutiny, lecanemab could come to market in early 2023. It was accepted for review under the accelerated approval pathway and granted priority review in July 2022, and the Prescription Drugs User Fee Act action date is set for Jan. 6.
The manufacturer, Lilly, also hopes to get accelerated approval of donanemab in early 2023 followed by an application for full approval with more data from its ongoing TRAILBLAZER-AD trial expected by the middle of next year.
Meanwhile, Roche was scheduled to present findings from the Graduate 1 and 2 studies of its anti-amyloid agent, gantenerumab, at the Clinical Trials on Alzheimer's Disease conference at the end of November.
“The aducanumab data alone was less than satisfying, but when you pull all of these agents together, there seems to be some kind of consistency as a class effect that these drugs have a modest outcome in modifying the disease course," said David A. Wolk, MD, FAAN, professor of neurology and chief of the cognitive neurology division of the University of Pennsylvania Perelman School of Medicine, director of the Penn Alzheimer's Disease Research Center, and co-director of the Penn Memory Center.
“That's not trivial, given the burden of Alzheimer's disease, where we have been with treating it so far, and the possibility of affecting the biology of the disease," he said. “And the fact that there's some correspondence across these drugs, which all clear amyloid but don't work exactly the same way, is also notable; one positive study helps support the other positive studies. While we need to see the lecanemab data presented to the scientific community, based on what we know it would not surprise me if all of these drugs hit their targets and endpoints, and the likelihood of approval given what we know now seems fairly good."
But as we learned with aducanumab, FDA approval does not always lead to wide adoption of a drug. The CMS coverage with evidence development decision means that Medicare only pays for the drug in the setting of FDA- or NIHapproved, placebo-controlled clinical trials; that decision includes not only aducanumab but also any future amyloid-targeting antibodies approved under the FDA's accelerated approval pathway. And for any future drugs in this class that receive traditional FDA approval and demonstrate clinical benefit, CMS has stated that it will provide broader coverage that includes CMS-approved studies, such as data collection through routine clinical practice or registries.
Dr. Wolk predicts that this is likely, at least for lecanemab. Broader adoption of an infused drug like lecanemab—which also has significant diagnostic and monitoring requirements—will dramatically change a dementia-care landscape that until now has largely consisted of oral agents with mild side effects, such as memantine (Namenda) and donepezil (Aricept).
“We're not completely ready for what will be needed if these are fully approved," Dr. Wolk said. “Even restricted, as they are likely to be, to people who fall into a relatively small group—those with mild cognitive impairment (MCI) and mild Alzheimer's disease—there will still be a fairly large population of patients interested in taking these drugs or at least wanting to be evaluated. It is going to require a real systemwide response that cannot be limited only to neurologists."
Scanning and Infusion Capacity
Experts identified three major areas where practice capacity may need to be expanded or enhanced—patient identification/diagnostic requirements, monitoring, and infusion capacity. Confirmatory tests, typically either amyloid PET scanning or cerebrospinal (CSF) fluid analysis, are needed to confirm the presence of amyloid plaques in the brain.
“If we rely on amyloid PET scanning, there will be major deficiencies in access in a number of areas, and probably significant problems with equitable distribution as well, so CSF biomarkers become even more important," said Eric McDade, DO, professor of neurology in the division of cognitive neurology at Washington University School of Medicine in St. Louis and the co-director of the Dominantly Inherited Alzheimer Network Trials Unit.
“A number of institutions, including ours, have been working on developing more high-throughput systems for incorporating CSF screening, because at this stage, even larger tertiary care centers likely do not have the capacity to perform CSF on the number of individuals who would need to be screened for these drugs in order to confirm Alzheimer's disease as a probable cause or significant contributor to their dementia."
Dr. McDade noted that blood-based biomarkers may be a possible first-stage screening tool.
“The studies for several of these agents have data on these biomarkers, and we have to be ready to understand their performance within large trial populations and be ready to introduce them as primary screening with CSF or PET as a backup when the blood markers are inconclusive," he said.
Because of the ARIA risk, patients receiving aducanumab have a baseline MRI scan before starting treatment and at regular intervals afterward.
“Even at a center the size of ours, it would be challenging to manage the volume of MRI scans that would be needed at baseline, during surveillance, and when there is suspicion of an unexpected change," Dr. Wolk said. “There is already a lot of competition and scheduling problems with the scanners we do have; I think many centers will have to make an investment in increased scanning capacity."
Most of these agents are being studied as monthly infusions (although some research has been done on subcutaneous delivery for at least some of them).
“In our system, which is quite large, there are infusion sites that could absorb at least some of the added capacity, but elsewhere the country, particularly in less metropolitan areas, access to infusion will be much more difficult," said Annette Langer-Gould, MD, PhD, regional lead for translational neuroscience with the Southern California Permanente Medical Group of Kaiser Permanente. “Offering home infusion services for certain patients is something that I believe the field will have to adapt to over time."
Dr. McDade said Washington University has been planning how to expand its infusion capacity in not only the neurology department but also the entire institution.
“Some institutions and private practices with large neuro-immunology clinics, specifically MS clinics, will likely be well equipped to manage these patients because of the large infusion centers they have already built up," he said, “but others may not be as well prepared and may have to consider whether to add capacity or identify private infusion centers in the community they can use."
Indeed, large private neurology practices may be particularly well positioned to manage Alzheimer's disease patients through the continuum of identification and screening, treatment and monitoring with these agents, Dr. Gelblum said.
“We have a very vertically integrated neurology practice; we do our own labs; we have significant imaging capacity and our own infusion centers," he said. “We have built in a lot of reinforcement and redundancy and have unimpeded access to all of the resources we'll need under one virtual roof. In order to safely and successfully implement these treatments, you need a large neurology practice setting with an integrated treatment paradigm."
Beyond systems capacity, workforce issues may emerge. Management of patients on these drugs will be significantly more complex than management of a patient on one of the existing Alzheimer's therapies.
“We don't have enough neurologists who have the expertise to correctly diagnose MCI and mild dementia due to Alzheimer's disease let alone manage all of the Alzheimer's patients in the country who may qualify for these drugs," Dr. Langer-Gould said. “There aren't many neurobehaviorally trained neurologists to begin with; they haven't been sought after by academic departments because most of what they do is counseling, not procedures, so they are not big billers. How do we build that workforce?"
Bringing these drugs to market also will require more highly trained neuroradiologists.
“A lot of the brain imaging findings that we see in this context can be very subtle," Dr. McDade said. “If you don't know what to look for, you won't necessarily see it, so there will be a need for specialization among neuroradiologists to feel comfortable reviewing these scans."
Dr. Wolk agreed, noting that one could argue about how well drugs such as memantine and donepezil work across conditions.
“And they may have some side effects, like increasing agitation in frontotemporal dementia, but those are pretty minor downsides if you're doing a trial of the drug, and it's pretty easy to stop," he said.
“But with these new agents, there are much more significant implications to getting the diagnosis right, making sure the person has the underlying condition and also can safely take these drugs, and then monitoring them over time. ARIA imaging abnormalities can sometimes start with very subtle symptoms, and if missed can lead to severe problems."
Dr. Langer-Gould also has concerns that the new class of anti-amyloid drugs may siphon resources from other areas of dementia care. She questioned whether the drugs would “shift resources and attention toward the relatively small population of people with MCI and early Alzheimer's disease, so there is less available to care for the large number of patients with mid- and later stages of AD and for those with other or mixed types of dementia who don't benefit from these drugs."
“And what effect will these approvals have on other clinical trials, such as placebo-controlled trials in anti-tau agents or other promising avenues?" Dr. Langer-Gould said. “Will they have to have an active comparator with an amyloid-depleting drug thereby drastically slowing our ability to find highly effective treatments for Alzheimer's disease?"
It does seem likely that the availability of new agents will increase the number of people diagnosed with MCI, Dr. Wolk said.
“At this point, for many primary care providers, it can be challenging to work up patients with mild cognitive issues. The diagnosis takes a lot of time, and it's not clear what the implications of making that diagnosis are. It often involves a lot of counseling and management of the home environment, safety planning, and other things that are a challenge in a busy primary care office. If there is a treatment they can offer, physicians across disciplines will likely feel at least somewhat more motivated to incorporate that into their practice."
Full FDA approval and CMS coverage of one or more of these anti-amyloid agents—should that happen—will require a full systemwide response beyond neurology, Dr. Wolk said. The health care system will need to undergo restructuring to it can “better evaluate, manage, and refer patients for drugs that will be in significant demand, that potentially have serious implications with regard to safety, and that require a fair degree of sophistication in management," he said.
“We'll be shifting a pretty common disease into a complicated and specialized algorithm for administration and management, in a system that just doesn't have that many experts," Dr. Wolk continued.
“Most centers that are not large multispecialty academic centers or large integrated neurology practices will not have the neurologic expertise to manage these patients, so there will need to be a lot of education for internists, geriatricians, and psychiatrists to be equipped with the fundamentals of the diagnostic process and making the decision to refer."
Neurology should take the lead in this response, Dr. McDade said.
“We are going to have to deal with a completely new way of thinking about and treating Alzheimer's disease, and it's completely untenable that it will only be done with dementia experts in academic medical centers," he said. “We are going to have to work on programs that allow neurologists who are non-dementia specialists to get up to speed on this quickly and be ready to serve comfortably on the front line for this.
“This is our field; Alzheimer's is one of the major neurological disorders of aging, and we need to position ourselves to take leadership on this."