This NeurologyLive® Peers & Perspectives series features experts in the diagnosis and treatment of Alzheimer disease discussing the recent approval of aducanumab, its implications for Alzheimer disease, and other promising therapies and diagnostic technologies in development.
BRINGING EFFECTIVE TREATMENTS for Alzheimer disease (AD) from clinical development programs into the hands of clinicians has been an ongoing challenge that neurologists and geriatricians, among others, are all too familiar with. This is in part why the FDA approval of aducanumab (Aduhelm; Biogen) in June 2021 brought so much discussion to the field. Many viewed the approval as a major step toward breaking through the barrier that has prevented so many other promising agents from making it to market, while others questioned the clinical effectiveness of the drug based on its somewhat shaky supporting data.
Regardless, aducanumab’s approval was undeniably a landmark decision by the regulatory agency and one that will likely have lasting effects in the months—and perhaps years—to come. After some clarity was brought by the FDA in July 2021 to its indication about the proper patient population it can treat, some of the conversations in the field have shifted toward the ripples that the FDA decision might cause.
To find out about the possible consequences of this approval on the field of AD care, a recent NeurologyLive® Peers & Perspectives series brought together Richard S. Isaacson, MD, director, Weill Cornell Memory Disorders Program, director, Alzheimer’s Prevention Clinic, and director, Neurology Residency Training Program, Weill Cornell Medical College/NewYork-Presbyterian Hospital; and Marc E. Agronin, MD, senior vice president, Behavioral Health, and chief medical officer, MIND Institute, Miami Jewish Health. The pair sought to parse out the impact this decision may have, not only on the care of patients with AD, but also on the overall treatment landscape.
In the weeks since aducanumab was approved, a few other agents in the pipeline have been granted breakthrough designations by the FDA, namely, Eli Lilly’s donanemab—an antibody that targets a modified form of amyloid-ß (Aß) called N3p—and Biogen’s lecanemab—another anti-Aß protofibril antibody, formally known as BAN2401. Isaacson pointed out that both agents are being evaluated in AD dementia and mild cognitive impairment and are headed to phase 3 studies, and mentioned galantamine, a cholinesterase inhibitor that was shown to potentially slow cognitive decline in AD earlier this year. Isaacson began by inquiring about these other agents, specifically pondering what effects this approval may have on the FDA’s willingness to approve investigational therapies that operate similarly to aducanumab.
“Yes, [I think the likelihood of success is increased for those agents], and I would throw into the mix antitau treatments also that are being looked at,” Agronin said. “This is a question that’s been raised, given the FDA’s approach here: Is this going to set a precedent to change the bar in terms of other treatments? I’ve been to some FDA review committees and it’s a tough environment for any treatment for AD. Almost everything has failed through it and with good reason: Either the data [are] there or [they are] not there. We need data and we need studies.”
Agronin continued by noting the impact that this approval, the first of its kind, may have on clinical trial participation in a negative way. He explained that now there may be less interest in participation because of the demand to get access to treatment, and as the screening process is very rigorous for the trials being conducted in AD, participation in studies can be almost burdensome for patients. “I have some studies where it’s a 2- or 3-month process of multiple scans, multiple scales, and someone is asking themselves, ‘Am I going to go through that process for 2 years to be on potential placebo? I can walk down the street and get this infusion,’” Agronin said.
These possible complications have led many to question the design of clinical trials in AD, and Agronin raised several questions: Do they need to be shorter in length? Do they need to move more quickly to open-label stages? Should aducanumab be an active comparator? All these questions, despite currently lacking answers, will likely weigh on those working as investigators in the field. The main concern for Agronin and Isaacson is the possible impact on research in AD.
But the rippling effect doesn’t stop at research. Much of the discussion on aducanumab in the weeks following its approval has centered around access to the therapy. Some, such as the Institute for Clinical and Economic Review, have published reports that its current list price of $56,000 annually far exceeds the cost-benefit ratio. On top of this, many questions remain to be answered about coverage for patients, both from insurers and from Medicare.
“My sense is—I’m trying to be very optimistic here—that I think this is going to be a very gradual rollout. I think what we’re going to see both from clinicians and payers is that there’s going to be a pretty high bar to qualify for the treatment to get payment for it,” Agronin said. “Sure, some people are going to walk in and just want to pay cash for this. I don’t think that’s going to be the majority. I think that will be few and far between, so I think it’s going to be done in a very measured way.”
Ultimately, Agronin and Isaacson agreed that perhaps the weightiest challenge for the physician community at this point is coming to consensus. Agronin noted that with the varying concerns being raised by colleagues in the field, getting clinicians across the US on the same page about the therapy’s potential benefit, proper indication, and clinical use will be of paramount importance going forward. Its importance cannot be overstated, according to Isaacson, particularly as it pertains to ensuring effective communication with patients.
“Patients do what they want to do, and [its approval] even opens up the door to [a scenario where] someone is on aducanumab, they’re in another clinical trial, and [drugs] could be mixing; there are lots of potential issues there that we need to have very frank conversations with patients about,” Isaacson explained. “I think that is going to be very few and far between—at least I hope it would be. However, there are studies being planned for that now. Obviously, if you’re on an antiamyloid drug in a clinical trial, you really should not be on the antiamyloid drug in practice; that’s easy. But what about an antitau drug in a clinical trial; can you be on the amyloid drug in practice? That probably mixes things up and confuses things.”
As an example, Isaacson pointed to an ongoing trial with semaglutide (Ozempic; Novo Nordisk), a glucagon-like peptide-1 (GLP-1)–targeted drug approved for the treatment of diabetes. The study, dubbed EVOKE (NCT04777396), is a phase 3 study aiming to enroll more than 3700 individuals to assess the drug’s impact on cognition and AD progression over a 2-year period.
“That study, to my understanding, allows someone to be on an antiamyloid drug. There may be some studies that people could go into and participate in as well as being on aducanumab. How do you track that? How do you analyze for that? Obviously, it’s a randomized trial, so hopefully, some of that will shake out, but it really adds just another level of statistical complexity, real-world complexity, and recruitment complexity when you have a drug like this available in the market,” Isaacson said.
Agronin pointed to similar and current confounding effects that are experienced in trials that include individuals on acetylcholinesterase inhibitors and memantine, noting that to Isaacson’s point, aducanumab may join the list as an acceptable background therapy for trial participants.
In addition to ridding the brain of Aß plaques, the addition of these investigational agents on top of approved therapy in trials may be the key to slowing the disease course. As Agronin put it, clearly more is needed than simply targeting a single pathology of AD, but it is important that studies that are looking at other modalities are not compromised along the way.
“I’m seeing over time—I would say across the board for not just Alzheimer studies but other clinical trials—there is a greater allowance for other modalities being used simultaneously,” Agronin explained. “Obviously, someone can’t be in more than 1 clinical trial at the same time, but I think realistically, that is probably going to become more the reality that either the studies allow these other treatments or they’re really going to have a hard time enrolling.”
To watch the entire series, “Recent Breakthroughs in the Treatment of Alzheimer Disease,” click here.