The US Food and Drug Administration (FDA) June 7 approval of the monoclonal antibody, aducanumab for Alzheimer's disease (AD)—after decades of failed clinical trials that target the clearance of amyloid-beta—has elicited a decidedly mixed response from neurologists who treat dementia.
The accelerated approval, neurologists told Neurology Today, was controversial given that one of two phase 3 studies failed to show a statistical clinical benefit of the drug, while the other study did. The positive study showed a modest signal on neuropsychological tests, but there was no functional improvement that was noticeable to patients or their family members.
The accelerated process means that Biogen can sell the drug but must agree to design and carry out a study to prove that there is a clinical benefit. The federal agency's decision was based on the biomarker changes showing that the monoclonal antibody reduced amyloid-beta from the brain. It could take years to accumulate such data, and if it doesn't have a clinical benefit the agency could then rescind the approval.
On the day of the FDA's decision, the Institute for Clinical and Economic Review (ICER) posted a news release about the approval of aducanumab. The organization conducted its own analysis of the data from all studies and said that the FDA “failed in its responsibility to protect patients and families from unproven treatments with known harms."
“Our review of the evidence was concordant with that of many independent experts: current evidence is insufficient to demonstrate that aducanumab benefits patients," the statement said. "The avenue forward has seemed clear: another study would be needed to reduce the substantial uncertainty about the drug's effectiveness, a requirement of even greater priority because of the drug's common and potentially serious side effects."
ICER will hold a public meeting in mid-July to address the decision and the question of “fair pricing for a drug that now seems likely to become one of the top selling drugs in the history of the United States." A draft report from the agency suggests that a fair price would be $2,500 to $8,300, and not the $56,000 annual cost that the company has been talking about.
What to Tell Patients
Meanwhile, neurologists are fielding calls from their patients, and racing to figure out how to put systems in place to deliver it. The monoclonal antibody will clear amyloid from the brain, but without an initial amyloid PET scan, lumbar puncture, or a blood test to measure amyloid-beta it is impossible to know whether the patient does in fact have amyloid in their brain, they said.
Most diagnostic decisions are based on clinical signs, and not pathological ones, they said. And the FDA labeling says nothing about who should be eligible for the drug and what measures should be taken to confirm the presence of amyloid.
Also, the monoclonal antibody requires testing for side effects that include brain swelling. The FDA labeling recommends brain scans at seven months and again at one year. But the Biogen studies show amyloid-related imaging-edema (ARIA-E) can develop in the first four months of treatment.
“This is an unprecedented decision," said Lon Schneider, MD, professor of psychiatry, neurology, and gerontology at the Keck School of Medicine of the University of Southern California (USC).
“This FDA approval was based on a biomarker, and the agency is saying that decreasing amyloid plaques are surrogate markers for clinical benefit. There is no evidence for that or against it. We just don't know," said Dr. Schneider, who is director of the California Alzheimer's Disease Center and co-director of the clinical core of the USC Alzheimer's Disease Research Center.
“The agency granted accelerated approval and, as per the agreement, Biogen will conduct the studies to determine a clinical benefit," Dr. Schneider added. “But how do you explain to patients that the drug might clear away amyloid from their brains, but we don't know if there will be any clinical benefit. We'll have to wait and see."
It is unclear how Biogen will design post-approval studies. Will it be a randomized, placebo-controlled trial or an observational one? In any case, “it will take years for the required study to confirm a clinical benefit," said Dr. Schneider.
“This is a great day for Biogen and its shareholders but a bleak day for the field of Alzheimer's research," added Michael Greicius, MD, associate professor of neurology at Stanford University. “The FDA and groups like the Alzheimer's Association have made the mistake of advocating for the illusion of progress in drug development and it will come at a cost to genuine progress in finding an effective treatment for this devastating disease."
Marwan Noel Sabbagh, MD, director of translational research at the Cleveland Clinic Nevada and the Lou Ruvo Center for Brain Health, and professor of neurology at the Cleveland Clinic Lerner College of Medicine, sees it another way.
“I see patients day in and day out and we need a solution. We need to start somewhere. It is a panacea? No. Is it a cure? No. But we need something. This will be a transformative moment for our field. We are trying to convert Alzheimer's from a terminal disease to a chronic one."
He knows that the drug has only a small effect on clinical decline, but “at its core, patients may be better than they would have been. If we can delay progression, it will have a huge impact." He agreed that the field might not be prepared for this kind of change.
No Approval from the Advisory Committee
In November of last year, the FDA held hearings to discuss findings from the two trials, and an FDA-appointed advisory committee recommended not to approve the drug. There were 11 members on the committee, and ten voted not to approve the drug and one abstained. [Read the Neurology Today story here.]
The FDA wrote a letter to the advisory committee on June 7 that made their recommendation to send the drug back for more testing. “Ultimately, the decision on whether aducanumab will be used for treatment will be made by patients, their families and caregivers, and health care professionals," Billy Dunn, MD, director of the FDA's office of neuroscience at the Center for Drug Evaluation and Research, wrote. “The public can be confident that the agency used a rigorous, science-based approach to assess this therapy, considering all of the evidence in the application, and also the tremendous unmet medical need for the many patients living with this disease."
At press time, three members of the FDA Peripheral and Central Nervous System (PCNS) advisory committee—Joel S. Perlmutter, MD, FAAN, Elliot Stein Family Professor of Neurology at Washington Univerity School of Medicine; David S. Knopman, MD, FAAN, professor of neurology at Mayo Clinic in Rochester, MN; and Aaron Kesselheim, MD, professor of medicine at Harvard—resigned from the committee to the decision.
“I have resigned today based upon this decision by the FDA," Dr. Perlmutter, told Neurology Today in an email. “As a member of the FDA advisory committee, we were not informed of any additional information that contributed to the decision by the FDA."
Three statisticians on the committee wrote an editorial in JAMA laying out the argument against its approval.
Dr. Knopman told CNN in an email: “I resigned from the PCNS committee because if I ever were asked to serve on a future panel, I wouldn't have wanted to be treated in the disrespectful way that the aducanumab external advisers were treated."
Since the advisory committee met in November, the federal agency has continued to work with Biogen and Eisai scientists, who are collaborating on the development and commercialization of the drug globally, to analyze the data to see if the benefits outweigh the risks. The accelerated pathway is saved for drugs that will be used for patients with serious or life-threatening conditions that provide a therapeutic advantage over existing drugs.
The new approval and the roll-out of the drug will bring many other challenges. For one thing, the monoclonal antibody, and three others in different stages of testing, were designed to clear out the toxic amyloid-beta that accumulates in between neurons. And that means it would only work in people with amyloid-beta in their brains. That said, most people don't get amyloid PET scans to confirm an AD diagnosis. Medicare does not yet cover the amyloid-PET scans for AD. Neurologists make a clinical decision, and many times they are not right.
Also, some AD experts say that the estimated cost of the drug, $56,000 a year, is too high a price to pay for a drug that may offer a modest clinical benefit. Medicare and private payers will have to determine whether they will pay for the treatment, who should be eligible to receive the drug, and if they will require tests to confirm the presence of amyloid-beta in the brain, and repeated brain scans to look for ARIA-E, and ARIAH-H, which includes microhemorrhages and superficial siderosis.
In the clinical trials, ARIA-E included temporary brain swelling that for most people did not result in any symptoms, but others had headache, dizziness, confusion, vision changes, and nausea.
These side effects will require monitoring with brain scans if the drug is prescribed, which adds another cost to the use of the drug.
Also, subset analyses from Biogen show that people with at least one copy of APOE4 have a much higher rate of ARIA, about 45 percent. They also showed the people with the allele who are over 70-years-old showed the most cognitive benefit. Will testing need to be done to verify APOE status, several neurologists wondered.
Will They Prescribe It?
Many neurologists, even those with concerns, say that they will offer the drug, lay out what they know, and ultimately let patients make the decision. “We won't say no," said Dr. Schneider. “At the same time, we will not actively promote its use."
Jason Karlawish, MD, co-director of the Penn Memory Center at the University of Pennsylvania and professor of neurology, medicine, and medical ethics and health policy, said that he believes the FDA “handed Medicare several challenging medical, ethical and policy issues with a broad label and no boundaries on the severity of the disease or whether patients have documented beta amyloid in their brains. It is now going to be in the hands of physicians and Medicare to decide how to rationally prescribe this medication."
Even with a strong argument against its use without more study, Penn is putting the infrastructure in place to offer the drug. “I will be a reluctant prescriber," said Dr. Karlawish. “I will explain the uncertainty of the benefits and risks and patients will make their own decisions. But I would not prescribe it without an amyloid test. We will just have to wait and see what happens, but we are in for a wild ride."
Dr. Knopman added that post-hoc analyses are useful to guide future studies “but not appropriate for drawing conclusions about whether a drug is efficacious." In fact, the post-hoc analysis suggested the drug had no benefit in women or in younger patients or in non-APOE4 carriers and people with mild cognitive impairment (MCI), he added.
“This creates uncertainty whether the therapy will have a benefit. Moreover, the FDA's accelerated approval process effectively avoided making any claims about the clinical benefits of aducanumab. Thus, the FDA did not really choose to comment on any of the clinical outcomes."
Dr. Knopman thinks some of these questions will be answered once the drug is in widespread use. But in the meantime, “it will definitely change dementia care practice. I will have to explain the pros and cons to my patients and tell them my views," added Dr. Knopman, who is an investigator in the ongoing open-label aducanumab study.
He said that the Mayo Clinic is working hard to put the infrastructure in place and that will involve nuclear medicine, radiology, and the infusion center. “Patients will definitely hear both sides of the story."
“The problem is that the data are so ambiguous," added Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation. “What's more, the labeling from the FDA doesn't address any subset of patients who might benefit from the drug. They just say for the treatment of Alzheimer's, which means anyone from MCI to severe dementia. This is concerning. The drug was only tested in people with MCI and mild dementia."
Dr. Fillit was also surprised that the label did not address testing to confirm the presence of amyloid-beta. “Still, if my patients want to try it I have no problem with that. I just can't tell them whether they will see a benefit."
Samuel E. Gandy, MD, PhD, professor of neurology and psychiatry and the Mount Sinai Chair in Alzheimer's Research, and director of the Mount Sinai Center for Cognitive Health, said that it is impossible to know what to advise patients until neurologists know how much the drug will cost and who will pay for it. Will patients qualify for scanning, and if so, who pays for that?
“It will be very challenging for patients without these answers," Dr. Gandy said.
“I don't see any reason not to prescribe it," he added. “The problem is explaining it to patients and managing their expectations. They may do better on cognitive tests, but their family might not notice a difference. This drug doesn't reverse the disease process but only appears to slow decline somewhat. I would not be enthusiastic about prescribing it in patients with advanced disease."
"Now that the FDA has approved aducanumab despite its shortcomings, I would urge Biogen to put some data to clarify the major criticism that is the 'failed trial,'" added Dr. Gandy. “The trial did not fail but was uninterpretable because the AD patients on placebo did not show cognitive decline.
“While I publicly opposed the FDA's aberrant and non-science-based approval based on the current dataset, now that the FDA has gone ahead and given me lemons, I will try to make lemonade," he said.
Ronald C. Petersen, MD, PhD, FAAN, director of Mayo Clinic's Alzheimer's Disease Research Center, thinks that the FDA's decision was reasonable.
“The drug does what it was intended to do biologically, remove amyloid, and since amyloid is one of the defining features of the disease, that makes sense. The clinical impact of the amyloid removal is less clear; hence the FDA has required a phase 4 study to document its efficacy."
“Given the nature of the disease," he added, “this position will address the needs of the patients while requiring further evidence of clinical utility. We are developing a program at Mayo to evaluate and treat our patients."
Paul S. Aisen, MD, the founding director of the USC Alzheimer's Therapeutic Research Institute and professor of neurology at the Keck School of Medicine of University of Southern California, agrees the monoclonal antibody “appears to be an effective treatment."
At the same time, he added, “there are serious statistical questions. One phase 3 study was positive, and one was negative. There are valid reasons for accelerated approval and for waiting for an additional trial; I see both perspectives. There is a great need for a disease-modifying treatment and a delay in approval has an enormous cost. These decisions are difficult."
“We frequently launch clinical trials with unanswered questions, and this can lead to changes in trial protocols mid-stream," he added. “The trials are complicated, and the interpretation of the data is complicated. This is a dataset that would not typically support approval of a new drug application. I think aducanumab works but the clinical outcome data is not fully consistent, and I do think another study makes sense." He and others hope that clearing amyloid early in the disease process will lead to more robust clinical benefits.
Pierre Tariot, MD, director of the Banner Alzheimer's Institute and professor at the University of Arizona College of Medicine, also has confidence in the FDA's decision to approve the drug. His center just received funding to build an in-house infusion center. “The FDA had to do a lot of analyses and make a very complicated judgement. I can't join the skeptics who say 'just say no.' There are a lot of unanswered questions. It is a tough call."
Many neurologists said they will have to determine how best to deliver and manage aducanumab. “There is not a lot of guidance on how to approach the clinical decisions," said Rany Aburashed, MD, chief of neurology at Memorial Healthcare in Michigan. “There are sub-populations of patients who may benefit. It will be important to see how the narrative unfolds. We will have a set protocol and my hunch is there will be amyloid testing before we prescribe the drug."
“I don't think it's ready for primetime," added Mary Sano, PhD, professor of psychiatry and the director of the Alzheimer's Disease Research at Mount Sinai School of Medicine. “I don't want to minimize the need for hope, but it doesn't come from something that is so imperfect. Many other drugs with this mechanism and little to no clinical benefit will come along and now have a pathway to approval despite failure to improve the clinical condition. While amyloid is cleared the efficacy is barely there and it only shows up at the very last time period. Also the studies only included amyloid positive subjects which is not even required in the approval."
“Finally," she continued, “only the high-dose group showed a signal, and it is a real challenge whether you can safely deliver the higher dose."
The Patient Perspective
Meanwhile, many patient organizations have pushed for approval of aducanumab, even with the mixed findings. “This approval is a victory for people living with Alzheimer's and their families," said Maria Carrillo, PhD, chief science officer at the Alzheimer's Association. “This is a historic moment. We are now looking to ensure that everyone who should get this drug has access to it. Time will tell. There was a sufficient amount of science to approve it now, and not wait five more years with more clinical trials. For patients now, five years will be too late."
“While this is a new day," added Alzheimer's Association president and chief executive officer Harry Johns, “this is just the beginning."