By Jacqueline Howard, CNN
Updated: Thu, 10 Jun 2021 12:06:26 GMT
Patients and their families are starting to inquire about the new Alzheimer's drug approved this week by the US Food and Drug Administration.
Shipments of the medication are expected to go out in just a couple of weeks. Hospitals are on tap to administer treatment when needed. And there is serious division in the FDA, especially around the drug's effectiveness.
Aducanumab, to be sold under the brand name Aduhelm, was approved to treat patients with Alzheimer's disease -- against the recommendation of an FDA advisory committee that concluded last year there is not enough evidence to support approval of the treatment. The FDA has not approved a novel therapy for Alzheimer's disease since 2003.
Patients now have many questions about aducanumab. At Memorial Healthcare in Michigan, the hospital's Institute for Neuroscience has been closely following the drug's development and already has a waiting list of potential patients who may meet the criteria to receive the treatment.
"Aducanumab isn't a magic pill that will cure Alzheimer's, so as providers we need to be diligent and thoroughly assess the treatment's rewards and risks with patients," Dr. Rany Aburashed, chief of neurology at Memorial Healthcare, told CNN in an email on Tuesday.
"What's really exciting is that aducanumab is the first new FDA-approved Alzheimer's treatment in nearly 20 years, and we're optimistic this will spark a wave of new research and innovation in this space. Patients are excited for that, too, and if aducanumab is the first step toward that brighter future, patients are eager to be part of it."
For now, here are some basic questions patients and their families might have about aducanumab, answered by doctors from across the United States.
Who is the drug for?
Aducanumab is approved for patients with Alzheimer's disease.
"The FDA authorization of Aduhelm is fairly broad, indicating it is for Alzheimer's disease as a whole," Aburashed said. However, the pharmaceutical company Biogen and its Japanese partner Eisai tested aducanumab, administered through intravenous infusion, in patients with mild cognitive impairment, the impaired thinking and memory loss that often develops into dementia.
So, "the clinical development program targeted early mild cognitive impairment and mild cases of Alzheimer's disease as opposed to more progressive cases," Aburashed said. "At Memorial Healthcare Institute for Neuroscience, we intend to be very focused on this subset of patients for treatment consideration, given some of the risks surrounding the drug."
Many molecular and cellular changes happen in the brain of someone with Alzheimer's disease and there are certain characteristics of the disease, including the buildup of plaques in the brain, made of proteins called beta amyloid.
Patients enrolled in the aducanumab studies that led to FDA approval had undergone positron emission tomography or PET scans of the brain to show evidence of "amyloid pathology," Dr. Julia Biernot, a neurologist with the University of Maryland Medical Center who specializes in Alzheimer's disease and dementia, told CNN in an email on Tuesday.
"I would personally not prescribe the drug unless there is biomarker evidence of amyloid positivity, along with clinical symptoms of Alzheimer's disease," said Biernot, assistant professor of neurology at the University of Maryland School of Medicine.
"Ultimately, there are many factors to consider when deciding to treat a patient with a newly approved medication, especially when there is some uncertainty about its clinical benefit," she added. "There may be a subgroup of patients that benefits from this drug. My own decision to prescribe it will be made in collaboration with the patient, and based on the patient's age, imaging findings to rule out contraindications, type and severity of symptoms, risk factors and overall diagnostic impression."
Why is there some controversy?
Aducanumab's road to FDA approval has been rocky, due to halted trials and a FDA advisory panel not entirely convinced of the drug's effectiveness.
In March 2019, two Phase 3 clinical trials of aducanumab were discontinued because a futility analysis found the trials were unlikely to meet their primary goals at completion.
"Studies were halted and the drug stopped development," Dr. Lon Schneider, Della Martin Chair of Psychiatry and Neuroscience and director of the California Alzheimer's Disease Center at the University of Southern California, told CNN on Tuesday.
Then, "a little bit later, the company analyzed all of its data, which included extra patients who were still being treated while the futility analysis was under way and they found that one of the studies was flat-out negative," Schneider said. "But the other study was nominally statistically significant in the cognitive outcomes, and from that the FDA was supportive of the company essentially putting in a new drug application."
In October 2019, Biogen announced that it was pursuing FDA approval. The company noted that in the new analysis, patients who received high doses of aducanumab experienced a reduction in clinical decline in one trial, but not in the other.
Then in November, the FDA's Peripheral and Central Nervous System Drugs Advisory Committee was asked to vote on several questions about evidence of the drug's effectiveness.
In briefing documents for that committee meeting, Biogen noted it found the patients treated with high-dose aducanumab showed 22% less clinical decline in their cognitive health at about 18 months -- meaning the progression of their early Alzheimer's disease slowed -- compared with those who received a placebo.
For the panel, that wasn't enough evidence.
In response to a question about whether it was reasonable to consider data from that one positive study as the primary evidence of aducanumab's effectiveness for the treatment of early Alzheimer's disease, none of the committee members voted yes -- 10 voted no and one was uncertain.
"The advisers, seeing the data, recommended unanimously that drug approval not move forward, that there was no substantial effectiveness," Schneider said.
"The FDA, long story short, working with Biogen since that meeting in November, came about and approved the drug -- but they didn't approve the drug under the normal conditions of standard approval for substantial effectiveness and safety," he said. "Instead, they approved the drug under what's called accelerated approval."
The FDA's "accelerated approval" program allows for the earlier approval of a drug for a serious or life-threatening illness even though more study into the drug's benefits may be needed.
Under accelerated approval, aducanumab will still be studied as part of a Phase 4 confirmatory trial to verify its clinical benefit. If the confirmatory trial does not verify the drug's benefit, then the FDA could remove the drug from the market.
But the precise causes of Alzheimer's disease are not fully understood and there is also still some debate around whether amyloid beta is the main cause of cognitive impairment in Alzheimer's patients -- and whether removing it will help.
How much does treatment cost?
Aducanumab comes with a hefty price tag.
Biogen said Monday the wholesale cost of treatment with aducanumab -- which requires an infusion once every four weeks -- is about $4,312 per infusion, making the annual cost around $56,000 for a high dose.
The company also noted that "for qualified, commercially insured" patients, their out-of-pocket costs could be reduced to as low as $0 under certain assistance programs. Patients covered by Medicare through a Medicare Advantage plan have a maximum annual out-of-pocket cap. Biogen mentioned working on initiatives with Cigna, the Veterans Health Administration, CVS Health and the National Association of Free and Charitable Clinics.
Still, "it is unclear at this point as Medicare and insurance companies will determine whether the cost of medications will be covered," Maryland's Biernot said. "The current estimated cost can certainly be a barrier which affects equitable access to this medication."
For the next four years, Biogen plans not to increase the price of aducanumab.
"We have voluntarily committed to not taking any price increase over the next four years. That's a really important commitment we're making, and we're also remaining open minded," Chirfi Guindo, Biogen's head of global product strategy and commercialization, said during an investors call on Tuesday morning.
Guindo said that the pricing for aducanumab was based on the costs of other "specialty biologics" -- such as cancer immunotherapies and psoriasis treatments -- that have recently launched. Biological products are isolated from a variety of natural sources, in contrast to most drugs that are chemically synthesized and whose structure is known.
"We have priced Aduhelm at roughly a third the level of the cancer immunotherapies and roughly 25% below the average level of psoriasis biologics," Guindo said. "So we consider this to be a really responsible price, and we consider this to be a price that is sustainable for the system."
When and where will it be available to patients?
Biogen expects to begin shipping product in about two weeks and there are more than 900 sites across the United States estimated to be ready to providing it, according to the company. The drug was approved to be administered as an intravenous infusion over about one hour every four weeks.
At Memorial Healthcare in Michigan, Aburashed said that the building has an infusion center where the treatment can be administered.
"It remains unclear as to when the drug will be ready for infusion, however, we have been working on operationalizing its use through strict pre-screening assessments of our mild and early dementia cases," Aburashed said.
"There are many variables involved with initiating this treatment and each case will be assessed individually prior to treatment," he said. "This is not a 'shotgun' approach to all Alzheimer's patients and careful consideration of individual patient characteristics and risk tolerance is imperative.
What are potential side effects?
Aducanumab's prescriber label warns of "amyloid related imaging abnormalities" or ARIA, which can be seen on magnetic resonance imaging or MRI scans as brain swelling or incidents of bleeding in the brain. Other common side effects of aducanumab can be headache, falling, diarrhea, and confusion, delirium or disorientation.
"ARIA seems to occur early in treatment during the first 12 weeks, 16 weeks or so," Schneider said, adding that people with a form of the apolipoprotein gene called APOE4 -- a risk factor for Alzheimer's --appear to be at increased risk of such events.
The drug label notes that in two studies, ARIA was observed in 41% of patients treated with the approved dose of aducanumab compared to 10% of patients who did not receive the treatment.
Why are MRIs recommended with this treatment?
The drug's label recommends for doctors to obtain brain MRIs prior to a patient's seventh and 12th infusion of aducanumab in order to monitor for cases of ARIA.
"MRIs are used to surveil for the main adverse event of this, which is quite significant: amyloid-related imaging abnormalities," Schneider said.
"They need to be screened for it, because most of it is asymptomatic. A good amount of it is symptomatic, because of the cognitive impairment or confusion and falls, but most of it is not. You have to pick it up on an MRI," he said. "So that's why an MRI is recommended in the labeling at the end of six months, and at the end of 11 months of treatment."
A physician might also consider conducting PET scans to determine whether a patient has mild cognitive impairment due to Alzheimer's disease.
"So we would be getting to know whether someone is amyloid positive on a PET scan. We want to know that also because we are using a medication that decreases plaque so we want to make sure that people have plaques that could be decreased," Schneider said.
How does it work?
Aducanumb differs from other treatments currently on the market, because it is the first of its kind to target amyloid beta plaques.
"This is the first antibody directed treatment for Alzheimer's disease that targets the main possible cause of the disease, which many feel is related to the deposition and accumulation of a protein called amyloid beta," Aburashed of Michigan said. "The antibody binds to aggregates of the amyloid protein and appears to preferentially target the amyloid plaques in the brain as opposed to those in the blood vessels."
What other treatments are available for Alzheimer's disease?
While aducanumab may be the first of its kind, other drugs to help manage symptoms of Alzheimer's disease have been in use for a while.
The drug donepezil, a pill formerly sold under the brand name Aricept and now available generically, was initially approved in the United States in 1996 and is still used often to treat Alzheimer's disease. It and other similar drugs help improve mental function but will not prevent the loss of mental abilities over time.
"Donepezil, or Aricept, which is now 25 years old on the market, and other drugs related before it, are still seen as standard treatment," Schneider said. "And the effects of donepezil after six months, or after being treated for six months, is larger than the effects that we see with aducanumab over the course of a year and a half. It's something to think about."
Donepezil and others like it, such galantamine and rivastigmine, belong to a class of medications called cholinesterase inhibitors, typically prescribed for mild to moderate Alzheimer's disease. Another medication known as memantine or Namenda, is used to treat the symptoms of moderate-to-severe Alzheimer's disease.