With Little Data to Go On, Clinicians Are Left To Figure Out Way Forward
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The FDA’s approval of aducanumab has given Alzheimer’s physicians a new treatment option, but little guidance on how to put it into practice. Clinicians are debating issues such as when to prescribe, who qualifies, and how to ramp up capacity (see Part 3 of this story). They also have to figure out how to communicate the potential risks and benefits to patients and their families, and how long to keep patients on drug. Biogen’s post-market study may answer these questions, but the nine-year timeframe means this is no help for clinicians now. Around the world, physicians are preparing to enter a challenging new phase of Alzheimer’s care.
- Clinicians say they will offer aducanumab to patients despite doubts.
- One quandary is when to stop treatment.
- Other countries are closely watching developments in the U.S.
To Prescribe or Not to Prescribe?
Beyond the logistical challenges of bringing monthly infusions into clinical practice lie ethical ones. Some clinicians doubt the value of aducanumab for their patients. Nonetheless, all clinicians Alzforum contacted said they would offer their patients the option to take it. “I believe that patients and families have a right to this treatment now that it is approved, and also that they should receive accurate information from knowledgeable providers about the risks and benefits to help their decision-making,” Suzanne Craft at Wake Forest School of Medicine in Winston Salem, North Carolina, wrote to Alzforum (full comment below).
Even outspoken critics of the FDA approval are taking this approach. David Knopman at the Mayo Clinic in Rochester, Minnesota, who had urged the FDA to demand a confirmatory trial before approving, told Alzforum, “If my patients and their families express interest, I will discuss the pros and cons with them.” Ditto for the National Institute on Aging’s Madhav Thambisetty, who as a fellow AdComs member had advised against approval but more recently wrote about his first physician consult discussing aducanumab with a son and his dad, whose disease was likely too advanced to benefit from the treatment.
Jason Karlawish at the University of Pennsylvania, Philadelphia, described his reluctance to prescribe aducanumab in an editorial prior to June 7. The approval is now forcing his hand because he also believes in respecting an Alzheimer’s patients’ autonomy. “After discussion with a patient and family about this drug, if they want to take it, I’ll prescribe it,” Karlawish told Alzforum. He noted that the clinical conversation would be quite unusual. “In clinical practice we don’t routinely begin with the point that the drug may not have a benefit,” Karlawish said.
How Long Should You Take It?
Biogen has not specified a maximum length of treatment. In the investor call, Al Sandrock, who leads R&D at Biogen, said that participants in extension studies continued to benefit from treatment for as long as five years, and anecdotally reported feeling worse after the infusions stopped.
At conferences, Biogen researchers have reported that two years of treatment at 10 mg/kg drove people's brain amyloid loads below threshold, but even after that, those on this highest dose continued to decline more slowly on cognitive tests than those in lower-dose groups (see Nov 2018 conference news). It is unclear if this beneficial effect required continued dosing, or was due to complete clearance of amyloid. In biochemical and mouse studies, aducanumab stops the formation of toxic Aβ oligomers, hinting that it could have benefits beyond plaque removal (Sep 2020 news; Nov 2020 news).
In trials of Lilly's investigational antibody donanemab, patients switch to placebo once their brain amyloid has dropped below a set threshold, and continue to take cognitive tests to track their rate of decline. No such data exist for aducanumab. The specter of indefinite dosing distinguishes aducanumab from expensive hepatitis or cancer drugs, which are curative or given for a limited, one-time course, and it has intensified the outcry over its list price.
What if people progress from mild to moderate dementia while getting these infusions? After all, aducanumab is claimed to slow progression by 23 percent over 18 months, not halt or reverse it. Should the doctor stop treatment when a patient worsens? This, too, remains unanswered, and the decision again may be left to insurers.
And how will physicians know for certain if a given patient is responding with a clinical benefit? With cholinesterase inhibitors, AD researchers attempted for some time to establish guidelines for stopping treatment, but the drugs’ small effects on “soft” AD clinical endpoints rendered the effort unsuccessful. “We essentially said we will treat as long as we can,” said Philip Scheltens of Vrije University, Amsterdam. For a treatment of monthly infusions, stopping criteria will be more important, because continued treatment at late stages could prolong suffering, said Liana Apostolova of Indiana University School of Medicine in Indianapolis. Apostolova and Scheltens spoke on June 21 in a four-hour webinar hosted by the Alzheimer's Association, playable here.
No Answers For Nine Years?
Many researchers are hoping Biogen’s post-market study will provide clarity. So far, Biogen has been tight-lipped on its design, noting only that it is in talks with the FDA. Some worry the study may not be rigorous enough to provide good data. “If the field leaves the execution of the Phase 4 trial as requested by the FDA to the free market alone, we will see mostly results from a complex patient population, resulting again in blurred and controversial signals,” Bart De Strooper at the U.K. Dementia Research Institute at University College London wrote to Alzforum.
In the cancer field, numerous drugs were approved based on surrogate markers, but post-marketing studies were slow in coming and FDA enforcement was lax. The drugs continued to be prescribed in a knowledge vacuum for years. In April 2021, the FDA reviewed post-market oncology data and concluded two drugs did not work for specific cancers: Keytruda for gastric cancer and Opdivo for hepatocellular carcinoma. The drugmakers stopped marketing their products for those diseases. Only 6 percent of accelerated approvals for oncology therapies have ever been withdrawn (Healio news).
Maria Glymour at the University of California, San Francisco, believes the nine-year timeframe for a confirmatory Phase 4 trial will delay certainty about whether aducanumab helps AD patients. “This feels like we have failed patients and families,” she wrote to Alzforum.
Will the World Follow Suit?
While aducanumab so far is approved for use in the U.S., Biogen has applied in Japan, Australia, Switzerland, the European Union, Canada, and Brazil. Some believe the FDA decision is likely to influence other regulatory authorities. After the FDA ruling, Japanese health minister Norihisa Tamura told the media, “This is a big step forward and a breakthrough method; we’ll make a final decision after a careful review on its safety and efficacy.”
Takeshi Iwatsubo at Tokyo University noted that media coverage of aducanumab approval in Japan has been positive, but said the country is not ready for clinical rollout. “We may have to formulate a guideline for the appropriate use of anti-Aβ antibody drugs,” he wrote to Alzforum. “We do feel much is left to be done prior to the implementation of these drugs.”
Like in Japan, German neurologists and psychiatrists have founded a network to help standardize clinical care. And like Iwatsubo, Jörg Schulz at RWTH Medical School, Aachen, and Johannes Levin of Ludwig-Maximilians-Universität München, hope that if the European Medicines Agency approves aducanumab, it will stratify patient eligibility by disease stage and risk factors, and define stringently how to prescribe aducanumab and monitor patients. For example, APOE4 carriers are known to be at higher risk of ARIA but also had the greatest benefit, according to Biogen’s FDA briefing materials. Clinicians are hoping for guidance on how to deal with this conundrum. “In Europe, we are anxiously waiting for the decision of the EMA,” Schulz wrote to Alzforum. “I hope Biogen will support the learning curve by rigorously controlling access to the drug,” Levin concurred (full comment below).
In post-Brexit U.K., approval will come through that country's own regulatory agency, the MHRA. “So far in the U.K. the professional community is divided, with views ranging across the spectrum from condemnation of FDA to optimism for this being the gateway to a new research era,” Catherine Mummery at the National Health Service told Alzforum. She, too, hopes that any approval will require biomarker confirmation and disease staging (comment below). Other clinicians in European countries, who withheld their names, expressed hope that the EMA will be free to deliberate based on the data before them, without the stakeholder pressure that bore down on the FDA.
Despite the many open questions now, many researchers take the long view. They think approval of the first amyloid-lowering drug could spur the field forward. “I hope this approval, in combination with the advent of blood-based AD biomarkers, will quickly usher in the era of preclinical testing and therapy,” Erik Musiek at Washington University in St. Louis wrote to Alzforum.
Gil Rabinovici at the University of California, San Francisco, called on the field to work together to overcome the many challenges this new therapy will bring. “While the debate on aducanumab over the past few months has been very contentious, I hope that now that the FDA decision is made, we can move forward together to define the critical next steps in AD care and research,” he wrote to Alzforum. This was the overall tenor at the January 21 Alzheimer's Association webinar as well. —Madolyn Bowman Rogers
References
News Citations
- How Will Aducanumab Approval Change Clinical Practice?
- Second Look at BAN2401 Data Still Positive, Despite Snafu
- Of Four Aβ Antibodies, Only Aducanumab Stems Tide of Toxic Oligomers
- In Mice, Aducanumab Neutralizes Aβ Seeds
External Citations
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Comments
Wake Forest University School of Medicine
We do plan to offer aducanumab to eligible patients at our center who request it, and who meet the characteristics of the participants in the Biogen trials, i.e., biomarker-confirmed Alzheimer’s disease without known contraindications. We have received a number of inquiries about availability from patients treated at Wake Forest.
Regarding the protocol we will use to implement treatment, we are finalizing details; we are not one of the 900 sites mentioned.
I believe patients and families have a right to this treatment now that it is approved, and also that they should receive accurate information from knowledgeable providers about the risks and benefits to help their decision-making, particularly given the uncertainty around the robustness/validity of the supporting data.
Also because of this uncertainty, it is critical that the Phase 4 and other post-approval monitoring be conducted carefully with independent oversight. Finally, there should be ongoing careful assessment to ensure equity in distributing the treatment to underserved groups, and to assess unanticipated adverse financial consequences that might be incurred either on an individual or societal level.
Ludwig-Maximilians-Universität München
I view this approval as a sign of hope for the patient community suffering from as-yet untreatable neurodegenerative diseases. Thorough research across the field enabled us to better understand disease course and dissect crucial processes with biomarkers. This has led to a biological definition of AD on which this new treatment is based. This is an enormous success. In this regard, AD is spearheading the entire field of common neurodegenerative diseases, and it is imperative that other fields such as Parkinson’s follow.
A therapy will help lift the stigma of AD and dementia, at least the part that is caused by the lack of disease-modifying treatment options. This could turn out to be important for our patients, and create a situation in which a greater proportion of patients with dementia get the diagnostic workup they deserve.
Critical voices on the process of this approval have strong arguments. Most important to my mind is the efficacy data for a treatment that may cause serious side effects. Biogen did not have the necessary data for a regular approval process. Aβ is an at-best controversial surrogate biomarker for clinical efficacy. This cannot be compared to the HIV situation, where accelerated approval was a great and lifesaving success. Of course, the pricing of the drug does not help to ease emotions. The fact that there are almost no risk-limiting restrictions on the patient population is close to careless.
However, in my view, there is some reason for hope that this drug might actually work, although it is not formally proven. The hope is based on very similar clinical effect sizes from lecanemab and donanemab, which also target Aβ. This is consistent with some of the aducanumab data.
I hope the European authorities will work quickly on the approval process and come to a clear conclusion. In case of approval, I hope to see the different stages and risk constellations (most importantly for ApoE, past intracranial hemorrhages) to be reflected in the approval. We need a clear stratification of potential benefit and associated risk.
Independent of this approval process, I hope Biogen will support the learning curve by rigorously controlling access to aducanumab. I would like to see the company take an action that the use of the drug has to be closely monitored for all cases.
In Germany, these developments have led to closer networking of university-based memory clinics across the country and across disciplines. Neurologists and psychiatrists a few months ago founded a new network. On this platform we issued a shared statement.
So far the public response in Germany is manageable. We received requests, but our patients and caregivers understand that we have to await the European authorities’ work on the approval application.
NHNN, UCL
It is very early days to gauge responses to aducanumab’s U.S. approval. So far in the U.K., the media have been cautiously positive; the initial public response has been a large number of enquiries of people asking to go onto an aducanumab trial.
The professional community is mixed in response, with views ranging across the spectrum from condemnation of FDA to optimism for this being the gateway to a new research era.
Discussions between the U.K. MHRA (our FDA equivalent) and Biogen are ongoing. MHRA will have to give approval separate from EMA.
I am a member of the BIOGEN aducanumab steering committee.
Macquarie University
In Australia, there is much excitement in the general community that finally a drug that targets disease causation rather than symptoms will be a game-changer.
Among clinicians there has been a varied response, from optimism to skepticism. As the controversy in the U.S. continued to rage, more clinicians who were very positive following approval are becoming increasingly concerned about aducanumab’s limitations not being properly addressed as to who would be eligible, and at what stage of the disease, and its exorbitant costs.
Australia is not yet ready with both sufficient number of dementia-trained specialists and dementia treatment facilities, but there is general optimism that these gaps will be filled in the next couple of years with federal government support.
I am confident that the TGA (Australia’s equivalent to the FDA) will better define who will be likely to benefit and restrict treatment to those groups. TGA approval is expected to be made in early to mid-2022.
A major challenge will be getting access to PET amyloid imaging as the number of facilities is currently limited. It is expected that lumbar puncture will now become more attractive to patients because of easier access and lower cost. There is much to be done.
Despite its limitations, clinicians generally recognize that this drug will be a forerunner to more effective and safer drugs in the future, just like the first symptomatic anti-cholinesterase drug tacrine was to the currently used donepezil. Many Australians are proud of our very own Colin Masters, who pioneered the isolation of amyloid plaques and extracted Aβ in the mid-80s. It has been the target for Aβ therapies, of which aducanumab is the first to be approved.
University of Melbourne
It is too early to see how this will play out in Australia. Generally our TGA takes more note of what the FDA does than what the EMA does. I believe the FDA decision was fair, balanced, and appropriate given the scientific evidence. I admit to bias, having worked on the Aβ theory since its beginning. But now is the time to celebrate some fantastic progress over the past four decades, and to do all we can to ensure that future developments don’t go off the rails. I have two sets of views related to this: academic and professional.
Academically, we now need to realize that not all the anti-Aβ antibodies are the same, and we need to understand their various mechanisms of action in much more detail. Aducanumab seems to be a conformational epitope to a native oligomeric form of Aβ species, involving more than just the N-terminus. Its competitors gantenerumab, lecanemab, and donanemab react with other oligomeric/protofibrillar epitopes, all in the N-terminus. All lower the Aβ-PET signals and drive down p-tau signals. But what exactly do the Aβ-PET signals mean? There’s a lot of loose talk that they represent plaques, but this needs to be confirmed from postmortem studies (both biochemical and morphological) in subjects in whom the “Aβ load” has been therapeutically lowered.
Then there are antibodies like solanezumab and crenezumab, which appear to react with mid-domain epitopes, and act by inhibiting secondary nucleation. They don’t seem to lower the PET signals to any large extent. Maybe they work through preventing growth of fibrillar species? All these aspects and many others need to be reconciled, and from this will come a better understanding of how to use these first-in-class therapeutics, either alone or in combination.
Professionally, we have a major responsibility to see that the roll-out of these disease-modifying therapies is conducted to the highest standard. It would simply be wrong if an anti-Aβ-directed therapy were used in people who do not have an Aβ-related disease. We in the medical profession share this responsibility with our professional societies, in partnership with regulatory authorities and the pharmaceutical industry. I am optimistic that this will be achieved, just as has happened with the roll-out of modern oncological therapeutics. I am also relaxed about the pricing issues. These will be driven by market forces as competition comes into play.
Neuroscience Research Australia
An Australian perspective on the aducanumab approval
I should start by saying that this is good news. The approval of the first new therapy for Alzheimer’s disease in almost two decades, and the first treatment directed at one of its underlying pathophysiologies, is a critical milestone. The clinical trials showed a reduction in Aβ plaques leading to an expectation of a reduction in clinical decline.
I am optimistic because with this advance there will be the opportunity to generate the critical Phase 4 efficacy data required to convert the accelerated approval into a full approval. And I’m also optimistic because clinical proof of the value of this plaque-reducing treatment, no matter how expensive, will open the door to further discovery and innovation within the biotech and pharma sectors, which should eventually provide what we are all seeking: an effective and affordable treatment for Alzheimer’s.
However, there are a number of significant barriers to the widespread use of aducanumab in Australia. The Australian government’s Therapeutic Goods Administration fulfills a similar role to the FDA and will review Biogen’s application, which is reported to be currently under review.
Accelerated approval in the U.S. relies on the use of a surrogate marker such as Aβ detected in the brain by PET scans. Whereas the FDA has approved several Aβ PET scan tracers, including florbetapir, florbetaben, and flutemetamol, to date none have been approved in Australia. So there will be parallel challenges in advancing clinical PET imaging for Alzheimer’s, which to date has only been used in research.
Australia has a universal health care system. The Pharmaceutical Benefits Scheme (PBS) is an Australian government program that subsidises medicines to make them more affordable, reducing the cost of life-saving drugs to just $AUD41.30 ($USD31) per prescription. However, the threshold for PBS listing is both clinical efficacy and value for money. New drugs typically receive marketing approval well in advance of PBS approval. Therefore, the first doses of aducanumab, once approved, are likely to be expensive, which will limit use.
Which patients might be eligible? Those with mild, moderate, or severe Alzheimer’s? Each presents a different clinical challenge but if the Aβ biomarker is the key, then PET scans (likely without the benefit of subsidized tracers) will be essential. It is obvious that there is a challenge of drug, biomarker, and clinical workforce skilled in these challenges.
Perhaps the optimal patients might be those with the presence of Aβ plaques, but before the diagnosis of Alzheimer’s. The Dominantly Inherited Alzheimer Network1 and other genetic “at risk” studies have used this biomarker, but identification of Aβ plaques in the presymptomatic population at large will present an almost impossible challenge until cheaper and non-invasive biomarker tests (possibly blood tests) could provide an initial screen.
There are some very significant hurdles before patients in Australia will be able to widely access aducanumab, including TGA approval, biomarker (PET?) screening, patient selection, and clinical workforce skills. These regulatory, marketing and clinical hurdles could easily make one a pessimist. But the pressing issues of the impact of dementia, which is the second leading cause of death in Australia, mean that we have to use this new opportunity to advance our understanding of disease and of its treatment, and bring new hope to those living with Alzheimer’s.
1I am a site investigator in the Dominantly Inherited Alzheimer Network.
Screen, Inc.
“Clinicians … have to figure out how to communicate the potential risks and benefits to patients and their families, and how long to keep patients on the drug. Biogen’s post-market study may answer these questions.” Is that what patients’ families will be told? That the “blurred signals” in five years from post-market studies will tell us when to stop treatment as abilities inevitably decline? That the informed consent of placebo-risking subjects will result in a non-random participation effect but will provide useful clinical information? At what point do researchers stand up for clinicians by refusing to allow science to be defiled?
“Even outspoken critics of the FDA approval” are taking the approach described by Suzanne Craft: “I believe that patients and families have a right to this treatment now that it is approved, and also that they should receive accurate information from knowledgeable providers about the risks and benefits to help their decision-making.” However, Jason Karlawish says, in a ghoulish understatement, that “In clinical practice we don’t routinely begin with the point that the drug may not have a benefit.”
Dr. Craft mentions the politically correct importance of “equitable distribution” and the possible “unanticipated adverse financial consequences that might be incurred either on an individual or societal level.” Unanticipated? PET scan for adequate diagnosis; periodic MRIs for dangerous side effects; amyloid level monitoring. And for what? Nominal, if any, improvement in functioning within the small subset of MCI patients who meet multiple criteria. Clinicians doing battle with families desperate for inclusion.
A “right to treatment“? So that clinicians can avoid the truth that they are afraid to say:
“Your dad might qualify for a drug that just was approved for use. Its effects are small and possibly were exaggerated by statistical shenanigans after essentially negative results were reported. It also is enormously expensive to establish your dad’s qualifications and then even more expensive to monitor him for serious side effects, much less the enormous cost of the treatment itself.”
“What would you do if it was your dad, doc?”
“I would let him live out his life with as much dignity and happiness as possible. Don't expect physical or mental exercise to help, and let him eat what he likes.”
“What would you do if it was you yourself, doc?”
“I have the advantage of my expertise. I would end my life before I put my family through what you are going through.”
Disclosure: Dr. Hill created Screen, Inc. where he developed the CANS-MCI touch screen cognitive test battery.
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