AAt this year’s Alzheimer’s Association International Conference (AAIC), entire sessions were dedicated to discussions of Biogen’s recently-approved, controversial drug Aduhelm (aducanumab), but their focus wasn’t what you’d expect. The talks began with the disclaimer that speakers wouldn’t be discussing whether they thought aducanumab should have been approved by the US Food and Drug Administration (FDA), but rather, how the industry — especially the Alzheimer’s clinical trials space — needs to adapt now that the drug will be available to patients with mild cognitive impairment.
“This is not a debate on approval,” said Stacie Weninger, PhD, president of the F-Prime Biomedical Research Initiative, in a focused topic session on the impact of drug approval on future clinical trials held on Tuesday July 27. “Now that [aducanumab] is approved, how will this affect clinical trials going forward?”
Dr. Weninger’s fellow panel members echoed that sentiment and sought to address some of the most pressing concerns around trial design, patient safety and data integrity in trials in this post-approval period for aducanumab.
“Such an event represents what should be a celebrated milestone, a culmination of decades of research, and millions, if not billions, of dollars of investment in science,” said Joshua D. Grill, PhD, a professor of psychiatry and human behavior in the School of Medicine at UC Irvine. “While it is a milestone, it is not the end of a journey. Hopefully, it will mark the beginning of a period of expansion of available treatments, but that expansion will require clinical trials. Those trials are likely to face controversy and debate in their appropriate design, most notably whether they include a placebo control.”
With this in mind, here are six considerations for Alzheimer’s clinical trials going forward and how some of the experts at AAIC 2021 plan to tackle these challenges.
1. Are Placebo Arms Still Ethical in Alzheimer’s Clinical Trials?
As Dr. Grill alluded to, one of the largest questions that Alzheimer’s researchers must address is whether new investigational therapies should continue to be compared to a placebo in Alzheimer’s clinical trials going forward. While a placebo-controlled trial is considered to be the most robust study design possible, there are ethical questions about whether it’s appropriate to withhold an approved drug from patients who have the potential to benefit from it.
It’s useful to look to other disease fields to understand the impact of drug approval on future clinical trials. For example, after Bayer’s Betaseron (interferon beta-1b) was approved as the first treatment for relapsing-remitting multiple sclerosis (MS) in 1993, subsequent trials eventually replaced their placebo control arms with an active comparator arm, explained Kathy Costello, vice president of programs at Can Do Multiple Sclerosis. Though Betaseron set the stage for this shift, the change in trial design only occurred after multiple other MS drugs were approved.
This approval also had an effect on the types of patients included in trials and changed the way in which outcomes were measured. As diagnostic methods for MS improved, patients in earlier stages of the disease with milder symptoms became the primary population enrolled in studies.
Approval of Betaseron and other subsequent disease-modifying therapies also provided options for patients participating in MS trials experiencing declining health, particularly if they had been randomized to the placebo arm.
“When patients experienced worsening symptoms, they would be removed from a trial and placed on an approved drug,” said Costello.
When it comes to making decisions about study design in new Alzheimer’s clinical trials, Dr. Grill and his colleagues have proposed four ethical principles that should be followed now that the first disease-modifying therapy has been approved. The first two principles are the need for data validity and for a study’s purpose to be to change clinical practice — two important tenants of all biomedical research.
But these aims must be balanced with the third principle of protecting study participants from unnecessary risks, like those that may result from preventing patients from accessing available therapies to maintain the integrity of the treatment and placebo arms of the trial. The fourth and final principle deals with the conditions necessary to ensure that a trial is truly ethical.
“Trials must be designed to address the current standard of care,” said Dr. Grill. “We conclude that this takes years to establish, and it is unlikely that a newly approved therapy will immediately become standard of care and make placebo-controlled trials unethical.”
Grill admits that there’s uncertainty around when, exactly, a new therapy achieves standard of care status and how the community will know when that achievement has been met. But he says one indicator will be how the approval of aducanumab affects ongoing trials.
And, in fact, Grill maintains that there is still a place for placebo-controlled trials in the post-aducanumab approval Alzheimer’s space, namely in breakthrough trials and in those that recruit patients who fail to respond to the approved therapy or decide not to take it for safety reasons. But he also presents the troubling potential for future placebo-controlled trials to be largely populated by patients unable to afford the available therapy, which is its own ethical dilemma.
Even if the Alzheimer’s research community deems it appropriate to continue with placebo-controlled trials for now, there is still the question of how to prevent patients already enrolled in such studies from dropping out in order to have the opportunity to take aducanumab.
2. Managing Patient Attrition in Ongoing Alzheimer’s Clinical Trials
“More than 125 drugs are still in the [Alzheimer’s disease] drug development pipeline,” said Dr. Grill. “What will people in those trials do now that the FDA has approved aducanumab? Will they drop out to take it? Large numbers of drop outs could impact those trials leaving them underpowered and at risk of failing to answer their scientific questions.”
Grill shared that, so far, he has had no patients drop out of his ongoing Alzheimer’s clinical trial to take aducanumab, and a few of his colleagues have seen only minimal attrition of just one patient from their studies. Payer coverage decisions could have a greater impact on this if large health insurers decide to add aducanumab to their formulary.
But there is even more concern in the industry that the approval of aducanumab will have a greater effect on patient participation in observational studies — particularly if the study design doesn’t accommodate the introduction of anti-amyloid therapy mid-trial.
“I think that generally speaking, people on aducanumab or other disease-modifying drugs, should be encouraged to enroll in observational studies,” said David S. Knopman, MD, a clinical neurologist at the Mayo Clinic. “Obviously, if the observational studies are looking at amyloid lowering, those individuals on an amyloid-lowering agent have to be properly identified and excluded from those analyses.”
Of course, these disclosures will have an effect on trial consent, with some patients being required to undergo the consenting process again whether or not they choose to take aducanumab and continue participating in the current trial.
“They should be allowed to receive the drug and to continue in the study,” said Dr. Knopman, sharing his opinion on how patient drop out in observational studies can be minimized. “Revised consent process and counselling needs to be provided.”
3. Approval of Aducanumab Based on a Biomarker
The fact that aducanumab received accelerated approval from the FDA based on a biomarker — reduction of amyloid — sets a clear precedent for Alzheimer’s clinical trials going forward. However, Biogen will still need to conduct additional studies to demonstrate to the FDA that aducanumab has clinical benefit.
However, the fact that eligibility for treatment with aducanumab will be based on a patient’s amyloid status also has implications for disclosure of data to patients currently enrolled in other trials now that that information is actionable.
Early symptomatic patients are the ones most likely to drop out of ongoing trials as they’re the target population for aducanumab. With this in mind, the AAIC 2021 panel shared their views on how both cognitive assessment and biomarker results should be disclosed to patients if they’re eligible for the approved therapy.
Mild cognitive impairment and dementia diagnoses should be disclosed to patients currently enrolled in trials as these are patients who would be eligible for treatment with aducanumab. Amyloid-beta status should also be disclosed, regardless of whether it’s measured via PET or CSF, and patients will need to be counselled on what elevated levels of this biomarker in the brain mean for their diagnosis. While amyloid-PET is considered to be more informative, it’s not widely available and is currently not covered by insurance.
There was also some disagreement among the panel members about whether biomarker results should be disclosed to patients who are cognitively normal but show increased amyloid in the brain. After all, wouldn’t early treatment with an anti-amyloid therapy be better than a delayed approach?
“I truly believe it should not be disclosed,” said Dr. Knopman. “That is not part of the indication of aducanumab, it was not studied in aducanumab, and even though this drug was approved without showing any clinical benefit, and only on the basis of lowering amyloid, that’s just a hypothesis … that removing [amyloid] earlier is better.”
Dr. Knopman points to the different ways in which amyloid is measured and the false negative rate of elevated amyloid in cognitively unimpaired individuals who will never develop symptoms as reasons to be very cautious when even considering whether they should be medicated at such an early stage.
4. New Alzheimer’s Clinical Trials Will Need to Consider a Combination Design
In his talk, Dr. Grill shared the pros and cons of the three possible Alzheimer’s clinical trial designs now available to study investigators considering the approval of aducanumab.
Sponsors could continue with a traditional new drug versus placebo trial design in which patients are prohibited from taking aducanumab while participating in the study. While this approach prioritizes data integrity such that the effect of the investigational drug on Alzheimer’s disease can be compared with the placebo in shorter, less-complex trials, it puts patients at risk of being unable to benefit from the amyloid-lowering effects of aducanumab.
The second trial design option is still placebo-controlled, but would allow for participants to take aducanumab as a background therapy. While this approach could help shape clinical practice by investigating how investigational therapies interact with the approved drug, it also presents significant challenges related to trial design, data validity and risk of drug-drug interactions.
Grill suggested that a 2×2 factorial design may be a more rigorous approach to test the investigational drug and the newly approved drug both in isolation and in combination, while still comparing each to a placebo. This design may be important in determining the safety and efficacy of combination therapies in treating Alzheimer’s.
Finally, non-inferiority, or superiority, trial designs will be applicable if, and when, aducanumab achieves standard of care status such that investigational therapies can be compared to the approved drug as opposed to placebo. While this design has the same benefit of the previous to inform clinical practice, it will be both time-consuming and expensive.
“Non-inferiority designs carry the troubling risk of demonstrating that a new drug is as good as the standard therapy without showing that either is actually effective,” warned Grill.
5. Safety Monitoring Considerations
Since amyloid-related imaging abnormalities (ARIA) were observed as adverse events in trials of aducanumab, studies in which patients are permitted to take the drug as a background therapy must now contend with the challenges of safety monitoring for this side effect. To further complicate matters, most cases of ARIA in the aducanumab trials were asymptomatic, so regular MRI must be built into trials to catch these events when they occur.
It’s also necessary that clinical investigators disambiguate adverse events to determine whether they were caused by the drug combo being investigated in the trial, or one of the compounds on its own. Though more complex, this is where factorial trial designs shine as they allow for the comparison of adverse events between different treatment arms and the placebo.
6. Connection with Tau Therapies
Another interesting point that came out of the discussion was how the approval of aducanumab might affect Alzheimer’s clinical trials of anti-tau therapies. In particular, it sparked an exploration of whether an anti-amyloid drug could show synergies when administered along with an agent targeting tau, or if the former could be used to essentially render a patient “amyloid-negative” before starting on an anti-tau therapy to potentially increase its efficacy.
“[Whichever] side you sit on the controversy … one of the silver linings of this time is that it opens the door for potential combination therapies,” said Reisa A. Sperling, MD, a neurologist at Massachusetts General Hospital, and professor of neurology at Harvard Medical School.
Dr. Sperling suggests that clinical investigators could consider suspending dosing of their investigational therapy until a patient has titrated up to a full dose of the anti-amyloid drug. She said that while anti-amyloid drugs may be able to impact accumulation of tau, much more data is needed to substantiate that link.
But studies investigating both classes of drugs in combination must also consider the potential that the tau-targeting agent might only receive approval to be prescribed alongside an anti-amyloid antibody like aducanumab. This is another case in which careful clinical trial design is of the utmost importance.
With a $56,000 price tag for a year’s worth of treatment, Aduhelm is far from the most expensive drug on the market. However, the cost is obviously not insignificant, and many have raised questions about who will pay for a therapy that’s been approved amidst such controversy.
While the drug is likely to be covered by Medicaid, Blue Cross Blue Shield has already announced that, for the time being, it won’t reimburse patients under certain plans for the cost of aducanumab.
“A lot of these issues are also going to evolve as we start to understand more about coverage and how accessible this treatment is going to be for patients and that’s going to impact how we think about it in clinical trials,” said Dr. Weninger.
And while the speakers on this panel at AAIC 2021 largely saw the approval of aducanumab as a positive for the Alzheimer’s community, they stressed that there is still such an unmet need for safe and effective therapies that can improve the quality of life for the 6 million people in the US living with dementia.
“I think what we can all agree on is that we still desperately need new therapeutics that will dramatically change the course of this disease,” said Dr. Weninger. “Therefore, this is a discussion about how we are going to continue the trials to find those therapeutics that will really make a difference.”
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