How will aducanumab’s approval influence people’s willingness to join, and stay in, future Alzheimer’s disease clinical trials? At the Alzheimer’s Association International Conference, held July 26-30 in Denver and online, researchers said the effect so far has been minimal, with most participants in current trials staying put. This is perhaps unsurprising—since aducanumab’s approval on June 7 (Jun 2021 news), clinical uptake has been slow, held back both by confusion over how to administer the drug and lack of insurance coverage for it (see Part 1 and Part 5 of this series).

  • Aducanumab’s approval has had little impact on trials so far.
  • Some trialists plan to incorporate aducanumab as a background therapy.
  • Investors show renewed interest in amyloid approaches.

However, speakers predicted that in the future, if aducanumab becomes widely used, then trialists may have to offer participants the option of staying on it as a background therapy while also taking an investigational drug. This would greatly complicate the interpretation of trial results. Some see a silver lining, however, noting that having aducanumab will make it easier to test combination therapies, such as evaluating synergy between tau- and amyloid-based approaches.

Meanwhile, accelerated approval of the first disease-modifying therapy for AD has energized the pharma industry. Two other companies may file under the same pathway, and investors are eager to sink more money into AD research. At the same time, controversy over aducanumab’s price and irregular approval process continues to swirl in Washington, D.C., with investigations ongoing in the U.S. House and at the Department of Health and Human Services. It looks as if the earthquake of aducanumab’s approval not only shook the Alzheimer’s field, but is reverberating through U.S. healthcare and regulation more broadly (see Part 8 of this series).

So Far: Few Dropouts, Prevention Trials Plugging Along
Addressing the common concern that a drug approval prompts study participants to leave investigational drug trials for the newly available drug, Joshua Grill of the University of California, Irvine, delineated three approaches for how trials can deal with the advent of aducanumab. One, trialists could prohibit use of the drug, meaning people who want to take the antibody would have to drop out of their current trial or choose not to enroll in future trials. Two, trialists could allow aducanumab as a background therapy, similar to how acetylcholinesterase inhibitors and memantine are handled now. Three, aducanumab could be used as an active arm in the trial, perhaps replacing a placebo control. At present, most trials will take the first or second options, with the third unlikely to happen until the clinical benefit of aducanumab is established, Grill said.

How will Aduhelm being on the market affect ongoing trials? It is unethical for researchers to withhold proven therapies from trial participants. This means that for all 125 AD drugs currently in trials, researchers must notify the participants of the availability of aducanumab. To continue in their trial, participants will have to sign updated consent forms that spell out the new option. This process is underway, but has had little effect on trials so far. Grill noted there have been no dropouts at his site, and four colleagues reported either no or only one dropout at theirs.

Initially, it seemed aducanumab’s approval might prove particularly problematic for prevention trials. Because the antibody targets a presymptomatic AD pathology, people in preclinical stages of disease might be most interested in taking the drug, noted Reisa Sperling of Brigham and Women’s Hospital, Boston. Sperling runs several secondary prevention studies, including A4 and AHEAD 3-45 (Nov 2020 conference news). If many participants dropped out to take aducanumab, that could cripple a trial’s statistical power to get meaningful data. At first this seemed a real possibility, since aducanumab was approved to treat simply “Alzheimer’s disease,” meaning people with presymptomatic disease would have been eligible for treatment. After getting pushback for this, the FDA on July 8 narrowed the label to people with symptomatic AD, removing this option. “We had some sleepless nights before the label was narrowed,” Sperling quipped at AAIC.

At this time, clinicians running prevention trials do not disclose amyloid status to asymptomatic participants. That is because of the remaining uncertainty over any individual participant’s future clinical course, and because no treatments are approved for presymptomatic disease. This practice may evolve as more data emerge on an individual person’s dementia risk after a positive amyloid test, and as more treatments become available, Sperling said. For example, if a drug were to be approved to treat presymptomatic AD, then researchers would have to reveal the results of amyloid testing to participants.

What about future trials? Now that there is an approved disease-modifying therapy, are placebo-controlled trials still ethical? Yes, Grill said, because aducanumab is not yet the standard of care for AD. Not everyone will want to be on it. Once a large number of participants start dropping out to take aducanumab, that will indicate the drug has become a standard of care, he added. But he believes that time is far in the future. “It takes time to understand the implications of approved therapies. We’re not close to achieving that yet [with aducanumab],” Grill said at AAIC.

Even if aducanumab use becomes widely accepted, there will always be people who don’t qualify for the antibody, or respond poorly to it, and who want to enter trials for other drugs, Grill noted. More ethically problematic, there will also be people who want to take Aduhelm but cannot afford it. Thus, there will continue to be participants interested in placebo-controlled trials. Still, the population available for trials will likely shrink, Grill said. If people who take aducanumab differ in consistent ways from those who don’t, then those who enter trials may no longer represent the broader patient population, Sperling said.

Aducanumab As Background Therapy?
One way around these problems would be to allow trial participants to take aducanumab as a background, standard-of-care therapy. This brings with it potential problems of its own, Sperling said. For one thing, if participants in ongoing trials were allowed to start aducanumab, this change would disrupt randomization and the balance of trial arms. This problem has to be weighed against the risk of dropouts if aducanumab is disallowed. For another, researchers would need to monitor for ARIA via MRI while aducanumab was being titrated. Should dosing of the investigational drug be suspended during titration? Once participants are on aducanumab, more questions arise. Should amyloid status be monitored throughout the trial? Should aducanumab be stopped if participants become amyloid-negative? There are no answers to these questions yet, Sperling said.

A particularly thorny question that will arise in the wake of aducanumab as background drug in trials is how to interpret the trial’s data. For both clinical outcomes and adverse events, how do researchers distinguish effects due to aducanumab from those due to the investigational drug? This would be especially complicated for trials of anti-tau agents, since anti-amyloid antibodies appear to indirectly suppress tau tangles, as well. One solution might be to require all participants to take aducanumab until plaques are cleared from their brains before they start on tau therapy, Sperling suggested.

One trial coming up against this dilemma in the near future is the DIAN-TU NextGen trial, which will have three tau arms and a shared placebo group. “We are considering the impact of approved amyloid drugs,” Michael Irizarry of Eisai said at AAIC. Eisai’s anti-tau antibody E2814 is one of three investigational agents in this trial; the other two have not been selected yet (Mar 2021 news). DIAN-TU researchers are surveying participants about their interest in aducanumab and similar drugs, Irizarry said. If many want to take them, the question becomes when should an amyloid-based therapy be started—before the investigational tau drug? At the same time? After? Because DIAN-TU is a small trial, researchers need to minimize heterogeneity introduced by anti-amyloid immunotherapy treatment as best they can, Irizarry noted.

With that in mind, one proposed design is for symptomatic DIAN-TU participants to start an amyloid antibody for six months, then be randomized to a tau or placebo arm. Asymptomatic participants, on the other hand, would start in a tau or placebo arm, but be allowed to add anti-amyloid as a rescue therapy if they develop cognitive problems down the road. This design is not yet set in stone, Irizarry noted. Another option would be to use a combination design, where no anti-amyloid treatment was allowed for 12 months while testing the tau therapy, then all participants would start on it. “[Aducanumab approval] is an exciting opportunity. We hope it accelerates testing of a range of therapeutics,” Irizarry said.

What about observational studies, which track the natural course of the disease? These studies—such as ADNI, AIBL, BioFINDER, LEADS, the Mayo Clinic Study of Aging, and others—have generated invaluable data on disease progression and biomarkers. Will aducanumab and similar drugs spell the end of this type of research?

Not at all, according to David Knopman of the Mayo Clinic in Rochester, Minnesota. He believes observational studies should lean into the new landscape of AD treatment. Participants should be told they are candidates for aducanumab treatment, and allowed to start on it if they wish while staying in the study. Likewise, Knopman said, patients who have started on aducanumab should be encouraged to enter observational studies. This will provide more data on how anti-amyloid therapy changes the progression of Alzheimer’s disease.

As with prevention studies, the advent of aducanumab treatment will bring new ethical issues for observational studies. Researchers will need to tell participants their amyloid status and give them the option to go on aducanumab. Trial personnel will have to offer counseling, and participants will update their consent. Attendees at AAIC noted that this alone will be a herculean task for large studies. “The issue of reconsenting gives me shivers,” said David Morgan of Michigan State University in Grand Rapids.

What Lies Ahead for Alzheimer's Drug Discovery?
Less certain is what will happen to AD drug research in the long run. AD scientists might draw some lessons from the multiple sclerosis field, where the first drug for relapsing-remitting MS, interferon β-1b, was approved in 1993. At AAIC, Kathy Costello, Johns Hopkins Hospital in Baltimore, noted that, as with aducanumab, interferon β-1b was approved on an expedited basis and was initially controversial. The drug was expensive, at $10,000 per year, and had side effects.

Unlike aducanumab, however, interferon β-1b was recommended for people with more advanced disease. Researchers developed “exit considerations” that flagged participants in trials of other MS drugs whose symptoms became more severe, so they could leave their trials and start interferon β-1b instead. This, in turn, pushed trials toward earlier MS stages, enrolling people with milder symptoms, and led to earlier diagnosis of MS. Because aducanumab seems to work better in people at the mildest symptomatic stage, it may have the opposite effect, pushing trials of other drugs later. On the other hand, since aducanumab is currently not approved for preclinical disease, it may encourage more prevention trials, too.

More than 20 years passed before interferon β-1b replaced the placebo control arm in MS trials, in 2014. The AD field can probably expect similarly slow uptake before anti-amyloid therapy becomes the standard of care, Grill said. At that point, trials would use different designs that determine if new drugs are equivalent or superior to anti-amyloid immunotherapy. He noted that these types of trials are more complicated to run.

Sperling believes aducanumab’s approval may have some positive effects. Its attendant media attention may boost awareness of Alzheimer’s trials among the general population, aiding early diagnoses and recruitment. The availability of aducanumab will finally empower combination trials, a longtime goal of many AD researchers who believe it will take a drug cocktail to robustly fend off clinical decline (Feb 2013 conference news; Apr 2013 conference news; Mar 2014 conference news). 

Specifically, researchers will be able to test the effects of combining anti-amyloid and anti-tau drugs. The Alzheimer’s Clinical Trials Consortium, which Sperling co-leads, will take action on this (Dec 2017 news). The ACTC is currently planning a trial of two anti-tau drugs. It will have six arms: anti-amyloid, tau drug 1, tau drug 2, amyloid plus tau1, amyloid plus tau2, and placebo. The plan is to run this trial placebo-controlled and double-blind for two years, then continue in open-label extension.

Participants must be at preclinical or early clinical stages and have brain amyloid and tau deposition within a defined range. The goal is to catch people at the phase of “taucatastrophe,” when tangle spread takes off beyond the confines of the entorhinal cortex and cognition starts to slide, Sperling said. The trial will investigate potential drug synergy between amyloid and tau approaches. An AAIC attendee noted the possibility that if plaques have to be cleared before tau drugs work, then simultaneous treatment might not benefit patients.

Many researchers expressed concern that aducanumab’s approval will stifle research into other types of drugs and mechanisms. That is not what happened in MS, Costello noted. Instead, interferon β-1b’s approval sparked more research into multiple disease pathways, and today, there are nearly two dozen MS drugs representing nine different mechanisms, Costello said.

Grill hopes the AD field will undergo a similar expansion. “[Aducanumab approval] is a milestone, but not the end of the journey,” he said at AAIC.

Investors are Keen, But Their Focus Remains on Amyloid
So far, aducanumab’s approval seems to have encouraged anti-amyloid approaches the most. Eli Lilly later this year will file for accelerated approval of its anti-amyloid antibody donanemab, Roche is considering doing the same for its candidate gantenerumab, and Biogen/Eisai are pushing for accelerated approval of a second antibody, lecanemab.

Those developments were no surprise. Less expected, perhaps, was AbbVie’s announcement that it, too, will advance a drug that targets plaque. “It’s quite clear that if you can remove plaque rapidly, then there will be a benefit,” company president Michael Severino said in the industry press (Endpoints News). At the same time, AbbVie is stopping its anti-tau antibody tilavonemab. This does not presage companies’ abandoning tau targets for amyloid, though, as tilavonemab had failed in progressive supranuclear palsy and targets tau’s N-terminus, which scientists now believe is ineffective (Mar 2021 news). 

Meanwhile, Acumen Pharmaceuticals, whose lead candidate targets Aβ oligomers and had been slow off the starting block, scored a successful public offering, a sign that investors are eager to pour funds into anti-amyloid approaches (Endpoints News). 

For their part, industry analysts are divided on whether the aducanumab approval will spur research more broadly. Some believe biomarker-based approvals will speed trials, energize researchers, and offer a roadmap for developing treatments for rare diseases (STAT news; STAT news). Others take the opposite view. Pointing out that some accelerated approvals, for example Sarepta’s Exondys 51 for muscular dystrophy, have not triggered innovation, they argue that innovation only happens when an approval deepens knowledge about disease mechanisms and encourages further research (STAT news).—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Aduhelm
  2. Donanemab
  3. Gantenerumab
  4. Lecanemab
  5. Tilavonemab

News Citations

  1. Aducanumab Approved to Treat Alzheimer’s Disease
  2. Aducanumab: Will Appropriate-Use Recommendations Speed Uptake?
  3. Will Insurance Cover Aducanumab? Jury is Out
  4. Flurry of Investigations Beset Aducanumab
  5. BAN2401 Forges AHEAD into Phase 3, Preclinical AD
  6. Aiming at the Tangle’s Heart? DIAN-TU Trial to Torpedo Tau’s Core
  7. Combination Drug Trials: Time to Open a New Front in AD?
  8. First Stab at Combination Therapy Yields Additive Effect
  9. Combination Trial Debate Energizes Keystone Symposium
  10. Clinical Trials Consortium Succeeds ADCS, Focuses on Prevention
  11. N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore

External Citations

  1. Endpoints News
  2. Endpoints News
  3. STAT news
  4. STAT news
  5. STAT news

Further Reading