How Will Alzheimer’s Trials, Treatment Change in 2023 and Beyond?

When Eisai and Biogen announced positive top-line results for their anti-amyloid antibody lecanemab, the trial became the first successful, completed Phase 3 Alzheimer's drug study in the Western world in more than 20 years. If lecanemab earns traditional approval from the U.S. Food and Drug Administration based on these results, as is widely expected, the effects could be seismic. For the first time, patients could get a prescription for a disease-modifying treatment along with their Alzheimer’s diagnosis. With two more antibodies in pivotal trials slated to read out completed Phase 3s within the next six months, and aducanumab already approved, the age of amyloid immunotherapy has truly been inaugurated.

  • Cost, safety, access will be main factors influencing lecanemab’s clinical use.
  • Treatment duration will be a key question.
  • Future trials may have to offer lecanemab as a standard of care, or combination therapy.

“This has been the most exciting news of my career,” said Bart De Strooper at the UK Dementia Research Institute, London. He noted that the data validate amyloid as a target at the symptomatic stage of AD (see comment). Eric Reiman at Banner Alzheimer’s Institute in Phoenix sees the results as a game-changer. “The magnitude and significance of the effects were what we were hoping for. This provides more confidence in the benefits versus risks [of amyloid immunotherapy] in the clinic,” he told Alzforum.

“This gives us a first disease-modifying approach that can be utilized in a treatment armamentarium to slow the relentless progression of the disease. That’s a significant moment in the history of AD,” Gene Kinney of Prothena told Alzforum.

The findings raise a slew of new questions. Chief among them is whether the data will move the Centers for Medicare and Medicaid Services to revise their National Coverage Determination for anti-amyloid antibodies, enabling widespread use. Other clinical questions include whether updated Appropriate Use Recommendations are needed, whether lecanemab treatment can be stopped at some point, and how to identify people who respond best.

Equally important is the potential effect on research. Will some participants leave ongoing trials to go on lecanemab? Will trialists have to offer lecanemab as a standard-of-care therapy to recruit participants? Any way you look at it, lecanemab appears set to upend the field.

What Factors Will Influence Clinical Use? Cost Tops the List
In their press release, Eisai/Biogen reported that lecanemab slowed clinical decline on the CDR-SB, ADAS-Cog14, ADCOMS, and ADCS MCI Activities of Daily Living with robust statistical significance, though the numerical advantage on the CDR-SB was small, amounting to a difference of 0.45 over 18 months (Sep 2022 news). The companies have said they will apply for traditional approval in the U.S., Europe, and Japan, though they have already submitted for accelerated approval in the U.S., with a decision expected by January 6 (May 2022 news; Jul 2022 news). This means lecanemab could be on the U.S. market within three months.

Will it be widely used? “I think that will come down to side effect profile and payer judgment,” said Ron Petersen at the Mayo Clinic in Rochester, Minnesota. Others agree that insurance coverage will drive how widespread clinical uptake will be.

Earlier this year, CMS had issued an NCD for all anti-amyloid antibodies, restricting coverage to clinical studies (Jan 2022 news). This “coverage with evidence development” applies even to antibodies that receive traditional FDA approval, the agency said, though the latter could use registry-based “real-world” studies rather than randomized trials.

Nascent registry initiatives, such as the Alzheimer’s Association’s ALZ-NET and UsAgainstAlzheimer’s AD Evidence Accelerator, could meet this need (Aug 2022 conference news; Feb 2022 news), and even in its decision, CMS indicated it might suspend the CED requirement altogether for antibodies that show strong evidence of efficacy in an ethnically and medically diverse population (Apr 2022 news).

Do lecanemab’s data fit the bill? Eisai and Biogen argue as much. The worldwide Clarity trial posted overall racial and ethnic diversity of 33 percent. Among U.S. participants, 25 percent came from minority groups, reflecting the makeup of the Medicare population and meeting the CMS requirement, the companies reported. If the Clarity data can also differentiate the drug’s effects in subgroups of people with different medical conditions and APOE genotypes, then the findings may clear CMS’ bar.

Clinicians urgently want to see these subgroup data, in order to know which patients are most likely to benefit from treatment. Data from other anti-amyloid antibodies indicate that the risk/benefit ratio is higher in patients who carry APOE4 or have certain cardiac or inflammatory conditions, such as strokes or lupus. In addition, some data suggest these drugs work better in patients who are younger or at an earlier stage of disease. Those factors could determine whether clinicians recommend the drug for a given patient.

Before CMS even reconsiders the matter, the U.S. Congress is already putting its thumb on the scale. Representatives Vern Buchanan (R-FL) and Nanette Barragán (D-CA) have introduced a bill in the House that would compel CMS to evaluate each anti-amyloid antibody on its own merits, and to eschew coverage decisions for an entire drug class in the future (Endpoints news).

Up Next: Safety
Safety will be the other big hurdle to overcome, as the risk of ARIA has kept many neurologists from recommending aducanumab to their patients. Researchers Alzforum spoke to were encouraged by Clarity’s top-line results suggesting less ARIA than was seen with aducanumab. Overall, 12 percent more people developed ARIA on lecanemab than on placebo. This took the form of either brain edema alone, or edema with microhemorrhages.

AD researchers are anxious to see the data on how ARIA risk varies with APOE genotype. In the Phase 2 lecanemab trial, Eisai reported that the heightened risk clustered in APOE4 homozygotes, with heterozygotes having the same odds as APOE3 carriers (Aug 2022 news). If that holds in Phase 3, it might lead clinicians to use the treatment for a broader range of patients.

Clinicians stressed the risk should not be taken lightly. “I don’t want us to be complacent about ARIA because the rate is lower. The main concern is the occurrence of serious ARIA, because that is where there’s likely to be disability or death,” said Stephen Salloway at Butler Hospital in Providence, Rhode Island. In the top-line Clarity results, Eisai reported that about 3 percent of participants on lecanemab developed symptomatic ARIA, but did not specify how many of those were severe.

Salloway is a member of the working group that developed the AUR for aducanumab (Aug 2021 conference news). He thinks it is important to issue an updated AUR specific to lecanemab. “Each drug is different,” he noted.

Plaque Removal: Getting Under Your Skin?
Another crucial factor will be how easily people can get the drug. In the Clarity trial, participants received 10 mg/kg intravenous lecanemab every other week. Not everyone lives near an infusion center or can get there that often. Eisai/Biogen are developing a subcutaneous formulation that could be administered at home. At this summer’s Alzheimer’s Association International Conference in San Diego, the companies reported that 720 mg of it, given weekly, produced comparable amyloid PET lowering to the intravenous dose. The subcutaneous formulation also caused less ARIA-E, due to slower absorption that kept the maximum plasma concentration at one-fourth that of intravenous lecanemab. It is unclear how quickly this formulation could be approved and brought to market.

Roche’s Phase 3 gantenerumab trials use subcutaneous injections already. Trials of donanemab and aducanumab are ongoing, and some newer anti-amyloid antibodies, such as Prothena’s PRX012, are being developed in this way from the start. The entire field appears to be moving in this direction, suggesting the need for infusion centers may be a short-term problem.

How Long Will I Be On This, Doc?
Can anti-amyloid immunotherapy be halted once plaques are gone? The field as a whole has not yet answered this question. Data from the open-label extension trial of lecanemab showed that plasma biomarkers rebound much faster than plaques, implying the need for maintenance dosing. Modeling predicted that a maintenance dose of 10 mg/kg lecanemab monthly, half the treatment dose, would be needed to keep biomarkers flat (Mar 2022 conference news).

Due to the cost of antibody therapy, and the possible need for continuous dosing, some researchers view the lecanemab trial as proof of concept that amyloid removal slows AD, but also think the world will need cheaper options. De Strooper suggested the field take another look at small-molecule suppressors of amyloid production, such as γ-secretase and BACE inhibitors. He said it’s time to take stock of what has been learned about these targets and their many substrates in recent years, and to take another stab at coming up with better compounds to inhibit them in a more nuanced way. Other groups are developing active immunization strategies to coax the body into making its own anti-amyloid antibodies. It is likely that competitive pressures will push companies over time to make anti-amyloid therapies cheaper and easier to take.

This is particularly true for therapies meant to be taken for decades in a prevention paradigm. “As you start to move into secondary or primary prevention, we think a vaccine makes a lot of sense,” Kinney said. Prothena has generated a vaccine that targets both amyloid and tau (Aug 2021 conference news).

What About Trials?
A lecanemab approval would shake up the current clinical trials landscape as much as clinical practice. If it gets traditional approval based on its efficacy data, institutional review boards might decide it would be unethical to withhold it from trial participants, said Sharon Cohen at the Toronto Memory Program. This means new trials would have to allow lecanemab as a standard of care, testing the trial's investigational drug at hand on top of lecanemab. For years already, trials have allowed participants to be on an acetylcholinesterase inhibitor or memantine as background treatment, and those trials that did not tend to draw criticism for that decision. Since lecanemab does not halt disease progression, there is room for other therapies to add value, Cohen noted.

Michael Donohue at the University of Southern California, San Diego, agreed that lecanemab’s use might become ubiquitous, altering trial designs. “We would start to see new studies designed with active control, and potentially factorial designs with combination therapies,” he wrote to Alzforum. Such trials would be more complicated to run and require more participants.

Researchers see benefits in this, noting that the availability of lecanemab would facilitate testing of concurrent therapies where each drug hits different aspects of the disease. In the case of other anti-amyloid treatments, trials could test whether they were equivalent to lecanemab in efficacy, while perhaps having advantages in cost, safety, or ease of use, Donohue noted.

At the moment, preclinical prevention studies are unlikely to be affected, as the Clarity trial enrolled people with mild cognitive impairment or mild dementia, hence lecanemab would be approved only for symptomatic AD. Lecanemab is being tested in a prevention paradigm in the AHEAD 3-45 study of cognitively healthy people with amyloid plaque deposition; that four-year study is recruiting and won't read out any time soon.

If an anti-amyloid antibody is eventually approved for preclinical use, prevention studies would still be feasible, according to Donohue’s research. At AAIC in July, he described a simulated prevention trial of a theoretical disease-modifying drug. The trial allowed people in the placebo group to receive the study drug as a “rescue” therapy once they started to develop memory problems. In the simulation, the rescue therapy did little damage to the trial’s statistical power.

Donohue told Alzforum this conclusion was based on the assumption of a nine-month delay before disease modification slows decline. In the Clarity time results, lecanemab appears to have had a measurable effect as soon as six months. That would lower the statistical power, Donohue noted. More broadly, some scientists now believe plaque removal changes the brain in still-mysterious ways that will require not only research, but also much patience before one sees cognitive and clinical benefits. The longer a trial continues after amyloid is mostly gone from the brain, the bigger the difference from placebo will be, they say.

Building Those Bigger Effects
Many researchers said the small effect size of lecanemab at this stage of AD raises the question of how clinically meaningful it is. Some clinicians pushed back on this, noting that its benefit is similar to that of acetylcholinesterase inhibitors, which delay symptom progression by about six months. “The 27 percent reduction in CDR-SB and the slowing of decline on ADLs are sufficient for me to prescribe the drug,” Reiman said. Petersen believes that, at the MCI stage, half a point on the CDR-SB is likely to be meaningful to patients. Marwan Sabbagh at the Barrow Neurological Institute in Phoenix summed up the bottom line: “It’s better than anything else we have seen so far.” Even critics of the amyloid hypothesis told Alzforum they would prescribe lecanemab, or even consider getting a PET scan themselves and trying to get access to the drug in an N-of-1 personal prevention mode.

All researchers contacted for this story agree more effective treatments are needed to halt or, better yet, reverse cognitive decline. Most think this will require concurrent therapies that target multiple pathologies. Reiman likened amyloid to a smoldering kindling that lights the fire of neurodegeneration, which then becomes self-sustaining. The fire may take the form of inflammation or aggregated tau, or both.

Lecanemab is already being trialed in the DIAN-TU NexGen platform trial of combined anti-amyloid and anti-tau therapies, which in its first arm will also test Eisai’s anti-tau antibody E2814 (Nov 2021 conference news). Randall Bateman at Washington University in St. Louis, who leads DIAN-TU, expressed delight at the lecanemab Phase 3 data, but said it still needs to be shown that lecanemab works in dominantly inherited AD. That trial will continue as designed.

Several other anti-amyloid antibodies remain in the pipeline, with the lecanemab findings bolstering expectations of success. “Given the complexity of Alzheimer’s disease, we anticipate multiple treatment options will be needed to meet the diverse needs of people living with the disease, their care partners and families,” Rachelle Doody at Roche wrote to Alzforum. Roche will present top-line results from the Phase 3 gantenerumab studies November 30 at the Clinical Trials on Alzheimer’s Disease Conference.

Some believe lecanemab’s positive results will boost investment in other Alzheimer’s therapies of all types. “This success should stimulate much broader investment in other relevant targets in various neurodegenerative diseases, as it is clear that perseverance and knowledge will ultimately prevail,” De Strooper predicted. Overall, researchers are sounding more optimistic than they have in a long time about the prospects for treating AD. “We’re going to transform Alzheimer’s from a terminal to a chronic disease,” Sabbagh said.—Madolyn Bowman Rogers

Comments

  1. We are excited to learn of the first positive completed Phase 3 clinical trial investigating an Aβ targeting therapy. The data will provide important insights around the role plaque removal plays in modifying Alzheimer’s disease. For decades, the Alzheimer’s community has made considerable advances in our understanding of the disease with the hope of transforming the lives of everyone impacted.

    Alzheimer’s is one of the biggest public health challenges of our time. Today, more than 55 million people are living with dementia—and with prevalence projected to increase to nearly 140 million by 2050, the impact of Alzheimer’s on societies will intensify as populations age. Given the complexity of Alzheimer's disease, we anticipate multiple treatment options will be needed to meet the diverse needs of people living with the disease, their care partners and families.

    At Roche and Genentech, we remain focused on the completion of our Phase 3 GRADUATE studies evaluating subcutaneous administration of gantenerumab in early Alzheimer’s. With GRADUATE we expect to deliver one of the most comprehensive datasets in the Alzheimer’s field. We’ve incorporated learnings from previous studies into our study design, including sample size (approximately 2,000 participants across two identically designed studies), study duration (27 months), and patient selection (enrolling people whose disease is more likely to progress during the study period). We are confident this design gives us the best opportunity to detect a clinical benefit with gantenerumab.

    Data from these studies will be available in Q4, 2022, and we look forward to presenting topline results at the Clinical Trials on Alzheimer’s Disease (CTAD) Conference on Wednesday, November 30, 2022.

    View all comments by Rachelle Doody
    • User Profile Image Nicolas Villain
      Sorbonne University - APHP - Pitié-Salpêtrière Hospital
    • Posted:

    As physicians, we don't prescribe drugs only based on p-values but on individual risk/benefit ratios.

    With Dr. Planche and Prof. Levy, we just published a meta-analysis of high-clearance anti-amyloid drugs that tries to put these p-values and percentages of reduction of cognition decline into perspective, i.e., better quantifying their benefits and risks (Villain et al., 2022). We were happy to observe that these drugs have comparable effect sizes and adverse effects rates across trials. But, as underlined in this article, the benefit highlighted is, so far, statistically significant but also far from being clinically meaningful.

    These minimal clinically relevant values are, by definition, subjective and subject to controversy. Still, in a 2019 paper with sound methodology, on data from 20,000 AD patients, even researchers from Eli Lilly acknowledged that a minimal clinically relevant value for MCI due to AD patients would be 1 point on the CDR-SB (and higher values for later stages) (Andrews et al., 2019). 

    Besides, these expected small benefits must be balanced with the risk of life-threatening ARIAs. From the publicly available data, we estimated that this risk is currently ~1 per 200 treated patients. We also illustrated in Figure 3 of our meta-analysis that these cases from the Clarity AD trial could be responsible for long-term sequelae. In France (65 million inhabitants), we estimated that these high-clearance anti-amyloid immunotherapies could concern ~300,000 patients. If our preliminary estimation of the serious ARIA frequency is correct, such cases illustrated in our meta-analysis could affect ~1,500 patients.

    Every specialized physician will likely have to deal with these situations several times per year if these drugs are approved. Besides, this occurred despite the strict exclusion criteria and close monitoring of clinical trials. In real-life clinical practice, this risk might be increased. This brings to my mind a satirical paper on a systematic review of "Parachute use to prevent death and major trauma related to gravitational challenge" published in 2003 (Smith and Pell, 2003). 

    When I share those data, be assured that my first concern goes to the patients and that it is not a coldhearted crusade for methodological perfection. As physicians in memory clinics, we know very well how painful and depressing the current situation is when we follow these patients and can only watch helplessly as they inexorably decline. On the other hand, I also still follow two patients with serious ARIAs. This week, one of their daughters sent me an e-mail where she told me, "To date, our mother weighs only 43 kilos, is constantly installed in a shell chair, and is losing her strength. On Monday, she told me, 'I am dying ...'" These situations made me wonder: Is a 0.45-point slowing of cognitive decline on CDR-SB after 18 months worth the try?

    References:

    Villain N, Planche V, Levy R. High-clearance anti-amyloid immunotherapies in Alzheimer's disease. Part 1: Meta-analysis and review of efficacy and safety data, and medico-economical aspects. Rev Neurol (Paris). 2022 Dec;178(10):1011-1030. Epub 2022 Sep 29 PubMed.

    Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (N Y). 2019;5:354-363. Epub 2019 Aug 2 PubMed.

    Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ. 2003 Dec 20;327(7429):1459-61. PubMed.

    View all comments by Nicolas Villain

  3. Anticipation that FDA will grant full approval of lecanemab (or another disease-modifying treatment) invites an exciting but challenging thought exercise: How will such treatments change research and practice for Alzheimer’s disease (AD)?

    We’ve considered some of the issues. Our top line point is that a new disease-slowing treatment is unlikely to make use of placebo controls immediately and categorically unethical (Grill and Karlawish, 2021). In this same paper, we anticipate the importance of factorial designs to the next phase of AD drug development. Such designs can enable efficient opportunities to test potential treatments against each other as well as for synergistic benefits (or risks), and still maintain the necessary rigor of comparison against placebo controls. These trials will likely enroll populations based on specific biomarker profiles—namely, each element of the ATN criteria—but also other biomarkers. In trials that enroll persons with MCI and dementia, protocols can better address not only the need to return these biomarker results to participants, but how best to do so.

    The field also needs to consider what options are available to individuals interested in enrolling in trials who do not qualify to do so, especially in the setting of increasingly narrow eligibility criteria. Addressing these needs will be key to fostering trust in research and accelerating drug discovery that answers key clinical questions.

    References:

    Grill JD, Karlawish J. Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials. Neurology. 2021 Sep 7;97(10):496-500. Epub 2021 Jun 4 PubMed.

    View all comments by Joshua Grill View all comments by Jason Karlawish

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References

Therapeutics Citations

  1. Leqembi
  2. Aduhelm
  3. Gantenerumab
  4. Donanemab

News Citations

  1. Finally: Big Win on All Outcomes for Lecanemab in Phase 3 Topline Results
  2. With Aduhelm in Retrenchment, Lecanemab Completes FDA Submission
  3. Lecanemab: FDA Set Accelerated Approval Decision for January 2023
  4. CMS Plans to Limit Aduhelm Coverage to Clinical Trials
  5. Bringing Aduhelm—and Antibodies to Come—Into Practice
  6. On Aduhelm, Medicare Agency Gets Pressure From All Sides
  7. Drilling Down into the CMS Aduhelm Decision—A Primer
  8. Aducanumab: Will Appropriate-Use Recommendations Speed Uptake?
  9. Using Lecanemab Trial Data to Determine Maintenance Dose
  10. Up-and-Coming Immunotherapies Target Aβ and Tau
  11. Lecanemab Sweeps Up Toxic Aβ Protofibrils, Catches Eyes of Trialists

External Citations

  1. reported
  2. Endpoints news

Further Reading

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