Despite the biomarker-based conditional approval of Biogen/Eisai’s aducanumab (trade name Aduhelm) for Alzheimer’s treatment, questions linger about how safe it is, how well it works, and whether it will improve people’s lives. Researchers addressed those issues at the Clinical Trials on Alzheimer’s Disease conference, held in Boston and online November 9-12.

  • Analysis of more plasma from aducanumab Phase 3 trials confirms drop in p-tau.
  • Alzheimer’s Association starts national registry to track clinical outcomes.
  • Cost and ARIA risk remain major barriers.

Oskar Hansson of Lund University, Sweden, presented an analysis of blood samples from the Phase 3 EMERGE and ENGAGE trials. It strengthened the argument that aducanumab lowers phospho-tau, and that that correlates with cognitive benefit. Meanwhile, the Alzheimer’s Association announced the formation of a registry to gather data on the real-world effects of approved disease-modifying AD treatments, in order to judge their value to patients. Right now, that category includes only aducanumab, but other drugs in this class are expected to follow next year. Eisai/Biogen’s lecanemab and Eli Lilly’s donanemab have both started submitting data to the FDA as part of a rolling submission for accelerated approval, and Roche’s Phase 3 gantenerumab studies will read out next year.

A CTAD talk on a reasonable price for those drugs concluded that they will only be cost-effective if they go for a time-limited, not indefinite, course of treatment. For aducanumab, cost and absent insurance coverage mean fewer patients than expected are on it so far. In a new blow to aducanumab’s prospects, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) voted down its marketing application at a recent November meeting. A final decision from the agency is expected next month (Endpoints News). Despite this no-confidence vote for aducanumab, researchers expect clinical use of anti-amyloid antibodies to grow starting next year.

“We are at the beginning of a new treatment era,” Steve Salloway of Butler Hospital in Providence, Rhode Island, said at CTAD, noting the advent of plasma and imaging biomarkers as well as amyloid-lowering drugs. “We have the opportunity to build on this.”

Dunking Tau. Plasma p-tau181 fell in people who took aducanumab as part of the Phase 3 EMERGE (left) and ENGAGE (right) trials, with higher doses (blue) having a greater effect than low (green). In people on placebo (gray), p-tau rose. [Courtesy of Biogen.]

Effect on Tau Looks Real
One question researchers are still asking is how amyloid-lowering drugs bolster cognition, when numerous studies have shown that it is tau pathology that degrades neuronal function. Many think it is because removing plaque lessens tau pathology as well, as seen in trials of several anti-amyloid antibodies. In aducanumab’s EMERGE and ENGAGE trials, p-tau181 and total tau edged downward in the cerebrospinal fluid during treatment, as did the tau PET signal (Dec 2019 conference news). Alas, these substudies were tiny, with 131 people in the CSF and just 36 in the tau PET subgroup, leaving wide open the possibility that this was statistical noise.

To settle this, Biogen researchers had the Pennsylvania-based CRO Frontage Laboratories analyze stored plasma samples from all ENGAGE and EMERGE participants who had given blood at baseline and at completion. Because many people did not finish the trials due to the early stoppage, ARIA, or other reasons, this group amounted to a little more than half the original participants, or 1,815 people. They had given blood an average of four times each, for 6,929 total samples. Frontage Labs measured p-tau181 in these samples using a Quanterix Simoa Advantage kit. These kinds of ultra-sensitive plasma assays were not widely available when the EMERGE/ENGAGE trials were running (Apr 2018 conference news; Apr 2020 conference news). 

At CTAD, Hansson presented these results. Plasma p-tau181 rose by around 9 percent in the 620 participants on placebo, reflecting worsening disease (Jan 2021 news). It fell about 15 percent in the 571 people on high-dose aducanumab, and almost as much in the 624 people on low-dose. This drop and the waning amyloid PET signal correlated, with a coefficient of about 0.4. Plasma p-tau181 dwindled the most in people whose plaque load receded to below the preset amyloid-positivity threshold of SUVR 1.1 by the end of the trial.

Notably, the drop in p-tau181 was associated with slower decline on the MMSE, CDR-SB, ADAS-Cog13, and ADCS-ADL, though it was not clear if this association was made on a per-patient or responder group level. The findings were significant, with p values typically below 0.01.

Gil Rabinovici, University of California, San Francisco, called the findings encouraging. He noted their agreement with the donanemab studies (see Part 2 of this series), where a slowing of tau tangle accumulation correlated with delayed cognitive decline (Mar 2021 conference news). “This confirms plaque clearance modifies downstream pathology,” Rabinovici said at the conference.

That said, the correlation between soluble p-tau181 and cognition was weak, with coefficients between 0.1 and 0.2. Rabinovici thinks this makes sense, because soluble p-tau is far upstream of neurodegeneration, and other factors influence the outcome along the way. Recent work from Hansson’s group suggests soluble p-tau mediates the relationship between plaques and tangles, with tangles then triggering neurodegeneration and cognitive decline (Mattsson-Carlgren et al., 2020; Mattsson-Carlgren et al., 2021). Rabinovici noted that data on how plaque removal affects neurodegeneration is sparse, and Hansson said that plasma NfL and other neurodegeneration markers are currently being assessed in the EMERGE/ENGAGE samples.

Researchers at CTAD speculated that plasma p-tau has potential as a future marker of drug response, but said the findings are too noisy to be informative at the level of an individual person. “I see the door opening for a wide application of these, but we’re not quite there yet,” said Jeffrey Cummings of the University of Nevada, Las Vegas.

A Slew of Post-Market Studies
Most new data on aducanumab will come from post-market studies, and a number of these have sprung up. Beyond the open-label extension study EMBARK and the real-world observational study ICARE, Biogen is still designing the FDA-required confirmatory trial.

At CTAD, Maria Carrillo of the Alzheimer’s Association announced a broader effort to evaluate disease-modifying AD treatments, called the National Treatment and Diagnostic Alzheimer’s Registry. Established in collaboration with the American College of Radiology, the American Society of Neuroradiology, and Brown University’s School of Public Health, the registry will enable healthcare providers to enter data on how new AD treatments affect their patients’ health and quality of life. The goal is to track how these therapies perform in the real world, and to guide policy and funding decisions, Carrillo said. Similar registries exist for other diseases, such as the National Cardiovascular Data Registry and the National Program of Cancer Registries. The association will help fund the registry’s start, and will tap personnel and administrative systems originally developed for the similar post-market IDEAS study of amyloid PET imaging (Aug 2017 conference news; Aug 2020 conference news). 

As for ongoing aducanumab studies, Sharon Cohen of the Toronto Memory Program offered a first look at baseline data from EMBARK. Cohen was an ENGAGE site investigator and sits on the aducanumab steering committee. EMBARK has enrolled some 1,700 participants, roughly half the cohort from the Phase 3 trials. Almost half of them were previously on placebo; the remainder had been off drug for an average of 1.7 years when they started the extension. They also include 29 people who were already in the long-term extension of the PRIME Phase 1 study, and thus some of them have been on this drug for going on nine years. Regardless of their aducanumab history, all EMBARK participants were titrated up to a 10 mg/kg dose, and will get this monthly for two years.

EMBARK includes those who chose to come back, not a random sample from prior trials. Cohen’s data show that EMBARK’s enrollees better maintained their abilities on the CDR-SB than those who did not come back; in other words, the healthiest returned for EMBARK. Nonetheless, they had more advanced disease at baseline than the original Phase 3 cohort did, as would be expected. Their average MMSE was 21, compared to 26 in EMERGE and ENGAGE at baseline, and they were almost five years past an AD diagnosis on average, as compared to one year at EMERGE and ENGAGE. There, 80 percent of participants started out with mild cognitive impairment, 20 percent with mild AD. At EMBARK baseline, 30 percent had MCI, 42 percent mild, 23 percent moderate, and 4 percent severe AD dementia.

What happened to their cognition during the period between? People who had been on aducanumab worsened at the same rate during the gap as those who had been on placebo, but they maintained the numerical advantage they had gained on the CDR-SB, MMSE, and ADAS-Cog13, Cohen reported. This is generally interpreted as a sign that disease progression was slowed while on drug. With symptomatic treatments, cognition worsens to control levels once the drug is withdrawn. The same pattern of sustained benefit was seen with lecanemab during treatment gaps (see upcoming story).

Only 155 of the EMBARK participants got amyloid scans, as had been the case in EMERGE and ENGAGE. Their PET signals remained low throughout the gap, showing that once plaque is gone, it stays gone for this time period. This matches previously shown findings from lecanemab and donanemab (Dec 2019 conference news; Aug 2021 conference news; Aug 2021 conference news). 

Hairy Eyeball On ARIA
Aducanumab is currently dogged by the question of how safe it will be in the general population, given the rates of ARIA seen even under trial conditions with rigorous safety protocols and the exclusion of cardiovascular disease (Oct 2021 news). The potential risk means patients need close monitoring via MRI. The Appropriate Use Recommendations AD leaders developed offer guidelines for when to scan, but do not specify the technical protocol (Aug 2021 conference news). 

At CTAD, Tammie Benzinger of Washington University in St. Louis described an effort to do just that. Working with imaging experts around the world, Benzinger developed a standard MRI protocol to be used at all ICARE sites in the United States. There are about 200 such sites at the moment, which enroll patients who were prescribed aducanumab by their doctor (Aug 2021 news). 

The standard protocol will require 20 minutes in the scanner, and calls for four scans. A 3D fluid-attenuated inversion recovery (FLAIR) scan, which suppresses CSF artifacts and is highly sensitive for detecting lesions, should be used to monitor for the edema known as ARIA-E (for review see Naganawa, 2015). To detect the microhemorrhages of ARIA-H, researchers should use a T2*-weighted gradient-recalled echo (GRE), which can detect iron deposits (Tang et al., 2014). Also part of the set is diffusion-weighted imaging, which detects ischemic strokes that can mimic the effects of ARIA, aiding differential diagnosis (Baliyan et al., 2016). Finally, the protocol calls for a 3D T1-weighted gradient echo (GE), a structural scan that will help assess brain atrophy and disease progression.

The 3D FLAIR and 3D T1-weighted GE will use the protocol from ADNI 3, while the T2*-weighted GRE will use that from EMERGE/ENGAGE. Parameters will be specified for both 3T and 1.5T scanners, Benzinger said. The protocol will be disseminated through conference talks, publications, physician groups, and scanner manufacturers. Having a standard protocol will help ICARE estimate the incidence of ARIA, track health outcomes, and compare adverse events in ARIA versus non-ARIA groups, Benzinger noted.

Such data are needed because ARIA continues to be a worry. In a poster at CTAD, Stanford University’s Sharon Sha described the case of an APOE4 carrier in Biogen’s Phase 1 PRIME long-term extension study who developed ARIA on six separate occasions over the course of nearly four years on drug. All six instances were asymptomatic and resolved after dosing was lowered or suspended. As a result of these treatment interruptions, the participant never received sustained dosing at the maximum 10 mg/kg, but did dip below the amyloid positivity threshold after 21 total doses, Sha reported (Hall et al., 2021). This case shows that ARIA can make multiple appearances even after years on drug, raising the question of how long patients need MRI monitoring.

More ominously, the FDA is investigating the death of a 75-year-old woman outside the U.S. who received aducanumab as part of the global EMBARK study. She was hospitalized and there, ARIA-E was seen on a brain scan. The case is logged in the FDA’s Adverse Event Reporting System (FAERS). An analyst who reviewed the case report, Brian Abrahams at RBC Capital Markets, believes her death was likely precipitated by epileptic seizures brought on by ARIA; Biogen states the case may be more complicated (Endpoints News). FAERS also contains six new reports of adverse events in U.S. patients on aducanumab, two of them seizures. Around 200 people are believed to have received the drug since June. Speaking off the record, a half-dozen clinicians at CTAD said they worry that all anti-amyloid antibody companies may be less than transparent about the extent and severity of ARIA they see.

Is Aduhelm Worth the Cost?
Perhaps the most roundly criticized aspect of this new drug is its price tag, $56,000 per year. At CTAD, Eric Ross of Massachusetts General Hospital, Boston, took a look at what pricing might be reasonable for anti-amyloid antibodies. He used data from aducanumab and donanemab, the latter of which is unique among current antibodies in requiring only a limited course of treatment (Mar 2021 conference news). Donanemab does not yet have a price, so Ross set a hypothetical one of $56,000 to directly compare it to aducanumab. To assess the value of these new treatments, Ross calculated their incremental cost-effectiveness ratio (ICER—not to be confused with the institute of the same name, see below) in relation to acetylcholinesterase inhibitors and memantine, the current standard of care for AD. A new treatment is usually considered cost-effective if it costs less than $150,000 per quality-adjusted life year (QALY) gained over existing treatments.

Alas, at an annual price of $56,000, both aducanumab and donanemab fell far short of that goal, with the former costing $1.8 million per QALY, the latter $300,000. The main reason for the difference was the time-limited nature of donanemab treatment. Donanemab dosing stops at a preset amyloid level, which half of Phase 2 trial participants reached within one year. For context, treatment with a rivastigmine transdermal patch, a currently available AD therapy, has a cost-effectiveness ratio of $93,000 per QALY when compared to donepezil pills (Yunusa et al., 2021). 

Aducanumab would become cost-effective at an annual price of $3,000, as calculated with EMERGE/ENGAGE efficacy data presented so far, Ross said. These data have not been published in a peer-reviewed journal yet. Using a more optimistic efficacy estimate derived from Biogen’s post hoc analysis of these trials, the annual price could be as much as $11,000. These estimates are near the $3,000-8,000 range suggested as a fair price by the Institute for Clinical and Economic Review (Aug 2021 conference news). Donanemab would be cost-effective at an annual price of $20,000 or less, due to its higher reported efficacy and shorter time course, Ross said.

“We are not at a cost-effective point yet for anti-amyloid antibodies, but we are not far away,” Ross concluded. “The treatment that will get us there will be of limited duration.”

Other anti-amyloid antibodies may debut at lower prices. Roche’s head of pharmaceuticals has hinted that his company may undercut Biogen’s price if gantenerumab is approved for clinical use (Reuters news). Society’s willingness to pay for an effective Alzheimer’s therapy could rise. A recent study noted that if non-healthcare costs and caregiver well-being are included when calculating QALYs, then a hypothetical treatment costing $192,000 per QALY could drop as low as $74,000 (Ito et al., 2021). 

Aducanumab’s cost is a roadblock to its rollout (NPR news; Endpoints News). Nonetheless, the prospect of greater uptake in 2022 already has the Centers for Medicare and Medicaid Services raising Medicare premiums, and has renewed calls in some quarters to let the agency negotiate prices (Endpoints News; Boston Globe).  

Clinicians at CTAD lamented the resistance of insurers and hospital systems to include aducanumab in their formularies. “I don’t think it’s reasonable for pharmacy committees to try to digest this nuanced dataset and rule on it,” Rabinovici said. “That takes the decision away from doctors. I don’t think this is good for patients, and I hope this will change.”

And aducanumab’s approval, controversy notwithstanding, means Alzheimerologists are looking ahead to upcoming trials of concurrent anti-amyloid antibody and other therapies in hopes of hitting multiple disease pathways. No one expects anti-amyloid antibodies to be able to stanch Alzheimer’s disease progression on their own. DIAN is already doing so with lecanemab and an anti-tau antibody, and others are planning such trials, as well. “Combination therapy is a necessity. Everyone is coming to that conclusion,” Ron Petersen of the Mayo Clinic in Rochester, Minnesota, said in a keynote address following his acceptance of the CTAD 2021 Lifetime Achievement Award.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Aduhelm
  2. Lecanemab
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News Citations

  1. Exposure, Exposure, Exposure? At CTAD, Aducanumab Scientists Make a Case
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  7. In Clinical Use, Amyloid Scans Change Two-Thirds of Treatment Plans
  8. IDEAS Finds Small Drop in Hospitalizations, Missing Goal
  9. Amyloid Clearance: Check. Cognitive Benefit: Um … Maybe.
  10. Lecanemab Post Hoc: Is Continual Treatment Required for Cognitive Benefit?
  11. On Donanemab, Plaques Plummet. Off Donanemab, They Stay Away
  12. Aduhelm Administration Remains a Trickle, ARIA a Concern
  13. Aducanumab: Will Appropriate-Use Recommendations Speed Uptake?
  14. Seeking Real-World Data on Whether Aducanumab Works
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External Citations

  1. Endpoints News
  2. National Cardiovascular Data Registry
  3. National Program of Cancer Registries
  4. Endpoints News
  5. Reuters
  6. NPR news
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Further Reading