14 Jun 2024

After a favorable review from a Food and Drug Administration advisory committee, Eli Lilly’s donanemab appears poised for marketing approval in the U.S. (Jun 2024 news). Are clinics ready? While last year’s approval of lecanemab is helping pave the way, donanemab’s unique aspects raise fresh questions. The June 10 AdComs grappled with issues such as whether tau PET scans are needed to identify the patients most likely to benefit, how clinicians will know when a patient has had enough donanemab, and if and when to put them back on. The committee also debated safety issues for certain subgroups. Due to a lack of data, they offered no definitive guidance on these points, and suggested leaving final decisions up to doctors and patients.

AdComs recommends not requiring tau PET before prescribing donanemab.
Guidance for when to stop dosing, and maybe restart, is unclear.
Donanemab has a more convenient dosing schedule than lecanemab, and more ARIA.

“The advisory committee’s votes will have the effect of making donanemab’s label nearly interchangeable with lecanemab’s, except for a more liberal, lower MMSE threshold,” predicted Lon Schneider at the University of Southern California, Los Angeles (comment below).

This means that for physicians, integrating donanemab into their practice may be akin to setting sail while finishing building the ship. Still, most clinicians Alzforum contacted welcomed the additional treatment option. They believe lecanemab and donanemab will complement each other, whereby lecanemab has a slight edge on safety and donanemab on less burdensome dosing. Each has advantages that will appeal to specific patients, researchers said.

Donanemab’s biologics licensing application rested on results from its single Phase 3 trial, with supportive evidence from Phase 2 (Jul 2023 conference news; May 2023 news; Mar 2021 conference news). In people with low to moderate tangle loads, the antibody slowed cognitive decline on multiple measures by about a third, while rapidly clearing amyloid. Because this efficacy was similar to lecanemab’s, many industry observers had expected the drug to be approved without an AdComs. FDA said it convened the committee to get expert input on donanemab’s label (May 2024 news).

The committee included three permanent voting members: ALS researcher Merit Cudkowicz at Massachusetts General Hospital, Boston; neuropathologist Thomas Montine at Stanford University School of Medicine, California; and Parkinson’s researcher Tanya Simuni at Northwestern University, Chicago. The other eight were temporary voting members: geriatrician Cynthia Carlsson at the University of Wisconsin, Madison; neurologist Nilüfer Ertekin-Taner at the Mayo Clinic in Jacksonville, Florida; biostatistician Dean Follmann at the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; neurovascular researcher Costantino Iadecola of Weill Cornell Medical College, New York; movement disorder specialist Kathleen Poston at Stanford; and neurologist Daniel Press at Beth Israel Deaconess Medical Center, Boston, as well as consumer representative Sarah Dolan at the Critical Path Institute in Tucson, Arizona, and patient representative Colette Johnston. Montine chaired the group. Conflict-of-interest rules tend to exclude many clinician-researchers who are actively involved in AD therapy development, particularly of anti-amyloid antibodies.

To Scan or Not to Scan?
What did this group recommend? Their first question was whether tau PET scans should be required for clinical use of donanemab. Trial participants were screened by tau PET, with those between 1.10 and 1.46 SUVr reaping the greatest benefits. Those above 1.46 fared less well, and those below 1.10 were enrolled into an open-label safety addendum that did not track cognition. About 8 percent of amyloid-positive people with cognitive impairment have a tangle load below 1.10, Lilly’s John Sims noted.

In the FDA’s presentation to AdComs, efficacy reviewer Kevin Krudys showed an analysis that broke out the high-tau group by itself. He reported that donanemab slowed progression in these patients by about 20 percent on the CDR-SB, and only 6 percent on the iADRS. This compares with 36 and 35 percent, respectively, for those with low to medium tangle loads. He also noted that biomarker changes in people below 1.10 SUVr, known as the “no-tau” group, were consistent with those in other groups, hinting at similar effects on the disease. “It’s reasonable to generalize [efficacy] across the spectrum of tau,” he concluded. This means patients would be selected based only on amyloid positivity combined with cognitive impairment in the MCI to mild dementia range.

This concerned the committee. Montine noted that the efficacy at higher tangle loads implies that people with advanced disease may hardly benefit, complicating a clinician’s decision whether to treat and when to stop. On the other end of the scale, Follman said he was uncomfortable extrapolating efficacy findings to the no-tau group based on biomarker readings alone, and suggested waiting for data from Trailblazer-Alz3, an ongoing secondary prevention study of donanemab in preclinical AD (Jul 2021 news; Nov 2021 conference news).

Ultimately, however, the committee felt requiring tau PET for selecting patients would be impractical. “Access to tau PET would be impossible for many communities,” Carlsson said, and most agreed. Poston noted that tau PET scans are only available at tertiary care centers. They recommended the label not demand this.

Cudkowicz asked whether a blood test might be able to detect high tangle loads. Lilly’s Mark Mintun noted that plasma p-tau levels correlate with tau PET at about r=0.7, but said the marker does not accurately predict tangles among amyloid-positive people. Nonetheless, Eric Siemers at Acumen Pharmaceuticals thinks this approach could hold potential for the future. “Future studies might use a plasma tau measure such as p-tau217, since these measures may be actually more sensitive than tau PET,” he wrote (comment below). Several candidate fluid tests of brain tangle load are being developed, but none are ready yet for this purpose (Aug 2023 conference news; Mar 2024 news).

In comments to Alzforum, Gil Rabinovici at the University of California, San Francisco, concurred with the committee’s recommendation not to require tau PET, but also urged the community to push to make both amyloid and tau PET more available, affordable, and covered by payors. “PET scans are used extensively to guide clinical decision-making in oncology, and we should not accept a lower standard in AD, as the field enters a new era of precision medicine,” he wrote to Alzforum (comment below). David Knopman at the Mayo Clinic in Rochester, Minnesota, noted that, because administering donanemab already requires deep multidisciplinary expertise, tau PET is likely to be accessible at many academic centers that will pioneer its use during its ramp-up phase, hence may be more available than the committee thought (see comment).

When to Stop, and Whether to Resume
Perhaps the most puzzling issue for the committee was how clinicians are to know when to stop treatment. Because donanemab targets a form of Aβ found only in plaques, Lilly recommends discontinuing dosing once plaque has been cleared. In Phase 3, participants were switched to placebo if their plaque load fell below 11 centiloids, or below 25 in two consecutive scans. In clinical practice, obtaining multiple amyloid PET scans would be cumbersome and expensive. How are clinicians to know when to test?

Quizzed by the committee on this point, Lilly’s David Hyman called the one-year mark a reasonable timepoint. In the trials, two-thirds of participants were amyloid-negative by then. Teresa Buracchio of the FDA noted that amyloid positivity could be determined by a simple visual read of the scan.

The committee considered this guidance inadequate. “When would you test again? How many times do you retest? I would want to have answers to implement this in the clinic,” Poston said. “A main point that emerged [from the AdComs discussion] is the complexity of handling the discontinuation of donanemab … I found this the murkiest aspect of an otherwise reasonable endorsement of the agent,” Dennis Selkoe at Brigham and Women’s Hospital, Boston, wrote to Alzforum.

Committee members asked how well cognitive benefits are maintained after stopping. In the 18-month trial, participants who completed their treatment course around the one-year mark continued to diverge from those on placebo over the next six months. The committee said more follow-up will be needed to find out what happens over longer timeframes, and whether patients should go back on donanemab if their decline picks up pace again.

“There’s a huge cost savings for stopping, provided that stopping is supported by long-term post-marketing data,” Simuni said.

Ertekin-Taner suggested that physicians check in with their patients regularly after dosing stops to monitor for worsening status that could trigger a decision to re-initiate treatment. Dolan asked that Lilly provide guidance to patients on what symptoms to watch for. At the moment, no such guidance exists. Lilly has calculated that it would take five years for patients who have completed treatment to become amyloid-positive again, but has not suggested when to restart treatment (Jul 2023 conference news).

A recent paper hints that the benefits of immunotherapy depend on more than simply clearing existing plaque. In a study of an amyloidosis mouse model given aducanumab, researchers led by John Fryer at the Mayo Clinic in Scottsdale, Arizona, found that treatment prodded microglia into an amyloid-devouring mode. After treatment stopped, microglia maintained this beneficial phagocytic phenotype for 3.5 months, but lost it by seven months (Cadiz et al., 2024). Donanemab has also been shown to clear plaque by stimulating microglia to gobble it up.

How to Minimize Risk?
As with other antRi-amyloid antibodies, safety was a major concern. Donanemab produces about twice as much ARIA-E as does lecanemab, with edema in a quarter of patients. About a fourth of them, i.e., 6 percent of all patients, develop symptoms. While serious complications are rare, three deaths in the Phase 3 trial, and two in the open-label extension, were linked to ARIA. Lilly’s Melissa Veenhuizen said that four of these patients carried one copy of the APOE4 allele. The fifth did not, but had superficial siderosis, iron deposits that flag previous microhemorrhages, in his brain at baseline. The main risk factors for ARIA-E are APOE4, superficial siderosis, or more than one microhemorrhage at baseline. The latter two are both signs of possible cerebral amyloid angiopathy (CAA), an otherwise invisible vascular disorder associated with worse outcomes from amyloid immunotherapy (Aug 2023 conference news).

Could these deaths have been prevented? Veenhuizen noted that about a third of ARIA-related serious adverse events occurred at the second monthly infusion, and almost another third at the third infusion. Very few occurred after six months. At the beginning of the Phase 3 trial, MRIs were done before the first, fourth, and seventh infusions. During the trial, Lilly added an MRI before the second infusion, enabling clinicians to halt dosing earlier if ARIA had developed. This cut the number of serious ARIA cases by a quarter, and symptomatic cases by a third, Veenhuizen said. Lilly recommends that the FDA label specify an MRI be added before the third infusion.

“We think additional MRIs will minimize risk. But we can’t entirely eliminate it,” Hyman told the committee. Reisa Sperling at Brigham and Women’s Hospital, who co-leads AHEAD, a secondary prevention study of lecanemab, told the AdComs that ARIA appears tied to both antibodies’ mechanism of action, hence its risks can only be mitigated. The company plans to offer training for physicians, as well as information cards patients can carry with them to inform health-care professionals they encounter of their donanemab use. This could help physicians spot signs of ARIA and avoid prescribing contraindicated medications.

The committee focused on the risk for APOE4 homozygotes. This group is more susceptible to ARIA than others, with more than half of them getting it on donanemab, versus 20 percent on placebo. In addition, this subgroup appeared to gain less clinical benefit from donanemab in the Phase 3 trial, Press noted. Follman disagreed, noting the number of homozygotes was small, and the group was not powered to show a clinical effect. Nonetheless, all members agreed the higher risk of ARIA worsens the risk-benefit ratio for homozygotes. Ertekin-Taner noted the importance of communicating this to people considering donanemab. At the same time, the committee felt APOE genotyping should be recommended, not mandated, and that the final decision be left up to patients and physicians. Buracchio noted that as with lecanemab, donanemab’s label will strongly recommend APOE genotyping.

Other risks were less clear. Very rarely, Alzheimer’s patients develop intracerebral hemorrhages, which are bleeds greater than 1 cm in size. Whether ICHs are more common on donanemab than placebo is unknown, due to a low incidence in the Phase 3 study, the FDA noted. Overall, there were three on donanemab, versus two on placebo, out of 1,000 patients in each group.

One specific situation is particularly hazardous. One person died after developing stroke-like symptoms while on donanemab and getting a thrombolytic drug in the hospital. This precipitated multiple intracerebral hemorrhages throughout his brain. Importantly, the FDA noted, ARIA symptoms can mimic stroke, leading to inappropriate treatment and catastrophic outcomes. Therefore, emergency room staff must be informed to use caution before administering clot-busting drugs to patients on amyloid immunotherapy. This is already the protocol at many hospitals where lecanemab is in use.

Stephen Salloway at Butler Hospital in Providence, Rhode Island, noted that the accumulating evidence indicates ARIA-related deaths occur in one of three ways: an ICH in a person with CAA; inflammatory ARIA-E that resembles CAA-related inflammation; or ARIA-E that mimics stroke and is mistakenly treated with thrombolytics. “These risks can be substantially mitigated by optimal patient selection and careful management of ARIA,” he wrote to Alzforum (comment below).

What about chronic use of blood-thinning drugs, i.e., anticoagulants and antiplatelet agents like aspirin? These medications were permitted in the Phase 3 trial but, other than aspirin, their use was rare. More than 300 patients took aspirin, while 91 took a different antiplatelet agent, and 98 took an anticoagulant. The medications did not appear to be associated with increased risk of ARIA-E, ARIA-H, or ICHs, but because of the limited numbers, the data remain inconclusive, the FDA noted.

In addition to these issues, donanemab causes infusion-related reactions in about 8 percent of patients. Typical symptoms are flushing, chills, nausea, and sweating. Most IRRs occurred during infusion or within 30 minutes afterward, and cleared up the same day. In three cases, or 0.3 percent of participants, the person developed anaphylaxis, a life-threatening immune reaction. Hyman noted that unlike for some anti-amyloid antibodies, administering anti-inflammatory drugs before infusing donanemab does not help prevent IRRs. Instead, Lilly recommends monitoring patients for 30 minutes after each infusion.

Lilly has proposed three post-market safety studies to further examine hypersensitivity reactions and the effects of antithrombotic drugs. One would be a registry study in the U.S., one a cohort study in the U.S., and the third a cohort study in Europe.

The committee lamented a lack of data on the risks and benefits of donanemab for certain populations, including underrepresented minorities, people with autosomal-dominant AD, and those with Down’s syndrome. Only 8 percent of Phase 3 participants were non-white, a persistent problem in Alzheimer’s studies. None had ADAD or Down’s. All of these groups might seek clinical care with donanemab. However, the committee opted not to recommend restrictions to the label. Hyman noted that Lilly is planning to launch studies in both ADAD and Down’s in the near future.

Donanemab or Lecanemab?
Overall, the committee believed that donanemab would be a valuable addition to the clinic. Press liked that donanemab is easier on the patient in that it requires monthly instead of twice-monthly dosing, and half an hour to infuse instead of an hour. This and the time limit on the treatment protocol could free up infusion center capacity and allow more patients to get treated, he said. Dolan thought the short course of treatment might motivate patients to stick with it.

Erik Musiek at Washington University in St. Louis predicted that adding donanemab to clinical practice would be relatively straightforward. “Patient screening criteria and the infrastructure and expertise needed to administer donanemab is likely to be the same as that needed for lecanemab, and monitoring for adverse events should be similar,” he wrote to Alzforum (comment below).

If both antibodies are available, which one should patients take? That depends on the patient, AD researchers stressed. “It is possible that lecanemab may be a better choice for higher-risk patients, such as APOE4 homozygotes, though real data will be needed to conclude this,” Musiek noted. Meanwhile, donanemab may make treatment more feasible for some patients. “Donanemab may be a good option for patients who are willing to accept those risks but live far away from an infusion center and would prefer dosing every four weeks,” Irina Skylar-Scott at Stanford wrote to Alzforum.

In the afternoon, 10 patients or caregivers who participated in donanemab trials spoke to the AdComs, all in favor of approval. Several ascribed remarkable improvements to the drug. One said her husband has become more talkative, walks with a normal stride again, and showers and gets dressed by himself once more. Another said her husband has gone from “sundowning,” i.e., becoming confused in the early evening, every day to once every six weeks. “Our experience in the trial has been life-changing,” she told the committee.—Madolyn Bowman Rogers

Donanemab Approval Likely to Pose New Quandaries for Clinicians

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