Next Goals for Immunotherapy: Make It Safer, Less of a Hassle

Series - International Conference on Alzheimer's and Parkinson's Diseases 2023:

Anti-amyloid immunotherapy has reached a milestone with the approval of two antibodies for clinical use; alas, the race is far from over. At the International Conference on Alzheimer’s and Parkinson’s Diseases, held March 28 to April 1 in Gothenburg, Sweden, researchers enumerated many challenges that remain before immunotherapy can become standard treatment for AD. The field needs to improve safety, figure out which types of patients are at higher risk of side effects, and make treatments more convenient, Dennis Selkoe of Brigham and Women’s Hospital, Boston, said in an opening talk. In addition, researchers must continue gathering data on whether these treatments offer substantial benefits to people with early AD.

  • Giving both lecanemab and anticoagulants boosts risk of serious side effects.
  • Lilly’s follow-on remternetug clears plaque faster than donanemab and avoids anti-drug antibodies.
  • Prothena’s high-affinity PRX012 may be dosed low and infrequently.

Various presentations at AD/PD dealt with these issues. Subjective quality-of-life assessments from the Phase 3 Clarity trial of lecanemab offered a fresh look at clinical meaningfulness. Calculations of “time saved” by various antibodies were used to make a case for slowed disease progression. On risk, Clarity data showed that people taking anticoagulants have greater odds of suffering the most serious side effect of immunotherapy, large brain bleeds. New Appropriate Use Recommendations suggest not prescribing the drug to this group.

Eli Lilly researchers shared data about two troublesome side effects of donanemab, infusion reactions and antidrug antibodies, and debuted a successor, remternetug, that appears to be free of these drawbacks. Finally, researchers at Prothena described their new Phase 1 antibody, PRX012, which may require less frequent administration than previous molecules, potentially easing the burden of treatment for patients.

“Cognitive decline is the challenge of our age,” Nick Fox of University College London said in Gothenburg. He reminded the audience that one in three people alive today are projected to develop dementia, and half will look after someone with the disease. He believes these new therapies will brighten this outlook. “We have the opportunity to preserve function longer, provide hope, and change the mindset about dementia. No more nihilism,” Fox said.

Vanishing Plaques. Remternetug mopped up amyloid with a speed that varied by dose (left); spaghetti plots show how many people on each dose became amyloid-negative within six months (right). [Courtesy of Yan Jin, Eli Lilly.]

How Much Does Amyloid Immunotherapy Really Help?
The question of whether the slight slowing of cognitive decline quantified in immunotherapy trials matters to patients has engendered fierce debate among clinicians. This is because the treatment effect is not large and obvious to everyone, and the meaningfulness of small effects is difficult to measure (Feb 2023 news).

In Gothenburg, Sharon Cohen of the Toronto Memory Program made the case that the cognitive benefit achieved thus far does matter to patients. Cohen, a site investigator for the Clarity trial, believes in asking patients themselves. She based her conclusion on quality-of-life assessments completed by trial participants and their caregivers. Clarity included three such measures: the European Quality of Life scale, the Quality of Life in AD, and the Zarit Burden Inventory. The 859 participants on lecanemab and 875 on placebo completed these assessments at baseline, and repeated them every six months over the 18 months of the trial.

The European Quality of Life scale measures five aspects of health: activities, self-care, mood, mobility, and pain; it goes from 0 to 100, high numbers being better. Clarity participants started with an average score of 82, as expected for an early AD population. Over the course of the trial, people on placebo lowered their rating of their own quality of life by four points, while those on drug lowered it two, for a 50 percent slowing of decline. The benefit showed up in the scores for activities, self-care, and mood, not mobility or pain, as might be expected for a drug that sharpens cognition.

On the Quality of Life in AD scale, which ranges from 13 to 52 and is scored by both patient and caregiver, average scores started at 39. The placebo group dropped by more than a point during the trial, the treatment group half a point, again halving the rate of decline. Caregivers perceived less treatment benefit, rating their loved one’s decline as nearly 2.5 points on placebo and a bit under 2 on lecanemab. Caregiver ratings correlated with those of patients across the cohort.

Finally, on the Zarit Burden Inventory, caregivers scored their own stress level from 0 to 88, where high numbers mean more stress. Their starting value was 17, and their stress worsened by 6 points in the placebo group and 3.5 in the treatment group, for a 38 percent slowing of decline. Unlike the other measures, which only became statistically significant at 18 months, on this scale the difference between groups became apparent at six months, and grew over time, Cohen showed.

On all three measures, benefits were consistent across APOE genotypes and other personal characteristics such as age and sex. Because these differences were self-reported, the data suggest that treatment gains were meaningful and detectable to patients and their loved ones, Cohen said.

Suzanne Hendrix of Pentara Corporation, Salt Lake City, assessed meaningfulness another way. She calculated how much sooner people on placebo reached the same level of cognitive decline that people on a given antibody had reached at the end of the study. In the donanemab Phase 2 Trailblazer trial, averaging data from the iADRS and CDR-SB, this calculation came to 5.5 months. In the lecanemab Clarity trial, combining data from the ADAS-Cog, CDR-SB, and ADCS-ADL, it was five months. Both trials were 18 months long, hence those values jibe with the one-quarter to one-third slowing seen with these antibodies. For aducanumab, averaging data from the Emerge and Engage trials on the same three measures as in Clarity, progression slowed by 2.5 months. This is less than for the other antibodies because Engage was negative.

For all three antibodies, the amount of “time saved” grew throughout the trials, as would be expected for disease-modifying therapies that bend the slope of progression. Hendrix believes time is an inherently meaningful measure that enables a comparison between different disease-modifying therapies.

Anticoagulants and Amyloid Immunotherapy—A Bad Combination?
How to balance the benefits of amyloid immunotherapy against its risks, chiefly the brain swelling and bleeding known as ARIA? In Gothenburg, Marwan Sabbagh of the Barrow Neurological Institute in Phoenix presented more data on how this varies in people taking anticoagulant or antiplatelet drugs, which can increase bleeding. Anticoagulant or acute thrombolytic use has been associated with three deaths in the open-label extension of the Clarity trial (Jan 2023 news).

Sabbagh first went over general data from this OLE. The trial enrolled 1,795 people, of whom 90 percent, or 1,612, rolled over into the extension. As in the placebo-controlled portion of the trial, in the combined core and OLE data, ARIA-E rates were lower than those of other antibodies. They averaged 13.6 percent, compared to around one-quarter for people on donanemab, and one-third on aducanumab (Mar 2021 news; Dec 2021 news). As expected, the risk varied by APOE4 genotype, with noncarriers at 7, heterozygotes at 12, and homozygotes at 35 percent. All of these numbers were similar to those in the trial itself. Likewise, the amount of symptomatic ARIA-E stayed steady in the OLE, at about 3 percent.

The Clarity trial differed from other antibody programs in that it allowed people on anticoagulant or antiplatelet therapy to enter. In the core trial plus OLE data, the 156 people on anticoagulants had somewhat lower incidence of ARIA-E and microhemorrhages than the 1,456 people not on these drugs. However, their risk of macrohemorrhage was six times higher, going from 0.4 to 2.6 percent. This amounted to four cases in this group.

Though macrohemorrhages are rare, they have much more severe effects than other forms of ARIA. Ominously, the risk of dying with an intracerebral hemorrhage was much higher for people on anticoagulants, rising from 0.1 to 1.4 percent. Sabbagh offered no details on these patient deaths. By contrast, the use of antiplatelet drugs such as aspirin or clopidogrel did not increase the risk of brain bleeds. Unlike with ARIA-E, there was no apparent effect of APOE genotype on macrohemorrhages.

The higher risks of brain bleeds for people on anticoagulants, and of ARIA-E in APOE4 homozygotes, worry many clinicians, leading to efforts to restrict antibody use for these groups until more is known. The lecanemab Appropriate Use Recommendations were published March 27, coinciding with the start of AD/PD (Cummings et al., 2023). In Gothenburg, Jeffrey Cummings of the University of Nevada, Las Vegas, gave an overview. Like the aducanumab AUR, the new publication suggests that lecanemab not be prescribed for people taking anticoagulants, or anyone with a clotting disorder, strokes, or seizures. People taking lecanemab should not be treated with acute thrombolytics such as tPA, though common antiplatelet medications are allowed.

Like the revised aducanumab AUR, the lecanemab AUR recommend APOE genotyping before starting therapy, so clinicians can discuss potential risks with patients. The AUR do not restrict prescription to APOE4 homozygotes, but other groups may. Cummings noted that the Department of Veterans Affairs has decided to provide lecanemab for its beneficiaries, though not if they carry two copies of APOE4.

Per the AUR, MRIs should be done at baseline, and before the fifth, seventh, and 14th biweekly infusions to monitor for ARIA. The AUR also suggest scans at one year for APOE4 carriers and people with any ARIA during the first year. The schedule differs from that recommended for aducanumab, in which scans are done before the fifth, seventh, ninth, and 12th monthly doses (Aug 2022 conference news).

Alireza Atri of the Banner Sun Health Research Institute in Sun City, Arizona, emphasized the need for clinicians to stay in regular contact with patients and track their progress and symptoms. “It’s not ‘diagnose, infuse, and adios,’” he said in Gothenburg. Selkoe spoke of an internal system among neurologists at his hospitals, whereby one of them will be on call especially for the hospitals’ amyloid immunotherapy patients at all times.

Blunted Efficacy. Anti-drug antibodies against donanemab slow plaque clearance, with people above the median amount of ADAs (gray) clearing about 10 centiloids less than those below the median (tan) over 18 months. [Courtesy of Garrett Mullins, Eli Lilly.]

Anti-Drug Antibodies to Donanemab: a Problem. Remternetug: a Solution
For donanemab, ARIA is not the only concern. From its beginning, this antibody has been plagued by the generation of anti-drug antibodies in most patients, as well as occasional severe infusion reactions (Dec 2022 conference news). In Gothenburg, Lilly researchers offered data on these side effects.

Lilly’s Paul Ardayfio discussed infusion reactions. In Phase 2, these occurred in 10 out of 131 people on drug, or 8 percent. Reactions affected the whole body, causing flushing, chills, headaches, nausea, cramping, or chest tightness. Two of the reactions were characterized as severe, though Ardayfio gave no details. Most resolved within one day. The reactions typically happened after the second, fourth, or fifth infusions. They were more likely in people who made more antidrug antibodies, with none occurring in the lowest tertile of ADAs.

Garrett Mullins of Lilly elaborated on these ADAs. In Phase 2, 92 percent of participants developed ADAs that neutralized donanemab. The amount ranged widely, with the median titer being 1:10,000, meaning the antibodies could still be detected after diluting blood samples 10,000-fold. These ADAs hastened the clearance of donanemab from blood, with the highest titers mopping up the antibody about a third faster than the lowest titers. The maximum blood concentration of donanemab was not affected, but at the low point, donanemab concentration dipped to half the level seen in people without ADAs. As a result, high ADAs lessened donanemab’s efficacy by about a quarter, and attenuated plaque clearance, Mullins said. In answer to an audience question, Mullins said the Phase 2 cohort was too small to tell if the effect of ADAs increased over time. Lilly is investigating this in Phase 3, and also whether the cognitive benefit is less in people with high ADAs.

The data hint at problems for long-term use of donanemab. To solve this, Lilly made a new antibody, remternetug, with similar binding characteristics to donanemab, but fewer safety issues. Lilly’s Yan Jin presented interim Phase 1 data in Gothenburg. The trial enrolled 41 people who had MCI or mild AD and at least 37 centiloids of plaque. It compared 250, 700, 1,400, and 2,800 mg monthly to placebo, as well as a titration cohort going from 700 to 1,400 mg remternetug. Most groups comprised five people on drug and one on placebo, except for the 700 and 1,400 mg cohorts, which had twice as many participants. Each group took remternetug monthly for six months, i.e. seven doses, followed by a one-year extension. As the trial is still running, Jin presented only six-month data on plaque reduction and safety.

In this brief period, plaque dropped by as much as 100 centiloids with treatment. Effects were dose-dependent. At 250 mg, no one dropped below the amyloid-positivity threshold, defined as 24 centiloids. In the 700 mg group, four out of 10 people did, and in higher dose groups, everyone. On 2,800 mg, everyone dropped below 24 centiloids within three months. This is faster clearance than with donanemab, which slashes plaque about 60 centiloids in six months, bringing 40 percent of people below the threshold.

Safety data are still blinded, so treatment and placebo groups cannot be compared. However, Jin noted that there were a total of 10 ARIA-E and seven ARIA-H cases. These were scattered among treatment arms, with no obvious dose correlation. All the ARIA-E cases occurred in APOE4 carriers. One was symptomatic, with the participant developing balance, visual, and language problems that went away after dosing was stopped.

Crucially, no ADAs were detected in any participant. There were also no systemic infusion reactions, although two people developed local reactions at the injection site. Remternetug is now in Phase 3.

Better Binding? In vitro data from new anti-amyloid antibody PRX012 (gold) shows it hangs onto Aβ protofibrils better than lecanemab (gray, left) and clears plaque more potently than donanemab (gray, right). [Courtesy of Prothena.]

Will a More Potent Antibody Make This Less Burdensome?
At the moment, aducanumab, lecanemab, and donanemab require monthly or biweekly infusions. This will limit the number of people who can take these drugs. All antibody programs are testing subcutaneous dosing, but even then, the need for monthly injections may discourage some patients.

Prothena scientists set out to develop a more powerful treatment that could be taken less often. In Gothenburg, Brian Campbell of Prothena explained why they believe their antibody PRX012 fits the bill. PRX012 was designed to bind all aggregated forms of Aβ, including oligomers, protofibrils, and fibrils, with high affinity. Like other anti-amyloid antibodies, it targets the N-terminus, but unlike them, once it binds, it does not let go. Its very slow off-rate allows it to bind with picomolar affinity, Campbell said. In head-to-head comparisons of lecanemab and PRX012, the former had a dissociation constant of 2 nM from protofibrils, the latter 0.1 nM, giving it 20 times higher affinity.

What about plaques? When the researchers added PRX012 and microglia to postmortem AD brain tissue, almost half the fibrillar Aβ was gone three days later—including pyroglutamated Aβ, even though PRX012 does not bind this form. This is because once plaques are opsonized by antibody, microglia gobble all plaque material indiscriminately, Campbell said (for a new hypothesis of how a little microglia eats a huge plaque, see next story in this series).

In a direct comparison with donanemab, PRX012 cleared the equivalent amount of pyroAβ at a concentration three to eight times lower, he claimed. Prothena had earlier showed that PRX012 bested aducanumab in a direct comparison of plaque clearing, as well (Aug 2021 conference news).

Because of these features, Prothena researchers believe PRX012 could be given at lower doses than other antibodies, the company’s Chad Swanson said in Gothenburg. PRX012 has completed Phase 1 single-ascending-dose testing, and is now in a multiple-ascending-dose trial. The trial tests infrequent, low doses, Swanson said, but provided no further details. Swanson noted that PRX012 antibody was designed to be given under the skin, making administration easier.

In answer to audience questions, Swanson said PRX012 enters the brain at about the same rate as other antibodies, at 0.1 times the concentration in blood, and has a similar half-life. Results from the trial are expected in 2024. Meanwhile, Prothena has teamed up with Walgreens to accelerate and diversify enrollment in the MAD, as well as future studies of the antibody (see press release).—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. Leqembi
  2. Donanemab
  3. Remternetug
  4. PRX012
  5. Aduhelm

News Citations

  1. No Easy Answers on Clinical Meaningfulness of Alzheimer’s Treatments
  2. Should People on Blood Thinners Forego Leqembi?
  3. Donanemab Confirms: Clearing Plaques Slows Decline—By a Bit
  4. Aduhelm Phase 3 Data: ARIA Is Common, Sometimes Serious
  5. Bringing Aduhelm—and Antibodies to Come—Into Practice
  6. Donanemab Mops Up Plaque Faster Than Aduhelm
  7. Up-and-Coming Immunotherapies Target Aβ and Tau

Paper Citations

  1. Cummings J, Apostolova L, Rabinovici GD, Atri A, Aisen P, Greenberg S, Hendrix S, Selkoe D, Weiner M, Petersen RC, Salloway for the Alzheimer’s Disease and Related Disorders Therapeutics Work Group S. Lecanemab: Appropriate Use Recommendations. https://dx.doi.org/10.14283/jpad.2023.30 The Journal of Prevention of Alzheimer's Disease

Other Citations

  1. next story

External Citations

  1. press release

Further Reading

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