25 Mar 2021

Buoyed by data crediting amyloid removal with ever-so-slightly slowed cognitive decline, many scientists are now optimistic about the prospects for anti-amyloid immunotherapy. Four “-mabs”—of the ganteneru-, lecane-, aducanu-, and donane- kinds—have proven to dramatically clear plaque, while also nudging downstream tangle pathology. Three of these have data showing they can tap the brakes on mental slippage, while high-dose gantenerumab has not yet read out on cognition.

Roche reports positive Phase 1 first-in-human data for its brain-shuttle technology.
One-year, open-label extension data for lecanemab shows rapid plaque clearance.
New analyses from aducanumab Phase 3 trials resemble earlier data.

The 15th International Conference on Alzheimer’s and Parkinson’s Diseases, held virtually March 9–14, featured updates on all these programs. Mark Mintun of Eli Lilly presented donanemab’s Phase 2 trial data (Mar 2021 conference news). Luka Kulic of Roche reviewed a strategy to amplify how much gantenerumab reaches its target when delivered via a “brain shuttle” technology, and showed that it appeared safe in a first-in-human trial. Chad Swanson of Eisai presented amyloid PET data from the first year of the lecanemab open-label extension. Meanwhile, Samantha Budd Haeberlein of Biogen shared new analyses of the same Phase 3 data for aducanumab, which awaits regulatory decisions in the U.S., the EU, and Japan on its pending licensing applications.

Overall, researchers were encouraged that signals from different molecules, approaches, and trials seem to be converging. “There are very similar efficacy findings in clinical measures and even downstream biomarkers,” Swanson said. Budd Haeberlein agreed, saying, “Reproducing effects across different molecules is a strength.” Mintun believes the totality of the data indicate that attacking amyloid does slow progression. “It’s been exciting for the field to see the amyloid cascade hypothesis get more support every year,” he said. Speaking to Alzforum, Randall Bateman, Washington University, St. Louis, said he, too, was struck by the commonalities across the different antibodies. “When you remove the majority of amyloid in mildly symptomatic people, that is when you see movement in other soluble markers, tau PET, and even cognitive/clinical outcomes,” he said. “The effects are in the range of 20 to 30 percent, individual secondary outcomes are weaker, and there is variance within and across studies. But when put together, it is a signal,” Bateman added.

Passing Through. Roche’s “brain shuttle” (orange/yellow) allows gantenerumab (green) to bind transferrin receptor (blue) and hitch a ride into the brain, where it binds Aβ. [Courtesy of Roche.]

Brain Shuttle Sneaks Gantenerumab Past the Blood-Brain Barrier
Initially, gantenerumab was nearly scuttled when low doses failed to budge endpoints in the Phase 3 Scarlet RoAD and Marguerite RoAD trials. Later data showed that fivefold higher doses mopped up plaque (Dec 2017 conference news; Aug 2018 conference news). The drawback to such high doses, besides the cost projections of manufacturing expensive biologics for millions of patients, is more frequent occurrence of amyloid-related imaging abnormalities (ARIA) that reflect swelling or microhemorrhages in the brain.

If antibodies better penetrated the brain parenchyma, they could be given at lower doses. Scientists at Roche and elsewhere have been working on a method to ferry large molecules into the brain. Roche’s approach conjugates a cargo to a Fab antibody fragment that recognizes transferrin receptor. These receptors sit on endothelial cells lining the brain’s blood vessels. They take up transferrin floating by in the blood and pass it through into the brain. By hijacking this system, researchers were able to boost brain uptake of a generic anti-amyloid antibody 50-fold in mice (Jan 2014 news; Jan news 2018).

At AD/PD, Kulic showed data for the hybrid molecule RG6102. It consists of the Fc portion of gantenerumab, i.e., its tail, conjugated to the Fab shuttle (see image above). In mice, a mouse version of RG6102 entered the brain in 12-fold higher quantities than unbound gantenerumab, penetrated brain tissue more evenly, and cleared plaque at lower doses. Immunofluorescence staining showed the mouse RG6102 suffused throughout the whole brain four hours after dosing, as compared to a few scattered dots near blood vessels for the unbound antibody. In non-human primates, RG6102 brain exposure exceeded that of unbound antibody by 6 to 42-fold, depending on the parameter and brain region assessed.

For Phase 1, Roche recruited 36 healthy young men to receive one infusion of RG6102. In this single-ascending-dose study, the first six volunteers received 0.1 mg/kg RG6102 or placebo, in a 4:2 ratio; the second six 0.4 mg/kg. For the higher doses, researchers infused six volunteers with RG6102 and two with placebo, testing 1.2, 3.6, and 7.2 mg/kg in turn. These doses are lower than the 1,020 mg, or around 15 mg/kg, given subcutaneously in the ongoing Phase 3 GRADUATE trials of gantenerumab, but cannot be directly compared because of the different bioavailability of drugs given by these two different routes.

The brain shuttle-gantenerumab construct behaved as expected, with a half-life of three to six days in plasma, and a linear relationship between the concentration in plasma and cerebrospinal fluid. The CSF/plasma ratio was 0.8 percent, indicating eight molecules out of every 1,000 entered the central nervous system. This compares to the 0.1 percent ratio for gantenerumab seen in previous studies. In other words, the brain shuttle amplified CNS exposure eightfold, similar to the effect seen in animals. “This is the first evidence for a brain-shuttling effect to the CNS compartment in people,” Kulic told Alzforum.

The researchers saw no ARIA in these volunteers, but did not expect to, either. In older people with brain amyloid, could higher amounts of gantenerumab in the brain lead to more ARIA? Kulic noted that ARIA is believed to be caused by the interaction of antibodies with vascular amyloid. Because the brain shuttle carries the antibody deeper into tissue and away from blood vessels, it may allow fewer opportunities for this interaction. “The different distribution of Brain Shuttle gantenerumab could potentially result in a different ARIA profile compared to monoclonal antibodies,” Kulic wrote to Alzforum. In addition, because more of the antibody gets into the brain, they may be able to use lower systemic doses to achieve the same effect on plaques.

Another risk is that, because transferrin ferries iron from blood to brain, hijacking the system could interfere with this physiological function. In answer to an audience question, Kulic noted that the volunteers developed no anemia or hematology-related adverse events. The researchers did see transient effects on immature red blood cells, which Kulic said they would monitor closely in later trials. Based on their modeling, they do not expect these effects to cause anemia.

Roche is now recruiting for a multiple-ascending-dose Phase 1b/2a trial of RG6102. They plan to enroll 120 people with prodromal to moderate AD and an amyloid PET scan above 50 centiloids. Participants will receive doses ranging from 0.2 to 3.6 mg/kg, given intravenously every four weeks and compared with placebo. The trial will focus on safety and tolerability, but also examine immunogenicity, pharmacokinetics, and changes in amyloid PET. It is expected to run until 2024.

“This study will inform us as to potential future clinical efficacy trials in AD,” Kulic said. “Our primary goal is that RG6102 will result in superior target engagement, faster Aβ clearance, and improved efficacy.” Roche is also exploring the potential of this technology to deliver other therapeutic cargoes to the brain.

How Fast Does Amyloid Leave? Depends on How Much Is There
Eisai/Biogen’s lecanemab, previously BAN2401, vanquished plaque in an 856-person Phase 2b study (Jul 2018 conference news). Participants who had completed this trial were invited back for an open-label extension after a gap of about two years. When they re-enrolled, Eisai scientists realized that during the gap, brain amyloid had resumed its accumulation in people who had been treated during the original trial, and it did so at the same slow rate seen in the placebo group during the blinded period. This added 0.1 to 0.2 SUVR per year (Dec 2019 conference news).

At AD/PD, Swanson extended this OLE baseline observation with new, one-year data. The OLE enrolled 180 people from 56 sites. All receive the highest tested dose of 10 mg/kg every other week, and are followed with plasma biomarkers and clinical assessments every six months. A subset of 39 people undergo florbetapir amyloid PET at six-month intervals; 10 of them had been on placebo previously, 19 on a 10 mg/kg monthly dose, and 10 on 10 mg/kg biweekly.

In all OLE participants, amyloid measurements nosedived during a year on lecanemab. Curiously, the higher a person’s starting plaque load, the faster it fell. The former placebo group, starting with a 1.36 SUVR at OLE baseline, dropped by 0.31. Those who had been on 10 mg/kg monthly in the original trial started the OLE at 1.19 and dropped by 0.12, while the 10 mg/kg biweekly group started OLE at 1.08 and fell only 0.05.

The upshot was that all three groups ended up between 1.03 to 1.07 SUVR on average. Around 80 percent of the OLE amyloid PET subgroup were amyloid-negative, defined as an SUVR below 1.17, after one year. “Amyloid burden seems to approach a floor,” Swanson summed up. Swanson did not present CSF or cognitive data from the OLE.

On Aducanumab, a Little More Analysis, Not Much Change
Aducanumab stumbled through Phase 3, with a futility analysis crash followed by a U-turn after more data were analyzed (Oct 2019 news; Dec 2019 conference news). Its path through the FDA’s licensing process is no less rocky. After blistering criticism from its advisory committee, the agency, under opposing pressures from various advocacy groups, requested more data from Biogen and delayed making a decision (Nov 2020 news; Feb 2021 news).

At AD/PD, Budd Haeberlein presented a dollop of new data. She discussed a tertiary outcome, the neuropsychiatric inventory NPI-10. It followed the pattern of the other clinical outcomes. In the EMERGE study, billed as positive, decline on the NPI-10 slowed by 87 percent in the high-dose group, significant at p=0.02, while in the low-dose group, it nudged down nonsignificantly by 33 percent. In the ENGAGE study, considered negative, decline on the NPI-10 accelerated a tad in the high-dose group, by 8 percent, while it slowed 83 percent in the low-dose group, significant at p=0.04. This matches the other clinical measures, where the ENGAGE low-dose group seemed to respond better than the high-dose group. Biogen attributes this to a higher percentage of fast progressors in the latter.

The NPI-10 includes a measure of caregiver burden. Budd Haeberlein said caregivers of patients in the EMERGE high-dose group reported 84 percent less burden compared to those looking after patients on placebo, but did not report caregiver burden numbers for the low-dosage group, or ENGAGE.

Alzheimer’s researchers have requested sensitivity analyses for these trials. These examine how changes in statistical methodology or assumptions affect trial outcomes, essentially as a way to determine how robust a trial’s findings are. Budd Haeberlein showed some of that data at AD/PD. She reported that sensitivity analysis found little effect from missing data due to patient withdrawals or the trial’s early termination, with all outcomes in EMERGE still favoring aducanumab. Tests that take into account the “normality” or distribution of the data gave results similar to the primary analysis. Excluding data gathered after ARIA onset made no difference in the outcomes, suggesting unblinding was not a factor, Budd Haeberlein said.

Budd Haeberlein presented a smidgen of new biomarker data. She had previously reported positive results on a medial temporal composite in a tiny tau PET substudy, comprising 12 patients on placebo, 14 on low dose, 11 on high. The tau PET signal rose slightly on placebo, and dropped slightly on the high dose. At AD/PD, she said the temporal and frontal composite measures followed the same pattern, rising on placebo and nudging down on the high dose. EMERGE and ENGAGE participants were pooled.

Budd Haeberlein also showed a new analysis of CSF biomarkers that suggested a correlation between a person’s degree of change from baseline and his or her cumulative dose. This relationship was stronger in EMERGE than in ENGAGE. The EMERGE CSF substudy comprised only 28 people on placebo, 33 on low dose, and 17 on high; the ENGAGE CSF substudy, 15 on placebo, 20 on low dose, and 18 on high.

While the field awaits the FDA’s decision on aducanumab, it seems certain that research on anti-amyloid antibodies will continue, regardless of whether the agency approves aducanumab this June or requires a confirmatory trial.

“This is the beginning, not the end. Twenty to 30 percent slowing is better than zero, but it’s not nearly where we need to go. Patients need much more than that,” Bateman said.—Madolyn Bowman Rogers

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Shuttle Unloads More Gantenerumab Into the Brain

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