Fast Plaque Clearance with Little ARIA? So Teases Trontinemab at AD/PD 2024
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A record 4,700 people from 70 countries attended the 18th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 5 to 9 in Lisbon, Portugal. Those who attended this hybrid meeting in person sometimes packed rooms to capacity to hear 692 onsite talks or forums—another record. Scientists expressed a new sense of confidence that Alzheimer’s disease can be slowed or halted. With amyloid immunotherapies in hand, much of the discussion centered around how they can be improved and where the field goes next.
- Ferried by brain shuttle, trontinemab clears plaque in three months.
- The amyloid immunotherapy produced almost no ARIA.
- The data are from a small cohort; in part 2 of the trial, numbers will increase.
- On donanemab and lecanemab, benefits are greater at low tau loads.
A consensus emerged that researchers need to target additional disease mechanisms and work toward combination therapies. Multiple sessions discussed the latest in tau biology, inflammation, and vascular research. Symposia focused on resilience mechanisms, prevention such as lifestyle changes, and advances in biomarkers. For Parkinson’s and other neurodegenerative proteinopathies, speakers showcased promising preclinical and biomarker data.
“Optimism is taking over. We have momentum,” Philip Scheltens of EQT Life Sciences Dementia Fund said in a forum sponsored by the Alzheimer’s Drug Discovery Foundation. Many noted that the recent successes have inspired biotech to make new investments in the field. “More deals are happening,” said Laurence Barker of the Dementia Discovery Fund. Susan Kohlhaas of Alzheimer’s Research U.K. has seen a change in patient attitudes as well, with people more likely to seek treatment for AD.
While the range of therapeutic approaches is broad, several sessions kept a spotlight on amyloid immunotherapy. Here, the buzziest data came from Roche, which reported that at the highest dose yet tested, its new antibody trontinemab virtually abolished plaque in three months in a small dose-finding study, while causing no ARIA in the eight participants who had reached this timepoint. Trontinemab combines the Fab fragment from gantenerumab with a transferrin-based “brain shuttle,” allowing the molecule to slip past the blood-brain barrier and perhaps avoid the bulk of the vascular amyloid that triggers ARIA. The data raised hopes that scientists can skirt this most troubling side effect. Meanwhile, Lilly and Eisai researchers shared new analyses from their immunotherapy programs that elucidated links between amyloid removal, tangle accumulation, and cognition.
During the conference, the U.S. Food and Drug Administration announced it would convene an advisory committee to consider Lilly’s application for traditional approval for its plaque-targeting antibody donanemab. Many had expected the antibody to be approved without this step, but Howard Fillit of the ADDF noted that this is the same procedure that was followed for Aduhelm and Leqembi. “[The] FDA decision is not a setback, but another step forward in the drug approval process, with the regulatory agency doing its due diligence before the distribution of the drug to patients,” Fillit said in a statement. Lawrence Honig of Columbia University, New York, told Alzforum he was not surprised by the decision.
Vanishing Plaque. Trontinemab clears plaque at lower doses than did previous antibodies. Participants taking 3.6 mg/kg (purple) fell below the positivity threshold (dotted line) by three months. [Courtesy of Roche.]
Better Efficacy, and Safety?
Trontinemab is the first anti-amyloid antibody in trials to use brain-shuttle technology, which Roche and other companies have been developing for years. In Phase 1, the shuttle approach delivered eight times more antibody into the brains of healthy volunteers than did conventional delivery (Mar 2021 conference news). At last fall’s Clinical Trials on Alzheimer’s Disease conference in Boston, Roche’s Luka Kulic reported six-month data from three dose cohorts in an AD Phase 1b/2a dose-finding study. The highest dose, 1.8 mg/kg, dropped plaque load by 62 centiloids at three months and by 84 centiloids at six. One person developed ARIA-E and one ARIA-H, for a 7 percent incidence of each (Nov 2023 conference news).
In Lisbon, Kulic added preliminary data from the highest planned dose, 3.6 mg/kg. As with the previous dose cohorts, the group comprised 15 people, of whom three received placebo. They averaged 72 years old and had either mild cognitive impairment or mild dementia due to AD, with an MMSE of 21. Kulic showed data from the eight participants on trontinemab who had reached the three-month timepoint as of last October, when the data were analyzed. Combined, the study enrolled a total of 59 people treated with four different doses.
People in the high-dose cohort started with an average amyloid PET score of 119 centiloids, a higher plaque load than in most immunotherapy trials. For comparison, participants in the negative Phase 3 gantenerumab studies started with 95. In three months, trontinemab mopped up 91 centiloids, plunging plaques below the amyloid positivity threshold of 24.1 centiloids in five participants, and below 11 centiloids in four of those (see image above). In other words, five of eight participants on trontinemab became amyloid-negative, with an average load of 21 centiloids at three months.
Preliminary safety findings looked good, with fewer concerns than at lower doses. There were no deaths, serious adverse events, or study withdrawals due to adverse events. In previous trontinemab cohorts, participants frequently developed infusion-related reactions, such as flushing and chills, after their first intravenous dose. These reactions were more frequent at higher doses, with three-fourths of people in the 1.8 mg/kg group experiencing them. However, in the fourth, 3.6 mg/kg dose cohort, clinicians pretreated participants with anti-inflammatories, such as acetaminophen, to head this off. As a result, less than half had this reaction. Kulic believes this side effect could be lowered further, or nearly eliminated, by pretreating with corticosteroids before the first dose.
Another issue in earlier cohorts was anemia, cropping up in a third of people in the 1.8 mg/kg cohort, for example, but also in people on lower doses and on placebo. Kulic believes frequent blood draws in the study may be partly to blame. The protocol was changed to stipulate iron supplements for participants who have low blood iron at baseline. So far, in the fourth cohort, one person developed anemia.
Likewise, anti-drug antibodies (ADAs), which lowered drug exposure by 70 percent in the lowest dose cohort but were less troublesome at higher doses, were more muted yet at 3.6 mg/kg. Only one person at this dosage developed ADAs, and this did not affect drug pharmacokinetics, Kulic reported.
Finally, the big question—what about ARIA? Despite the speed of amyloid removal, ARIA remained low at the 3.6 mg/kg dose, with no cases in the first eight people to reach three months of treatment. Though the numbers are small, Kulic called the data encouraging. Other work has linked ARIA to antibody interactions with vascular amyloid, which trontinemab’s delivery route may largely bypass (Aug 2023 conference news).
Kulic said Roche will select the most promising dose to take into part two of the study. That extension will expand the number of participants to 210 in order to gather more safety data before moving to Phase 3. The decision on which dose to take forward has not yet been made, Kulic said.
“These early results with trontinemab are exciting, and suggest that a brain-shuttle delivery has the potential to clear fibrillar amyloid rapidly and extensively without increasing circulating antibody levels,” Christopher van Dyck of Yale School of Medicine in New Haven, Connecticut, who co-chaired the session, told Alzforum. He noted that circulating antibody levels have been linked to the risk of ARIA. However, he cautioned that more data will be needed to understand the potential risks of the brain shuttle mechanism.
Dueling Antibodies. In a head-to-head study, donanemab (green) cleared plaque faster than aducanumab (gray). [Courtesy of Eli Lilly.]
Donanemab Data Highlight Benefits of Starting Early
Data from donanemab, too, suggest that fast plaque clearance does not hike the risk of ARIA. Lilly had previously reported 12-month data from its Trailblazer-Alz4 trial. This pitted donanemab head-to-head against aducanumab, with no placebo arm. In the first year, donanemab banished 80 centiloids, compared with aducanumab’s 56 (Jul 2023 conference news).
In Lisbon, Stephen Salloway of Butler Hospital in Providence, Rhode Island, reported on the final timepoint of 18 months. Aducanumab had almost caught up, removing an average of 72 centiloids to donanemab’s 84 (see image above). Partly, this was because plaque levels in the donanemab group had nearly bottomed out at the one-year timepoint, with 71 percent of people already amyloid-negative, compared with 22 percent of those on aducanumab. At the final timepoint of 18 months, 78 percent of those on donanemab were amyloid-negative, versus 43 percent of those on aducanumab. To put it another way, it took a person on donanemab an average of 359 days, or about a year, to completely clear amyloid. On aducanumab, this took 568 days, or seven months longer. Donanemab has not yet been tested head-to-head against lecanemab.
Despite the faster plaque removal, ARIA-E remained lower on donanemab, at 24 percent versus aducanumab’s 35. “We can lower plaque quickly without [worsening] safety issues,” Salloway concluded, noting that ARIA incidence does not directly relate to the speed or amount of plaque clearance.
Early Start Crucial. A model based on Phase 3 donanemab data predicts that treatment effects will be greater in people who start at an earlier disease stage, with trajectories (green) suggesting delayed progression to loss of independence, i.e., CDR-sb score of 11 (dotted line), compared with untreated AD (gray). [Courtesy of Eli Lilly.]
Other analyses in Lisbon focused on the antibody’s cognitive effects. Lilly’s Mark Mintun had previously modeled how donanemab changed the trajectory of cognitive decline, using data from the Phase 3 Trailblazer-Alz2 trial. He found the drug’s benefits were dramatically better for those at an earlier stage of disease, slowing decline by 88 percent, compared with 6 percent for those later in disease (Nov 2023 conference news).
In Lisbon, Mintun used the model to predict how much this slowing might delay progression to advanced disease stages. A person’s baseline tangle load determined where that person started in the disease trajectory. People with a baseline tau PET below 1.10 SUVR were defined as “low tau,” those between 1.10 and 1.46 as intermediate, and those above 1.46 as high. Because AD patients value keeping their independence, naming this as one of the most meaningful treatment outcomes, Mintun calculated the time to probable loss of independence, using a CDR-SB of 11 as a proxy.
In his model, a high-tau participant taking donanemab would stay independent about five months longer than if he or she were on placebo. At an intermediate to low tangle load, the person would keep their independence for an extra 11 months. For those in the intermediate-to-low tau group who were less cognitively impaired, at the MCI stage, this delay jumped to 37 months, or more than three years (see image above). Mintun cautioned that this is simply a model, and its assumptions need to be validated with additional data. However, he believes the findings emphasize the importance of starting plaque clearance early, before tangles have spread.
John Morris of Washington University, St. Louis, came to a similar conclusion using different methodology. To derive average rates of cognitive decline for people at different disease stages, Morris analyzed data from AD patients being seen at the Knight Alzheimer’s Disease Research Center in St. Louis. He determined disease stage by CDR-SB score, rather than by pathology, but, like Mintun, used a CDR-SB of 11 as the threshold for loss of independence. Then he calculated how much independent time a person would gain from a hypothetical therapy that slowed decline by 30 percent, which is about the same efficacy as lecanemab and donanemab. For someone who started at a CDR-SB of 1, the least impairment, it would take an additional 2.2 years to lose their independence. Someone who started at a CDR-SB of 4.5, or mild dementia, would gain only 0.9 years of independent life, Morris said.
Tangles, Interrupted. On placebo (blue, left), tangle load in the medial temporal lobe (x axis) determines how fast tangles spread in the parietal lobe (y axis); on lecanemab (pink), this relationship disappears. For cognition (right), lecanemab does not change the effect of MTL tangle load on the rate of decline, but it slightly reduces the amount. (CFB=change from baseline.) [Courtesy of Eisai.]
Lecanemab Disrupts Tangle Growth
Data from the lecanemab program reinforces this. Previous analyses had divided the Phase 3 Clarity population into a low-tau group, with baseline SUVRs below 1.06, and an intermediate-to-high tau group above that threshold. The low tau group had the greatest cognitive benefit, with 60 percent of them actually improving on their baseline CDR-SB scores over 18 months (Nov 2023 conference news).
In Lisbon, Eisai’s Arnaud Charil tied baseline amyloid and baseline tangle load to tangle growth. He divided the brain into seven composite regions, and noted that within each, the amyloid PET signal at baseline was associated with the baseline tau PET signal. If the amyloid PET signal was less than 1.2 SUVR, the tau PET signal in that region was typically negative. Above that threshold, baseline tau PET was positive. However, future tangle accumulation depended on baseline tau PET, rather than baseline amyloid. Charil showed that the higher the baseline tau signal, the more tangles accumulated over the next 18 months on placebo. On lecanemab, however, this relationship was broken. Tangle accumulation became negligible, and was unrelated to the baseline tangle load (see image above left). “Treatment with lecanemab disrupts tau accumulation,” he said.
How does this affect cognition? Here, lecanemab did not break the relationship between tangles and cognitive decline, but it did lessen the effect. For the placebo group, higher baseline tangles in any brain region correlated with steeper decline on the CDR-SB. On lecanemab, higher tangles still correlated with steeper decline, but this decline was slightly less pronounced than on placebo. Graphically, the slope was the same on lecanemab or placebo, but the line was shifted downward (see image above right). As with donanemab, benefits were higher in people who started with lower tangle loads. Because this analysis compares baseline tangle load in each brain region to the rate of cognitive decline, it is not equivalent to the common analyses that track the rate of decline over time and show an altered slope on lecanemab. This analysis indicates that even on drug, people who start with more tangles will have faster decline than those with fewer tangles. This again stresses the importance of early treatment.
Data from these programs have convinced many researchers that anti-amyloid antibodies will hold a key role in treating AD. “Immunotherapies will be widely used,” Barker of the DDF predicted, adding, “We’re already thinking about how to position new drugs in combination with them.” At the same time, some people will not be able to take these drugs, due to having high vascular amyloid or other contraindications. “Amyloid immunotherapy is not for every patient,” Scheltens cautioned.—Madolyn Bowman Rogers
References
Therapeutics Citations
News Citations
- Unlocking Blood-Brain Barrier Boosts Immunotherapy Efficacy, Lowers ARIA
- Is ARIA an Inflammatory Reaction to Vascular Amyloid?
- Donanemab Data Anchors Upbeat AAIC
- Treat Before ‘Aβ Bothers Tau,’ Scientists Say at CTAD
Other Citations
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Comments
University of Sydney
Firstly, I think these results are fantastic and show the possibilities of BBB-crossing immunotherapy.
The big question I would have thought is, have the patients been cured? Moreover, or alternatively, if the patients had been treated in their 20s, 30s, or 40s perhaps, would they have been pre-emptively cured or is tau still the main problem? Or are either plaques, tangles, or both a possible symptom of other causative factors at play? If both tau reduction and the above results were achieved, what would be the outcome?
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