08 Nov 2024

Fewer than 1 percent of amyloid-targeted monoclonal antibodies like lecanemab and donanemab reach their targets in the brain. The excess doses required to make up for this problem raise the risk of hazardous brain bleeding, reflected in high rates of amyloid-related imaging abnormalities (ARIA). While the drugs have been approved in the U.S. and some other countries, regulators in Europe have balked, partly due to their risk/benefit ratio. How to improve this? Enter transferrin receptor-based systems that usher antibodies into the brain through its capillaries, where they might avoid the bulk of vascular amyloid thought to provoke ARIA. A handful of these BBB-penetrating candidates are being developed, but so far only one—Roche’s trontinemab—has made its way into clinical trials.

At the Clinical Trial on Alzheimer’s Disease conference, held October 29 to November 1 in Madrid, Roche presented further data from an ongoing dose-finding study, reporting only three mild, asymptomatic ARIA cases so far. At the two highest doses tested, the antibody rapidly vanquished Aβ plaques. The good news was tempered by a death from a cerebral macrohemorrhage after the second dose. MRI scans revealed superficial siderosis and probable cerebral amyloid angiopathy (CAA) at baseline. In response, Roche added these conditions to its exclusion criteria for ongoing and future trials.

Despite this, scientists at CTAD broadly expressed enthusiasm that trontinemab and other TfR-based therapies will pave the way to deliver these antibodies, and other drugs, more safely and efficiently into the brain.

In her keynote speech, Catherine Mummery of University College London called the trontinemab data “fantastically exciting.” She views such strategies as a promising way to make better monoclonal antibodies. “Using active transport mechanisms to get these drugs across the blood-brain barrier will dramatically accelerate the levels of amyloid removal, and equally importantly, really reduce those rates of ARIA,” Mummery said.

Essentially a version of gantenerumab equipped with a so-called Brain Shuttle, trontinemab is an anti-Aβ IgG1 antibody with full effector function and with a TfR-specific Fab fragment attached to one of its Fc domains (image below). In healthy volunteers, the shuttle boosted CNS exposure by eightfold relative to gantenerumab (Mar 2021 conference news).

Tront Transfer. Trontinemab features an anti-Aβ antibody with an anti-TfR “Brain Shuttle” attached (left). Binding to TfR on brain endothelial cells ushers it into the brain via transcytosis (middle). It then engages plaques in the parenchyma, where it exerts full effector function (right). [Courtesy of Luka Kulic, Roche.]

Roche subsequently started dose-finding studies in volunteers with mild cognitive impairment and mild to moderate AD, from which it has been dropping nuggets of data at conferences. Its ongoing Phase 1b/2a study, called Brain Shuttle AD, initially enrolled 60 people split equally among four ascending-dose groups. They received 0.2 mg, 0.6 mg, 1.8 mg, or 3.6 mg trontinemab, or placebo, every four weeks for 28 weeks. At last year’s CTAD, Roche’s Luka Kulic had shown six-month findings from the first three doses and, earlier this year at AD/PD, added preliminary three-month findings from the highest-dose group (Nov 2023 conference news; Mar 2024 conference news). At that time, Kulik said both the 1.8 mg and 3.6 mg doses dramatically reduced amyloid plaques by three months. In the 1.8 mg group, one person developed ARIA-E, another ARIA-H. Among the eight people who had received the 3.6 mg dose for three months, none had yet developed ARIA.

In Madrid, Kulic presented 28-week data from the now-completed part of the trial. He also presented preliminary findings from two additional cohorts, which were added to gather more safety data on the two highest doses. These dose-expansion cohorts will enroll an additional 60 participants each, who will receive either the 1.8 mg or 3.6 mg dose, or placebo, every four weeks for 28 weeks. This second phase is ongoing and, as of the September 2 interim analysis, 60 participants had enrolled in the 1.8 mg group and 40 in the 3.6 mg group. The two groups had received an average of 5.4 and 2.9 doses, respectively.

Kulic first showed safety data from 60 participants who finished Part 1, combined with 100 participants so far enrolled in the ongoing Part 2. For Part 1, Kulic had no new safety issues to report beyond what had been presented at AD/PD, namely that some people reacted to the infusions. This was mitigated in the highest-dose group through pretreatment with anti-inflammatory drugs. Among the 100 participants enrolled in Part 2, Kulic reported two serious adverse events. One was an infusion-related reaction that occurred on a Friday afternoon, prompting clinicians to transfer the participant to a hospital. Kulic said this participant had a fever that quickly subsided.

Alas, the other case proved fatal. Three weeks after receiving her second 1.8 mg dose of trontinemab, a 78-year-old woman developed a right frontal lobar macrohemorrhage. She died two days later. Looking back at her initial screening MRI, the scientists spotted superficial siderosis in her occipital cortex, as well as additional lesions, signifying probable CAA. Amyloid PET scans indicated substantial Aβ accumulation in the same region. She also carried an ApoE2 allele, which is a risk factor for CAA, Kulic said.

The protocol for ongoing and future trontinemab trials has since been amended to exclude people with superficial siderosis. This is in line with published appropriate use recommendations for lecanemab, as well as those for donanemab presented at CTAD (Cummings et al., 2023; see next story).

This death was attributed to trontinemab. The drugs in its class are thought to largely sidestep CAA by crossing the BBB within capillaries, where TfR is most highly expressed, whereas CAA accumulates along larger vessels. So what gives? Brain shuttle developers discussing the findings at CTAD commented that while the lion’s share of trontinemab does cross via capillaries, some still manages to enter the brain via larger vessels, including arterioles and arteries. This could explain how trontinemab may have provoked a hemorrhage in this case, although the mechanism remains poorly understood.

“This shows that even if you deliver the antibody to the whole brain via TfR, you can still have consequences, especially if vascular health is poor,” said Costantino Iadecola of Weill Cornell Medical College in New York. He said that in this case, the superficial siderosis spotted on the screening MRI was likely “the tip of a very big iceberg,” and a slew of other vascular problems likely existed beneath the surface. This is especially likely given that the subsequent macrohemorrhage occurred in a different part of the brain, he said.

Going forward, Iadecola thinks scientists may need to go beyond excluding people with superficial siderosis, which is a potential indicator of severe CAA and other underlying cerebrovascular problems. Screening could include a comprehensive neurovascular assessment that takes into account several MRI measures, such as superficial siderosis, white-matter hyperintensities, microbleeds, and enlarged perivascular spaces. Perhaps an algorithm could incorporate all of these indices to calculate a neurovascular health score, he suggested.

At CTAD, Kulic proceeded by presenting data on other safety-related outcomes. TfR-targeted drugs come with a risk of anemia, due to high expression of TfR by reticulocytes. One way to deal with this this is to soften the antibody’s effector function, as Denali scientists have done with their antibody transport vehicle (ATV). For its part, trontinemab spares reticulocytes by way of steric hindrance, whereby engagement of the TfR-specific Fab temporarily blocks access to the antibody’s effector domain. In Madrid, Kulic reported that 13 percent of participants in Part 1 and 8 percent of participants in Part 2 have developed anemia, which was mild and went away. Roche decided to reduce the number of blood draws in Part 2 and is expecting fewer cases as a result, Kulic said.

What about ARIA? Kulic reported that, as was seen in the trial’s Part 1, few participants in Part 2 developed ARIA-E, despite receiving the two highest doses. So far, two people, both in the 1.8 mg dose group, had ARIA-E in this second, ongoing part of the study. Both cases were mild and asymptomatic, he said.

To Kulic’s mind, these ARIA rates are low given how robustly trontinemab lowers amyloid. At CTAD, he reported amyloid-PET data out to 28 weeks from Part 1 of the study (image below). Participants started with amyloid levels around 120 centiloids. By week 12, those in the 1.8 mg and 3.6 mg groups had lost 62 and 89 CL, respectively, bringing a majority of participants in the 3.6 mg group into the realm of amyloid negativity, below the 24 CL cutoff. By week 28, most participants in both these groups were below the cutoff, having lost an average of 84 and 107 CL, respectively.

Going, Going, Gone. In people on 1.8 mg (dark blue) or 3.6 mg (purple) of trontinemab, plaque load dropped by 12 weeks. By 28 weeks, most participants in both groups had crossed into amyloid negativity. Amyloid-PET scans of one person show removal (right). [Courtesy of Luka Kulic, Roche.]

Finally, Kulic reported preliminary CSF biomarker data from Part 1. At week 25, CSF total tau, p-tau181, and neurogranin had dropped dose-dependently, with concentrations of each falling by around 30 percent in the 3.6 mg dose group. This was not statistically significant owing to the small sample size.

Taking questions after his talk, Kulic said that because the 3.6 mg dose caused no more ARIA, anemia, or other adverse events than 1.8 mg, the study moved on to testing a higher dose. The 3.6 mg dose had not reached a plateau on the dose-response curve for amyloid removal, suggesting room for improvement, he said.

Iadecola agrees that trontinemab’s effect on amyloid-PET and CSF biomarkers looks promising. He cautions the studies were too small to draw conclusions about ARIA rates. One thing is clear: “Trontinemab is not going to be immune from causing ARIA,” he said.

Still, excitement about this data, and optimism about other TfR-based therapies coming down the pike, was palpable at CTAD. Other contenders are moving through preclinical studies, with trials in sight. Denali Therapeutics, based in South San Francisco, recently reported that its ATV delivered anti-Aβ antibodies throughout the parenchyma of 5xFAD mice. It features reduced effector function to protect reticulocytes, which the scientists believe suffices to rally microglia to take down Aβ (Pizzo et al., 2024).

Per-Ola Freskgård of BioArctic thinks compromising the ATV’s effector function might hobble its efficacy against Aβ. His company is developing what they call the BrainTransporter (BT), a construct that retains full effector function. BT includes a single chain variable antibody fragment that binds a novel site in TfR, Freskgård told Alzforum. The binding site is in the protease-like domain of TfR, which is positioned near the cell membrane.

In his talk accepting the CTAD Lifetime Achievement Award in AD Therapeutic Research, BioArctic’s Lars Lannfelt flashed one data slide showing how the BT dramatically improved an anti-Aβ antibody’s passage into an amyloid-ridden, 5xFAD mouse brain, and its engagement with plaques even in deep subcortical regions (image below). Lannfelt referred to the BT and similar TfR-based strategies as “the future” of Aβ immunotherapies.

BioArctic BT. Compared to an unmodified anti-Aβ antibody (green, left), a BT-equipped antibody better penetrated the brain of a mouse model of amyloidosis, where it engaged plaques in the brainstem and thalamus (bottom right). [Courtesy of Lars Lannfelt, BioArctic]

The week after CTAD, Freskgård presented preclinical findings with the BT at the Protein & Antibody Engineering Summit in Barcelona. There, he reported that the BT construct boosted passage across the BBB by 70-fold relative to an unmodified antibody, and did so without harming red blood cells. The BT construct rapidly and broadly penetrated the brain parenchyma, reaching deep subcortical structures, according to BioArctic. In April, the company signed a research evaluation agreement with Eisai to pursue development of “BAN2802,” an undisclosed AD drug equipped with BT technology. Freskgård would not disclose whether lecanemab or a different anti-Aβ antibody is being used in the BT construct.

ALIA-1758 is yet another BBB-crossing, investigational anti-Aβ immunotherapy. Developed by Aliada Therapeutics, it features an antibody trained against pyroglutamate Aβ equipped with an active transport system that was originally developed by Johnson & Johnson. It targets both TfR and CD98—receptors expressed by brain endothelial cells—for passage into the brain. ALIA-1758 is being tested for safety in healthy volunteers (see ClinicalTrials.gov). Abbvie recently shelled out $1.4 billion to acquire Aliada and carry ALIA-1758 into future trials.—Jessica Shugart

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References

Therapeutics Citations

1. Trontinemab
2. ALIA-1758

News Citations

1. Shuttle Unloads More Gantenerumab Into the Brain 25 Mar 2021
2. Unlocking Blood-Brain Barrier Boosts Immunotherapy Efficacy, Lowers ARIA 11 Nov 2023
3. Fast Plaque Clearance with Little ARIA? So Teases Trontinemab at AD/PD 2024 15 Mar 2024
4. Donanemab: Small Tweak in Titration, Big Gain in Safety? 8 Nov 2024

Paper Citations

1. Cummings J, Apostolova L, Rabinovici GD, Atri A, Aisen P, Greenberg S, Hendrix S, Selkoe D, Weiner M, Petersen RC, Salloway S. Lecanemab: Appropriate Use Recommendations. J Prev Alzheimers Dis. 2023;10(3):362-377. PubMed.
2. Pizzo ME, Plowey ED, Khoury N, Kwan W, Abettan J, DeVos SL, Discenza CB, Earr T, Joy D, Lye-Barthel M, Roche E, Chan D, Dugas JC, Gadkar K, Meisner R, Sebalusky J, SilvaAmaral AC, Becerra I, Chau R, Chow J, Clemens AJ, Dennis MS, Duque J, Fusaro L, Getz JA, Kariolis MS, Kim DJ, Leung AW, Nguyen HN, Thomsen ER, Sanchez PE, Shan L, Silverman AP, Solanoy H, Tong R, Calvert ME, Watts RJ, Thorne RG, Weinreb PH, Walsh DM, Lewcock JW, Bussiere T, Zuchero YJ. Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution. 2024 Jul 26 10.1101/2024.07.26.604664 (version 1) bioRxiv.

External Citations

1. ClinicalTrials.gov

Further Reading

No Available Further Reading