Therapeutics

Trontinemab

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Overview

Name: Trontinemab
Synonyms: RO7126209, RG6102 , Brain shuttle gantenerumab
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1/2)
Company: Hoffmann-La Roche

Background

RO7126209 is a new version of the anti-amyloid monoclonal antibody gantenerumab, engineered to more easily cross the blood-brain barrier using Roche’s “brain shuttle” technology. A Fab fragment that binds the human transferrin receptor is attached to the effector (Fc) domain of the gantenerumab monoclonal antibody. RO7126209 circulating in the bloodstream binds the transferrin receptor on the endothelial cells that make up the blood-brain barrier. This leads to its endocytosis and release into the brain parenchyma.

Preclinical work has been published using the mouse version of gantenerumab fused to a single mouse transferrin receptor-binding Fab fragment. In AD mouse models, 50 times more antibody entered the brain and bound to amyloid plaques, compared with unmodified gantenerumab. RO7126209 stimulated plaque clearance by immune cells at doses far lower than did the parent antibody, without initiating immune responses to endothelial cells or other transferrin receptor-bearing bystander cells (Jan 2014 news; Jan 2018 news).

In other preclinical studies, brain shuttle delivery of either BACE1 peptide inhibitors or the protease neprilysin were able to reduce brain amyloid in AD mice (Campos et al., 2020; Ruderisch et al., 2017).

Denali Therapeutics is working on a similar transferrin receptor-mediated brain delivery system (May 2020 news). Roche’s is the first to enter Phase 1 testing in humans.

Findings

In August 2019, Roche began a Phase 1 study of the safety, tolerability, immunogenicity, and pharmacokinetics of RO7126209 in up to 64 healthy men in North Carolina. Volunteers in five sequential cohorts received a single dose of antibody or placebo by intravenous infusion. An adaptive design escalated doses based on results of prior cohorts. Primary outcomes are adverse events, laboratory findings, and vital signs up to two months after dosing. Investigators are also measuring CSF antibody concentrations three or five days after dosing, and anti-RO7126209 antibodies up to two months after. The study was completed in July 2020 with an actual enrollment of 34. Results were presented in March 2021 at AD/PD. Doses of 0.1, 0.4, 1.2, 3.6, and 7.2 mg/kg showed a linear relationship between plasma and CSF concentrations, with a plasma half-life of three to six days. RO7126209's CSF/plasma ratio was 0.8 percent, eightfold higher than gantenerumab's. No anemia or hematology-related safety events were observed, with the exception of a transient effect on immature red blood cells (Mar 2021 conference news, see also Dec 2021 conference news; Grimm et al., 2023).

In March 2021, a Phase 1 trial called Brainshuttle AD began evaluating multiple doses in 120 people who have prodromal or mild to moderate Alzheimer’s disease and a positive amyloid PET scan. Participants are to receive one of four doses from 0.2 to 3.6 mg/kg of RO712620 or placebo, given by infusion once every four weeks for 28 weeks, with 28 weeks of follow-up. The primary outcome is safety; secondary outcomes are change in brain amyloid, drug concentrations in plasma and CSF, and number of people with anti-drug antibodies. In mid-2023 the trial was expanded to 210 participants, boosting the number of patients in the lowest-dose cohorts, and adding two new cohorts comparing dose frequency of four or 12 weeks. Change from baseline in brain amyloid was added to the primary outcomes. A two-year open-label trial was also added, in which amyloid-negative people received antibody every 12 weeks, and amyloid-positive every four weeks, until they attain amyloid negativity, i.e., 24 centiloids or less. In April 2024, the trial was expanded again, to 285 participants, adding a fifth, higher dose and extending the follow-up period for previous dosing groups. The trial runs at nearly 50 sites in North and South America, Asia, Australia, and Europe, until January 2027.

Initial data from the multiple dosing were presented at the 2023 CTAD conference (Nov 2023 conference news). Forty-four participants with between 90 and 100 centiloids of plaque at baseline received infusions of 0.2, 0.6, and 1.8 mg/kg, or placebo every four weeks. The company reported a dose-dependent lowering of amyloid. The highest dose completely cleared plaque in three of four participants after six months, an effect estimated to be 40 or 50 times more potent than gantenerumab. Side effects were mainly mild infusion reactions, and anemia. Antidrug antibodies developed in one-quarter of people on the highest dose, and were more frequent at lower doses. There was no ARIA at lower doses, and two cases in the 1.8 mg/kg group were asymptomatic or mild. At the March 2024 AD/PD conference, the company presented interim data on the highest planned dose of 3.6 mg/kg (Mar 2024 conference news). Of eight participants who began with an average of 119 centiloids of plaque, five dropped below the positivity threshold at three months. The group had an average reduction of 91 centiloids, with no ARIA or serious adverse events, or study withdrawals due to adverse events. One person developed anemia, and one developed antidrug antibodies that did not affect drug pharmacokinetics.

For details on RO7126209 trials, see clinicaltrials.gov.

Last Updated: 09 May 2024

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References

News Citations

  1. Shuttle Unloads More Gantenerumab Into the Brain
  2. Brain Shuttle Could Halve Amount of Gantenerumab Needed
  3. Unlocking Blood-Brain Barrier Boosts Immunotherapy Efficacy, Lowers ARIA
  4. Fast Plaque Clearance with Little ARIA? So Teases Trontinemab at AD/PD 2024
  5. Brain Shuttle Ferries Antibodies Across the Blood-Brain Barrier
  6. Antibody Shuttle Rouses Anti-Aβ Response in Brain without Waking the Periphery
  7. Molecular Transport Vehicle Shuttles Therapies into Brain

Therapeutics Citations

  1. Gantenerumab

Paper Citations

  1. Grimm HP, Schumacher V, Schäfer M, Imhof-Jung S, Freskgård PO, Brady K, Hofmann C, Rüger P, Schlothauer T, Göpfert U, Hartl M, Rottach S, Zwick A, Seger S, Neff R, Niewoehner J, Janssen N. Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans. MAbs. 2023;15(1):2261509. Epub 2023 Oct 12 PubMed.
  2. Campos CR, Kemble AM, Niewoehner J, Freskgård PO, Urich E. Brain Shuttle Neprilysin reduces central Amyloid-β levels. PLoS One. 2020;15(3):e0229850. Epub 2020 Mar 10 PubMed.
  3. Ruderisch N, Schlatter D, Kuglstatter A, Guba W, Huber S, Cusulin C, Benz J, Rufer AC, Hoernschemeyer J, Schweitzer C, Bülau T, Gärtner A, Hoffmann E, Niewoehner J, Patsch C, Baumann K, Loetscher H, Kitas E, Freskgård PO. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport. EBioMedicine. 2017 Oct;24:76-92. Epub 2017 Sep 7 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Sade H, Baumgartner C, Hugenmatter A, Moessner E, Freskgård PO, Niewoehner J. A human blood-brain barrier transcytosis assay reveals antibody transcytosis influenced by pH-dependent receptor binding. PLoS One. 2014;9(4):e96340. Epub 2014 Apr 30 PubMed.