Therapeutics

RO7126209

Overview

Name: RO7126209
Synonyms: 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)
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 news).

In March 2021, a Phase 1 trial 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. The trial will run until October 2024.

For details on RO7126209 trials, see clinicaltrials.gov.

Last Updated: 22 Apr 2021

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References

News Citations

  1. Shuttle Unloads More Gantenerumab Into the Brain
  2. Brain Shuttle Ferries Antibodies Across the Blood-Brain Barrier
  3. Antibody Shuttle Rouses Anti-Aβ Response in Brain without Waking the Periphery
  4. Molecular Transport Vehicle Shuttles Therapies into Brain

Therapeutics Citations

  1. Gantenerumab

Paper Citations

  1. . Brain Shuttle Neprilysin reduces central Amyloid-β levels. PLoS One. 2020;15(3):e0229850. Epub 2020 Mar 10 PubMed.
  2. . 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. . 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.