trontinemab (RG6102) / Roche, Royalty - LARVOL DELTA

Roche presents new insights in Alzheimer’s disease research across its diagnostics and pharmaceutical portfolios at AAIC (Roche Press Release) - P1b/2a | N=285 | Brainshuttle AD (NCT04639050) | Sponsor: Hoffmann-La Roche | "New data on the latest results for trontinemab from the completed dose-expansion part of the 1.8 mg/kg and 3.6 mg/kg cohorts from the ongoing Phase Ib/IIa Brainshuttle AD study continued to show rapid and robust reduction of amyloid plaques in the brain as measured by amyloid positron emission tomography (PET). In the 3.6 mg/kg cohort, trontinemab reduced amyloid levels below the 24 centiloid positivity threshold in 91% of participants (n=49/54) after 28 weeks of treatment; 72% (n=39/54) achieved deep clearance below 11 centiloids....Trontinemab continues to show a favourable safety and tolerability profile. Amyloid-related imaging abnormalities-edema/effusion (ARIA-E) continued to be observed in <5% of participants (blinded data; N=4/149 across 1.8 and 3.6mg/kg dose cohorts)."

P1/2 data • Alzheimer's Disease

Design of the Phase III TRONTIER 1 and 2 studies of trontinemab in early symptomatic Alzheimer’s disease featured, with initiation planned in 2025 (Roche Press Release) - "In a 90-minute Featured Research session, designs were shared for the Phase III studies, TRONTIER 1 and 2, which will initiate later this year, investigating the efficacy and safety of investigational trontinemab in people with early Alzheimer’s disease. The primary endpoint will measure the change in cognition and function based on the Clinical Dementia Rating – Sum of Boxes scale after 18 months of treatment. Secondary endpoints will include assessments of cognition, function, behavioural symptoms, and quality of life. A pre-screening study, TRAVELLER, based on a brief clinical assessment and a plasma biomarker, which will be identified using the Elecsys pTau217 test, has also been initiated, to enable broader community outreach and extend access to these trials to more diverse populations representative of Alzheimer’s disease."

Clinical protocol • Alzheimer's Disease • CNS Disorders

Translational minimal physiologically based pharmacokinetic model for transferrin receptor-mediated brain delivery of antibodies. (PubMed, MAbs) - "Clinical validation using human PK data from plasma and CSF for the monovalent anti-TfR bsAb trontinemab demonstrated good predictive performance without major model recalibration. The availability of the TfR mPBPK model is envisaged to provide better understanding of the relationship between TfR binding affinity, dose, and brain exposure, which would lead to more robust selection of lead candidates and efficacious dosing regimens."

Journal • PK/PD data

IXICO assists FDA clearance of new Alzheimer’s blood-based diagnostic (Vox) - "Today, the company announced that its 'gold standard' analysis of PET scans had helped one of its clients, Fujirebio, obtain FDA approval for its breakthrough new blood test for AD - thus further extending IXICO 's neuroimaging biomarker capabilities beyond clinical trials to the analysis and validation of diagnostic biomarkers...later this year, two potentially blockbuster new Alzheimer's treatments are hopefully moving into Phase 3 clinical trials - namely Bristol Myers Squibb’s Cobenfy and Roche’s trontinemab. Here, advanced digital imaging is also the quickest, cheapest, safest and most effective way to understand, monitor and treat brain disorders, alongside playing a vital role in obtaining FDA approval and conducting post-marketing surveillance."

Diagnostic • FDA approval • New P3 trial • Alzheimer's Disease

BP42155: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=285 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2027 ➔ Mar 2028 | Trial primary completion date: Dec 2027 ➔ Mar 2028

Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • APOE

BRAIN SHUTTLES TO NOVEL RECEPTORS TO OVERCOME LIABILITIES OF FIRST -GENERATION SHUTTLED ANTI-AMYLOID THERAPEUTICS (ADPD 2025) - "For example, Roche's trontinemab uses a shuttle to Transferrin Receptor ( TfR) to enhance PK and plaque clearance while reducing ARIA of the anti -amyloid beta (anti -Aβ) antibody gantenerumab. Our work demonstrates that liabilities of TfR shuttles can be improved by engaging novel targets on the BBB and further advances a potential shuttle for clinical development that could improve upon the profile of existing TfR -Abeta mAbs such a s trontinemab."

Hematological Disorders • TFRC

Genentech and Roche Present Novel Therapeutic and Diagnostic Advancements in Alzheimer’s at AD/PD 2025 (Businesswire) - P1b/2a | N=285 | Brainshuttle AD (NCT04639050) | Sponsor: Hoffmann-La Roche | "Highlights included presentations from the ongoing trontinemab Phase Ib/IIa Brainshuttle AD study demonstrating dose-dependent rapid amyloid depletion from the brain and the potential of the Elecsys pTau181 plasma test to rule out amyloid pathology. A Phase III program for trontinemab will be initiated later this year....Preliminary results for trontinemab from 114 participants in the 1.8 or 3.6 mg/kg double-blind period suggest rapid and deep, dose-dependent reduction of amyloid plaques in the brain as measured by amyloid positron emission tomography (PET). Trontinemab reduced amyloid levels below the 24 centiloid threshold in 81% of participants (n=21/26) in the 3.6 mg/kg dose group after 28 weeks."

P1/2 data • Alzheimer's Disease

INTERIM BIOMARKER RESULTS OF TRONTINEMAB, A NOVEL BRAINSHUTTLETM ANTIBODY IN DEVELOPMENT FOR THE TREATMENT OF ALZHEIMER'S DISEASE (ADPD 2025) - P1/2 | "Conclusions Preliminary Results from the ongoing BrainshuttleTM AD study suggest that amyloid negativity can be achieved in most participants at higher doses within 28 weeks or less. New biomarker data will be presented to further support trontinemab as a potential AD treatment."

Biomarker • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • GFAP

TRONTINEMAB - FROM EARLY PRECLINICAL GROUNDWORK TO THE CLINICAL VALIDATION OF THE BRAINSHUTTLETM PLATFORM (ADPD 2025) - P1/2 | "It is hypothesized that the ability to use low doses and to deliver the therapy more directly into the brain parenchyma may result in additional safety benefits like a reduced ARIA risk. Due to these unique properties, trontinemab holds the promise to unlock the full potential of disease modifying Aβ-targeting antibody treatments in AD, leading to rapid plaque removal and further slowing of disease progression with low ARIA incidences."

Preclinical • Alzheimer's Disease • CNS Disorders

BP42155: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=285 | Active, not recruiting | Sponsor: Hoffmann-La Roche | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders • APOE

BP42155: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Dec 2028 ➔ Dec 2027 | Trial primary completion date: Dec 2028 ➔ Dec 2027

Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • APOE

Roche sees rapid amyloid clearing in Alzheimer's study, adjusts protocol after patient death (FierceBiotech) - P1/2 | N=285 | Brainshuttle AD (NCT04639050) | Sponsor: Hoffmann-La Roche | "The patient death occurred in a dose expansion part of the study, the second of three segments. The 78-year-old woman experienced a brain bleed in her right front lobe, dying on day 44 of the study...The assessment triggered a protocol change so participants with superficial siderosis—chronic bleeding that can be caused by CAA and impacts the brain or spinal cord—are excluded from the trial...Results from the completed first part of the trial demonstrate 'rapid and robust amyloid plaque depletion' in the two higher dose groups—1.8 mg/kg and 3.6 mg/kg—after 12 to 28 weeks of treatment, according to Roche. For the 3.6 mg/kg arm, amyloid plaque depleted by 91 centiloid units (CL) after 12 weeks and dropped 107 CL after 28 weeks."

P1/2 data • Alzheimer's Disease • CNS Disorders

Latest Interim Results from the BrainshuttleTM AD Study, a Phase Ib/IIa Study of Trontinemab in People with Alzheimer's Disease (CTAD 2024) - No abstract available

Late-breaking abstract • P1/2 data • Alzheimer's Disease • CNS Disorders

Anti-amyloid Antibody Drugs as Disease-Modifying Therapies for Alzheimer's Disease (PubMed, Brain Nerve) - "Notable drugs such as aducanumab, lecanemab, and donanemab have shown potential in clinical trials, leading to the approval of aducanumab and lecanemab, and approval is also expected for donanemab. Other anti-amyloid drugs such as remternetug and trontinemab are also under development...This paper outlines the current status of DMT for AD, including the clinical trial results and current applications of these drugs. It also discusses the existing challenges to improve the safety and accessibility of DMTs."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

BP42155: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Sep 2027 ➔ Dec 2028 | Trial primary completion date: Sep 2027 ➔ Dec 2028

Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • APOE

Brainshuttle technology: Focus on trontinemab and newly emerging therapies (AAIC 2024) - No abstract available

BP42155: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=285 | Recruiting | Sponsor: Hoffmann-La Roche | N=210 ➔ 285

Enrollment change • Alzheimer's Disease • CNS Disorders • APOE

RAPID DOSE-DEPENDENT AMYLOID PLAQUE DEPLETION WITH TRONTINEMAB, A NOVEL BRAINSHUTTLETM ANTIBODY IN DEVELOPMENT FOR THE TREATMENT OF ALZHEIMER'S DISEASE (ADPD 2024) - P1/2 | "Trontinemab showed rapid dose-dependent amyloid plaque depletion at dose levels, at which standard anti-amyloid beta antibodies have little effect on amyloid plaque pathology. Preliminary results from the ongoing BrainshuttleTM AD study suggest that amyloid negativity can be achieved in most participants within 28 weeks or less."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans. (PubMed, MAbs) - "This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aβ) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial."

Journal • Alzheimer's Disease • CNS Disorders

The anti-amyloid beta "brain shuttle" antibody trontinemab rapidly reduces amyloid plaques in people with Alzheimer's disease (CTAD 2023) - P1, P1/2 | "In preclinical studies in nonhuman primates, trontinemab showed substantially improved exposure in the brain parenchyma compared with gantenerumab. Preliminary results from the ongoing Ph Ib/ IIa Brainshuttle AD study of trontinemab suggest that rapid amyloid plaque clearance may be achieved at significantly lower dose levels than with typical anti-amyloid mAbs, in line with the TfR1-based brain shuttle platform approach. The preliminary safety, tolerability and pharmacodynamic data support further investigation of trontinemab as a potential nextgeneration amyloid targeting therapy for AD."

Alzheimer's Disease • CNS Disorders • TFRC

BP42155: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=210 | Recruiting | Sponsor: Hoffmann-La Roche | N=120 ➔ 210 | Trial completion date: Jan 2025 ➔ Sep 2027 | Trial primary completion date: Jan 2025 ➔ Sep 2027

Enrollment change • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • APOE

IMPACT OF CONTINUOUS SITE ENGAGEMENT ON STUDY CONDUCT: INSIGHTS FROM THE "BRAIN SHUTTLE AD" STUDY AND THE CONTINUOUS SCREENING MODEL (ADPD 2023) - P1/2 | "Aims: During regular site engagement meetings with investigators of the Brain Shuttle gantenerumab Phase Ib/IIa study (NCT04639050), the fixed screening window was identified as a hurdle for both sites and participants... Ongo ing site -partnering activities, led to an early change in trial design, which ensured that feedback from both the sites and participants were successfully addressed, while safety and data integrity were maintained. Continual site partnership yields mutual benefit to all parties, as demonstrated in this study. Results of a planned survey that aims to validate the impact of this approach will be presented."

Roche’s ’high risk’ failure has industry circling the wagons on future of Alzheimer’s research (FierceBiotech) - "...Maria Carrillo, Ph.D., also flagged an updated version of gantenerumab that Roche is developing that uses 'brain shuttle technology' to move the drug across the blood-brain barrier and boost concentrations of the active ingredient in the brain....Carrillo is particularly interested in the secondary endpoints that include additional cognitive and functional assessments, which did not read out Monday."

Media quote

BP42155: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=120 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Oct 2024 ➔ Jan 2025 | Trial primary completion date: Oct 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • APOE

Brain Uptake of Brain Shuttle Gantenerumab (RG6102) (PEGS 2022) - "Brain uptake of therapeutic antibodies has been reported using different experimental systems and diverse methodologies, but the precise measurement of drug levels in all relevant brain compartments is often hampered by technical difficulties. We present the comprehensive characterization of a Brain Shuttle anti-amyloid antibody in Cynomolgus monkeys, including modeling-supported plasma and brain pharmacokinetics, and provide first evidence for brain uptake in humans."