trontinemab (RG6102) / Roche, Royalty - LARVOL DELTA

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."

Early engagement with the wider patient community in early-phase clinical trial design: Insights from the CareRing caregiver community in designing the Brainshuttle AD trial. (PubMed, Alzheimers Dement) - P1/2 | "Caregiver support and time commitments go far beyond study visits. The guidance provided by caregivers in the CareRing initiative has helped us adapt the design and holistic management of the Brainshuttle AD trial, and co-create/refine specialized support for both caregivers and participants."

Journal • Alzheimer's Disease • CNS Disorders

PK/PD modeling framework to inform the clinical development of RG6102, an amyloid-targeting investigational drug with enhanced brain penetration properties (CTAD 2021) - P1, P1/2 | "It combines the anti-amyloid beta (Aβ) antibody gantenerumab with a “Brain Shuttle” module that binds to the transferrin receptor 1 (TfR1), facilitating transport across the blood-brain barrier. A PK/PD modeling framework relying on learn-confirm iterations informed the early clinical development trials of RG6102 by combining information across compounds and species. In particular, a model-based approach was valuable to guide first-in-human dosing and inform the design of the first study in healthy volunteers as well as the first study in patients with AD."

Clinical • PK/PD data • Alzheimer's Disease • CNS Disorders • TFRC

Brainshuttle AD: A Phase Ib/IIa Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RG6102 in Participants with Prodromal or Mild-to-Moderate Alzheimer’s Disease (CTAD 2021) - P1/2 | "It combines the anti-amyloid beta antibody gantenerumab with a transferrin receptor 1 (TfR1) binding “Brain Shuttle” module, enabling active receptor-mediated transport across the blood-brain barrier. The Brainshuttle AD study will evaluate the safety and tolerability profile of RG6102, and establish whether faster and more extensive amyloid plaque clearance in participants with AD can be achieved through active TfR1 receptor-mediated transcytosis of an anti-amyloid mAb to the brain. Disclosures: HS is a fulltime employee of and owns stock in F. Hoffman-La Roche Ltd. AV is a full-time employee of and owns stock options in F. Hoffman-La Roche Ltd."

Clinical • P1/2 data • PK/PD data • Alzheimer's Disease • CNS Disorders • Dementia • Amyloid PET • APP • TFRC

[VIRTUAL] EARLY ENGAGEMENT WITH THE WIDER PATIENT COMMUNITY IN EARLY-PHASE CLINICAL TRIAL DESIGN: INSIGHTS FROM THE CARERING CAREGIVER COMMUNITY IN DESIGNING THE BRAINSHUTTLE AD TRIAL (AAIC 2021) - P1/2 | "The calls included presentations of the Roche brain shuttle technology and draft protocol for the Phase IB/IIA Brainshuttle AD trial evaluating RO7126209 in prodromal or mild-to-moderate AD (NCT04639050), and allowed caregivers to provide input on the protocol and holistic support that could alleviate the burden of participation... Caregiver support and time commitments go far beyond study visits. The guidance provided by caregivers in the CareRing initiative has helped us adapt the design and holistic management of the Brainshuttle AD trial, and co-create/refine specialized support for both caregivers and participants."

Clinical • Alzheimer's Disease • CNS Disorders

[VIRTUAL] Engaging the Alzheimer’s disease (AD) CareRing caregiver community in designing the Phase IB/IIA Brainshuttle AD trial (EAN 2021) - P1/2 | "The calls introduced the draft protocol for the Phase IB/IIA Brainshuttle AD trial evaluating brain-shuttle gantenerumab in prodromal or mild-to-moderate AD (NCT04639050), and allowed caregivers to provide input on the protocol and holistic support that could alleviate the burden of participation for participants and caregivers. The CareRing initiative allows us to collaborate with caregivers to design early-phase clinical trials that meet participant and caregiver needs, while also answering scientific questions. Early engagement with the broader patient community will help ensure trial designs enable the target population to participate should they wish. Established internal networks can support this type of initiative."

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