RG6315 / Roche - LARVOL DELTA

Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies. (PubMed, Toxicol Sci) - "Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb that is currently in Phase 1 clinical trials, was well tolerated in GLP mouse and cynomolgus monkey toxicology studies and the RO7303509-related effects were limited to non-adverse histopathologic findings in the teeth and injection-site reactions. In conclusion, inhibition of TGFβ in an isoform-specific manner is generally safe in nonclinical toxicology species and could be explored for therapeutic intervention."

Journal • Preclinical • Cardiovascular • Fibrosis • Hematological Disorders • Immunology • Oncology • TGFB1 • TGFB2

Dual inhibition of TGFβ2,3 is severely toxic, whereas selective inhibition of TGFβ1, 2, or 3 and dual inhibition of TGFβ1,2 is generally tolerated In mouse and cynomolgus monkey toxicology studies. (PubMed, Toxicol Sci) - "Importantly, RO7303509 (MTBT1466A), an anti-TGFβ3 inhibiting mAb that is currently in Phase 1 clinical trials, was well tolerated in GLP mouse and cynomolgus monkey toxicology studies and the RO7303509-related effects were limited to non-adverse histopathologic findings in the teeth and injection-site reactions. In conclusion, inhibition of TGFβ in an isoform-specific manner is generally safe in nonclinical toxicology species and could be explored for therapeutic intervention."

Journal • Preclinical • Cardiovascular • Fibrosis • Hematological Disorders • Immunology • Oncology • TGFB1 • TGFB2

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial completion date: Nov 2025 ➔ Jul 2025 | Trial primary completion date: Apr 2025 ➔ Jul 2025

Trial completion date • Trial primary completion date • Immunology • Scleroderma • Systemic Sclerosis

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Active, not recruiting | Sponsor: Genentech, Inc. | Trial primary completion date: Dec 2024 ➔ Apr 2025

Trial primary completion date • Immunology • Scleroderma • Systemic Sclerosis

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Active, not recruiting | Sponsor: Genentech, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Scleroderma • Systemic Sclerosis

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Genentech, Inc. | Trial primary completion date: Apr 2024 ➔ Dec 2024

Trial primary completion date • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers. (PubMed, Rheumatol Ther) - "RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy."

Clinical • Journal • P1 data • PK/PD data • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • POSTN • TGFB1 • TGFB2

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: May 2025 ➔ Nov 2025

Trial completion date • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

Isoform-selective TGF-β3 inhibition for systemic sclerosis. (PubMed, Med) - "We establish a rationale for targeting TGF-β3 in SSc with a favorable therapeutic index."

Journal • Fibrosis • Immunology • Inflammation • Scleroderma • Systemic Sclerosis • TGFB1

Utilizing PK and PD Biomarkers to Guide the First-in-Human Starting Dose Selection of MTBT1466A: A Novel Humanized Monoclonal Anti-TGFβ3 Antibody for the Treatment of Fibrotic Diseases. (PubMed, J Pharm Sci) - "In a mouse model of bleomycin-induced lung fibrosis, changes in expression of TGFβ3-related genes, serpine1, fibronectin-1, and collagen 1A1 were used as PD biomarkers to determine the minimum pharmacologically active dose of 1 mg/kg. MTBT1466A PK in healthy volunteers was predicted reasonably well using a PK model with allometric scaling of PK parameters from monkey data. Taken together, this work provides insights into the PK/PD behavior of MTBT1466A in preclinical species, and supports the translatability of the preclinical data into the clinic."

Biomarker • Journal • P1 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases • NECTIN1 • SERPINE1 • TGFB1

A phase Ia, randomized study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO7303509, an anti-TGFβ3 monoclonal antibody, in healthy volunteers (EULAR 2023) - "The lack of an effect on TGFβ pathway biomarkers likely indicates that TGFβ3 is inactive during homeostasis, which suggests that targeting this pathway may have a favorable safety profile. These data support the further development of RO7303509 for the treatment of fibrotic diseases."

Clinical • PK/PD data • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • POSTN • TGFB1 • TGFB2

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Genentech, Inc. | Trial primary completion date: Apr 2025 ➔ Mar 2024

Trial primary completion date • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

"The Development and Characterization of a Highly Sensitive Mature TGFβ3 Assay to Evaluate Anti-TGFβ3 Target Engagement |A. Francesca Setiadi; Saloumeh K. Fischer @genentech| https://t.co/p1RKlYpdUk #monoclonalantibody #MTBT1466A #pharmacodynamics #biomarkerassay #AAPSJ @AAPSComms" (@theaapsjournal)

Biomarker assay • PK/PD data • TGFB1

The Development and Characterization of a Highly Sensitive Mature TGFβ3 Assay to Evaluate Anti-TGFβ3 Target Engagement. (PubMed, AAPS J) - "MTBT 1466A is a monoclonal antibody designed to bind to mature human TGFβ3 in human tissue and systemic circulation...The assay demonstrated specificity to mature TGFβ3, with a lower limit of quantification of 31.3pg/mL. Although baseline levels of mature TGFβ3 were below the assay detection limit in 40% of animals within our study, 2- to 16-fold increases were observed in many of the animals following multiple-dosing regimen."

Journal • TGFB1

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Genentech, Inc. | Trial completion date: Jun 2024 ➔ Apr 2025 | Trial primary completion date: Jun 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of RO7303509 in Participants With Systemic Sclerosis (clinicaltrials.gov) - P1 | N=100 | Recruiting | Sponsor: Genentech, Inc. | Initiation date: Jul 2022 ➔ Oct 2022

Trial initiation date • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis