A Phase Ib, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Multiple-Ascending Doses of RO7303509 in Participants With Systemic Sclerosis

The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of RO7303509 treatment in participants with systemic sclerosis (SSc) during a multiple-ascending-dose (MAD) portion of the trial. In the MAD phase, increasing doses of study drug will be tested sequentially. For each dose tested, the MAD stage will consist of a treatment period of 12 weeks followed by either a safety follow-up period of 13 weeks or continued treatment in an optional open-label safety extension (OSE) stage of 52 weeks to assess the long-term safety. All patients in the OSE stage will receive RO7303509 and no patient will receive placebo.

Start Date16 Jan 2023

Sponsor / Collaborator

Genentech, Inc.

ISRCTN13175485

/ CompletedPhase 1

A Phase Ia, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single-ascending doses of RO7303509 in healthy volunteers

Start Date29 Sep 2020

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with RO-7303509

100 Translational Medicine associated with RO-7303509

100 Patents (Medical) associated with RO-7303509

Literatures (Medical) associated with RO-7303509

01 Jun 2024·Rheumatology and therapy

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers

Article

Author: Yang, Xiaoyun ; Han, Lyrialle W ; Jamalian, Samira ; Hassan, Sharmeen ; Kunder, Rebecca ; Monemi, Sharareh ; Sheng, X Rebecca ; Tuckwell, Katie ; Yang, Xiaoying ; Pan, Lin ; Yadav, Rajbharan ; Glickstein, Sara ; Hsu, Joy C

INTRODUCTION:

Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs).

METHODS:

This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations.

RESULTS:

The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (C_max) and area under the concentration-time curve from time 0 to infinity (AUC_0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition.

CONCLUSION:

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.

TRIAL REGISTRATION:

ISRCTN13175485.

TOXICOLOGICAL SCIENCES

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

Article

Author: Yadav, Rajbharan ; Sun, Tianhe ; Liang, Wei-Ching ; Turley, Shannon J ; Corpuz, Janice ; Adedeji, Adeyemi O ; Wu, Yan ; Arron, Joseph R ; Mitra, Mayur S ; Duarte, Isabel ; Halpern, Wendy ; Lepherd, Michelle

Abstract:

The transforming growth factor-β (TGFβ) cytokine family, which comprises 3 pleiotropic cytokines (TGFβ1, TGFβ2, and TGFβ3), plays a key role in many diseases including cancer and fibrosis. The role of TGFβ in disease is well established and efforts to develop therapies via inhibition of the 3 isoforms and their receptors have been pursued for decades. Unfortunately, progress in this pursuit has been limited as complete inhibition of the TGFβ signaling pathway using small molecule inhibitors of TGFβ receptor or following administration of potent pan-TGFβ (inhibiting TGFβ1, TGFβ2, and TGFβ3) neutralizing monoclonal antibodies (mAb) has been associated with adverse toxicities including cardiac valvulopathies, hemorrhage, and anemia in nonclinical toxicology species. Here we have evaluated the toxicities associated with selective inhibition of individual (TGFβ1 alone, TGFβ2 alone, or TGFβ3 alone) or dual (TGFβ1,2 or TGFβ2,3) TGFβ isoforms in mice and/or cynomolgus monkeys using mAbs targeted against these isoforms. Our data show that dual inhibition of TGFβ2,3 resulted in adverse toxicities in several organs, including cardiovascular toxicity. However, selective isoform-specific inhibition of TGFβ1, 2, or 3 is generally tolerated and devoid of adverse toxicities in nonclinical toxicology studies. 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 nonadverse 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.

TOXICOLOGICAL SCIENCES

Interference with systemic negative feedback as a potential mechanism for nonmonotonic dose-responses of endocrine-disrupting chemicals

Article

Author: Yadav, Rajbharan ; Liang, Wei-Ching ; Sun, Tianhe ; Turley, Shannon J ; Corpuz, Janice ; Adedeji, Adeyemi O ; Wu, Yan ; Arron, Joseph R ; Mitra, Mayur S ; Duarte, Isabel ; Halpern, Wendy ; Lepherd, Michelle

Abstract:

Environmental endocrine-disrupting chemicals (EDCs) often exhibit nonmonotonic dose-response (NMDR) relationships, posing significant challenges to health risk assessment and regulations. Several molecular mechanisms operating locally in cells have been proposed; however, whether and how systemic negative feedback—a global structure of all homeostatic endocrine systems—may render NMDRs is poorly understood. We hypothesized that an EDC may produce nonmonotonic effects by competing with the endogenous hormone for receptors simultaneously (i) at the central site to interfere with the feedback regulation and (ii) at the peripheral site to disrupt the hormone’s endocrine action. We constructed a dynamical model of a generic hypothalamic–pituitary–endocrine axis with negative feedback to evaluate the hypothesis and biological conditions that favor NMDR. Our modeling found that when an EDC interferes sufficiently with the central feedback action, the net endocrine effect at the peripheral target site can be opposite to what is expected of an agonist or antagonist at low concentrations. J/U or Bell-shaped NMDRs arise when the EDC has differential binding affinities and/or efficacies, relative to the endogenous hormone, for the peripheral and central receptors. Novel quantitative relationships between these biological parameter variabilities and associated distributions were discovered, which can distinguish J/U and Bell-shaped NMDRs from monotonic responses. In conclusion, the ubiquitous negative feedback regulation in endocrine systems may act as a universal mechanism for counterintuitive and nonmonotonic effects of EDCs. Depending on the key receptor kinetic and signaling properties of EDCs and endogenous hormones, certain individuals may be more susceptible to these complex endocrine effects.

News (Medical) associated with RO-7303509

24 Apr 2025

·www.fiercebiotech.com

Tariffs will make financial case for pharma M&A \'more difficult,\' says Roche CEO

Roche Pharma’s CEO Teresa Graham said on a call that the company has not yet seen an impact from workforce cuts at the FDA.\n Big Pharma\'s M&A plans will likely take a hit if the U.S. government under the Trump administration lives up to its threats of imposing tariffs on the industry, Roche’s CEO has warned.In a first-quarter earnings call with journalists Thursday morning, Thomas Schinecker said that, for now, the Swiss pharma’s mantra for finding new acquisitions continues to be: “Does the deal make financial sense?”But Schinecker added that if pharmaceutical tariffs do come into force, the industry will find it “more difficult to make financial sense of any M&A deals.”“My assumption would be that you will see an industry worldwide situation where people probably reduce the effort at this stage, and we\'ll see how things develop,” the CEO continued. “You know, things can change very quickly in this environment.”Against a backdrop of continued threats by the Trump administration to extend tariffs to include pharmaceutical imports into the U.S., Roche announced earlier this week that it will be investing $50 billion in the country over the next five years. These ambitions include the “significant expansion and upgrading” of three existing pharmaceuticals and diagnostics R&D centers as well as previously disclosed plans to consolidate the pharma’s cardiovascular, renal and metabolism R&D work at a new center in Harvard’s Enterprise Research Campus.One impact that the administration is already having on the drug development landscape is widespread cuts to the FDA’s workforce. But Roche Pharma’s CEO Teresa Graham told journalists on the same April 24 call that this has not yet impacted the company’s interactions with the agency.“Obviously, we\'re watching very closely the evolutions within [the Department of Health and Human Services] and the FDA,” Graham said. “At this time, we are not seeing any slowdown, either in development or approval processes, and things seem to be fairly business as usual for the pharma side.”Meanwhile, Roche used its first-quarter earnings results to disclose that it had dropped two candidates from its phase 1 pipeline. One of these was RG6315, which was being developed for systemic sclerosis. Roche’s Genentech unit had decided to halt work on the drug for “strategic reasons” rather than because of any safety concerns, a spokesperson told Fierce.The other terminated program was P-MUC1C-ALLO1, an allogeneic CAR-T that Genentech had come into possession of as part of Roche’s $1.5 billion acquisition of Poseida Therapeutics in November 2024. That specific program had not been part of Roche’s previous partnership with Poseida, the spokesperson pointed out.

$Tariffs will make financial case for pharma M&A \'more difficult,\' says Roche CEO$

AcquisitionPhase 1

18 Apr 2024

·www.pharmaceutical-technology.com

Inflammation among current dementia research focus, says Alchemab CSO

Alchemab CSO Jane Osbourn also believes a more holistic approach to dementia care beyond drug treatment is needed. Credit: Getty images/ TEK IMAGE/Science Photo Library. Inflammation, cell metabolism and neuronal health are current key areas of focus for dementia researchers, according to Jane Osbourn, chief scientific officer (CSO) at Alchemab. Osbourn was speaking on a panel discussing novel approaches to treat neurodegeneration at the 2024 Anglonordic Life Science Conference being held in London, UK on 18 April. She outlined that the past five to 10 years have led towards a better understanding of dementia’s causes. “Obviously one cause is toxic protein aggregation, which has been a hypothesis for decades and is being addressed, but we’re starting to see more understanding of other causes such as inflammation, cell metabolism and neuronal health, and I think those are the areas that will now form the next wave of products that can then be used in combinations. “I think understanding the causes, and what we are doing as an industry about them – such as whether we can do anything about neuronal health or making the brain more resilient against inflammation – are just some of the questions under consideration at this time.” See Also: RG-6315 by Genentech USA for Inflammation: Likelihood of Approval Ftortiazinon by Gamaleya Federal Research Center of Epidemiology and Microbiology for Urinary Tract Infections: Likelihood of Approval On the collaborative nature of being able to get cohorts together, Osbourn added: “I think in recent times there’s been a step change in collaboration and consortia, and getting patients to enable biomarkers, diagnosis and trials, which is going to really help in gaining further insights.” Osbourn highlighted the impact of ageing dementia populations. “Ageing is a risk for neurodegeneration, and we’re all becoming much more aware of the significance of that in terms of the impact on patients, carers, and society. I think there’s a massive societal risk around the dementia population ageing in terms of how they integrate with society. “Society is built for people who are able, have memory, can use online tools – and one of my personal concerns is around a need to look more closely at how we are supporting people through dementia; not just by drugs but in a more holistic way.” Speciality pharmaceutical group Essential Pharma recently completed the acquisition of Reminyl oral capsules from Johnson & Johnson company Janssen Pharmaceutica. Reminyl is an established central nervous system (CNS) drug for mild to moderately severe dementia of the Alzheimer type. Sabirnetug is a humanised, monoclonal antibody under clinical development by Acumen Pharmaceuticals and currently in Phase I for Dementia Associated With Alzheimer’s Disease.

Phase 1Acquisition

100 Deals associated with RO-7303509

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Fibrosis	Phase 1	United States	Genentech, Inc.	31 May 2023
Scleroderma, Systemic	Phase 1	United States	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	Argentina	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	Belgium	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	France	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	Israel	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	Poland	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	Portugal	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	Serbia	Genentech, Inc.	16 Jan 2023
Scleroderma, Systemic	Phase 1	Spain	Genentech, Inc.	16 Jan 2023

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