TD-1058 First-In-Human study
Research type
Research Study
Full title
A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, 4-Part Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TD_1058 Administered by Inhalation of Single Ascending Doses in Healthy Subjects (Part A), Multiple Ascending Doses in Healthy Subjects (Part B) and Subjects with Idiopathic Pulmonary Fibrosis (Part C), and Following Administration of Inhaled Non-radiolabelled and Intravenous radiolabelled Microtracer Doses in Healthy Subjects (Part D)
IRAS ID
285744
Contact name
Dave Singh
Contact email
Sponsor organisation
Theravance Biopharma Ireland Limited
Eudract number
2020-003003-34
Duration of Study in the UK
1 years, 2 months, 15 days
Research summary
Research Summary
TD-1058 is a potential new drug being developed for the purpose of treating Idiopathic Pulmonary Fibrosis (IPF) which is a condition in which the lungs become scarred and breathing becomes increasingly difficult. IPF is a debilitating lung disease of unknown cause, and the most common and lethal of the idiopathic interstitial pneumonias. The disease is characterised by chronic inflammation and progressive fibrosis resulting in destruction of lung architecture, reduced lung capacity, and impaired oxygenation resulting in poor quality of life.
TD-1058 is a small molecule inhibitor of ALK5, the kinase domain of Transforming Growth Factor-β (TGF-β) type 1 receptor.
The Transforming Growth Factor-β (TGF-β) pathway is one of the key drivers of fibroblast to myofibroblast transition (FMT). As myofibroblasts accumulates in lung tissue, the stiffness of fibrotic areas increases. Due to the central role of the myofibroblast in IPF and the requirement of TGF-β to generate and stimulate this cell type, the TGF-β pathway has been implicated as a key driver of IPF pathology.
This is the first study with TD-1058 in humans, and is designed to evaluate the safety, tolerability, and PK in healthy subjects (Parts A and B) and in subjects with IPF (Part C). It is also designed to evaluate PD endpoints in healthy subjects (Part B) and in subjects with IPF (Part C). The inclusion of subjects with IPF is to allow for potential assessment of target engagement to guide future studies in IPF patients. A randomized, doubleblind, placebo-controlled design has been selected to allow for unbiased analysis of safety and tolerability data. The study will be conducted in a dose escalation format in order to characterise doses (up to 2500 µg/day) that are anticipated to be safe and efficacious in the treatment of IPF.
Summary of Results
Single and multiple ascending inhaled doses of TD-1058 at all dose levels (up to 2500 μg) were generally well-tolerated by the healthy subjects in this first in human study (FIH) study.
• Plasma TD-1058 exposure increased in a dose-proportional manner from 500 to 2500 µg.
• Arithmetic mean percent of unchanged TD-1058 excreted in urine was very low (≤ ~3%) following a single dose of TD-1058 ranging from 50 to 2500 µg.
• Following 150, 500, 1250 µg and 2500 µg TD-1058 QD, plasma AUC accumulated roughly 2 to 4 fold whereas minimal to no accumulation was observed for plasma TD 1058 Cmax after 14 days of dosing.
• Steady state was achieved by the end of Day 7 following 150, 500, and 1250 µg TD 1058 QD and by the end of Day 5 following 2500 µg TD-1058 QD.
• No change in ex vivo transforming growth factor beta (TGF-β)-induced phosphorylation of SMAD3 in blood was observed post-daily (QD) TD-1058 administration via inhalation for 14 days consistent with a lack of systemic target engagement.
• Treatment with inhaled TD-1058 led to a dose-dependent reduction (relative to placebo) of ex vivo TGF-β-induced pSMAD3 expression in bronchoalveolar cells with 10% to 57% reduction was observed at 2.5 hours post dose in subjects dosed with 1250 μg or higher. In addition, a dose-dependent reduction relative to placebo in SMAD7 gene expression in brushing was observed with a significant 18% to 70% reduction observed at 1250 μg or higher.REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
20/NW/0294
Date of REC Opinion
18 Sep 2020
REC opinion
Favourable Opinion