scholarly journals A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis

2019 ◽  
Vol 53 (3) ◽  
pp. 1801992 ◽  
Author(s):  
Pauline T. Lukey ◽  
Stephen A. Harrison ◽  
Shuying Yang ◽  
Yim Man ◽  
Beverley F. Holman ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Mammalian Target Of Rapamycin ◽  
Common Adverse Event ◽  
Controlled Study ◽  
Pharmacokinetic Analysis ◽  
Experimental Medicine ◽  
Repeat Dose ◽  
Target Engagement ◽  
Double Blind

Phosphatidylinositol 3-kinases (PI3Ks) and mammalian target of rapamycin (mTOR) play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Omipalisib (GSK2126458) is a potent inhibitor of PI3K/mTOR.A randomised, placebo-controlled, double-blind, repeat dose escalation, experimental medicine study of omipalisib in subjects with IPF was conducted (NCT01725139) to test safety, tolerability, pharmacokinetics and pharmacodynamics. Omipalisib was dosed at 0.25 mg, 1 mg and 2 mg twice daily for 8 days in four cohorts of four subjects randomised 3:1 to receive omipalisib or placebo (two cohorts received 2 mg twice daily).17 subjects with IPF were enrolled. The most common adverse event was diarrhoea, which was reported by four participants. Dose-related increases in insulin and glucose were observed. Pharmacokinetic analysis demonstrated that exposure in the blood predicts lung exposure. Exposure-dependent inhibition of phosphatidylinositol 3,4,5 trisphosphate and pAKT confirmed target engagement in blood and lungs. 18F-2-fluoro-2-deoxy-d-glucose(FDG)-positron emission tomography/computed tomography scans revealed an exposure-dependent reduction in 18F-FDG uptake in fibrotic areas of the lung, as measured by target-to-background, ratio thus confirming pharmacodynamic activity.This experimental medicine study demonstrates acceptable tolerability of omipalisib in subjects with IPF at exposures for which target engagement was confirmed both systemically and in the lungs.

scholarly journals SAR156597 in idiopathic pulmonary fibrosis: a phase 2 placebo-controlled study (DRI11772)

2018 ◽  
Vol 52 (6) ◽  
pp. 1801130 ◽  
Author(s):  
Ganesh Raghu ◽  
Luca Richeldi ◽  
Bruno Crestani ◽  
Peter Wung ◽  
Raphael Bejuit ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Vital Capacity ◽  
Interleukin 4 ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
The Mean ◽  
Dose Levels ◽  
Igg4 Antibody

A phase 2b trial (NCT02345070) was conducted to evaluate the efficacy and safety of two dose levels/regimens of SAR156597 (a bispecific IgG4 antibody that binds and neutralises both circulating interleukin-4 and interleukin-13), in comparison with placebo, administered to patients with idiopathic pulmonary fibrosis (IPF) over 52 weeks.DRI11772 was a multinational randomised double-blind placebo-controlled phase 2b trial. Patients aged >40 years with a documented diagnosis of IPF received SAR156597 200 mg once every week (QW), SAR156597 200 mg once every 2 weeks (Q2W) or placebo, over 52 weeks. The primary efficacy end-point was absolute change from baseline in forced vital capacity (FVC) % predicted at 52 weeks.Of 327 randomised patients, 325 received treatment with placebo (n=109), SAR156597 Q2W (n=108) or SAR156597 QW (n=108). The mean change from baseline in FVC % pred at 52 weeks was –5.8%, –5.2% and –6.3% for the placebo, Q2W and QW arms, respectively (Q2W versus placebo, p=0.59; QW versus placebo, p=0.63). The safety profile observed in the three treatment arms was generally similar, although serious adverse events were more common in the QW arm than in the other arms.The DRI11772 study failed to demonstrate benefit of SAR156597 in the treatment of IPF.

scholarly journals Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis

2014 ◽  
Vol 45 (5) ◽  
pp. 1382-1392 ◽  
Author(s):  
Takashi Ogura ◽  
Hiroyuki Taniguchi ◽  
Arata Azuma ◽  
Yoshikazu Inoue ◽  
Yasuhiro Kondoh ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Area Under The Curve ◽  
Japanese Patients ◽  
Common Adverse Event ◽  
Tolerability Profile ◽  
Maximum Plasma ◽  
Double Blind

A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis.50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo.Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone.In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone.

scholarly journals Effects of Nintedanib on Quantitative Lung Fibrosis Score in Idiopathic Pulmonary Fibrosis

2020 ◽  
Vol 14 (1) ◽  
pp. 22-31
Author(s):  
Lisa Lancaster ◽  
Jonathan Goldin ◽  
Matthias Trampisch ◽  
Grace Hyun Kim ◽  
Jonathan Ilowite ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Disease Progression ◽  
Lung Fibrosis ◽  
Open Label ◽  
High Resolution Computed Tomography ◽  
Double Blind ◽  
Phase Iiib ◽  
Exploratory Data ◽  
Relative Change

Background: Nintedanib slows disease progression in patients with Idiopathic Pulmonary Fibrosis (IPF) by reducing decline in Forced Vital Capacity (FVC). The effects of nintedanib on abnormalities on high-resolution computed tomography scans have not been previously studied. Objective: We conducted a Phase IIIb trial to assess the effects of nintedanib on changes in Quantitative Lung Fibrosis (QLF) score and other measures of disease progression in patients with IPF. Methods: 113 patients were randomized 1:1 to receive nintedanib 150 mg bid or placebo double-blind for ≥6 months, followed by open-label nintedanib. The primary endpoint was the relative change from baseline in QLF score (%) at month 6. Analyses were descriptive and exploratory. Results: Adjusted mean relative changes from baseline in QLF score at month 6 were 11.4% in the nintedanib group (n=42) and 14.6% in the placebo group (n=45) (difference 3.2% [95% CI: −9.2, 15.6]). Adjusted mean absolute changes from baseline in QLF score at month 6 were 0.98% and 1.33% in these groups, respectively (difference 0.35% [95% CI: −1.27, 1.96]). Adjusted mean absolute changes from baseline in FVC at month 6 were −14.2 mL and −83.2 mL in the nintedanib (n=54) and placebo (n=54) groups, respectively (difference 69.0 mL [95% CI: −8.7, 146.8]). Conclusion: Exploratory data suggest that in patients with IPF, 6 months’ treatment with nintedanib was associated with a numerically smaller degree of fibrotic change in the lungs and reduced FVC decline versus placebo. These data support previous findings that nintedanib slows the progression of IPF.

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