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Management of idiopathic pulmonary fibrosis
Published in Muhunthan Thillai, David R Moller, Keith C Meyer, Clinical Handbook of Interstitial Lung Disease, 2017
Damian AD Bruce-Hickman, Helen Garthwaite, Melissa Heightman, Bibek Gooptu
The enzyme, lysyl oxidase-like (LOXL)2, contributes to fibrosis by catalysing the cross-linking of fibrillar collagen, thereby reducing compliance. It may also have further profibrotic actions, as cross-linking appears to result in reduced TGF-β1 signalling and reduced fibroblast recruitment (148). LOXL2 levels in patients from recent clinical trials correlated with disease progression and with mortality risk (149). Simtuzumab is a monoclonal antibody that inhibits LOXL2, but a phase 2 trial (ClinicalTrials.gov NCT01769196) of this drug was recently halted after failure to show treatment benefit at a mid-stage data analysis.
Nonalcoholic steatohepatitis (NASH) cirrhosis: a snapshot of therapeutic agents in clinical development and the optimal design for clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Pankaj Aggarwal, Mazen Noureddin, Stephen Harrison, Sophie Jeannin, Naim Alkhouri
Simtuzumab is a monoclonal antibody that targets fibrogenesis by inhibiting the lysyl oxidase-like 2 enzyme that catalyzes the cross-linking of collagen. In two-phase 2B trials, simtuzumab was found to be ineffective in patients with bridging fibrosis or compensated NASH cirrhosis. In a double-blinded study for those with bridging fibrosis (F3) (n = 219), patients were randomized 1:1:1 between three arms (75 mg subcutaneous (SQ) injection weekly, 125 mg SQ injection weekly, or placebo). Simtuzumab did not meet the primary endpoint of decreasing hepatic collagen content as determined by histology. In a separate study (n = 258), patients with NASH cirrhosis (F4) were similarly randomized one of three arms (200 mg intravenous (IV) infusion every other week, 700 mg IV infusion every other week, or placebo. The study was stopped at 96 weeks due to the lack of efficacy of simtuzumab in reducing hepatic venous pressure gradient (HVPG) [34].
The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success
Published in Expert Opinion on Investigational Drugs, 2020
Joost P.H. Drenth, Jörn M. Schattenberg
Simtuzumab, is a humanized monoclonal antibody directed against LOXL2, binds to and inhibits LOXL2 enzymatic activity and has been investigated because of the potential to prevent or reverse fibrosis progression. The phase 2 program consisted of two separate multi-center studies and included one study of 219 patients with bridging fibrosis and one study of 258 patients with compensated cirrhosis. Each study consisted of three arms with proportional cohorts of simtuzumab or placebo [22]. Simuzumab was dose orally 75 mg and 125 mg in patients with bridging fibrosis, while simtuzumab was given intravenously every other week (200 or 700 mg) to compensated cirrhotics. The planned duration of the trial was 240 weeks but both studies were terminated early and data from 197 patients from both trials were assessed at 48 weeks and 96 weeks. Endpoints differed per trial. In patients with bridging fibrosis, the primary end point was changed from baseline to week 96 in hepatic collagen content, as measured by morphometry of liver specimens, for patients with cirrhosis, the primary end point was changed in hepatic venous pressure gradient from baseline to week 96. Interestingly, all three treatment arms of patients with bridging fibrosis had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between simtuzumab arms and the placebo arm. The results were unaffected after adjusting for diabetes status, weight loss and baseline serum lysyl oxidase like two levels. In cirrhotics, both dosages of simtuzumab did not change hepatic venous pressure gradient compared to placebo.
Antibody-based therapies for idiopathic pulmonary fibrosis
Published in Expert Opinion on Biological Therapy, 2020
Giacomo Sgalla, Mariachiara Flore, Matteo Siciliano, Luca Richeldi
Simtuzumab is a human monoclonal antibody directed against lysyl oxidases Like-2 (LOXL2), a group of enzymes that catalyze matrix protein cross-linking. Their physiological role consists in helping stabilize the ECM, facilitating the cross-linking of type 1 collagen molecules that generate the structure on which fibroblasts grow. The increased cross-linking of matrix proteins could contribute to the pathologically increased matrix stiffness that characterizes fibrotic diseases. Elevated LOXL2 levels contribute to myofibroblast differentiation and matrix production, further driving fibrosis progression [13].