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Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease
Author(s) -
Muir Andrew J.,
Levy Cynthia,
Janssen Harry L.A.,
MontanoLoza Aldo J.,
Shiffman Mitchell L.,
Caldwell Stephen,
Luketic Velimir,
Ding Dora,
Jia Catherine,
McColgan Bryan J.,
McHutchison John G.,
Mani Subramanian G.,
Myers Robert P.,
Manns Michael,
Chapman Roger,
Afdhal Nezam H.,
Goodman Zachary,
Eksteen Bertus,
Bowlus Christopher L.
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30237
Subject(s) - medicine , gastroenterology , primary sclerosing cholangitis , placebo , clinical endpoint , hazard ratio , cirrhosis , fibrosis , adverse effect , hepatology , confidence interval , randomized controlled trial , pathology , disease , alternative medicine
Lysyl oxidase like‐2 (LOXL2) plays a central role in fibrogenesis and is elevated in the serum and liver of patients with primary sclerosing cholangitis (PSC). We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody directed against LOXL2, in patients with PSC. Patients with compensated liver disease caused by PSC were randomized 1:1:1 to receive weekly subcutaneous injections of simtuzumab 75 mg, simtuzumab 125 mg, or placebo for 96 weeks. The primary efficacy endpoint was mean change in hepatic collagen content assessed by morphometry between baseline and week 96. Additional endpoints included change in Ishak fibrosis stage and the frequency of PSC‐related clinical events. Overall, 234 patients were randomized and started treatment. At week 96, the mean change from baseline in hepatic collagen content was –0.5% for patients receiving simtuzumab 75 mg ( P = 0.73 versus placebo), +0.5% for patients receiving simtuzumab 125 mg ( P = 0.33 versus placebo), and 0.0 for patients receiving placebo. Compared with placebo, neither dose of simtuzumab led to significant reductions in Ishak fibrosis stage, progression to cirrhosis, or frequency of clinical events. Overall, 80 (34%) patients had fibrosis progression and 47 (20%) experienced PSC‐related clinical events. In a multivariate model of baseline factors, PSC‐related clinical events were more frequent in patients with advanced fibrosis (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.02‐4.06; P = 0.045), higher alkaline phosphatase (HR per 10 U/L, 1.01; 95% CI, 1.00‐1.02; P = 0.015), and higher enhanced liver fibrosis score (HR per unit, 1.26; 95% CI, 0.98‐1.61; P = 0.073). Overall, rates of adverse events and laboratory abnormalities were similar between groups. Conclusion: Treatment with the LOXL2 inhibitor simtuzumab for 96 weeks did not provide clinical benefit in patients with PSC.