Ganesh Raghu1, Bernt van den Blink2, Mark J Hamblin3, A Whitney Brown4, Jeffrey A Golden5, Lawrence A Ho6, Marlies S Wijsenbeek7, Martina Vasakova8, Alberto Pesci9, Danielle E Antin-Ozerkis10, Keith C Meyer11, Michael Kreuter12, Donna Moran2, Hugues Santin-Janin13, Francois Aubin13, Geert-Jan Mulder2, Renu Gupta2, Luca Richeldi14. 1. Center for Interstitial Lung Diseases, Department of Medicine and Laboratory Medicine, University of Washington, Seattle, WA, USA. Electronic address: graghu@uw.edu. 2. Promedior, Lexington, MA, USA. 3. Pulmonary and Critical Care Medicine, University of Kansas Medical Center, Kansas City, KS, USA. 4. Inova Fairfax Hospital, Falls Church, VA, USA. 5. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. 6. Center for Interstitial Lung Diseases, Department of Medicine and Laboratory Medicine, University of Washington, Seattle, WA, USA. 7. Department of Respiratory Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands. 8. Department of Respiratory Medicine, First Faculty of Medicine of Charles University and Thomayer Hospital, Prague, Czech Republic. 9. School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. 10. Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA. 11. Department of Medicine, Division of Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 12. Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg and German Center for Lung, Research, Heidelberg, Germany. 13. Venn Life Sciences, Paris, France. 14. Fondazione Policlinico Universitario A Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.
Abstract
BACKGROUND:Patients with idiopathic pulmonary fibrosis (IPF) treated withPRM-151, a recombinant human pentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. METHODS:Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. FINDINGS: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of -3·6% per year and in 6-min walking distance of -10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from -8·7% per year in weeks 0-28 to -0·9% per year in weeks 28-52, p<0·0001) and 6-min walking distance (from -54·9 m per year to -3·5 m per year, p=0·0224). INTERPRETATION: Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF. FUNDING: Promedior.
RCT Entities:
BACKGROUND:Patients with idiopathic pulmonary fibrosis (IPF) treated with PRM-151, a recombinant humanpentraxin 2 protein, in a phase 2 double-blind, randomised controlled trial had significantly reduced decline in percentage of predicted forced vital capacity (FVC) and stabilised 6-min walking distance compared with placebo over a 28-week period. Here we report the 76-week results of an open-label extension study. METHODS:Patients who completed the 28-week double-blind period of the PRM-151-202 trial were eligible to participate in the open-label extension study. Patients previously enrolled in the PRM-151 group continued this treatment and those previously in the placebo group crossed over to PRM-151. All patients received PRM-151 in 28-week cycles with loading doses of 10 mg/kg by 60 min intravenous infusions on days 1, 3, and 5 in the first week of each cycle followed by one infusion of 10 mg/kg every 4 weeks. The primary objective of the open-label extension study was to assess the long-term safety and tolerability of PRM-151, which were assessed by analysing adverse events (AEs) up to week 76 in all patients who received at least one dose of PRM-151 during the open-label extension study. Exploratory efficacy analyses were done by assessing changes from baseline in percentage of predicted FVC and 6-min walking distance, with descriptive statistics to week 76 and with random-intercept mixed models to week 52. This study is registered with ClinicalTrials.gov, number NCT02550873, and with EudraCT, number 2014-004782-24. FINDINGS: Of 116 patients who completed the double-blind treatment period, 111 entered the open-label extension study (74 from the PRM-151 group and 37 from the placebo group). 84 (76%) of 111 patients received concomitant IPF therapy (pirfenidone n=55 or nintedanib n=29). AEs were consistent with long-term IPF sequelae. 31 (28%) patients had serious AEs. Those occurring in two or more patients were pneumonia (six [5%] of 111), IPF exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]). 21 (19%) patients had severe AEs, of which IPF exacerbation and IPF progression each occurred in two (2%) patients. Two (2%) patients experienced life-threatening AEs (one had pneumonia and one had small-cell lung cancer extensive stage). A persistent treatment effect was observed for PRM-151 in patients who continued treatment, with a decline in percentage of predicted FVC of -3·6% per year and in 6-min walking distance of -10·5 m per year at week 52. In patients who started PRM-151 during the open-label extension study, compared with the slopes for placebo, decline reduced for percentage of predicted FVC (from -8·7% per year in weeks 0-28 to -0·9% per year in weeks 28-52, p<0·0001) and 6-min walking distance (from -54·9 m per year to -3·5 m per year, p=0·0224). INTERPRETATION: Long-term treatment with PRM-151 was well tolerated and the effects on percentage of predicted FVC and 6-min walking distance were persistent on continuation and positive in patients who crossed over from placebo. These findings support further study of PRM-151 in larger populations of patients with IPF. FUNDING: Promedior.
Authors: Andrea Doni; Raffaella Parente; Ilaria Laface; Elena Magrini; Cristina Cunha; Federico Simone Colombo; João F Lacerda; António Campos; Sarah N Mapelli; Francesca Petroni; Rémi Porte; Tilo Schorn; Antonio Inforzato; Toine Mercier; Katrien Lagrou; Johan Maertens; John D Lambris; Barbara Bottazzi; Cecilia Garlanda; Marina Botto; Agostinho Carvalho; Alberto Mantovani Journal: Nat Commun Date: 2021-06-18 Impact factor: 14.919