Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: safety, pharmacokinetics and exploratory efficacy

Abnormal fibrogenic repair response upon alveolar injury is believed to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PRM-151 (recombinant human pentraxin-2, also known as serum amyloid P), has been shown to reduce fibrosis in preclinical lung fibrosis models, and was well tolerated with a favourable pharmacokinetic profile in an earlier single-dose phase I study. A randomised, double-blind, placebo-controlled, multiple ascending dose trial was performed to assess the tolerability and pharmacokinetic and pharmacodynamic characteristics of multiple doses of PRM-151 in IPF patients. Subjects in three successive cohorts (1, 5, or 10 mg.kg-(1) versus placebo) received intravenous study drug on days 1, 3, 5, 8 and 15, and were followed-up to day 57. PRM-151 was well tolerated at all dose levels, with no serious adverse reactions. Administration of PRM-151 resulted in two-to eight-fold dose-dependent increases in circulating pentraxin-2 levels. Forced vital capacity and 6-min walk test showed trends towards improvement in the combined PRM-151 dose groups. On high-resolution computed tomography scans, stable or improved lung volume unoccupied by interstitial lung abnormality was noted in some PRM-151 subjects compared to placebo subjects on day 57. The efficacy of PRM-151 in IPF remains to be investigated in dedicated future trials

Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis

PRM-151, recombinant human Pentraxin-2 (PTX-2) also referred to as serum amyloid P (SAP), is under development for treatment of fibrosis. A First-in-Human (FIH) trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects (PRM-151:placebo; 2:1). SAP levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous SAP. At a dose level of 10 mg/kg, at which a physiologic plasma level of SAP was reached, two additional healthy volunteers and three pulmonary fibrosis (PF) patients were enrolled enabling comparison of the pharmacokinetic SAP profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes (CD45+/Procollagen-1+ cells) in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two pulmonary fibrosis patients non-specific, transient skin reactions (urticaria and erythema) were observed. PRM-151 administration resulted in a 6- to 13-fold increase in mean baseline plasma SAP levels at dose levels of 5, 10, and 20 mg/kg. The estimated t(1/2) of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research. (C) 2013 Elsevier Ltd. All rights reserved

The Long Pentraxin PTX3 Promotes Fibrocyte Differentiation

Monocyte-derived, fibroblast-like cells called fibrocytes are associated with fibrotic lesions. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP is a member of the pentraxin family of proteins that includes C-reactive protein (CRP; PTX1) and pentraxin-3 (PTX3). All three pentraxins are associated with fibrosis, but only SAP and CRP have been studied for their effects on fibrocyte differentiation. We find that compared to SAP and CRP, PTX3 promotes human and murine fibrocyte differentiation. The effect of PTX3 is dependent on FcγRI. In competition studies, the fibrocyte-inhibitory activity of SAP is dominant over PTX3. Binding competition studies indicate that SAP and PTX3 bind human FcγRI at different sites. In murine models of lung fibrosis, PTX3 is present in fibrotic areas, and the PTX3 distribution is associated with collagen deposition. In lung tissue from pulmonary fibrosis patients, PTX3 has a widespread distribution, both in unaffected tissue and in fibrotic lesions, whereas SAP is restricted to areas adjacent to vessels, and absent from fibrotic areas. These data suggest that the relative levels of SAP and PTX3 present at sites of fibrosis may have a significant effect on the ability of monocytes to differentiate into fibrocytes