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

Abstract

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.

Introduction

Idiopathic Pulmonary Fibrosis (IPF) is the most common Idiopathic Interstitial Pneumonia (IIP) [1]. It is a chronic, progressive, irreversible and lethal disease that generally occurs in middle-aged and elderly adults. IPF is a disease of unknown cause although recurrent epithelial injury and aberrant wound healing are thought to lead to fibrosis. Symptoms of IPF include chronic and progressive exertional dyspnea, cough, a poor quality of life and eventually death. Therapeutic options are limited for all forms of pulmonary fibrosis [2], and the only treatment proven effective in prolonging survival is lung transplantation with a post-transplantation 5-year survival for IPF patients of approximately 44% [3]. Efficacious therapy for pulmonary fibrosis remains elusive [4], and particularly pharmacotherapeutic options are limited.

In IPF, monocyte-derived cells play a central role in the fibrotic scarring process, as they take part in the production of (excess) collagen and cytokines such as PDGF, TGF-β, IL-1, MCP-1 and TNF-α [5], [6], [7]. The fibrocyte is a unique mesenchymal progenitor cell that differentiates from monocytes, and may be an important source of (myo)fibroblasts during tissue repair and tissue remodeling [8], [9], [10]. Elevated levels of fibrocytes are associated with increased fibrosis and adverse clinical outcomes. The mean survival of IPF patients with fibrocyte counts exceeding 5% of total blood leukocytes was 7.5 months compared with 27 months for IPF patients with lower fibrocyte counts [11]. Therefore, the fibrocyte may be a target for therapy in IPF, with fibrocyte counts as possible biomarker [10], [12].

The differentiation of circulating monocytes into fibrocytes [13], [14], [15] and pro-fibrotic (M2) macrophages [16] is controlled by Serum Amyloid P (SAP, also called Pentraxin-2, PTX-2), a naturally occurring protein that circulates in the bloodstream with a crucial role in regulating wound healing [17]. It has been shown that maintaining an elevated level of SAP in blood or locally at a site of injury can prevent excess scarring and the progression of fibrosis. Indeed, exogenous administration of SAP has been shown to reduce fibrosis in various animal fibrosis models such as in rodent models of ischemia reperfusion injury [18], bleomycin-induced lung fibrosis and lung fibrosis mediated by TGF-β overexpression [19], by decreasing the numbers of fibrocytes and pro-fibrotic M2 macrophages [15], [19], [20]. The decreased accumulation of fibrocytes by SAP might be due to reduced leukocyte recruitment via lowering the levels of inflammatory cytokines [15]. In patients with IPF, the SAP level has been implicated to correlate with lung function [19]. Furthermore, SAP directly inhibited M2 macrophage differentiation of monocytes into a pro-fibrotic phenotype [19]. Taken together, these data suggest that the targeting of pro-fibrotic macrophages and fibrocytes by SAP-directed therapies might be a reasonable approach to the treatment of IPF.

PRM-151, the recombinant form of human SAP (rhSAP), is such a compound that could potentially be used to prevent, treat, and reduce fibrosis. Preclinical data using human serum-derived SAP and PRM-151 demonstrated a potent anti-fibrotic activity of SAP in models of lung injury, skin injury, kidney injury and radiation-induced injury [15], [16], [17], [18], [19], [20], [21]. We performed a First-in-Human (FIH) trial to provide an initial assessment of the safety, tolerability, and pharmacokinetics (PK) of PRM-151 after administration of single intravenous (IV) doses. Importantly, a rational study design was chosen, consisting of 1) an efficient single ascending dose part in small cohorts of healthy subjects to assess the safety, tolerability, and pharmacokinetics of PRM-151, aiming to cover a range of PRM-151 doses resulting in plasma SAP levels with expected anti-fibrotic activity, and 2) an expanded cohort at a PRM-151 dose level that resulted in a desired SAP plasma level in the first study part. In this second study part two additional healthy volunteers and three Pulmonary Fibrosis (PF) patients were included, which not only allowed an initial comparison of the compound's pharmacokinetic and safety profile between healthy subjects and fibrosis patients, but also allowed the selection of a suitable biomarker for initial demonstration of biological activity of PRM-151 in PF patients. Especially the latter is of crucial importance for modern drug development, as the availability of such a pharmacodynamic measure will enable a more rational and efficient future development of the compound in the target population.