title: 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 t1/2 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.
authors: Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands. Electronic address: MDillingh@chdr.nl.
authors: M R
authors: MR
authors: Dillingh
authors: B
authors: B
authors: van den Blink
authors: M
authors: M
authors: Moerland
authors: M G J
authors: MG
authors: van Dongen
authors: M
authors: M
authors: Levi
authors: A
authors: A
authors: Kleinjan
authors: M S
authors: MS
authors: Wijsenbeek
authors: M L
authors: ML
authors: Lupher
authors: D M
authors: DM
authors: Harper
authors: J A
authors: JA
authors: Getsy
authors: H C
authors: HC
authors: Hoogsteden
authors: J
authors: J
authors: Burggraaf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006207:Half-Life; D018398:Homeodomain Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000503:physiopathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000683:Serum Amyloid P-Component / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; C552898:PRM-151; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component
keywords: AE; ELISA; ERS/ATS; European Respiratory Society/American Thoracic Society; FACS; FIH; Fibrocyte; First-in-human clinical trial; IIP; IL-1; IPF; LPS; MCP-1; Macrophage; PBMC; PD; PDGF; PF; PK; PRM-151; PTX-2; Pentraxin-2; Pulmonary fibrosis; SAP; Serum amyloid P; TGF-β; TNF-α; adverse events; enzyme linked immunoassay; firt-in-human; fluorescence activated cell sorter; idiopathic interstitial pneumonia; idiopathic pulmonary fibrosis; interleukin-1; lipopolysaccharide; monocyte chemoattractant protein-1; pentraxin-2; peripheral blood mononuclear cell; pharmacodynamics; pharmacokinetics; platelet derived growth factor; pulmonary fibrosis; serum amyloid-P; transforming growth factor-β; tumor necrosis factor-α