Efficacy and safety of inhaled calcium lactate PUR118 in the ozone challenge model--a clinical trial.
BACKGROUND
The ozone challenge model can be used to assess the efficacy of anti-inflammatory compounds in early phases of clinical drug development. PUR118, a calcium salt based formulation engineered in the iSPERSE(TM) dry powder delivery technology, is a novel anti-inflammatory drug for COPD. Here we evaluated the efficacy and safety of three doses of PUR118 in attenuating ozone-induced airway inflammation in healthy volunteers.


METHODS
In a single-blind, phase 1B proof of concept study, 24 subjects were enrolled to sequentially receive three doses of PUR118 (5.5 mg, n = 18; 11.0 mg, n = 18; 2.8 mg, n = 16). Each dose was inhaled 3 times (1, 13, 25 h, preceded by 2 puffs salbutamol) before the ozone exposure (250 ppb, 3 h intermittent exercise). Sputum was induced 3 h after the end of exposure.


RESULTS
Sputum neutrophils, sputum CD14+ cells, as well as concentrations of IL1B, IL6, IL8, MMP9, and TNFA in sputum supernatant significantly increased after ozone exposure (n = 24). The percentage of sputum neutrophils (n = 12 who completed all treatments) did not change following treatment with different doses of PUR118. The high dose treatment group (n = 16) showed a decrease in the percentage and number of sputum macrophages (p ≤ 0.05) as well as a decrease in blood neutrophils (p = 0.04), and an increase in blood CD14 + cells (p = 0.04) compared to baseline. All dosages of PUR118 were safe and well tolerated.


CONCLUSIONS
Ozone challenge resulted in the expected and significant increase of sputum inflammatory parameters. Treatment with multiple rising doses of PUR118 was safe and three applications within 25 h prior to the ozone challenge had small effects on ozone-induced airway inflammation.


BACKGROUND
ClinicalTrials.gov: NCT01690949. Registered 12 September 2012.
Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, 30625, Hannover, Germany. olaf.holz@item.fraunhofer.de.|Member of the German Center for Lung Research (BREATH), Hannover, Germany. olaf.holz@item.fraunhofer.de.
Olaf
O
Holz
Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, 30625, Hannover, Germany.
H
H
Biller
Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, 30625, Hannover, Germany.
M
M
Mueller
Pulmatrix, Inc., Lexington, MA, USA.
K
K
Kane
Pulmatrix, Inc., Lexington, MA, USA.
M
M
Rosano
Pulmatrix, Inc., Lexington, MA, USA.
J
J
Hanrahan
Pulmatrix, Inc., Lexington, MA, USA.
D L
DL
Hava
Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, 30625, Hannover, Germany.|Member of the German Center for Lung Research (BREATH), Hannover, Germany.
J M
JM
Hohlfeld
D000280:Administration, Inhalation; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D017610:Calcium Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007773:Lactates / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects; D010126:Ozone / Q000009:adverse effects*; D012137:Respiratory System / Q000187:drug effects*; D016037:Single-Blind Method; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; C508606:CXCL8 protein, human; D017610:Calcium Compounds; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D007773:Lactates; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha; C110051:calcium lactate; D010126:Ozone; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9