Safety, pharmacodynamics and pharmacokinetics of TPI 1020 in smokers with asthma

SummaryBackgroundTPI 1020 is a novel compound with potential for anti-neutrophil effects. TPI 1020 exerts its effects by a dual mechanism of action involving corticosteroid activity and controlled donation of nitric oxide.ObjectivesWe assessed the safety, pharmacodynamic and pharmacokinetic activity of ascending doses of TPI 1020 compared to budesonide in asthma.MethodsSmokers with mild asthma (n = 27) were randomized to receive either 600 mcg of TPI 1020 (n = 13) or 400 mcg of budesonide (n = 14) bid for 2 weeks followed by 1200 and 800 mcg bid, respectively, for an additional week.ResultThere was no serious adverse event and all but one adverse event were mild or moderate (severe headache with budesonide). Patients receiving TPI 1020 reported three-fold fewer treatment-emergent AEs (n = 13) than those receiving budesonide (n = 39). TPI 1020 had similar effects as budesonide on FEV1, PEF, rescue medication, asthma scoring system, methacholine response, sputum eosinophils and exhaled NO. Sputum neutrophils (%) tended to decrease more with TPI 1020 (32.6% decrease versus 3.7% increase for budesonide); the decrease occurring only in patients with high neutrophils at baseline. A significant difference favoring TPI 1020 was noted for CRP. Budesonide caused a statistically significant decrease in 24 h urinary free cortisol over 22 days (median of 4.4–2.8 mcg/ml, p = 0.01) whereas TPI 1020 had no such effect (4.4–5.8 mcg/ml), suggesting lower systemic corticosteroid exposure following TPI 1020 treatment.ConclusionTPI 1020 appears safe in asthmatic smokers and warrants further investigation in respiratory conditions.