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

Summary 

Background

TPI 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.

Objectives

We assessed the safety, pharmacodynamic and pharmacokinetic activity of ascending doses of TPI 1020 compared to budesonide in asthma.

Methods

Smokers with mild asthma (n=27) were randomized to receive either 600mcg of TPI 1020 (n=13) or 400mcg of budesonide (n=14) bid for 2weeks followed by 1200 and 800mcg bid, respectively, for an additional week.

Result

There 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 24h urinary free cortisol over 22days (median of 4.4–2.8mcg/ml, p=0.01) whereas TPI 1020 had no such effect (4.4–5.8mcg/ml), suggesting lower systemic corticosteroid exposure following TPI 1020 treatment.

Conclusion

TPI 1020 appears safe in asthmatic smokers and warrants further investigation in respiratory conditions.

Keywords: Airway inflammation, Asthma/drug therapy, Nitric oxide, Neutrophils

Abbreviations: ACSS, asthma control scoring system, AUC, area under the curve, BUN, blood urea nitrogen, CBC, complete blood counts, Cmax, maximal concentration, COPD, chronic obstructive pulmonary disease, CRP, C-reactive protein, ECG, electrocardiograms, eNO, exhaled nitric oxide, FEV₁, forced expiratory volume in 1s, ITT, intent to treat, PEF, peak expiratory flow, LPS, lipopolysaccharide, NO, nitric oxide, PC₂₀, provocative concentration that causes a 20% fall, PD, pharmacodynamic, PK, pharmacokinetic, ppm, parts per million, QTc, QT interval corrected for rate, SD, standard deviation, SE, standard error, SEM, standard error of the mean, Tmax, time at maximal concentration, UFC, urinary free cortisol