MR889, a neutrophil elastase inhibitor, in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled clinical trial

Abstract

We investigated whether MR889, a synthetic cyclic thiolic elastase inhibitor, administered for a period of 4 weeks to chronic obstructive pulmonary disease (COPD) patients, is well-tolerated, and whether it modifies biochemical indices of lung destruction.The study was a double-blind, randomized, placebo-controlled clinical trial in COPD patients. Thirty subjects were administered MR889 orally at a dose of 500 mg b.i.d. for 4 weeks, and 30 received placebo following the same schedule. In addition to safety parameters, MR889 efficacy was checked by a pretreatment/posttreatment evaluation of levels of plasma elastin-derived peptides and urinary desmosine.There were no statistically significant differences between pretreatment and posttreatment efficacy parameter levels either in the control group or in the treated group. However, in a subset of treated patients with a short disease duration, the level of urinary desmosine dropped significantly with respect to pretreatment values (p=0.004).We conclude that MR889 is safe to administer to COPD patients for a period of at least 4 weeks. During this time, MR889 does not modify biochemical markers of lung destruction in unselected COPD patients. Nevertheless, a subset of treated patients with fairly short disease duration showed a post-treatment reduction of desmosine urine levels, thus justifying the need for further studies to prove the efficacy of MR889 in modulating indices of lung destruction in COPD.

Desmosine as a biomarker of elastin degradation in COPD: current status and future directions

“…However, since analysis of individual levels of urine DES showed in some cases a consistent drop, data have been analysed in relation to disease characteristics. When patients were subdivided by duration of disease, MR889-treated subjects with more recent onset of symptoms (,13.3 yrs in this series), showed a significant decrease of urinary DES after treatment (p,0.004), compared with that in MR889-treated patients with a longer duration of symptoms or in the two subgroups of placebo-treated subjects [32]. The baseline FEV1 of the two subgroups with shorter duration disease was slightly, but not significantly, better than that of the two subsets with longer disease.…”

“…A few years later, a similar study design was applied to a trial dealing with an oral synthetic elastase inhibitor [32]. MR889 is a cyclic thionic, reversible, slow-binding, competitive serine proteinase inhibitor specific for neutrophil elastase [33].…”

Chronic obstructive pulmonary disease: molecular and cellularmechanisms

“…It is not certain whether the drugs failed or the clinical trials were not adequately designed. An NE inhibitor MR889 had no effect on urinary desmosine in unselected COPD patients, but a small reduction was seen in patients with a relatively short history [194]. The macrolide antibiotics erythromycin and flurithromycin have also been shown to inhibit NE activity [195] and this might account for their beneficial effect on mucus hypersecretion [196].…”

AZD9668: Pharmacological Characterization of a Novel Oral Inhibitor of Neutrophil Elastase

“…By measuring effects on markers relevant to human lung disease, these data show that AZD9668 inhibits NE-mediated lung injury. Likewise, 6 weeks of treatment with 2-(2-thiophencarboxythio)-N-[dihydro-2(3H)-thiophenone-3-yl]-propionamide (MR889), a synthetic cyclic thiolic NE inhibitor, reduced desmosine levels in a subgroup of patients with COPD with short disease duration (Luisetti et al, 1996).…”