A Controlled trial of 6 week's treatment with a novel inhaled PDE4 inhibitor of COPD. J. Vestbo, L. Tan, G. Atkinson, J. Ward; the UK-500,001 Global Study Team. (Eur Respir J; 2009 Feb 12. Epub ahead of print).
Anti-inflammatory drugs are lacking in COPD and inhibitors of the phosphodiesterase type-4 (PDE4) enzyme have been suggested as an interesting class of drugs to treat inflammation in COPD. We report the findings of a Phase II trial of a novel inhaled PDE4-inhibitor. Three doses of the compound UK-500,001 were tested, 0.1mg, 0.4mg and 1mg twice daily (BID), in a double-blind placebo-controlled 6 week trial in 209 patients with moderate or severe COPD. The primary efficacy parameter was trough FEV1 after 6 weeks of treatment, and secondary endpoints included other lung function endpoints, and symptom scores assessed at 2 weekly intervals. The study was stopped following a planned interim analysis for futility. No effect was observed at any dose after 6 weeks of treatment on the primary efficacy parameter, other measures of lung function or symptom scores. However, after the first 2 weeks of treatment, there was an improvement in the 1mg BID dose group compared to placebo on a number of outcome measures. The drug was well tolerated although PDE4-inhibitor related side effects were observed, especially in the highest dose group. Our findings question the role of inhaled PDE4-inhibitors in COPD.
Comments. There have now been several trials with oral PDE4 inhibitors including roflumilast and cilomilast that have shown efficacy but have produced significant side effect,s particularly gastrointestinal upset. PDE-4 inhibitors have been shown to reduce neutrophilia induced by lipopolysaccharide (LPS) and tumor necrosis factor-alpha in animal studies. Hence, this study looked at the use of an inhaled PDE4 inhibitor formulation with the primary endpoint being improvement in trough (Pre-dose) FEV-1 in a 6 week trial. After the first 150 patients were recruited, an interim futility analysis determined that there was no statistically significant benefit of the study drug over placebo and the study was terminated. While the authors do not appear optimistic as to the future of this particular inhaled formulation of a PDE4 inhibitor for treatment of COPD, the results are informative. Patients had GOLD stage II-III disease (mean FEV-1 1.45 L or 51%) with mean reversibility of around 15%. Hence, this is a group with similar characteristics to patients in registration trials for combination treatment with fluticasone/salmeterol and the tiotropium studies where there was a statistically significant improvement in trough FEV-1 but these are or have bronchodilator components, and the PDE-4 inhibitor is primarily an anti-inflammatory agent. We have not seen improvements in FEV-1 with inhaled steroids alone and hence it should not be surprising that this drug would not demonstrate a significant improvement in a primary endpoint that focuses on bronchodilation in a group that has generally less than a 200 cc improvement to standard bronchodilators. Further, there were some signs of improvement in secondary endpoints with regard to symptom scores and trough FEV-6, IC and FVC, but not enough patients were recruited to have enough power to detect statistically significant improvements. While there remain concerns about the use of these medications in terms of their efficacy versus safety, it is important that we consider the appropriate outcomes as primary endpoints (i.e. exacerbations, exercise endurance, symptom reduction) over appropriate periods of time before we discount their utility in COPD.
Superoxide dismutases, lung function and bronchial responsiveness in a general population. M. Siedlinski, C.C. van Diemen, D.S. Postma, J.M. Vonk, H.M. Boezen. (Eur Respir J; 2009 Feb 12. Epub ahead of print).
Oxidative stress is an important causative factor in the onset and progression of smoking-related lung diseases like chronic obstructive pulmonary disease (COPD). Superoxide Dismutases (SODs) can prevent an increase in oxidative burden .1,390 subjects from the prospective Vlagtwedde-Vlaardingen cohort were genotyped for 2 Single Nucleotide Polymorphisms (SNPs) in SOD2 and 4 SNPs in SOD3, that were further analyzed for associations with the presence of bronchial hyperresponsiveness (BHR; PC10 < / = 8 mg.ml(-1) of histamine), COPD (defined as GOLD stage > / = II), lung function level and the longitudinal course of FEV1.The intronic C5774T SNP of SOD2 was significantly associated with the presence of COPD and BHR in the total population. The T/T genotype for this polymorphism and the Val/Val genotype for the SOD2 Ala16Val substitution were risk factors for BHR in individuals without COPD. The SOD3 Arg213Gly substitution was associated with slower FEV1 decline in never smokers exclusively, and the SOD3 G(-4466)T SNP was associated with a lower Vital Capacity level.Both SOD2 polymorphisms are associated with BHR, a risk factor for COPD, while SOD2 C5774T additionally confers a risk for COPD in the total population. We furthermore confirm previously reported associations of SOD3 SNPs with lung function in the general population.
Comment. We have recognized that only a subset of smokers appear prone to develop COPD as a result of the effects of cigarette smoke. This has led to the search for susceptibility genes. The SODs represent excellent candidate genes to study for potential single nucleotide polymorphisms that may confer increased risk. This study had a large general population base cohort that was fairly homogeneous individuals of Caucasian Dutch descent that have been followed up to 25 years with spirometry measured every three years.
Association between CRHR1 polymorphism and improved lung function in response to inhaled corticosteroid in patients with COPD. W.J. Kim, S.S. Sheen, T.H. Kim, J.W. Huh, J.H. Lee, E.K. Kim, J.H. Lee, S.M. Lee, S. Lee, S.Y. Kim, T.R. Shin, H.I. Yoon, Y.M. Oh, S.D. Lee. (Respirology, 2009 Mar;14(2):260–3. Epub 2008 Dec 11).
Background and objective Inhaled corticosteroids are used to treat COPD and asthma. An association between sequence variants in the corticotrophin-releasing hormone receptor 1 (CRHR1) gene and improved lung function in asthmatics treated with inhaled corticosteroids was reported recently. This study investigated the association between the change in lung function in response to inhaled corticosteroids and single-nucleotide CRHR1 polymorphisms in patients with COPD.
Methods COPD patients (n = 87) with a positive smoking history were recruited from the pulmonary clinics of 11 hospitals in Korea. Patients were treated with fluticasone propionate and salmeterol for 12 weeks and lung function was measured at baseline and after the 12-week treatment. Eighty-four of the 87 subjects were successfully genotyped. RESULTS: Seventy-one patients with the wild-type GG genotype and 13 patients with the heterozygous GT genotype in rs242 941 were evaluated. After 12-week treatment, the change in FEV(1) was significantly higher in patients with wild-type GG genotype (6.0 +/− 0.8% of predicted FEV(1)) than in GT heterozygotes (−0.8 +/− 1.8, P = 0.003).
Conclusions Improved FEV(1) following inhaled corticosteroid and a long-acting beta2-agonist was associated with CRHR1 genetic polymorphism in patients with COPD.
Comments. While this is a relatively small study with perhaps not as a diverse subject population as might be found elsewhere, it provides insight into the clear importance of genetics not only in determining susceptibility but also to responses to therapy. While it is likely that the genetics of steroid responsiveness in COPD is much more complex than this single nucleotide polymorphism, it does point to this line of investigation being highly informative.