Philippe Bareille

Treatment with a peroxisomal proliferator activated receptor gamma agonist has a modest effect in the allergen challenge model in asthma: A randomised controlled trial

PURPOSE A considerable body of non clinical evidence has accumulated to support peroxisomal proliferator-activated receptor gamma agonists as candidate anti-inflammatory drugs in asthma. We utilized rosiglitazone as a tool compound in the inhaled allergen challenge model of asthma. METHODS A single centre, double-blind, randomised, placebo controlled, two period cross-over study. Subjects received rosiglitazone 4mg and placebo twice daily for 28 days in random order. On day 28, inhaled allergen challenge was performed 1 hour post-dose. A methacholine challenge was performed on day 29 and an adenosine monophosphate challenge on day 14. Exhaled nitric oxide was measured on days 1, 14, 28, 29. Blood was collected pre dose on days 1, 14 and 28 and analysed for markers associated with PPAR activity and systemic markers of inflammation. RESULTS The late asthmatic reaction (LAR) change from post saline FEV(1) from 4-10 hrs post allergen on day 28 was statistically significant for the weighted mean LAR. The difference in weighted mean was 0.06 L (95% CI 0.01 to 0.11) which equates to a 15% attenuation of the response during placebo treatment. This was accompanied by trends in other markers of efficacy and anti-inflammatory activity but none were considered major effects. DISCUSSION Treatment with a PPARgamma agonist (rosiglitazone) was associated with a modest (15%) reduction in the late asthmatic reaction in the allergen challenge model of asthma. Based on the results of this study, PPARgamma agonist monotherapy is unlikely to represent a clinically useful intervention in human asthma. Registered with www.clinicaltrials.gov (NCT00318630).

Fluticasone furoate versus placebo in symptoms of grass-pollen allergic rhinitis induced by exposure in the Vienna Challenge Chamber

ABSTRACT Objective: The Vienna Challenge Chamber (VCC) offers a controlled and controllable paradigm in which to reproducibly evaluate the efficacy of anti-allergic treatment. The aim of this study was to assess the efficacy of the novel intranasal corticosteroid fluticasone furoate (FF) in the VCC. Methods: The single-centre, randomised, double-blind, placebo-controlled, two-period crossover study was conducted in 59 adult males with grass pollen allergic rhinitis (AR). Patients received either Fluticasone furoate 200 mcg once-daily, or placebo intranasally for 8 days. AR symptoms were induced during 4-hour allergen challenges with grass pollen in the VCC at the end of each 8-day treatment period. A first challenge was conducted at 1–5 hours post-dose, followed by a second challenge at 22–26 hours post-dose. The primary endpoint was total nasal symptom score (TNSS; sum of itch, sneeze, rhinorrhoea, obstruction symptoms assessed on a categorical scale of 0–3) weighted mean over 2–5 hours post-dose. Secondary endpoints included: TNSS weighted mean over 23–26 hours post-dose and global symptom score, eye symptom score, nasal secretions and nasal airflow weighted means over 2–5 and 23–26 hours post-dose. Results: Fluticasone furoate showed consistent attenuation of AR symptoms in both the early and late challenges. Compared with placebo, weighted mean of TNSS was reduced on average by 4.14 point-scores at 2–5 hours post-dose and 3.63 point scores at 23–26 hours post-dose. These positive effects were also seen across all secondary endpoints. Conclusion: An 8-day treatment course of intranasal FF 200 mcg given once-daily statistically significantly reduced symptoms of AR including associated eye symptoms. Statistical significance was declared where the relevant two-sided 95 % confidence interval did not contain zero. This positive effect was sustained over 24 hours suggesting that fluticasone furoate could be efficacious as a once daily steroid.

The effects of a TRPV1 antagonist, SB-705498, in the treatment of seasonal allergic rhinitis.

BACKGROUND Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 μg (FP), FP 200 μg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Specificity of human anti‐variable heavy (VH) chain autoantibodies and impact on the design and clinical testing of a VH domain antibody antagonist of tumour necrosis factor‐α receptor 1

During clinical trials of a tumour necrosis factor (TNF)‐R1 domain antibody (dAb™) antagonist (GSK1995057), infusion reactions consistent with cytokine release were observed in healthy subjects with high levels of a novel, pre‐existing human anti‐VH (HAVH) autoantibody. In the presence of HAVH autoantibodies, GSK1995057 induced cytokine release in vitro due to binding of HAVH autoantibodies to a framework region of the dAb. The epitope on GSK1995057 was characterized and dAbs with reduced binding to HAVH autoantibodies were generated; pharmacological comparability was determined in human in‐vitro systems and in‐vivo animal experiments. A Phase I clinical trial was conducted to investigate the safety and tolerability of the modified dAb (GSK2862277). A significant reduction in HAVH binding was achieved by adding a single alanine residue at the C‐terminus to create GSK2862277. Screening a pool of healthy donors demonstrated a reduced frequency of pre‐existing autoantibodies from 51% to 7%; in all other respects, GSK2862277 and the parent dAb were comparable. In the Phase I trial, GSK2862277 was well tolerated by both the inhaled and intravenous routes. One subject experienced a mild infusion reaction with cytokine release following intravenous dosing. Subsequently, this subject was found to have high levels of a novel pre‐existing antibody specific to the extended C‐terminus of GSK2862277. Despite the reduced binding of GSK2862277 to pre‐existing HAVH autoantibodies, adverse effects associated with the presence of a novel pre‐existing antibody response specific to the modified dAb framework were identified and highlight the challenge of developing biological antagonists to this class of receptor.

Efficacy and safety of once-daily GW870086 a novel selective glucocorticoid in mild-moderate asthmatics: a randomised, two-way crossover, controlled clinical trial.

Abstract Objective: To assess the efficacy of inhaled, repeat doses (28 days) of the glucocorticoid agonist GW870086, which has been designed to inhibit gene transrepression of the glucocorticoid receptor while preserving its transactivation. Methods: This was a randomised, placebo-controlled, two-way crossover study, approved by the independent ethics committees of the study centres. Subjects with FEV1 40–85% of the predicted normal value (n = 36) received GW870086 (1 mg, once-daily) and placebo. Results: No significant change from baseline in forced expiratory volume in one second (FEV1) was seen following administration of GW8780086 1 mg relative to placebo; mean FEV1 (day 28), relative to placebo, was (95% confidence intervals [CI]) −0.077 L (−0.192, 0.038). A moderate positive placebo response was observed on Days 14 and 28: Mean FEV1 (95% CI) was 0.115 L (0.040, 0.189) and 0.115 L (0.019, 0.212), respectively. The placebo response was more notable in treatment period 1 and was larger than the response to GW870086 1 mg on day 28, irrespective of period. Peak expiratory flow rate results were consistent with FEV1 and no difference was seen between the GW870086 and placebo for rescue medication usage. Conclusion: This total lack of effect suggests that repeat-dose GW8700861 mg has suboptimal efficacy in mild to moderate asthma.

TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis.

BACKGROUND The transient receptor potential vanilloid 1 (TRPV1)-expressing sensory C-fibers may play a role in the development of nasal hyper-responsiveness and symptoms of non-allergic rhinitis (NAR). OBJECTIVE To evaluate the effects of a TRPV1-antagonist, SB-705498, on cold dry air (CDA)-induced symptoms in patients with NAR. METHODS This randomized, double-blind, placebo-controlled, crossover study evaluated 14 days of once daily, topical intranasal SB-705498 12 mg in 40 patients with NAR using a CDA challenge experimental model in an environmental exposure chamber (EEC, Cetero Research, Mississauga, Ontario). The primary endpoint was total symptom score (TSS), expressed as weighted mean over 60 minutes (WM0-60) or maximum TSS at 1 hour and 24 hours postdosing. RESULTS Treatment with SB-705498, relative to placebo, did not improve WM0-60 or maximum TSS at 1 hour and 24 hours post-dosing on days 1 or 14. Mean (95% CI) treatment differences (SB-705498 - placebo) on day 14 were, for WM0-60 at 1 hour: -0.12 (-0.60, 0.36); for maximum TSS at 1 hour: -0.03 (-0.58, 0.51). SB-705498 had no impact on any other efficacy parameters. SB-705498 was well tolerated and pharmacokinetics analysis supported the dosing regimen. CONCLUSION SB-705498 12 mg for 14 days did not alleviate the CDA-induced symptoms of NAR. Despite engagement of the TRPV1 receptor, there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

The improved efficacy of a fixed‐dose combination of fluticasone furoate and levocabastine relative to the individual components in the treatment of allergic rhinitis

Allergic rhinitis (AR) is a common chronic disease, which has significant detrimental effect on well‐being and quality of life as well as substantial socio‐economic impact. Combination pharmacotherapy is utilized by 40–50% of patients to treat their symptoms.

Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury

Background Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. Methods We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. Results Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. Conclusion These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. Trial registration number ClinicalTrials.gov NCT01587807.

Clinical efficacy and tolerability of a novel selective corticosteroid in atopic dermatitis--two randomised controlled trials.

Topical corticosteroids remain the first-line therapy for atopic dermatitis (AD). Hence, we investigated the efficacy and safety profile of a novel selective corticosteroid, GW870086. We performed 2 randomised, double-blind, controlled studies with 25 AD patients and 20 healthy subjects. The changes in the Three-Item Severity (TIS) score and the skin thickness were the primary end points, respectively. The adjusted TIS score (day 22) shows that the novel corticosteroid resulted in a non-significant, but dose-dependent reduction compared to placebo (GW870086 0.2% vs. placebo = -0.38, GW870086 2% vs. placebo = -0.89). Significant skin thinning was observed in the second study on days 14 and 21 when patients were treated with the comparator but not with the novel corticosteroid compared to placebo. The clinical efficacy of the new selective corticosteroid was not superior to placebo, although a dose-dependent improvement upon treatment was noticed without the onset of skin thinning.

The pharmacodynamics, pharmacokinetics, safety and tolerability of inhaled fluticasone furoate and vilanterol administered alone or simultaneously as fluticasone furoate/vilanterol.

To investigate the potential for systemic pharmacokinetic (PK) and pharmacodynamic (PD) interactions between inhaled fluticasone furoate (FF) and vilanterol (VI) when delivered simultaneously via the ELLIPTA™ dry powder inhaler (DPI).