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Asthma or COPD: efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor


Many patients with asthma or chronic obstructive pulmonary disease ( COPD ) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug.
Researchers have assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 ( PDE3 ) and PDE4 inhibitor, RPL554 for its ability to act as a bronchodilator and anti-inflammatory drug.

During the period 2009-2013, researchers undertook four proof-of-concept clinical trials in the Netherlands, Italy, and the UK. Nebulised RPL554 was examined in study 1 for safety in 18 healthy men who were randomly assigned ( 1:1:1 ) to receive an inhaled dose of RPL554 ( 0.003 mg/kg or 0.009 mg/kg ) or placebo by a computer-generated randomisation table.

Subsequently, six non-smoking men with mild allergic asthma received single doses of RPL554 ( three received 0.009 mg/kg and three received 0.018 mg/kg ) in an open-label, adaptive study, and then ten men with mild allergic asthma were randomly assigned to receive placebo or RPL554 ( 0.018 mg/kg ) by a computer-generated randomisation table for an assessment of safety, bronchodilation, and bronchoprotection.
Study 2 examined the reproducibility of the bronchodilator response to a daily dose of nebulised RPL554 ( 0.018 mg/kg ) for 6 consecutive days in a single-blind ( patients masked ), placebo-controlled study in 12 men with clinically stable asthma.
The safety and bronchodilator effect of RPL554 ( 0.018 mg/kg ) was assessed in study 3, an open-label, placebo-controlled crossover trial, in 12 men with mild-to-moderate COPD.
In study 4, a placebo-controlled crossover trial, the effect of RPL554 ( 0.018 mg/kg ) on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum was investigated in 21 healthy men.
In studies 3 and 4, randomisation was done by computer-generated permutation with a block size of two for study 3 and four for study 4. Unless otherwise stated, participants and clinicians were masked to treatment assignment.
Analyses were by intention-to-treat.

Safety was a primary endpoint of studies 1 and 3 and a secondary endpoint of studies 2 and 4. Overall, RPL554 was well tolerated, and adverse events were generally mild and of equal frequency between placebo and active treatment groups.

Efficacy was a primary endpoint of study 2 and a secondary endpoint of studies 1 and 3. Study 1 measured change in forced expiratory volume in 1 s ( FEV1 ) and provocative concentration of Methacholine causing a 20% fall in FEV1 ( PC20MCh ) in participants with asthma.
RPL554 produced rapid bronchodilation in patients with asthma with an FEV1 increase at 1 h of 520 mL ( p less than 0.0001 ), which was a 14% increase from placebo, and increased the PC20MCh by 1.5 doubling doses ( p=0.004 ) compared with placebo.

The primary endpoint of study 2 was maximum FEV1 reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV1 from placebo on day 1 ( 555 mL ), day 3 ( 505 mL ), and day 6 ( 485 mL; overall p less than 0.0001 ).

A secondary endpoint of study 3 ( patients with COPD ) was the increase from baseline in FEV1. RPL554 produced bronchodilation with a mean maximum FEV1 increase of 17.2%.

In healthy individuals ( study 4 ), the primary endpoint was percentage change in neutrophil counts in induced sputum 6 h after lipopolysaccharide challenge. RPL554 ( 0.018 mg/kg ) did not significantly reduce the percentage of neutrophils in sputum ( 80.3% in the RPL554 group vs 84.2% in the placebo group; difference -3.9%; p=0.15 ), since RPL554 significantly reduced neutrophils ( p=0.002 ) and total cells ( p=0.002 ) to a similar degree.

In four exploratory studies, inhaled RPL554 is an effective and well tolerated bronchodilator, bronchoprotector, and anti-inflammatory drug and further studies will establish the full potential of this new drug for the treatment of patients with COPD or asthma. ( Xagena )

Franciosi LG et al, The Lancet Respiratory Medicine 2013; 1: 714-727

XagenaMedicine_2013



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