A unique inhaled drug, RPL554, was effective and well-tolerated as a bronchodilator, bronchoprotector, and anti-inflammatory drug in patients with chronic obstructive pulmonary disease (COPD) or asthma, according to findings from exploratory clinical studies.
The results were published online October 24 in the Lancet Respiratory Medicine.
RPL554 is a dual inhibitor blocking the activity of 2 phosphodiesterase enzymes: phosphodiesterase 3 (PDE3) and PDE4.
Standard treatment for asthma or COPD typically includes an inhaled bronchodilator and anti-inflammatory glucocorticosteroid. However, severe forms of these diseases are often refractory to this pharmacotherapy. Long-acting β2 agonists may even worsen asthma symptoms, and corticosteroids may have significant adverse effects.
"We desperately need new effective therapies for COPD patients that target different pathways," Professor Jadwiga A. Wedzicha, MD, from University College London, United Kingdom, and author of an accompanying comment, told Medscape Medical News. "Currently we have bronchodilators that are either long-acting beta agonists or long-acting anti-muscarinics, and inhaled corticosteroids."
The investigators therefore performed 4 proof-of-concept clinical trials in the Netherlands, Italy, and the United Kingdom to determine the bronchodilator and anti-inflammatory efficacy and safety of RPL554.
Study 1 was a safety study conducted between February 2009 and January 2013. The investigators randomly assigned 18 healthy men 1:1:1 to receive an inhaled dose of nebulized RPL554 (0.003 mg/kg or 0.009 mg/kg) or placebo.
The study also included an open-label, adaptive phase in which 6 nonsmoking men with mild allergic asthma received single doses of RPL554 (3 received 0.009 mg/kg and 3 received 0.018 mg/kg). To evaluate safety, bronchodilation, and bronchoprotection, the investigators enrolled an additional 10 men with mild allergic asthma who were randomly assigned to receive placebo or RPL554 (0.018 mg/kg).
Study 2 was a single-blind (patients masked), placebo-controlled study of 12 men with clinically stable asthma. The investigators tested the reproducibility of the bronchodilator response to nebulized RPL554, 0.018 mg/kg daily, for 6 consecutive days. Efficacy was the primary endpoint, and safety was a secondary endpoint.
Study 3 was an open-label, placebo-controlled crossover trial examining the safety and bronchodilator efficacy of RPL554, 0.018 mg/kg, in 12 men with mild-to-moderate COPD.
Study 4 was a placebo-controlled, crossover trial in 21 healthy men. The investigators studied the effect of RPL554, 0.018 mg/kg, on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum. Safety was a secondary endpoint.
For each study, the researchers analyzed data with an intention-to-treat population, and the participants and clinicians were blinded to treatment assignment unless otherwise indicated.
RPL554 Appears to Be Safe, Effective
RPL554 was well-tolerated overall. Placebo and active-treatment groups had equal frequency of adverse events, which were generally mild.
"Although other PDE4 inhibitors can cause gastrointestinal side effects when given orally, none were reported at any dose of RPL554 tested in these trials," lead investigator Professor Clive Page, MD, from King's College London, United Kingdom, said in a journal news release.
In study 1, participants with asthma had rapid bronchodilation with RPL554 with an increase in forced expiratory volume in 1 second (FEV1) of 520 mL at 1 hour (95% confidence interval [CI], 320 - 720 mL; P< .0001). The provocative concentration of methacholine causing a 20% fall in FEV1 was increased by 1.5 doubling doses (95% CI, 0.63 - 2.28 doses; P = .004) for RPL554 compared with placebo.
In study 2, RPL554 was associated with a similar maximum mean increase over placebo in FEV1 6 hours after dosing on day 1 (555 mL; 95% CI, 442 - 668 mL), day 3 (505 mL; 95% CI, 392 - 618 mL), and day 6 (485 mL; 95% CI, 371 - 598 mL; overall P < .0001) in patients with asthma.
Patients with COPD who enrolled in study 3 had a mean maximum FEV1 increase of 17.2% ± 5.2% from baseline in response to RPL554. This bronchodilator response is at least as effective as that of salbutamol, a widely use β2 agonist.
Study 4 showed that in healthy individuals, the proportion of neutrophils in induced sputum 6 hours after lipopolysaccharide challenge was not significantly lower with RPL554 (0.018 mg/kg) than with placebo, because RPL554 reduced neutrophils (P = .002) and total cells (P = .002) to a similar extent. The percentage of neutrophils in sputum was 80.3% in the RPL554 group and 84.2% in the placebo group (difference, −3.9%; 95% CI, −9.4% to 1.6%; P = 0.15). Nonetheless, inhibition of the bacterial component lipopolysaccharide by RPL554 suggests it has significant anti-inflammatory activity.
Additional Research Needed
"These studies give us a glimpse into the potential bronchodilator, bronchoprotective, and anti-inflammatory effects of this drug," Dr. Page said in the journal news release. "So far trials have run for 7 days or less and there is a need to look at longer-lasting effects. Further studies are needed to better understand the full potential of this new therapy for COPD and asthma."
Dr. Wedzicha, who was not involved in the trials, notes that RPL554 "could be one of the most substantial advances for some time in the management of patients with chronic airway obstruction," but agrees additional research is needed.
Limitations of the studies done thus far include their short duration, small sample sizes, open-label or single-blind design in some of the studies, and possible lack of generalizability to women or other populations not enrolled in the studies.
Careful evaluation of any cardiovascular effects of RPL554 will be important over the longer term, particularly if RPL554 is eventually used with other bronchodilators, as cardiac comorbidity is common in patients with COPD. Additional surveillance for possibly increased risk for infection with RPL554 will also be needed, as inhaled corticosteroids may increase airway bacterial colonization in patients with COPD.
"The data show an encouraging safety profile, but more work will have to be done on safety when larger studies are done," Dr. Wedzicha told Medscape Medical News. "RPL554 is a very sensible approach, as it targets two pathways in COPD that are key to disease progression and symptomatic burdens."
Verona Pharma funded these studies and has various financial relationships with some of the other study authors, including current or former employment. Some of the study authors also reported various financial disclosures involving AstraZeneca, GlaxoSmithKline, Chiesi, Boehringer Ingelheim, Forest, Takeda, Roche, Novartis, Cipla, Almirall, and/or Merck. Dr. Wedzicha has received honoraria for lectures or advisory boards, or both, from Takeda, Novartis, GlaxoSmithKline, Pfizer, Vifor Pharma, Boehringer Ingelheim, and Bayer, as well as research grants from GlaxoSmithKline, Takeda, Novartis, Johnson & Johnson, and Chiesi. She has no financial disclosures involving Verona Pharma.
Lancet Resp Med. Published online October 25, 2013. Article abstract, Comment extract
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