Ariflo (Cilomilast) - Oral PDE-IV Inhibitor for
Ariflo (cilomilast) is an oral selective phosphodiesterase (PDE) IV inhibitor under development by GlaxoSmithKline Pharmaceuticals for treatment of COPD. After the demise of Merck's PDE-IV inhibitor (licensed from Celltech Group) in April 2003, Ariflo has emerged as the frontrunner in this new class of agents for inflammatory airways diseases, such as COPD.
GlaxoSmithKline filed for drug approval with the US FDA at the end of 2002 and in January 2003 with the European Medicines Evaluation Agency (EMEA). In October 2003 the FDA issued an approvable letter for use of Ariflo in maintenance of lung function in COPD patients poorly responsive to salbutamol, despite an earlier decision by the FDA advisory panel to reject approval.
Before issuing final approval, however, the FDA has requested additional efficacy and safety data. This is likely to focus on sustainability of clinical benefits and safety of Ariflo in long-term use.
COPD drug treatments
Primarily smoking-related, COPD is a progressive disorder of the lungs characterised by airflow obstruction. It is an umbrella term used to define diseases that cause airflow obstruction, such as chronic bronchitis, emphysema or combinations of both. Estimates suggest that 80% to 90% of all cases of COPD are caused by smoking, with smokers ten times more likely to die from COPD compared with non-smokers.
Worldwide as many as 600 million people have COPD. In the mid-1990s COPD was the fifth leading cause of mortality worldwide. The World Health Organisation predicts that by 2020 it will be the third leading cause of death in the world.
Drugs which address the underlying tissue damage in COPD and prevent the progressive decline in lung function which is a hallmark of this disease are urgently needed. Currently available agents, such as inhaled corticosteroids, β-agonists and anticholinergics, offer only symptomatic relief.
The phosphodiesterases are enzymes responsible for hydrolysis of cyclic adenosine monophosphate (cAMP), a naturally occurring substance that mediates suppression of inflammatory cell activation. PDE-IV is the predominant phosphodiesterase isoenzyme in respiratory tissues and is therefore a suitable target for therapy of inflammatory airways diseases such as COPD.
By inhibiting PDE-IV, drugs such as Ariflo increase levels of cAMP and reduce inflammatory cell activation in the respiratory tract. Results from pre-clinical investigations with Ariflo suggest it may:
- Reduce bronchoconstrction
- Reduce inflammation and subsequent damage to respiraotry tissues
- Reduce cough and dyspnoea (breathlessness)
Selective PDE-IV inhibitors, such as Ariflo, have potential to not only target symptoms of the disease but to also ameliorate the underlying components of airway obstruction and inflammation. Thus, they represent a completely new approach to the treatment of COPD.
Efficacy and safety of Ariflo in COPD patients
The efficacy and safety of Ariflo has been investigated in a series of clinical trials in patients with COPD. Phase II trial data was presented at the 1999 annual meeting of the European Respiratory Society in Madrid, Spain.
Results of the double-blind, placebo-controlled, randomised, dose-ranging study in 424 patients showed that a twice-daily dose of Ariflo 15mg significantly improved lung function (an average 10% improvement from baseline in FEV1) as well as reducing breathlessness and bronchodilator use. Quality of life as measured by the St. George's Respiratory Questionnaire (SGRQ), a disease-specific tool, also improved following treatment with Ariflo.
A large-scale phase III trial of Ariflo in over 2,000 patients with stable COPD has confirmed the promising early findings.
Results from the six-month double-blind, placebo-controlled phase III trial showed that treatment with twice-daily Ariflo 15mg produced a sustained improvement in lung function as well as a reduction in the risk of acute exacerbations in patients with COPD. Again an improvement in QOL as measured by the SGRQ was observed in the Ariflo-treated group.
The trial data, which was presented in May 2001 at the annual meeting of the American Thoracic Society, also showed that Ariflo was safe and well tolerated. Consistent with the mode of action of PDE-IV inhibitors, the most common treatment-related adverse with Ariflo are nausea, diarrhoea and abdominal pain.
Among drugs in development for COPD, the selective PDE-IV inhibitors are seen as a potentially important new class of agents for this devastating lung disease. Dose-limiting gastrointestinal toxicity has however been a major concern with these agents.
Several investigational drugs have caused excessive nausea and their development discontinued. No PDE-IV inhibitors have been approved in the US or Europe for COPD. If approved, Arfilo will be the first of this new class of drugs on the market. As an oral preparation it may offer advantages over the inhaled preparations which dominate treatment of COPD.
PDE-IV inhibitors are a major focus of GlaxoSmithKline's research and development effort. The company signed an agreement with elbion AG in July 2002 for worldwide development and commercialisation rights to the PDE-IV inhibitor AWD12-281. Phase I trials by inhaled delivery of AWD12-281 are underway in patients with COPD.