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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).
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.
PDE-IV INHIBITION
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 Arfilo 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.
MARKETING COMMENTARY
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.
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