Therapy Analysis - Asthma
Pharma trends and treatments
A trends search on Pharmaprojects (graph 1) data shows that the number of asthma drugs in preclinical development has declined since 2002, whereas the proportion of new candidates in clinical trials has generally increased, particularly those in Phase II. This suggests that while the discovery of new candidates has been slow, those that are already in preclinical and early clinical trials have nevertheless been successful enough to reach Phase II. Activity within the Phase III market on the other hand, has been less energetic; the number of compounds in Phase III has declined since 2005. This may be due to the fact that the utilization of a vast array of novel approaches results in a large number of candidates being deemed unsuccessful before they reach the later stages of development. This may also explain the worrying reduction in the number of registrations and launches of asthma drugs over recent years.
Although there is no cure, asthmatics have access to two types of medications to control their asthma. Firstline 'quick relief' or 'rescue' treatment normally includes inhaled fast-acting B2AR agonists such as the widelyused, inhalable salbutamol sulfate, which acts on the GPCRs in the smooth muscle cells of the airways to cause bronchodilation and reverse an asthma attack. Alternatively, anticholingergics such as ipratropium bromide, also a bronchodilator, may be used to relieve new or acute asthma symptoms, and this drug is frequently paired with a short-acting B2AR agonist, however it is not often used as it can be up to an hour before it takes effect.
The effects of quick relief treatments are short-lived, and so those with persistent asthma use long-term preventatives such as inhaled, long-acting B2AR agonists, often in combination with inhaled glucocorticoids such as beclometasone, budesonide and fluticasone, which act to reduce inflammation to prevent symptoms such as wheezing. However, steroids are nonselective and tend to be unsuitable for paediatric use, while B2AR agonist treatment requires high dosing, so it tends to give rise to side effects such as increased heart rate and feelings of nervousness. ..despite the draw-backs of modern drugs, asthma treatments have still shown marked improvments over time..Furthermore, B2ARs can be ineffective in some patients - particularly smokers - and some scientists argue that they are less effective than corticosteroids in maintaining control over the condition. Indeed, in one study in patients who used a combination of the two, reducing their B2AR antagonist dose was actually found to improve their symptoms.
Despite the draw-backs of modern drugs, asthma treatments have still shown marked improvments over time. Previously the first-line choice for asthma, the long-acting bronchodilator theophylline was confirmed to have bronchodilatory activity in 1859, originally discovered by doctors investigating the efficacy of folk remedies, one of which was, intriguingly, coffee. The elucidation of the xanthines' long-elusive mechanism of phosphodiesterase inhibition however, revealed that they were targeting phosphodiesterases in general, causing multiple unwanted effects in other organ systems including the gastrointestinal system. Although theophylline is still sometimes administered orally for nocturnal or severe persistent asthma, the xanthines lost popularity with the arrival of the more selective and efficacious medications such as the B2AR agonists.
The identification of the mutations involved in heritable asthma has led to gene therapy approaches being explored, but it is an avenue few companies have exploited. Pharmaprojects lists only one gene therapy candidate, a Notch pathway agonist under collaborative development by Celldex (Medarex) and PowderMed. This compound, which inhibits IL-4 production, has not yet reached clinical development, and further news on its development is awaited.
