Indacaterol: a new long-acting bronchodilator effective in patients with COPD

Curated by Luigi Ferritto (1), Walter Ferritto (2), Giuseppe Fiorentino (3)

COPD: Size of the Problem

Chronic Obstructive Pulmonary Disease (COPD) is a chronic and only partially reversible condition of the airways, slowly progressive, caused by chronic inflammation of the airways and lung parenchyma. COPD is considered to be the fourth leading cause of death in Europe and the USA (at least 65, 000 deaths a year), recent studies have noted that mortality is increasing worldwide.

The total incidence is 6-8%, it mainly affects adult males, but a considerable increase in cases involving women has been noted in recent years.

The origin is a phlogosis of chronic character that lasts for years and affects the respiratory tract in the individual; this inflammation leads to a gradual loss of lung function. This dysfunction is not completely reversible, even if it is treated, and is caused mainly by smoking. Among the less common causes of COPD there is also passive smoking, environmental and occupational exposure to fine particles and chemicals.

Furthermore, a genetic predisposition to the disease (α1-antitrypsin deficiency) has been suspected for some time, which would explain the occurrence in some people unlike others with equal risk factors.

The disease had an exponential growth at the end of the last century, its presence in England alone in seven years increased by 25% in men and in 69% of women.

Indacaterol and COPD

From now on, there is a new ally to combat COPD; in fact the European agency (EMEA) has approved Indacaterol, a new drug developed by Novartis for the treatment of this disease.

Available via inhalation with once-a-day administration, Indacaterol has been approved at dosages of 150 and 300 mcg.

Previously known as QAB149, the drug was marketed under the Onbrez Breezhaler ® brand.

Indacaterol is the first beta-2 stimulant with 24-hour activity; before its introduction, an ultra long-acting anticholinergic, tiotropium, was already present, while, currently, the only long-acting beta-2s are salmeterol and formoterol which, however, have an average activity of 17 hours.

Indacaterol has shown a high selectivity towards beta-2 receptors, a rapid action activity and a long duration of action, which exceeds 24 hours; in fact, it is characterized by a rapid onset of the effect - thanks to a short receptor interaction that eliminates both tachyphylaxis and tolerance problems - guaranteeing over time (52 weeks) an effect on the pre-dose FEV1 completely superimposable to the initial effect.

It has no antagonistic effects against beta-2 active drugs to be used when needed and has an excellent cardiovascular safety profile when compared to other beta-2 stimulants. Indacaterol induces muscle relaxation, consequently an increase in the diameter of the respiratory tract, typically reduced in COPD and in asthma, while its anti-inflammatory action derives from the inhibition of the release of mediators by the pulmonary mast-cells.

The indacaterol represents the forefather of a new class of beta2-adrenergic bronchodilators, ( ULTRA-LABA ), structurally distinct from formoterol, salmeterol and salbutamol that thanks to its chemical characteristics (Indacaterol Maleate, Amphiphilic Molecule and Micronized in dry powder for inhalation use) was the first bronchodilator with a duration of action of about 24 hours which allows its daily administration.

Clinical Effectiveness

At the time of marketing, 4 clinical studies on COPD patients were available. The first compared the duration of action of indacaterol with tiotropium and was used to find the most appropriate dosage of the drug (dose finding study), was presented in Respiratory Medicine and compared different doses of indacaterol in the first period, then moving on to a treatment based on tiotropium. The concentrations of indacaterol on which it is concentrated are between 150 and 300 mcg. After 24 hours after the drug was administered, the various dosages tested showed a fairly homogeneous response in terms of bronchodilation, and this led the company to choose the definitive dosage (150 and 300 mcg). In comparison with tiotropium and placebo, indacaterol showed a better bronchodilation profile.

A second study was conducted on tolerability with different dosages up to doses of 600 mcg; even at these dosages (twice the maximum recommended dose) no worrying side effects emerged in terms of glycaemia, heart rate and QT interval. Thus at dosages of 400 and 600 mcg the drug is well tolerated.

A third study still evaluated the safety and tolerability after single inhalation of increasing doses of indacaterol, up to 3000 mcg. The primary objective was safety: the study showed nothing significant and it should be remembered that these doses were 10 times higher than the dosage used in clinical practice.

The latest study compared indacaterol, salmeterol and formoterol in terms of FEV1 as well as inspiratory capacity. This study demonstrated the excellent efficacy of indacaterol also in terms of inspiratory capacity, meeting the needs traced by a recent document of the ERS / ATS related to the outcomes to be considered to evaluate the efficacy of treatments in COPD patients.

Indacaterol behaves as a highly effective beta-2 adrenergic, with a faster onset of salmeterol and a significantly longer duration of action than either formoterol or salmeterol. The most common side effects reported following the use of the drug in clinical trials are nasopharyngitis, cough, upper respiratory tract infections and headache. They were normally mild or medium in size and became less frequent with continued therapy.

From the data in possession so far it can be deduced that:

Indacaterol possesses the characteristics of the ideal bronchodilator:
1. Selectivity
2. 24-hour bronchodilator effect
3. Rapid onset of action
4. Effective
5. Good security profile
6. No antagonism towards rescue medication
7. Simple inhalation device that requires low inspiratory flows (PIF ≥ 50L / min)
The indacaterol clinical development program has produced data indicating:
- Prolonged bronchodilation for 24h which allows for once daily administration.
- Improvement of FEV1 in 24h
- FEV1 Pre-dose improvement.
- Clinically significant bronchodilation from the 1st dose
- Bronchodilation that persists after repeated intakes
- Rapid onset of bronchodilation (5 ')
- Effective reduction of symptoms
- Increased resistance to physical exercise
- Net improvement in the quality of life of the patients
- Excellent tolerability profile