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Breathing easier

Indacaterol has surpassed the current standard of care for COPD in pivotal phase III trials

Dandelion being blownResults from the phase III INSIST study have shown that once-daily treatment with Novartis' indacaterol inhaler (Onbrez Breezhaler) is significantly better at improving lung function and reducing breathlessness in patients with chronic obstructive pulmonary disease (COPD) than twice-daily salmeterol, which is the current mainstay treatment from GlaxoSmithKline (GSK) for this potentially life-threatening lung disease.

COPD is not one single disease, but is rather an umbrella term used to describe chronic lung diseases that cause limitations in lung airflow (including chronic bronchitis and emphysema). The most common symptoms of COPD include shortness of breath, excessive sputum production and a chronic cough.

The World Health Organization (WHO) estimates that approximately 210m people worldwide suffer from COPD, with almost 90 per cent of COPD-related deaths occurring in low- and middle-income countries. While the primary cause of COPD is tobacco smoking (including second-hand or passive exposure), other risk factors include air pollution, occupational exposure (to, for instance, vapours, irritants or fumes) and frequent lower respiratory infections during childhood. Although there is no cure for COPD, the disease is preventable and various forms of treatment can help control its symptoms and increase quality of life for patients. COPD generally worsens slowly over time and because of this, it is most frequently diagnosed in patients aged 40 years or older.

Lack of awareness is possibly the single most important barrier to progress in the diagnosis, treatment and care of patients with COPD. Although the WHO projects that COPD will be the third leading cause of death worldwide by 2030, the disease is often undiagnosed.

Medical therapies currently available for COPD include bronchodilators (for example, ß2-adrenoceptor agonists, anticholinergics, theophylline), anti-inflammatory agents (such as corticosteroids), mucolytics and antibacterial agents (generally only used for acute exacerbations of COPD). Also noteworthy is the recent launch of roflumilast (Daxas, Nycomed) in Germany and the UK, which were the first launches of the drug worldwide. Roflumilast represents the first in a new class of COPD therapies to be launched in the last decade and is the first oral antiinflammatory treatment for use in such patients.

While there are several therapies currently in late-stage clinical trials for COPD — including aclidinium bromide (Eklira, Almirall Prodesfarma/Forest Laboratories), vilanterol/fluticasone furoate (Relovair, GSK), andolast (Rottapharm Madaus) and beclometasone/formoterol (Fostair/Foster/Inuvair, Chiesi Farmaceutici) — this article will focus specifically on the ß2-adrenoceptor agonist and bronchodilator indacaterol.

 

Drug launches

Generic name

Trade name (Company)

Indication

Country

Roflumilast

Daxas (Nycomed)

Chronic obstructive pulmonary desease

Germany, UK

Tramadol

Tramal Capsule (Nippon Shinyaku)

Cancer pain

Japan

Mitiglinide

Glufast (Eisai)

Type 2 diabetes mellitus

China

Bendamustine

Symbenda (Eisai)

Low-grade non-Hodgkin's lymphoma; chronic lymphatic leukaemia

Singapore

Doxepin

Silenor (Somaxon Pharmaceuticals)

Sleep maintenance insomnia

US

Tobramycin/dexamethasone

TobraDex ST (Alcon)

Inflammatory ocular diseases and/or infections (including blepharitis)

US

Interferon-beta-1b

Betaferon (Bayer Schering Pharma)

Multiple sclerosis

China


Introducing indacaterol
Indacaterol (also known as QAB 149) is a long-acting, ß2- adrenoceptor agonist (LABA), which was discovered and developed by Novartis as a once-daily, dry powder inhalation product for use in patients with COPD. It has been approved for this indication in over 40 countries worldwide, including EU countries. The first global launch of indacaterol occurred in Germany in December 2009; further launches for COPD have since occurred in Ireland, Denmark and the UK. Late-stage clinical trials investigating indacaterol for the treatment of asthma are also underway in the EU, North and South America and Japan. Indacaterol has been formulated in capsules containing powder for inhalation (in 150μg and 300μg doses), which can then be placed into the inhaler (known as Concept-1) and subsequently inhaled via the mouth. Collectively, the drug-plus-device is branded as the Onbrez Breezhaler.

Indacaterol works by attaching to ß2-adrenergic receptors found in the muscle cells of many organs. When patients inhale using the Onbrez Breezhaler, indacaterol reaches these receptors in the airways and activates them, which results in relaxation of the airway muscles and helps to keep the airways open, allowing the patient to breathe more easily.

Development of indacaterol for COPD in the US has been somewhat hampered by a request from the Food and Drug Administration (FDA) that additional studies be conducted. Novartis originally submitted its New Drug Application (NDA) to the FDA in December 2008. The NDA sought approval for the use of indacaterol as a maintenance treatment of airflow obstruction in patients with COPD. However, in October 2009, the regulatory agency issued a Complete Response Letter requesting additional information on the proposed dosing for indacaterol. Novartis is expected to submit this information to the FDA by the end of the year.

The original NDA submission was based on a phase III clinical trial programme comprising three pivotal studies (ININVOLVE, ININHANCE and INLIINLIINLIINLIGHT-1), which had enrolled approximately 4,400 patients with moderate-to-severe COPD. In these studies, different doses of indacaterol were compared with placebo, tiotropium bromide (Spiriva, Boehringer Ingelheim) or formoterol.

In all three studies, the primary efficacy endpoint was a measure of bronchodilation: the trough forced expiratory volume in one second (FEV1) at week 12. Indacaterol was significantly superior to the comparator agents in all studies. Furthermore, indacaterol was well tolerated, with the most common adverse events reported being worsening of COPD, respiratory tract infections and/or cough.

Insist on indacaterol?
Data from the multinational phase III study ININSIST (initiated in January 2009) has shown that patients with COPD treated with indacaterol 150μg once daily achieved significantly better bronchodilation at week 12 (the primary endpoint), compared with standard-of-care salmeterol 50μg twice daily delivered via a DISKUS inhaler (Advair, GSK).

Compared with salmeterol, indacaterol significantly increased the percentage of patients who achieved a clinically relevant reduction in breathlessness (62.7 per cent vs 69.4 per cent), and the number of days when rescue medication was not required (the mean difference between treatments was 4.4 per cent).

Findings from the ININSIST study have been supported by recently published data from the INLIINLIINLIINLIGHT-2 study, and also affirm Novartis' confidence in indacaterol and its other indacaterol-based combination therapies (indacaterol/mometasone and glycopyrrolate/indacaterol), which are in phase II and III development, respectively, for COPD.

It seems only fitting that in 2010, The Year of The Lung (as declared by the Forum of International Respiratory Societies), the future for COPD looks somewhat brighter, with the possibility that indacaterol could be a superior option to standard of care and the first global launch of roflumilast — offering patients with this potentially fatal disease a chance to breathe easier.

The Author
Pipeline was written by Asha Vaidya of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought.

For information on Adis services, contact Kuljeet Sohanpal on +44 (0)207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com

To comment on this article, email pm@pmlive.com

13th December 2010

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