Novartis compound paves way for potent COPD combinations

Novartis presented a series of abstracts at the American Thoracic Society International conference held in , on May 23, 2005 on the novel, long-acting beta-2 agonist indacaterol (QAB-149). The drug provides effective and well-tolerated bronchodilation for up to 24 hours, with convenient once-daily dosing a major advantage over existing long-acting inhaled beta-2 agonists. This, when combined with a rapid onset of action and clean side effects profile, suggest that QAB-149 clearly has blockbuster potential, serving as a platform for Novartis to expand its presence in the asthma/COPD market through the development of dual, and potentially triple action, combination products.

Clinical results confirm safety with 24-hour efficacy

Inhaled beta-2 agonists are commonly used asthma and COPD medications which act as bronchodilators, relaxing and enlarging the airways in the lungs, making breathing easier. Beta-2 agonists come in two forms: short-acting and long-acting. Short-acting beta-2 agonists, such as salbutamol, work quickly (within 5 minutes) and last for four to six hours. Long-acting beta-2 agonists (LABAs), such as formoterol and salmeterol, work for at least 12 hours and are considered first-line therapy for the long-term relief of symptoms in patients with moderate-severe asthma or COPD.

A total of 42 patients with intermittent or mild to moderate asthma were randomized to one of five crossover treatment sequences to receive single doses of QAB-149 50 micrograms, 100 micrograms, 200 micrograms, 400 micrograms, or placebo with a five to 14 day washout in between. The primary efficacy variable was a measurement of the difference in lung function (FEV1 - forced expiratory volume in one second) between QAB-149 and placebo at 30 minutes and 21 hours post-dose. All values for the 200 micrograms and 400 micrograms doses were statistically superior to placebo at all time points from five minutes to 24 hours post dose. Mean differences in FEV1 from placebo 24 hours post-dose relative to baseline were 13.0% and 15.0% for the 200 micrograms and 400 micrograms doses respectively.

For comparison, data from Phase II trials in asthma patients receiving 40 micrograms of GlaxoSmithKlines's once-daily LABA, 159797, demonstrated a 15% improvement in FEV1 24 hours post-dose relative to baseline. GSK has yet to publish information on the disease characteristics and baseline demographics of patients in this trial, although initial results suggest that QAB-149 and 159797 may offer comparable efficacy relative to baseline.

At all doses, safety and tolerability of QAB-149 was similar to placebo, with no serious adverse events experienced in any group and the most common minor adverse effects being headache and cough, the former an adverse effect which also occurs in around 10% of patients treated with GSK's twice-daily LABA, Serevent (salmeterol).

Once-daily dosing a key marketing position

The ideal long-acting beta-2 agonist should have true 24 hour control of symptoms from a once-daily dose, a fast onset of action, excellent compliance and a safety window comparable to currently available LABAs. QAB-149's major advantage over existing long-acting inhaled beta-2 agonists is its long duration of action (24 hours) at the 200 micrograms and 400 micrograms doses, which met the target increase in FEV1.

Initially, QAB-149 is being developed as monotherapy, with Phase III asthma and COPD studies planned to start in mid 2005, followed by regulatory submissions in 2007. Novartis also intends to develop a dual-action, once-daily combination therapy for COPD based on QAB-149 and the long-acting muscarinic antagonist (LAMA), AD-237, which Novartis in-licensed from the based biotechnology company Vectura in April 2004. The development of a dual-action bronchodilator therapy should improve adherence to correct treatment regimens, while providing important therapeutic benefits, as these drugs have distinct and complementary pharmacological actions in the airways. With efficacy and safety demonstrated in Phase II trials for both QAB-149 and AD-237, Novartis is well-positioned to launch a first-to-market dual-action combination therapy for COPD, which Datamonitor predicts will attain sales in excess of $1.0 billion by 2015 in the major pharmaceutical markets.

The development of once-daily dual-action LABA/LAMA combination products may serve as a basis for improved 'triple therapy' combinations through co-formulation with novel anti-inflammatory compounds, such as inhaled phosphodiesterase-IV inhibitors, that could deliver three complementary therapeutic effects for patients with COPD. While the development of 'triple therapy' combinations will face additional regulatory hurdles, requiring extensive comparative clinical trials which may have to demonstrate clinical superiority as well as improved compliance compared to dual action therapies, they are likely to be central to the lifecycle management of LAMA/LABA combination beyond 2015.

Taking on the Advair challenge

Novartis is also exploring the potential combination of QAB-149 with an inhaled corticosteroid (ICS) in order to access the high-value ICS/LABA combination market, worth $4.6 billion in 2004. This market is currently dominated by GSK's Seretide/Advair, a combination of fluticasone and salmeterol, with sales of $4.1 billion in 2004 and a 28% share of global asthma/COPD sales. GSK is forecast to launch a once-daily "Super Advair" combination in the first half of 2010. Early results suggest that as a possible successor to Advair, this combination clearly has blockbuster potential and will become the new gold standard in the combination therapy class at the turn of the decade, with "Super Advair" predicted to achieve peak sales of $5.0 billion by 2015.

In 2003, Schering-Plough and Novartis announced a plan for the joint development of a fixed inhaled combination of Foradil (formoterol) and Asmanex (mometasone) for asthma and COPD. The combination product entered Phase I trials in 2004, with a launch forecast for the first half of 2012.

However, a formoterol/mometasone combination will be unable to compete effectively with GSK's "Super Advair", as it will have a twice-daily dosing regime, given that the duration of action of formoterol is around 12 hours. While the current alliance only appears to cover the development of a combination mometasone/formoterol product, greater value lies in bringing together QAB-149, with mometasone, as this could deliver a combination product with a once-daily profile.

Early results suggest that QAB-149 clearly has blockbuster potential, serving as a platform for Novartis to expand its presence in the asthma/COPD market through the development of dual, and potentially triple action, combination products. Its once-daily profile a clear differentiator to current LABA products on the market. However the drug remains in the early stages of development and as such any firm assessments of its clinical prospects must wait until Novartis offers its next pipeline update later this year.

Related research:

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·          Commercial Insight: Asthma and COPD - Control is the Goal

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