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Wednesday 11 October 2006

Datamonitor: Asthma/COPD combo products here to stay

By: Pharmalive

London - Sufferers of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are breathing easier due to being increasingly treated with fixed dose inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) combination therapies.

The appeal of these combinations is three-fold: improved patient compliance, simplified disease management and the certainty of bronchodilator and steroid co-administration. Until recently, there were only two such combination inhalers available: GlaxoSmithKline's (GSK) Advair/Seretide (fluticasone/salmeterol) and AstraZeneca's (AZ) Symbicort (budesonide/formoterol). Advair/Seretide, with sales of just over $4.9 billion* in 2005, dominates not only its class but also the total asthma/COPD market. However, according to a new report** by independent market analyst Datamonitor (DTM.L), Symbicort's recent US approval and Chiesi's recent European approval of an ICS/LABA combination drug, signal a major change in the market dynamics.

The battle between currently marketed drugs

With 42 million asthma sufferers and 28m COPD sufferers, the asthma/COPD treatment market* was worth around $17 bn in 2005, and is dominated by the ICS/LABA combination class, which accounted for 32% of sales ($5.5 bn). Datamonitor expects this market share to grow to $12.2 bn in 2015, with the entry of up to three new products onto the market. GSK's Advair/Seretide was the first product in this class to reach the market (in 1999) and has been dominating it ever since. AZ launched its combination product, Symbicort, in Europe in 2001 and received the FDA's approval in July 2006.

Realising the importance of and difficulty ensuring patient compliance, AZ has sought to differentiate its product from Advair/Seretide through an alternative, more patient-empowering treatment approach dubbed SMART (Symbicort Maintenance and Reliever therapy). This concept uses Symbicort to provide a stable dosing regime, just like Seretide, but with the additional ability to increase the dose (i.e., the number of puffs) during symptom exacerbation, instead of using short-acting rescue bronchodilators like Ventolin. AZ filed for European approval of Symbicort SMART in November 2003, but the application was withdrawn in November 2004 as a result of discussions during the Mutual Recognition Process. However, in September 2005, AstraZeneca started a second attempt to get the SMART approach approved in Europe after data from two additional studies became available. If successful, the concept of Symbicort as maintenance and reliever medication will be a key differentiating factor from Seretide. However, according to Datamonitor respiratory analyst Lisette Oversteegen: "there is debate about whether this type of treatment is appropriate for all patient groups, as this approach only works with patients who have a general understanding of the treatment of their disease."

The advantages of combination drugs

Non-compliance is a significant problem in the treatment of asthma and COPD, especially in later stages of disease. These patients have a multitude of drugs to deal with on a daily basis and are often confused on their exact treatment regime. Furthermore, patients tend to forget to take their ICS medication because, unlike a bronchodilator, it does not give them immediate relief, Oversteegen says. "Since the regular use of anti-inflammatory drugs is key to treating the underlying disease, the combination drug's advantage is the automatic intake of the ICS alongside the bronchodilator, making disease management easier for both patients and physicians," she says.

Another advantage of these combination drugs is that patients always inhale their LABAs in combination with an ICS. Recent concerns regarding the dangers of LABA monotherapy in the treatment of asthma led to the 1996 Salmeterol Multicenter Asthma Research Trial (confusingly also called SMART), which investigated salmeterol (a type of LABA) in the treatment of asthma. A possibly increased mortality rate in certain subgroups of asthma patients using this drug was found (Nelson et al., 2006), leading to safety warnings on LABA drug labels. Datamonitor believes that very few physicians prescribe LABAs as monotherapy and that non-compliance is the main reason for patients using LABAs without ICS's. "A combination of these two drug classes in a fixed dose combination should go a long way in dealing with this issue," Oversteegen says.

New combination drugs to come

The third combination product on the market is Chiesi's Foster (beclometasone/formoterol), approved in Germany in September 2006. The critical factor for a successful launch of this drug will be its price relative to Advair/Seretide and Symbicort. Datamonitor estimates that Foster will generate sales of around $330 bn* in 2015, depending on the pricing-strategy Chiesi will choose.

The outlook for this market shows even more competition in the future, with several novel ICS/LABA combination products set to enter the US market in the coming years. The first and most important will be GSK's Super Advair, expected to be launched in 2010. This product, while based on two completely new drugs, can be viewed as essentially a once-daily reformulation of Advair/Seretide. A lot is riding on the timing of Super Advair's approval as Advair's US patent expires around the same time, in May 2010. GSK needs to switch as many patients as possible to Super Advair before the entry of Advair generics. Assuming this and that it offers significant advantages over the current Advair, GSK should be able to retain most of its ICS/LABA combination drug sales.

The expected launch of Altana and Sanofi-Aventis' Alvesco Combo (ciclesonide/formoterol), forecast for the first half of 2011, is the next significant event in the ICS/LABA combination drug class, as the product appears to have a very good competitive profile. Ciclesonide provides important safety advantages over existing corticosteroid treatments, especially in patients requiring high-dose ICS. However, this product's future remains uncertain because ciclesonide is still not approved in the US and European regulators only licensed a lower than expected maximum dose of 160mcg once-daily, Oversteegen says. "Altana's previous failure to gain approval for Alvesco's possibly more efficacious 320mcg dose once-daily does not spell the end of the development of a fixed-dose combination product. A lower dose of ciclesonide could still sensibly be used in a combination product given that the LABA has a synergistic effect."

"However, if Altana cannot get the higher dose approved, it would undermine the marketing concept of Alvesco being a safer steroid," she says.

SkyePharma/Kos Pharmaceuticals' fluticasone/formoterol and Schering-Plough/Novartis' mometasone/formoterol are ICS/LABA combinations currently in development. They are estimated to be launched in mid and late 2010, respectively. A more exciting combination however, is Schering-Plough/Novartis' mometasone/QAB-149 (indacaterol). Currently still in pre-clinical development, this drug has the potential to combine once-daily dosing with a flexible dosing regime (like SMART) and could therefore be Super Advair's biggest threat, if launched successfully.

With new dosing regimes, competitive pricing and upcoming generic entry, the ICS/LABA class is facing challenging times, Oversteegen says. "The key players in this field will need to differentiate their products carefully from their competitors' in order to generate and maintain sufficient traction, and with the first generics expected from 2010, pricing pressure will only rise."

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