GlaxoSmithKline and AstraZeneca breathe easier after FDA panel

Analysis

Given the hype, piles of briefing documents and long run up to the FDA advisory committee’s decision on long acting beta 2 agonists (LABAs), there were few real surprises on the day. As expected, both Symbicort and Advair, which combine LABAs with an inhaled steroid got the thumbs up for their use in adults and adolescents, while Advair managed by a whisker to win the panels backing for its use in children aged four to 11.

Although the panel did not go as far as saying that mono LABA therapies should be removed from the market, the two under consideration, Foradil, sold in the US by Schering-Plough and GlaxoSmithKline’s Serevent, received recommendations that they should not be used in adults. The panel also agreed unanimously that risks for children aged 11 and under with both drugs outweighed the benefit, which almost certainly spells the end for the treatments in this age group. The safety conscious regulator, which is due to make its final decision on all the drugs under review early next year, is also likely to enforce their withdrawal from use in adults too.

Small fry

The impact on the makers of the two drugs is expected to be minimal; last year Foradil had sales of $362m, which are expected to drop to $325m in 2014. The drug also lost patent protection back in February 2006 and its worth to Schering-Plough is only $344m, compared with a value of $36.6bn for the whole of Schering-Plough’s marketed products, according to EvalutePharma’s NPV Analyzer.

Like Foradil, Serevent only plays a minor role in Glaxo’s portfolio of marketed drugs; sales were $538m last year and will decline to $270m by 2014, following its patent expiry in August this year. Serevent's worth to Glaxo is $815m, a sum dwarfed by Advair at $17.5bn, which is the company's best selling drug and accounts for 24% of Glaxo’s total marketed product portfolio valued at $74.3bn.

Additionally, it is estimated that about half the sales of both drugs are for chronic obstructive pulmonary disease (COPD), rather than asthma, which are expected to continue at the same levels.

But such has been the long-term concerns about LABA’s without the use of a steroid - they have been scrutinised by the FDA since the early 90s when the risks associated with their use first surfaced - that currently most of the LABAs in development now as mono-therapies are for COPD.

The reason why there is so much anxiety about the use of LABA’s without steroids, is that as a mono-therapy they are thought to mask increasing inflammation of the airways, meaning that patients are not aware of the severity of an asthma attack until it is too late. While all of the mono-therapies already carry warnings on their labels that they should be used with steroids, the panel was concerned that the warnings were not prominent enough and that there was widespread evidence they were being used without steroids.

All out

Worryingly for the drugmakers it had at one point looked as if rather than just LABAs without steroids the panel might also take a hard line on LABAs with steroids, which is one of the reasons why, with that danger averted, shares in both GlaxoSmithKline and AstraZeneca today managed to hold up and avoid the losses suffered by the wider London market. 

If the panel had decided against the use of LABAs with steroids the hardest hit company would have been AstraZeneca. Symbicort, unlike Advair is not yet approved in COPD, an indication where the Glaxo drug receives about half its sales, and last year sales hit $7bn. Symbicort is one of the most important drugs in AstraZeneca’s pipeline, with 2014 sales forecast to grow to $2.36bn.

But despite some of the apprehension that has hung over the panel's decision, it was almost inconceivable that the committee would completely ban LABAs with steroids, given both the lack of alternative treatments and the relatively good, if not perfect, safety profile of the drugs. The table below shows the current treatments in development for asthma that do not rely on LABAs.

Non LABA Asthma Treatments
            WW Sales ($m)            
  Rank Product Company Pharmacological Class Indication Summary 2008 2009 2010 2011 2012 2013 2014 Launch WW Launch US
                             
Phase III 1 Daxas Nycomed Phosphodiesterase IV inhibitor COAD/COPD [Phase III]; Asthma [Phase III] - 28 70 116 168 220 273 31/12/2009 31/12/2009
  2 House Dust Mite Allergy ALK-Abelló Allergy vaccine Rhinitis, perennial [Phase III]; Asthma [Phase III] - - 4 11 17 34 51 - -
  3 MCC-847 Mitsubishi Tanabe Pharma Leukotriene D4 antagonist Asthma [Phase III]; Rhinitis, seasonal allergic/Hay fever [Phase II] - - - 2 3 5 7 31/12/2010 -
                             
Phase II 1 LAS 34273 Forest Laboratories Muscarinic M3 antagonist Bronchitis, chronic [Phase III]; COAD/COPD [Phase III]; Asthma [Phase II] - - - 55 125 220 315 - -
  2 Firazyr Shire Bradykinin B2 antagonist Hereditary angioedema [Approved]; Asthma [Phase II]; Liver disorders [Phase II]; Oedema [Pre-clinical]; Osteoarthritis [Abandoned in R&D] 2 20 47 85 128 175 220 - -
  3 Bosatria GlaxoSmithKline Anti-IL-5 MAb General allergy indications [Filed]; Asthma [Phase II]; Polyp formation, recurrent [Phase II] - 9 26 52 91 130 170 - -
  4 IMA-638 Wyeth Anti-asthma agent Asthma [Phase II] - - - - 17 33 50 31/12/2012 31/12/2012
  =4 QAE397 Novartis Respiratory agent Asthma [Phase II]; COAD/COPD [Abandoned in R&D] - - - - - 25 50 31/12/2013 -
  6 256066 GlaxoSmithKline Phosphodiesterase IV inhibitor Asthma [Phase II]; Rhinitis, seasonal allergic/Hay fever [Phase II]; COAD/COPD [Phase II] - - - - 16 33 49 31/12/2010 31/12/2010
  7 870086 GlaxoSmithKline Glucocorticoid agonist Asthma [Phase II] - - - - 14 28 42 30/06/2012 30/06/2012
  =7 679586 GlaxoSmithKline Anti-asthma MAb Asthma [Phase II] - - - - 14 28 42 30/06/2012 30/06/2012
  9 ME3301 Meiji Seika Kaisha Anti-asthma agent Asthma [Phase II]; Rhinitis, seasonal allergic/Hay fever [Phase II] - - - 20 25 30 35 31/12/2011 -
                             
Total           2 58 146 340 618 962 1,303    

As can be seen many of them are only used in asthma as a secondary or third indication and the truly innovative products such as Xolair, which is only used in allergy induced asthma and Glaxo’s 679586, by virtue of being monoclonal antibodies will have massive price disadvantages over conventional therapies, even if they are more targeted and therefore safer.

As such, while it is hard to call decisions of the FDA, on several occasions this year it has gone against the council of its advisory committee, in all likelihood it will follow the advise of the panel and Advair and Symbicort will retain their crowns as the two most prominent treatments for asthma.

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