There are several ways in which the treatment paradigm for chronic obstructive pulmonary disease could develop, and GlaxoSmithKline has made a firm bet on one of them, yesterday starting a second pivotal trial combining a LAMA with a LABA and steroid in a single inhaler.
It is not the first to do this; that honour belongs to Chiesi, one of whose own phase III trials has a far tougher design and will read out first. Both companies face a threat from several related approaches from AstraZeneca, as well as the risk of a looming COPD price war akin to that already sweeping the asthma market.
Glaxo’s triple comprises fluticasone, vilanterol (the ingredients of Breo) and umeclidinium, and both pivotal trials set a low bar, comparing the combo against either Relvar/Breo, Anoro or Symbicort. Thus they are not true head-to-heads, a move that is either shrewd or cynical, depending on your view of pharma.
Chiesi, on the other hand, is running a phase III trial of a beclometasone, formoterol plus glycopyrrolate versus beclometasone plus formoterol and Spiriva – a different LAMA. This tough standard will seemingly answer the question of whether there is any point giving a fixed-dose combo versus two separate inhalers together, a likely cheaper option.
Why is this important? Because Glaxo estimates that 20% of COPD patients already take a triple therapy, for instance taking Advair together with Spiriva; indeed work on dosing LABAs, LAMAs and steroids together has been under way for years.
Glisten, a Novartis study presented at last year’s European Respiratory Society meeting, showed that adding either Spiriva or glycopyrronium to Advair significantly improved lung function and quality of life. An earlier trial also showed this, though there was no effect on COPD exacerbations – an important potential claim.
Thus unless Glaxo can make a strong case for efficacy and the benefit of patient compliance there might be little to persuade payers to shell out for a fixed-dose triple combo versus the status quo. One argument in Glaxo’s favour is that its inhaler is dosed once a day, while Chiesi’s is twice daily.
|Novel COPD combination players|
|FF/UMEC/VI||GlaxoSmithKline||Phase III||NCT02164513 (Impact)||10,000||Triple vs Relvar/Breo vs Anoro||Jul 2017|
|Phase III||NCT02345161 (Fulfil)||1,800||Triple vs Symbicort||Mar 2016|
|LAICS||Chiesi||Phase III||NCT01917331 (ex-US)||1,863||Triple vs Foster||Jan 2016|
|Phase III||NCT01911364 (ex-US)||3,686||Triple vs Foster + Spiriva||Feb 2016|
|PT010||AstraZeneca||Phase II||Company claims phase II started Q2 2014; no record on Clinicaltrials.gov|
|Phase I||NCT02189304||60||Healthy volunteers||Sep 2014|
|AZD2115||AstraZeneca||Phase II||NCT02109406||30||Moderate to severe COPD||Sep 2014|
|GSK961081||GlaxoSmithKline||Phase II||NCT01319019||437||Chronic COPD||Sep 2011|
|Phase I||NCT02064504||48||+/- fluticasone; healthy volunteers||May 2014|
|LAS190792||AstraZeneca||Phase I||NCT02059434||55||Asthma and COPD||Nov 2014|
|AZD8999||AstraZeneca||Phase I||Company claims phase I started Q4 2013; no record on Clinicaltrials.gov|
With the imminent expiries of patents on Advair and Spiriva it is hardly surprising that leading players are looking at combinations to maintain revenues. But, assuming that the market can bear the price to begin with, the likely cost of a triple combo might limit its applicability to the US, and yet Chiesi is firmly focused on the EU.
Astra is a key competitor: by virtue of its takeover of Pearl Therapeutics it has a combo of budesonide, formoterol and glycopyrrolate, which goes under the code PT010 and started phase II in the second quarter of last year, it says.
Whether because of formulation difficulties, pricing fears or confidentiality, no other player has disclosed work on a combo of this type. It might be logical to assume that Boehringer Ingelheim is involved, but being a private firm the company keeps its cards close to its chest; Novartis tells EP Vantage that it regularly “reviews ... the possibility of a triple combination.”
Two in one
A separate threat for Glaxo is development of another pharmacological approach: a muscarinic antagonist/beta agonist (MABA). Because this has the actions of both a MABA and LABA, combining it with a steroid would theoretically achieve the same effect as a triple combo.
The company to beat here is also Astra, which through deals with Argenta, Pearl and Almirall has no fewer than five MABAs in development (Astra’s bargain basement move sends competition a message, July 30, 2014). The key advantage of the MABA is reduced complexity; if the theory pans out only two molecules need to be combined to achieve the effect of three.
Interestingly, though Astra has made much of work in this area, Clinicaltrials.gov lists no active MABA studies. Glaxo’s own MABA, GSK961081, completed three phase II trials some time ago, and seems to be going nowhere fast.
It seems logical to view Glaxo’s pivotal combo programme as a prioritisation of this over the MABA approach. The company might have set itself a low bar, but it will still have to make a strong pharmacoeconomic argument at a time when pricing is increasingly coming under scrutiny.
Chiesi’s study will give the market a taste of what to expect.