Glaxo tries to turn a triple play

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
Project Company Status Trial ID Enrolment Design/setting Completion
Triple combinations
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
MABAs
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
LAS191351 AstraZeneca Preclinical
LAS194871 AstraZeneca Preclinical
MABA Chiesi  Preclinical

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.

To contact the writers of this story email Jacob Plieth or Amy Brown in London at news@epvantage.com or follow @JacobEPVantage or @AmyEPVantage on Twitter

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