COPD: Monotherapy, Combination Therapy and Triple Therapy - which way forward?

Basic Therapies

Chronic obstructive pulmonary disease (COPD) is set to become the third leading cause of death worldwide. One of the most common non-communicable diseases, it affects at least 329 million people, and costs the global economy some $2.1 trillion. Despite this, there are currently no drug treatments which can delay progression or decrease disease mortality. The mainstays of management remain based around improving symptoms, maintaining lung function and preventing repeated exacerbations. Basic therapies include lifestyle changes and short-acting bronchodilators, and where these do not relieve symptoms, other options are available.

Treatments include long-acting beta 2-adrenergic agonists (LABA) such as salmeterol, formoterol or indacaterol, and long-acting muscarinic antagonists (LAMA), such as tiotropium, glycopyrronium and aclidinium, as well as inhaled corticosteroids (ICS) such as budesonide or fluticasone. Unsurprisingly, the pharma industry is in fierce competition to develop new drug combinations to capture a part of the COPD market that is expected to reach $11 billion by 2022.

Market leaders

The gold-standard treatment is from GlaxoSmithKline (GSK), the LABA/ICS combination Advair/Serotide (salmeterol plus fluticasone). First approved in the 1990s, its total sales reached approximately $5.3 billion in 2013. Patent protection expired in the US in 2010, and in the EU in 2013, and though generics have appeared in the EU, there are none so far in the US. In the face of mounting competition, a slide in Advair’s sales in inevitable. The other big hitter is from Boehringer Ingelheim (BI), the Spiriva Handihaler (tiotropium bromide), with annual sales of around $3 billion. Though not facing imminent patent expiry like Advair, BI has updated its Handihaler, first introduced in 2004, with the Respimat. This reduces the tiotropium dose by replacing dry powder with an inhaled mist, and was approved in the EU in 2007. The FDA delayed approval with concerns over increased cardiovascular risks associated with long term use of tiotropium bromide, and finally approved the therapy in 2014. Together, Spiriva and Advair currently account for around 75% of the COPD market. They continue to face competition from AstraZeneca’s LABA/ICS combo Symbicort Turbohaler (budesonide plus formoterol), and the Foradil Aerolizer (formoterol fumarate) from AstraZeneca/Merck/Novartis. Both of these are now off-patent.

Other therapies include an ultralong-acting beta-agonist (ULABA) indacaterol, as used in Novartis’ Onbrez Breezhaler/Arcapta Neohaler, EU approved in 2010 and in the US the following year. A pooled analysis of three studies shows that this ULABA is significantly more effective than tiotropium at improving breathlessness in COPD. AstraZeneca and Takeda have also explored a different path to COPD treatment with Daxas/Daliresp (roflumilast). First approved in 2010, it is currently the only oral long-acting anti-inflammatory PDE-4 inhibitor available, and provides a competitor for indacaterol. So far roflumilast sales have been limited due to side effects and restrictions in some EU markets. Despite this, research shows that in patients receiving roflumilast as part of a triple therapy treatment, it cuts the rate of severe exacerbations by a quarter. A competitor is second generation PDE-4 inhibitor Ariflo (cilomilast) from GSK which was first filed for COPD in 2002 but which has yet to be approved.

Next stage therapies

The pharma industry has increasingly focused on switching from twice- to once-daily dosing. For example, GSK’s once-daily inhaler system Incruse Ellipta (umeclidinium bromide) was approved as long-term maintenance treatment in both the US and EU in 2014. An exception to this trend is AstraZeneca/Menarini’s LAMA aclidinium bromide, approved as Tudorza Pressair in the US in 2012 and as Eklira/Bretaris Genuair in the EU. Taken twice daily, the drug differentiates itself on improved night time efficacy and placebo-like safety. In May 2013, GSK’s Breo Ellipta (fluticasone furoate/vilanterol) became the first ICS/LABA formulation approved in the US with a once-daily dosing. It was given EU approval as Relvar Ellipta. However questions remain over its clinical value compared with Symbicort and Advair/Serotide.

The industry has also pursued new combination therapies: in particular, LAMA/LABA therapies which take advantage of easier dosing regimens and improved efficacy compared with the older ICS/LABA blends. In fact the COPD sector is becoming crowded with new LAMA/LABA permutations, which are expected to gather a third of the total COPD market. The first once-daily fixed-dose LABA/LAMA, Novartis’ Ultibro (glycopyrronium and indacaterol) was approved in September 2013. Trials show it to be more effective than Advair at preventing exacerbations, a fact which might seem surprising given the lack of ICS component. Next came LAMA/LABA Anoro Ellipta (umeclidinium bromide and vilanterol), from GSK, which was approved in the USA in December 2013 and the EU in 2014.

More recently, Novartis and Pfizer have gained EU approval of the once-daily LAMA/LABA combination Ultibro Breezhaler (indacaterol and glycopyrronium bromide). This therapy is currently filed in the US. AstraZeneca and Boehringer Ingelheim (BI) have their own competitors in this class: AstraZeneca’s LABA/LAMA combo Duaklir Genuair (formoterol fumarate and aclidinium bromide) was approved in the US and EU in 2014, while BI’s Striverdi Respimat (olodaterol) was approved in the EU the year before. Analysts believe that the launch of Striverdi Respimat is a strategic move to make physicians and patients familiar with an olodaterol-based inhaler prior to the launch of BI’s more lucrative once-daily fixed-dose LABA/LAMA Spiriva Respimat Soft Mist Inhaler (olodaterol and tiotropium). This is now filed in both EU and US, and is expected to launch on both sides of the Atlantic by the end of 2015.

From dual therapy to triple therapy

Though many COPD patients already receive treatment with three drug therapies, it requires the use of different inhalers. Now the industry aims to combine ICS, LABA and LAMA into a single device. This will be more convenient for patients but more importantly, may also reduce the likelihood of exacerbations, compared to separate inhaler therapies. Probably the leading contender in this class is GSK’s fluticasone, umeclidinium and vilanterol triple therapy, which is currently in Phase III trials comparing it to AstraZeneca's twice-daily therapy Symbicort (budesonide and formoterol) on lung function, exacerbation rates and safety in 1,800 COPD patients. Results are expected by 2017. Other triple combination inhalers in development for COPD include Chiesi's CHF 5993 (beclometasone/formoterol/glycopyrrolate) which is in Phase III trials, and AstraZeneca's PT010 (budesonide/formoterol/glycopyrronium) which is in Phase II trials.

Will triple therapy revolutionise COPD treatment? One 2011 study revealed lung function, dyspnoea and quality of life data show statistically significant changes with triple therapy compared to LABA monotherapy, yet the changes do not reach clinical importance. It also revealed that triple therapy does decrease the number of hospitalisations for severe/acute COPD exacerbations compared with long-acting anti-cholinergic bronchodilator monotherapy. However it suggests there is insufficient evidence to determine if triple therapy is superior to dual bronchodilator therapy. A more recent study suggests that removing the steroid component from a triple therapy has no impact on the frequency of exacerbations among moderate-to-severe COPD patients. For now, the jury is out.

Future therapies

There are currently around two dozen therapies in Phase II trials. Amongst the most exciting antibody treatments such as GSK’s Bosatria (mepolizumab), which targets interleukin-5. Its competitor, MEDI 563 (benralizumab), from Medimmune and AstraZeneca, failed to meet the primary endpoint in a Phase IIa trial in COPD as it did not reduce the acute exacerbation rate compared with placebo in the overall population. PDE-4 inhibitors are also under investigation: Chiesi’s inhaled CHF 6001 is showing promise, and is ‘extremely well tolerated in extended safety studies’. Also in Phase II is GSK 961081, a single molecule with both muscarinic antagonist and beta 2 agonist activities (MABA). The developers hope it will provide greater efficacy than single mechanism bronchodilators and with equal or better tolerability, and it could provide a basis for improved combination therapy with an inhaled corticosteroid. Finally, there are device options for COPD treatment such as targeted lung denervation (TLD). Developed by Holaira, the technology is a catheter-based system which – like anticholinergic COPD drugs such as Spiriva – targets the parasympathetic nerves in the lungs. The one-time bronchoscopic procedure aims to ablate the nerves at the top of the lungs, thereby relaxing the airways beyond it.

References

Management and prevention of exacerbations of COPD. Aaron SD. BMJ 2014;349:g5237.

Is COPD in its age of enlightenment? Jenkins C. Lancet Respir Med 2014;2:960-2.