Analysts have estimated that the current annual global market for COPD drugs is worth about $3 billion, possibly tripling to over $9 billion by 2010, as safer and more convenient therapies for this mainly smoking related disease are introduced. Spiriva sales have already exceeded BI's expectations, and it looks set to become a blockbuster. Meanwhile, a number of agents from a completely new class of drugs, phosphodiesterase-IV inhibitors, are in the pipeline for COPD.
Spiriva first to market
The privately-owned German pharmaceutical company Boehringer Ingelheim is a major force in the treatment of COPD. It makes two of the older standard treatments: Atrovent (ipratropium bromide), an anticholinergic and Combivent (ipratropium/salbutamol), an anticholinergic/beta2-agonist combination. These must be taken several times a day and offer only limited symptomatic relief.
In June 2002, BI launched Spiriva, which it says is the first drug to be specifically developed for COPD. Spiriva is a long-acting anticholinergic drug with kinetic selectivity for muscarinic M1 and M3 receptors. Importantly, it is the first once-a-day inhaled bronchodilator for the maintenance treatment of COPD. Spiriva was first launched in the Netherlands, and has since been introduced in a number of European markets, Canada and Australia, with further launches planned in 2003.
The drug was filed in the US in 2001 and could be launched there in 2004, according to BI. There have been some delays in the US, where discussions on various issues such as packaging and moisture sensitivity are reported to be ongoing with the FDA; the agency issued an 'approvable' letter for Spiriva in December 2002. Spiriva's labelling in many countries includes data demonstrating that it can significantly improve breathlessness (dyspnoea). In the US, however, dyspnoea has been rejected as a specific treatment indication, although the FDA has recommended approval for maintenance of COPD-associated bronchospasm. A launch in Japan may occur in 2004.
Spiriva is being co-marketed with Pfizer, under the terms of a 2001 worldwide licensing deal, with peak sales of more than $1 billion expected for both companies. Sales are so far reported to have reached around €40 million, after just a few months on the market, and to be exceeding BI's original expectations.
In 2002, it was announced that BI and Pfizer had begun a new large-scale, four-year study to look at the impact of long-term treatment with Spiriva on lung function in COPD. The UPLIFT trial will enroll up to 6,000 patients in 37 countries and examine whether Spiriva reduces the rate of lung function decline over time. It will also assess quality of life, exacerbations, hospitalisations and mortality. The first results from the study are expected in 2007.
Asthma drugs gain COPD approvals
BI views Spiriva as a successor to Atrovent and is actively encouraging the switching of patients, which will result in a sales slump for Atrovent. According to analysts, Spiriva's growth is also likely to squeeze the market for the established anticholinergic/beta2-agonist combinations, and have a negative impact on products such as Combivent.
It will also provide strong competition - particularly thanks to Pfizer's marketing muscle - for GlaxoSmithKline's Advair/Seretide (flucatisone/salmeterol), which has been filed for use in COPD (it has previously been available for asthma), and AstraZeneca's Symbicort (formoterol/budesonide), which was approved in Europe for COPD in February 2003, also following approval in asthma. Both Advair/Seretide and Symbicort are beta2-agonist/corticosteroid combinations.
Advair/Seretide is now GSK's leading product, with sales of £514 million in the first quarter of 2003 - up 48%. The EU's CPMP issued a positive opinion on its use in COPD in January 2003, and GSK plans to submit further data for this indication to the FDA by mid-2003, having received a second 'approvable' letter in December 2002; it was reported that the FDA had some concerns about long-term side-effects of the corticosteroid component. Analysts predict Advair/Seretide sales of over £3.5 billion by 2006.
Alongside Symbicort, AstraZeneca has also developed the bronchodilator element formoterol alone, Oxis, for COPD, and it completed the EU's mutual recognition procedure for this indication in January 2003; formoterol was developed by Yamanouchi. Analysts predict AstraZeneca's COPD franchise will be worth in the region of $800 million in 2006.
In April 2003, two other main players in the asthma market, Schering-Plough and Novartis, announced that they would collaborate on the development of a beta2-agonist/corticosteroid product for asthma and COPD, based on Schering-Plough's Asmanex (mometasone furoate) and Novartis' formoterol product Foradil; both products are currently approved for use in asthma, and Foradil for COPD.
What future for PDE-IV inhibitors?
Further down the pipeline, COPD is an interesting area of research. The main focus is on a new class of drugs known as phosphodiesterase-IV inhibitors. No PDE-IV drug has yet been approved for COPD (or asthma), however, and candidates have been hindered by safety problems. Even so, companies have stated that this class shows promise, though in April 2003, Merck & Co discontinued development of Celltech's PDE-IV inhibitor, citing safety concerns; Celltech later said one patient had developed colitis. Merck said it would continue to investigate its earlier-stage PDE-IV inhibitors.
Notable pipeline products for COPD include:
- Ariflo (cilomilast): an oral PDE-IV inhibitor from GSK, pending approval in the US. It is viewed as one of GSK's most important R&D projects, with peak sales projections of $700 million
- roflumilast: another oral PDE-IV inhibitor, in Phase III trials, originated by Altana and being co-developed with Pfizer (with Tanabe in Japan). Analysts give peak sales predictions of €1-1.3 billion
- ONO 6126: a PDE-IV inhibitor from Ono, in Phase II trials
- talnetant: a different type of compound, a tachykinin (neurokinin 3) antagonist, commenced Phase II trials in 2002 with GSK
- 842470/AWD 12281: originally developed by Viatris, this PDE-IV inhibitor is being developed by elbion, which granted GSK worldwide development and commercialisation rights in July 2002. Phase I trials in COPD are underway
- IC 485: Phase II trials are scheduled for the third quarter of 2003 for this PDE-IV inhibitor, in development with Icos
- CP 671305: a PDE-IV inhibitor in Phase I trials with Pfizer for COPD
A growing problem...
COPD is a term that covers emphysema and chronic bronchitis, two chronic diseases characterised by obstruction to air flow. According to the American Lung Association, COPD is the fourth leading cause of death in the US, with an annual cost to the nation of approximately $30 billion. The World Health Organisation predicts that it will become the third leading cause of death worldwide in the first quarter of this century, and a major cause of disability. Around 80-90% of cases are caused by smoking: a smoker is 10 times more likely than a non-smoker to die of COPD.
The demographic and epidemiological statistics, combined with the lack of current effective treatments, suggest that COPD presents with pharmaceutical industry with an R&D challenge, but one that could prove highly lucrative over the coming years.