The
COPD (chronic obstructive pulmonary disease) market is a
complex one, as at the moment, many drugs of various types
are used in the treatment of the condition. Some of these
drugs are also used for asthma, another condition that requires
brochodilation. In 2002, however, Boehringer Ingelheim launched
the first specific drug for COPD - Spiriva
(tiotropium bromide), which is co-marketed by Pfizer.
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.
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