On the eve of Breast Cancer Awareness Month 2003, the
Cancer Research UK charity announced the launch of IBIS
II (International Breast cancer Intervention Study II).
This will enrol 10,000 women at an increased risk of developing
breast cancer, and examine the effects of AstraZeneca's Arimidex (anastrozole)
on the prevention of breast cancer over 10 years.
Arimidex, an oral aromatase inhibitor, is now the leading
branded, hormonal breast cancer treatment, according to
IMS data (see below). IBIS II will be the first examination
of its utility in the prevention of the disease, and follows
in the path of a similar study, IBIS I, which used AstraZeneca's
older drug, Nolvadex (tamoxifen).
Tamoxifen
previous gold standard treatment
IBIS I examined the oral anti-oestrogen tamoxifen in more
than 7,000 women judged as being at high risk for developing
breast cancer. Tamoxifen, already the gold standard treatment,
was shown to reduce this risk by one-third. The drug only
had an effect on the development of oestrogen-receptor
(hormone) positive breast tumours, but worked regardless
of age, risk status, or concomitant use of HRT. As an adjuvant
treatment, it can also cut the rate of second cancers by
46%.
Long-term prevention of breast cancer, however, is a controversial
area, as tamoxifen is not without side-effects. In 1998,
Nolvadex became the first drug to receive FDA approval
for the prevention of breast cancer in women at increased
risk, but many physicians believe the adverse effects reduce
its value as a prophylactic except for women with a greatly
increased danger of developing breast cancer - perhaps
identified genetically. Problems include a 2-3 fold increased
risk of endometrial cancer: this may be acceptable to women
with breast cancer, but less so for otherwise healthy women.
There is a similar increase in rates of thrombo-embolism
with the drug. In IBIS I, there were more deaths in the
tamoxifen arm, but in other trials, it has led to lower
death rates or had a neutral impact. This suggests the
IBIS I deaths could have occurred by chance, but blood
clots are seen as the most important complication. Researchers
noted, however, that the risk was no greater than that
seen with HRT.
Could Arimidex be safer?
Researchers believe that Arimidex could reduce the risk
of breast cancer in post-menopausal women by at least 50%.
Both tamoxifen and anastrozole work via oestrogen. Tamoxifen
prevents the action of oestrogen on breast cells, but produces
oestrogen-like effects in the endometrium, hence the increased
risk of cancer there. Anastrozole prevents the production
of oestrogen, and seems to have fewer side-effects such
as hot flushes; it does not appear to be linked to blood
clots. On the down side, Arimidex does not have tamoxifen's
beneficial effect on bone density, so this aspect will
be carefully monitored during IBIS II, which will compare
anastrozole to placebo.
AstraZeneca has already demonstrated Arimidex's superiority
over tamoxifen with the 9,366-patient ATAC (Arimidex, Tamoxifen
Alone or in Combination) trial. After a median follow-up
period of almost four years, Arimidex showed statistically
significant benefits over tamoxifen in all efficacy endpoints,
such as a 14% reduction in the risk of recurrence, and
had a favourable tolerability profile.
Nevertheless, Arimidex could face competition: in 1999,
the five-year STAR (Study of Tamoxifen And Raloxifene)
trial began in North America. This is comparing the effectiveness
of tamoxifen and Lilly's selective oestrogen receptor modulator Evista in
reducing the risk of breast cancer in 22,000 post-menopausal
women. Like anastrozole, raloxifene could have similar
breast cancer prevention properties to tamoxifen, but be
less associated with the development of endometrial cancer.
Moreover, it is already indicated for the prevention of
osteoporosis.
Femara's success in recurrent breast cancer
In its trials for early breast cancer, it was observed
that women on anastrozole were 40% less likely to be diagnosed
with a second cancer in the opposite breast (contralateral
disease) compared with women taking tamoxifen. Amongst
the 10,000 participants of IBIS II, 4,000 will be women
diagnosed with DCIS4, a non-invasive form (ductal carcinoma
in situ) of breast cancer, which some believe is a pre-cancerous
condition. As it forms in the milk ducts and very rarely
spreads, DCIS is usually only identified via mammography,
but women with the condition are more likely to develop
a new tumour in the opposite breast.
Shortly
after the launch of the IBIS II trial, Novartis announced
findings from the international MA-17 study.
This had enrolled nearly 5,200 post-menopausal women with
early breast cancer (98% hormone-positive) who had been
treated with tamoxifen for five years, and then received
extended adjuvant treatment with Novartis' oral aromatase
inhibitor, Femara (letrozole); this is already the
fourth best-selling hormonal breast cancer treatment according
to IMS, and could now have blockbuster potential.
While tamoxifen is often initially highly effective, over
time researchers believe it may actually begin to stimulate
the oestrogen receptor rather than blocking it, meaning
its effectiveness begins to wear off. For this reason,
tamoxifen therapy is usually discontinued after five years
- even though cancer still recurs in 50% of cases after
this point. The MA-17 trial was the first to examine continuing
treatment with a second drug, and had a median follow-up
of 2.4 years (up to five years in some cases).
The interim results, published on the New England Journal
of Medicine's website, suggested that Femara led
to a 43% reduction in risk of overall recurrence compared
with placebo, as well as a 46% reduction in contralateral
disease. The trial was halted early so that women in
the placebo arm could consider switching to treatment
with Femara, which Novartis believes is more effective
than Arimidex. The drug is currently indicated for the
first-line treatment of locally advanced or metastatic
breast cancer in post-menopausal women, or the treatment
of advanced breast cancer in post-menopausal women with
disease progression following anti-oestrogen therapy.
Professor
Jack Cuzick from Cancer Research UK, head of the IBIS
II study,
commented, "Letrozole is a very similar
drug to anastrozole... The new findings are further evidence
that aromatase inhibitors look like becoming the most effective
hormone treatments for breast cancer in post-menopausal
women, with the potential to save a great many lives."
Like tamoxifen, letrozole is not without side-effects.
In the MA-17 trial, adverse events more common in treated
women included hot flushes, arthralgia and myalgia; the
incidence of bone fractures and newly-diagnosed osteoporosis
was also higher. Some researchers criticised the early
halting of the trial, as this lessened its clinical value
in terms of demonstrating a clear survival benefit or providing
more long-term data on adverse effects. The participants,
however, will continue to be monitored, and a second Phase
III adjuvant study with Femara, BIG 1-98, recently completed
the enrolment of more than 8,000 women.
AstraZeneca at the forefront
AstraZeneca,
then still ICI, first launched Nolvadex in 1973. European
patents for Nolvadex expired in the 1980s,
but in the US, it had patent protection until August 2002.
The company then received a six-month paediatric exclusivity extension until
February 2003, after conducting studies in girls with McCune-Albright
syndrome, a rare genetic disease affecting hormonal and sexual
development. Well before tamoxifen's loss of exclusivity,
in 1995 AstraZeneca launched Arimidex to allow the company
to maintain its leading position in the hormonal breast cancer
treatment market. Moreover in 2002, it introduced a new once-monthly
intravenous oestrogen antagonist, Faslodex (fulvestrant),
for the second-line treatment (following tamoxifen failure)
of advanced breast cancer.
Market share (%) of breast cancer treatments
(L2B class)
12 months to March 2003
Source: IMS
MIDAS
*Note: 'Others' mainly consists of L2B2 class hormone
treatments for prostate cancer
Generic tamoxifen sales now almost equal those of Arimidex,
and by the first quarter of 2003 had overtaken sales of
Nolvadex. The four leading unbranded tamoxifen products
come from Barr, which had an 11% share of the cytostatic
hormone antagonist (L2B) class, AstraZeneca itself, with
3.3%, plus Schering AG (which uses the name Jenoxifen)
and Teva, both with 0.4%.
Within the L2B class, anti-oestrogens (L2B1) and aromatase
inhibitors (L2B3) are predominantly used for breast cancer.
The top-selling product in the class is AstraZeneca's Casodex (bicalutamide), an anti-androgen (L2B2) for prostate cancer,
which took 30.6% of the overall L2B market in 1Q03. AstraZeneca
also makes Zoladex (goserelin), an LHRH analogue for both
advanced and early-stage breast cancer. Overall, in 1Q03,
AstraZeneca had a 60% share of the L2B market, according
to IMS.
Barr sees generic tamoxifen revenues halved
In
1Q03, tamoxifen was Barr's leading product. It gained
a head start in the US market for generic Nolvadex
through a licensing deal with AstraZeneca, which expired
in August 2002 (though Barr's supply lasted until December).
This was established after Barr challenged the then Zeneca's
patent: a confidential settlement was reached in 1993 under
which Zeneca supplied Barr with tamoxifen for re-sale as
a generic - priced 15% less than Nolvadex. The alliance
allowed AstraZeneca to manage the US patent expiry of Nolvadex
most effectively: in May 2003, a US District Court dismissed
an antitrust suit which claimed that it had prevented true
generic competition and artificially inflated tamoxifen
prices.
In February 2003, Barr and a number of other generic manufacturers launched 10 and 20mg generic tamoxifen products in the US following the end of Nolvadex's paediatric exclusivity period. Barr had expected to launch its 10mg tamoxifen product on August 20 2002, but the FDA retroactively altered the approval date for its generic. Barr challenged the FDA's decision in court, claiming that the date decided in 1987 was unequivocal, but was unsuccessful. This led to Barr seeing its tamoxifen revenues fall from $366.3 million in its fiscal year to June 2002, to $120.9 million in the year to June 2003. In 2002, the US market for Nolvadex and generic tamoxifen was worth approximately $500 million.
This
article was written by Selena Class, Deputy Executive
Editor of IMS
Company Profiles. For more information
on how IMS can help you understand the breast cancer market,
please contact Fil Manuguid from IMS Consulting.
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