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The angiotensin II receptor
antagonists (ATIIAs), or 'sartans', are the fastest-growing
antihypertensives. They are more selective than the ACE
(angiotensin converting enzyme) inhibitors, and are associated
with fewer side effects. Since the end of 2000, clinical
trial data have been released suggesting that the ATIIAs
may have potential in a number of areas.
Merck & Co was the first
company to launch an ATIIA, Cozaar (losartan), in
1994, after co-developing the drug with DuPont. Novartis
followed with Diovan (valsartan)
in 1996, and there are now six ATIIAs on the market. Most
are also available in a diuretic combination formulation.
Angiotensin II antagonists available
|
Compound
|
Launched
|
Marketing
Corp.
|
Brand
name
|
Diuretic
comb.
|
|
candesartan
|
1997
|
Takeda
|
Blopress
|
Blopress
Comp, Blopress R
|
| |
|
AstraZeneca
|
Atacand
|
Atacand
Plus, Atacand HCT
|
|
eprosartan
|
1997
|
Solvay
|
Teveten
|
Pending
|
|
irbesartan
|
1997
|
Sanofi-Synthelabo
|
Aprovel
|
Co-Aprovel
|
| |
|
Bristol-Myers
Squibb
|
Avapro
|
Avalide
|
|
losartan
|
1994
|
Merck &
Co
|
Cozaar
|
Hyzaar
|
|
telmisartan
|
1998
|
Boehringer
Ingelheim
|
Micardis
|
Micardis
HCT
|
| |
|
GlaxoSmithKline
|
Pritor
|
n/a
|
|
valsartan
|
1996
|
Novartis
|
Diovan
|
Co-Diovan
|
Source: LifeCycle
Merck & Co still dominate
the C9C (angiotensin II antagonists, plain) therapy class.
For the 12 months to June 2001, MIDAS
- the viewing and analysis platform for IMS HEALTH data
- shows that Cozaar was the lead product, with a 37% share
of the plain ATIIA market, followed by Diovan, with 18.1%.
Third is Takeda's Blopress, with 11.7%, but when
combined with AstraZeneca's brand of candesartan cilexetil,
Atacand (8.8%), the molecule would overtake valsartan
and be in second place with 20.5%. In fourth (Bristol-Myers
Squibb) and sixth (Sanofi-Synthelabo) place is irbesartan,
sold as Avapro and Aprovel respectively (Karvea
is another brand name).
C9C % market
share - June 2001
Source: MIDAS (global sales, excluding
the Netherlands)
Kidney disease
In September 2001, the New England
Journal of Medicine published results from the landmark
PRIME studies. These demonstrated that Bristol-Myers
Squibb and Sanofi-Synthelabo's irbesartan protected against
the progression of kidney disease in patients with hypertension
and Type 2 diabetes.
In 590 patients with hypertension,
Type 2 diabetes, and microalbuminuria (early stage kidney
disease), irbesartan led to a 70% reduction in progression
to later stage disease, diabetic nephropathy. A second trial
was in 1,715 patients with proteinuria (late-stage kidney
disease) on top of hypertension and Type 2 diabetes. Irbesartan
caused a 20% reduction in progression to doubling of serum
creatinine, end-stage renal disease or all-cause mortality
compared to placebo, and a 23% reduction compared to amlodipine
(Pfizer's Norvasc).
Moreover, there was a 37% reduction in hospitalizations
due to congestive heart failure compared to amlodipine.
The NEJM also published the results
of similar trial examining the effect of Merck & Co's
Cozaar (losartan) in patients with Type 2 diabetes and nephropathy.
The RENAAL study included 1,513 patients from 29
countries. There was a 28% reduction in the risk of developing
end-stage renal disease when losartan was included in the
antihypertensive treatment regimen, and hospitalizations
for CHF decreased by 32%.
Not to be outdone, Novartis is
running the ABCD-2V trial to compare the effects
of moderate versus intensive blood pressure control on the
prevention and progression of diabetes complications in
both normotensive and hypertensive Type 2 diabetics. In
September 2001, it also launched the NAVIGATOR study.
This has been designed to determine whether Diovan and/or
Novartis' oral antidiabetic Starlix (nateglinide)
used long term can reduce or delay the development of Type
2 diabetes and cardiovascular disease in 7,500 patients
with impaired glucose tolerance who are at high cardiovascular
risk.
Around 40% of diabetics will
eventually develop kidney disease, which can ultimately
lead to kidney failure and the need for dialysis or transplantation.
BMS and Sanofi-Synthelabo have now filed irbesartan for
approval in the US and Europe for this indication, and the
supplemental NDA has received six-month priority review
status. Sanofi-Synthelabo said irbesartan had sales of €665
million in 2000, and it expects these to reach €1.5 billion
by 2005 partly due to the impact of the PRIME findings.
Better than ACE inhibitors?
AstraZeneca's CALM trial
compared the effects of Atacand (candesartan) and/or its
ACE inhibitor Zestril (lisinopril) on blood pressure
and urinary albumin excretion in patients with microalbuminuria,
hypertension and Type 2 diabetes. Both drugs were shown
to be equally effective, and there was a synergistic effect
when the two were combined.
Zestril is now nearing patent
expiry. In an editorial in the NEJM, one researcher raised
the question of why the large trials published in the journal
had not included ACE inhibitors. Could it be that their
shrinking lifespan means the marketing companies want to
push the newer ATIIAs? If the cheaper ACE inhibitors were
shown to be as effective, it would obviously impact ATIIA
sales. Nevertheless, they do have other benefits, most notably
reduced side effects, such as cough.
Heart failure
Perhaps the first ground-breaking
results with the ATIIAs came in November 2000, with the
presentations of findings from Val-HeFT. The 5,010
patient study looked at the efficacy of Novartis' Diovan
(valsartan) in heart failure, and the results were positive
enough for the FDA to grant the sNDA priority review status
in June 2001:
- 3.3% reduction in combined
all-cause mortality and morbidity
- 27.5% reduction in hospitalization
due to heart failure
- plus improved quality of
life and slowing in disease progression
AstraZeneca is also running the
CHARM programme to see if Atacand will have similar results
in heart failure. Enrollment was completed in March 2001.
The Val-HeFT results contrasted
with those of the 1999 ELITE-2 trial, which compared
Merck & Co's Cozaar to the ACE inhibitor captopril (BMS'
Capoten) in heart failure patients. In terms of overall
survival advantage, there was no benefit with losartan,
and indeed captopril was slightly superior (17.7% mortality
versus 15.9%). The news caused Merck & Co to shelve
its plans for seeking approval for Cozaar in heart failure,
and cast doubt on the whole ATIIA class as a major improvement
to the ACE inhibitors.
Myocardial infarction etc.
Novartis is now examining Diovan's
impact on long-term survival after heart attack. VALIANT
completed its enrollment of more than 14,500 post-MI patients
in June 2001, and will compare Diovan alone, a combination
with the ACE inhibitor captopril, and captopril alone. Results
will be available in 2004.
Diovan is also the subject of
the VALUE study, which is comparing the ATIIA to
the calcium antagonist amlodipine in the reduction of cardiac
mortality and morbidity in high-risk hypertensive patients.
Boehringer Ingelheim is running a similar trial (ONTARGET)
with Micardis (telmisartan) and the ACE inhibitor
ramipril in 28,000 patients, and a parallel study (TRANSCEND)
with telmisartan alone in 5,000 patients intolerant to ACE
inhibitors.
Other trials are proceeding with
ATIIAs in the prevention of stroke and dementia, diabetic
retinopathy, glomerular nephritis, the prevention of hypertension
in borderline patients, and as an add-on therapy to ACE
inhibitors for lowering blood pressure.
Growth looks set to continue
Any additional indications can
only boost sales of the ATIIAs, particularly in chronic,
widespread
conditions such as diabetes and heart failure. As demonstrated
by the chart below, the ATIIAs are currently the only class
of antihypertensive compounds demonstrating significant
growth - 35% for the plain (C9C) ATIIAs and 58% for the
diuretic combinations (C9D) over the year to June 2001.
This compares to a 15% drop for the C2 'other antihypertensives'
class, and flat growth or a slight decline for the diuretics
(C3), calcium antagonists (C8) and plain ACE inhibitors
(C9A) - only the beta-blockers registered growth, but just
1%.
Sales growth
of selected antihypertensive classes
Years to June 30
Source: MIDAS
Although they still have some
way to go to overtake the calcium
antagonists, or even
the old beta-blockers, as the primary treatment for hypertension,
the ATIIAs seem to have become well established in a highly
competitive market, and are now fighting it out amongst
themselves to prove their individual potency, safety, and
efficacy.
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