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Bristol-Myers
Squibb launched the world's first angiotensin-converting
enzyme (ACE) inhibitor, Capoten (captopril) in 1981. Over
the next decade, the ACE inhibitors (C9A class) quickly
joined beta-blockers and calcium antagonists as a mainstay
treatment for hypertension.
Apart
from a small percentage of patients in whom ACE inhibitors
cause cough, the drugs are well tolerated. In 1994, however,
Merck & Co launched the first angiotensin
II antagonist,
Cozaar (losartan). It was followed by Novartis’ Diovan
(valsartan) in 1996, and there are now several ATIIAs on
the market. They work via a similar mechanism to the ACE
inhibitors, but have even fewer side-effects and in particular
have a reduced propensity to cause cough.
Many thought this newer class
of drugs would eventually replace the ACE inhibitors. Whilst
the ATIIAs are indeed the fastest-growing group of antihypertensive
products, the ACE inhibitors have seen something of a resurgence
over the last couple of years, thanks to some impressive
results from large clinical trials.
C9A
market share
12
months to March 2002
Source: Monthly
MIDAS (retail pharmacy markets in the USA, Canada, Germany,
Italy, France, Spain, UK, Brazil, Mexico, Argentina, Australia,
New Zealand and Japan)
The lead ACE inhibitor
is AstraZeneca’s Zestril (lisinopril), which is also
marketed as Prinivil by Merck & Co; both brands
of lisinopril received six-month extensions to their US
exclusivity, but these expired on June 29 2002. Second is
Merck & Co’s own Vasotec/Renitec (enalapril),
which lost US patent protection in mid-2000. Copies are
now sale by Watson, Mylan and other generic manufacturers,
and according to IMS’ Monthly
MIDAS sales analysis
platform, Vasotec sales dropped 37% in the year to March
2002. In May 2002, Biovail acquired the North American rights
to Vasotec and the diuretic combination product Vaseretic
from Merck & Co; the Canadian specialty company is also
developing a once-daily enalapril product. The third best-selling
ACE inhibitor is Pfizer’s Accupril (quinapril).
Ramipril storms ahead
The fifth best-selling ACE
inhibitor is Aventis’ Tritace/Delix (ramipril), first
launched in France in 1989. It is licensed to King for the
US and Puerto Rico where it is co-promoted by Wyeth and
King’s Monarch subsidiary as Altace, which is the
world’s number eight ACE inhibitor. Tritace registered 41%
growth according to Monthly MIDAS in the year to March 2002,
while Altace grew an impressive 76%. Ramipril is also marketed
by AstraZeneca in 14 countries, as Pramace/Ramace.
Much of this growth is thanks
to Aventis and King’s publicizing of the HOPE (Heart Outcomes
Prevention Evaluation) study results. HOPE involved 9,541
patients aged 55+ with either vascular disease or diabetes
and one other risk factor for heart disease. Followed for
up to 4.5 years, the results showed that ramipril led to
a 22% reduction in cardiovascular death, heart attack or
stroke compared to placebo. This was three times greater
than the result expected purely from the ACE inhibitor’s
effect on blood pressure, suggesting additional, unknown
protective properties.
More findings from the HOPE
trial were published in the British Medical Journal
in March 2002, demonstrating that ramipril reduced the overall
risk of stroke by 32%, and the risk of fatal stroke by 61%.
Treated patients also experienced less cognitive and functional
impairment. A separate report highlighted ramipril’s ability
to prevent and gradually reverse left ventricular hypertrophy.
In April 2002, Delix was approved
in Germany for the prevention of stroke, heart attack and
cardiovascular death in patients with diabetes or at high
risk for cardiovascular disease. It is the only ACE inhibitor
with this indication (for which it has similar clearance
in the US and Canada), and according to a HOPE sub-analysis
published in June 2002, is very cost-effective. Ramipril
generated €709 million in ex-US sales for Aventis in 2001;
in the first quarter of 2002, sales rose 31.8% to €206 million.
It may face generic competition from 2004.
For 1Q02, King reported a 76%
increase in Altace sales to $99.5 million and the company
predicts full-year 2002 sales of $415-505 million. At the
end of March 2002, King launched a direct-to-consumer marketing
campaign for Altace featuring golfer Jack Nicklaus. According
to IMS data, Altace became the ACE inhibitor market leader
by new prescription market share amongst US cardiologists
in May 2002, with 21.3%, taking the same spot among endocrinologists’
prescriptions the following week.
Potential in diabetes
Further analysis of the HOPE
study data suggested that ramipril could lead to a 34% reduction
in new diagnoses of diabetes among patients with no prior
history of the disease. These findings are being examined
further in the DREAM (Diabetes Reduction Assessment with
ramipril and rosiglitazone Medication) trial; rosiglitazone
is the oral
antidiabetic marketed
as Avandia by GlaxoSmithKline. It is also thought
that ACE inhibitors may reduce macro- and microvascular
diabetic complications.
AstraZeneca's CALM (Candesartan
And Lisinopril Microalbuminuria) trial compared the effects
of its ATIIA Atacand (licensed from Takeda) and/or
Zestril on blood pressure and urinary albumin excretion
in patients with microalbuminuria, hypertension and Type
2 diabetes. Both drugs were shown to be equally effective
(Zestril was slightly superior), and there was a synergistic
effect when the two were combined. As generic copies of
Zestril will soon be available, it will obviously provide
a much cheaper treatment option to the newer drug.
In 2000, the US National Institutes
of Health halted AASK (African American Study of Kidney
disease and hypertension) early when it became clear that
Altace or AstraZeneca’s beta-blocker Toprol XL (metoprolol)
were superior at postponing renal failure in patients with
kidney disease and proteinuria compared to the calcium antagonist
amlodipine (Pfizer’s Norvasc). Paradoxically, the
latter group of drugs were the preferred antihypertensives
for the African American population, who are more susceptible
to hypertension-related kidney failure. A later analysis
suggested that Altace was superior to Toprol XL, reducing
the risk of clinical events by 46% against amlodipine compared
to the beta-blocker’s 37%.
The Scandinavian Captopril
Prevention Project (CAPPP) showed that Capoten was superior
to a beta-blocker/diuretic combination in preventing cardiovascular
events in hypertensive diabetics, especially those with
metabolic decompensation. In early 2002, the National Institute
of Clinical Excellence for England and Wales recommended
that ACE inhibitors should be prescribed to Type 2 diabetics
at high risk of renal disease.
Other indications
The utility of ACE inhibitors
in stroke is still being ascertained. PROGRESS (Perindopril
pROtection aGainst Recurrent Stroke Study) suggested that
perindopril, marketed by Servier as Coversyl and
Solvay as Aceon, when administered with the diuretic
Natrilix (indapamide), could lead to reductions of
25-50% in the risk of further strokes, heart attacks and
cognitive impairment among stroke patients. Monotherapy
with perindopril alone, however, led to no discernible reduction
in the risk of stroke. The earlier CAPPP study found that
captopril users were actually 1.25 times more likely to
suffer a stroke than those given other antihypertensives,
but a later sub-analysis found this was not true in diabetics,
raising doubts about the earlier findings, especially in
light of the HOPE results.
Many of the ACE inhibitors
are now approved for use in congestive heart failure. Accupril
has undergone trials to examine its impact on the incidence
of ischemic events following coronary artery bypass surgery,
and in a small trial, Zestril was shown to reduce the frequency
of migraine attacks by over 20%. More intriguingly, analysis
of patient records suggested that older women taking ACE
inhibitors for hypertension enjoyed delayed muscle loss
and disability.
With post-marketing studies still
ongoing in a number of indications, it would seem that the
ACE inhibitors are not yet ready to give up their position
in the therapeutic arsenal. While brand name companies try
to extend their product
lifecycles, the class
will also provide a lucrative source of revenue for generic
manufacturers over the next few years, with many more patients
set to benefit from their effects.
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