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Finding
the Magic in Fixed Combinations
Once
maligned, combination pills now reaping billions.
By John Ansell, Director, John Ansell
Consultancy
July 13, 2006
Back
before the regulatory hammer came down in the 1960s,
fixed combinations were mostly a motley bunch that
included bizarre pairings of tranquilizers with just
about anything. Today that’s all changed, and it
keeps getting better. Drugs made by combining
established single agents aren’t just respectable;
several of them are major blockbusters.
GlaxoSmithKline’s Advair and Merck’s Vytorin are
the biggest successes, with more than $5 billion and
$2 billion in annual sales, respectively. At least
four other fixed combinations have surpassed the $1
billion mark for annual sales.
Table
1.
|
Product
|
Generic
Names
|
Therapeutic
Area
|
Company
|
Sales
($000s) |
| Advair |
luticasone
+ salmeterol |
Respiratory |
GlaxoSmithKline |
5,465 |
| Vytorin |
simvastatin
+ ezetimibe |
Cardiovascular |
Merck
& Co./
Schering-Plough |
2,400 |
| Augmentin |
amoxicillin
+ clavulanate |
Antibiotic |
GlaxoSmithKline |
1,212
|
| Lotrel |
amlodipine
+ benazepril hydrochloride |
Cardiovascular |
Novartis |
1,075 |
| Combivir |
lamivudine
+ zivoduvine |
Antiviral |
GlaxoSmithKline |
1,061 |
| Symbicort |
budesonide
+ formoterol |
Respiratory |
AstraZeneca |
1,006
|
Those
numbers have encouraged a bandwagon effect, and now
more and more companies are combining popular
single-agent treatments as new products. But not all
fixed combinations are big winners. So what separates
the winners from the losers? It helps to analyze and
compare some examples.
The
cardiovascular arena is where some of the biggest
successes, and failures, have occurred. Fixed
combinations have been important heart drugs for some
50 years, particularly in treating hypertension.
Today, the new trend is lipid-lowering combinations.
Statins were a huge step forward, but scientists have
learned a lot more about how high cholesterol leads to
deadly arterial plaque. The push is on to make drug
therapy even more effective.
Vytorin
pairs Merck’s simvastatin (Zocor), already a highly
successful drug on its own, and Schering-Plough’s
ezetimibe (Ezetia), a cholesterol absorption
inhibitor. The two companies set up a joint venture in
2001 specifically to develop this combination. Vytorin
quickly became the world’s second-best-selling fixed-
combination product ever because it tackles lipid
levels convincingly in two entirely different ways.
Now
Pfizer is developing its own double-barrelled lipid
blaster: atorvastatin (Lipitor) in combination with
the investigational lipid-lowering agent torcetrapib.
The latter is first among a new class of drugs called
cholesteryl ester transfer protein (CETP) inhibitors.
The two drugs have potentially complementary effects.
Lipitor lowers LDL, while torcetrapib raises the
“good” HDL. This unique combination is now in
Phase III trials and entails a major trial costing
Pfizer $800 million. Hints of synergy between the two
drugs have emerged, though not yet confirmed. Pfizer
aims to get to market with this combination by 2008.
The major holdup now is worry about hypertension,
which could be a side effect of the treatment.
Pfizer
hopes torcetrapib plus Lipitor will provide such an
improvement over results from any other single statin,
that doctors will switch patients to the new
combination regardless of what they were previously
taking. But other statin makers are also finding
partners for their pills. Most recently, AstraZeneca
is pairing up Crestor (rosuvastatin calcium) with
Abbott’s Tricor (fenofibrate) in clinical trials.
Crestor will also be tested in combination with
Abbott’s “next-generation” fenofibrate --
ABT-335. (For more, see next week’s Exclusive
Analysis report on “Battle of the Super Statins.”)
Success
is by no means guaranteed for just any combination.
Pfizer’s Caduet combines the company’s two
top-selling products -- Lipitor and Norvasc (amlodipine),
respectively the number 1 and number 6 best-selling
products globally in 2005. This was the first-ever
fixed combination to treat patients who are both
hyperlipidemic and hypertensive. Caduet was launched
in its first market, the United States, in 2004. Sales
were slow to start with but reached $77 million in the
first quarter of 2006, and Pfizer appears to be
soldiering on with the product. One reason Caduet may
have had a tough start is that it treats two different
conditions with one pill. Physicians tend to address
each condition separately, so it may take time for
them to see the advantages of a single pill for both.
A
famous flop in this arena is NitroMed’s BiDil. A
fixed combination of isosorbide nitrate and
hydralazine for heart failure in African-American
patients launched in 2005, BiDil was launched on the
premise that this disease is fundamentally different
in this population. That is a controversial idea.
Despite trial results that gave strong support to
their claim, the drug’s manufacturers have not yet
been able to bring this idea, and their drug, into
mainstream practice.
Asthma
is also a hotbed of combination products. Apart from
GlaxoSmithKline’s Advair (salmeterol xinafoate/fluticasone propionate), with sales of $5.5
billion, AstraZeneca’s Symbicort (budesonide/eformoterol)
has surpassed $1
billion in annual sales. (See figure 1, below.) Also, Schering-Plough and
Novartis are working on a fixed combination of the
former’s corticosteroid asthma therapy Asmanex (mometasone
fumarate) and the latter’s Foradil (formoterol). But
other developers wishing to jump on this bandwagon may
be disappointed. SkyePharma has failed to find takers
for a similar combination, formoterol with fluticasone,
which it has been developing.
Besides
cardiovascular drugs, asthma treatments, and
antivirals (against multi-strain diseases), fixed
combinations are moving into a growing number of
areas. These include:
·
Vaccines.
Combination vaccines
to prevent diphtheria, pertussis, and tetanus have
long been available. Since the 1980s, MMR vaccines
against the childhood diseases of mumps, measles, and
rubella have become established. Proquad, Merck’s
latest vaccine of this type, also prevents chickenpox.
Other recent combination vaccines include components
to prevent diseases such as polio, meningitis, and
hepatitis B.
·
Diabetes.
This was not traditionally an area for fixed
combinations. But the most recent novel class of
drugs, the thiazolidinediones (TZDs), cannot be used
alone. Dual formulations containing
GlaxoSmithKline’s TZD Avandia (rosiglitazone) are
now gaining ground, including Avandamet (rosiglitazone
with metformin) and Avaglim (rosiglitazone with
glimepride). Sales of Avandamet alone reached $319
million in 2005. Takeda launched Actoplus Met (pioglitazone
plus metformin) the same year, and has a combination
of pioglitazone with glimepiride in registration.
GlaxoSmithKline also has a fixed combination of
Avandia with simvastatin in Phase III development for
the treatment of diabetes and high cholesterol. Also,
a new class of antidiabetic drugs in advanced
development -- the DPP-IV inhibitors -- are likely to
be used in combination. Merck & Co.’s Januvia (sitagliptin
phosphate) and Novartis’ Galvus (vildagliptin) have
both recently been filed for approval with the FDA.
Promising clinical results suggest that using them
alongside existing drugs is likely to provide better
results than just using existing therapies.
·
Glaucoma.
In recent years
combinations have been developed aimed at increasing
efficacy, markedly simplifying administration, and
thus increasing compliance. The first of several such
products was Merck & Co.’s Cosopt (timolol plus
dorzolamide), launched in 1998.
·
Parkinson’s
disease.
Combinations such as Merck & Co.’s Sinemet (carbidopa
plus levodopa) became standard therapy 30 years ago.
Newer, triple combinations include novel additional
components, such as entacapone, which is used in
Stavelo (Novartis/Orion).
·
Migraine.
Following positive clinical results for a combination
of GlaxoSmithKline’s Imitrex (sumatriptan) with the
NSAID naproxen, GlaxoSmithKline filed for registration
with the FDA recently; the product could well reach
the market by the end of 2006.
·
Osteoporosis.
Fosamax is a leading product of Merck & Co., with
sales in 2005 of $3.19 billion. In 2005, the range extension Fosamax Plus D (alendronate +
vitamin D) was launched, taking fixed combinations
into another new therapeutic area.
·
Stroke.
In 2005, the FDA
approved the first fixed combination antihypertensive
product to help prevent stroke: Merck & Co.’s
Hyzaar (losartan + hydrochlorothiazide).
Improving
outcomes seems to be the magic ingredient for a truly
successful fixed combination. Many such products
flourish just because their convenience improves
compliance -- a tremendous benefit in diseases such as
diabetes or asthma. But on other fronts, such as
cardiovascular disease, doctors are less impressed by
simple convenience. Instead, they want to see
measurable improvements in outcomes to justify a
switch.
Avoiding
adverse events is also important. Oral contraceptive
combinations containing an oestrogen plus a
progestagen have been long been regarded as more
effective and less likely to cause adverse reactions.
As a result, they greatly outsell plain progestagen
products. Hormone replacement therapy, meanwhile, has
plummeted since 2002 mainly because concerns about
side effects eclipsed good news on the efficacy side.
In this case, combination therapies showed the worst
side effect risks of all. Lilly’s Symbyax (olanzapine
with fluoxetine), launched in 2004 for bipolar
depression, also failed to get traction on the market
because of an unacceptable side-effect profile.
The
most interesting trends lie ahead, however. As more
disease mechanisms are revealed and scientists learn
to identify key mechanisms that are interlinked, fixed
combinations could play an increasingly important role
in discovering true synergies that go beyond an
additive effect. The trick will always be to make
certain that the good effects outweigh any possible
bad ones.
Figure
1. Sales of Advair and Its Component Products Since
1993 ($000s).
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