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Avastin vs. Lucentis in Wet Age-Related Macular Degeneration By: Wendy Bedale

July 6, 2010


I have blogged several times about the Avastin vs. Lucentis controversy.  Irv Aron , a retired consultant in the Medical Laser industry, blogs regulary about this topic as well in Irv Arons' Journal.  Last week, he posted a paper written by Wendy Bedale for a class at the University of Wisconsin Madison.  I thought this was an excellent and informative paper.  I have contacted Wendy and have gotten her permission to post the article, unedited in its entirety.  I am sure you will find it very interesting.

Thank you Wendy for allowing me to republish this!

Avastin vs. Lucentis in Wet Age-Related Macular Degeneration

By: Wendy Bedale
In my home I have a beautiful
Halloween jack-o-lantern quilt and a cozy fleece blanket crafted by my
Aunt Maureen. Each year my Christmas tree is adorned with many
hand-painted Christmas ornaments she has given me, including a little
sled, all of which she made by hand. For my wedding, I received a dozen
decorative hand towels embroidered with hearts, shamrocks, fall leaves.
She is generous with her talents and her gifts.
A few Christmases ago Aunt Maureen gave me a resin basket festooned with snowmen. She apologized because it wasn’t handmade.
Around that time I noticed that
emails from her were now printed in a giant font. And on occasions when
I visited her in Florida, her eyeglasses were very thick.
She was going blind.
This isn’t really a story about
Aunt Maureen, however. It is about a miracle drug for macular
degeneration, or rather, two miracle drugs: Lucentis and Avastin, one
expensive, the other almost dirt cheap. It is about the drug company,
Genentech, that developed both drugs, and the difficult and
controversial decisions made in developing and marketing these drugs.
It is about pioneering doctors who want to help their patients, and
patients who take risks for the chance to see again.
Aunt Maureen suffers from
age-related wet macular degeneration, or AMD. AMD is the leading cause
of vision loss in the elderly, affecting about 1.5% of the population
over the age of 40 [1]. In the early stages of AMD, a patient might
notice that straight lines look wavy, or that the center part of their
vision is blurry and without color. AMD doesn’t involve physical pain,
but the loss of vision in otherwise healthy individuals is devastating.
“It really started acting up
when I was in my mid-40s,” said Aunt Maureen. “My doctor told me I
would be blind by the time I was 60.”
Aunt Maureen has some of the
risk factors for AMD: older age, female, of Northern European descent
[1,2]. She has lived in Florida for about fifteen years now, and high
exposure to sunlight is more common in AMD patients [3]. However, she
doesn’t smoke and doesn’t have a history of cardiovascular disease or
chronic kidney disease, which are other important risk factors [1].
There is also evidence of a genetic component to AMD [3], although none
of Aunt Maureen’s immediate family has had any problems with their
vision. AMD is not always predictable, nor is it preventable.
is a disease of the retina. The retina is the part of the eye lining
most of its inner surface. Like film in a camera, light strikes the
retina and forms an image. The macula is part of the retina, the part
that is in the back central region of the eye. It is responsible for
the clear, sharp central vision needed to drive, read, embroider or
paint [3].
There are two forms of AMD: dry
and wet. The dry form is less severe and may not affect vision
significantly. Dry AMD may or may not progress to the more severe wet
form, which affects about 10% of AMD patients [1]. Aunt Maureen
initially had the dry form of the disease, but progressed to the wet
form about ten years ago.
Wet AMD is called “wet” because
fluids, especially blood, are responsible for the damage to the eye.
For unknown reasons, new blood vessels behind the eye start to grow in
AMD patients. The new blood vessels grow and grow. Blood and other
fluids leak from these blood vessels, damaging the macula. In most
cases, the damage is irreversible, like the damage done to a photo
album stored in a damp basement. The damaged macula can no longer
process images clearly and sharply [1].
However, if the renegade blood
vessel growth could be stopped before leakage occurs, additional damage
and visual loss might be prevented. Therapies for AMD target these
blood vessels. Some, like laser therapies, seek to obliterate the blood
vessels, but these approaches have been described as being “like using
a blowtorch to stop weeds”, according to retinal specialist Dr. Anne
Fung of San Francisco [4].
“Treatment of macular
degeneration was very depressing five years ago,” says Dr. Ron Danis, a
retinal specialist at the University of Wisconsin-Madison. He cites a
patient named Donna, who had a long history of AMD in both eyes. Five
years ago she was legally blind, and Danis had run out of therapeutic
options for her.
More recently, biotechnology
has allowed a more targeted approach to treating AMD. Newer drugs for
wet AMD block specific molecules that trigger growth of the new blood
But why do these unwanted blood vessels grow?
Although not as dramatic as a
severed earthworm re-growing a missing segment, all animals possess
some ability to regenerate tissue, even in adulthood. New tissue is
needed to repair injuries or during pregnancy, for example. The new
tissue requires sustenance in the form of oxygen and other nutrients,
which is provided by blood. So the body has sophisticated mechanisms to
switch on the growth of new tissue, including the new blood vessels
needed in those tissues.
The growth of the new tissues
is stimulated by proteins known as growth factors, which are chemical
messengers produced and distributed in the body under carefully
regulated conditions. There are many different growth factors for many
different types of tissues. Some help build bone, others nerves, skin,
red blood cells, and so on. One class of growth factors called vascular
endothelial growth factors, or VEGFs, triggers new blood vessel growth.
Scientists call this process angiogenesis.
Sometimes, however, as in the
case of wet AMD, angiogenesis gets turned on when it should not be. AMD
is not the only disease associated with unwanted angiogenesis. Any
cancer tumor bigger than 1 mm (about the size of a grain of sugar)
requires a supply of blood in order to continue to grow [5], so like
thieves tapping into an oil pipeline, tumors create their own blood
vessels to feed themselves.
In the mid-1990s, the discovery
of specific growth factors in the body that stimulated angiogenesis
lead scientists to hypothesize that blocking these same growth factors
might stop cancer from growing. One of these scientists was Dr.
Napoleone Ferrara.
Ferrara is a legend at
Genentech, itself a legend in the biotechnology industry. Genentech is
considered to be the first true biotechnology company, founded in 1976
in South San Francisco, where it is still located. Genentech’s products
are pharmaceutical products, but not typical small molecule, chemically
synthesized drugs. Genentech’s drugs are proteins, which are very large
molecules, and they are produced using recombinant DNA technology. Such
drugs are classified as “biologics” since they are produced through the
assistance of living cells such as bacteria.
The recent purchase of
Genentech by pharmaceutical giant Roche makes Genentech part of a huge
corporate entity. However, Genentech still operates more like a small
university than a money-making machine, according to a source at
Genentech. Dr. Danis, who has been involved with numerous clinical
studies sponsored by Genentech, concurs. Genentech’s goal is to make
drugs that make real differences in patients’ lives, according to the
source at Genentech, not just “me too” drugs or drugs that extend life
by a mere month. Genentech has been involved in the development of at
least 15 drugs that are currently marketed in the US and worldwide [6].
Ferrara arrived at Genentech in
1988. The handsome physician originally moved to the United States from
Italy in the 1980s to study a hormone involved in reproduction called
relaxin [7,8]. How he ended up discovering VEGF is a lesson in the
circuitous paths that science often takes. And his application of this
basic discovery to develop drugs that stopped angiogenesis is an
example of every scientist’s dream of a significant breakthrough.
The idea of blocking
angiogenesis to treat cancer was first described in 1971 by the late
Dr. Judah Folkman, considered the “father of angiogenesis” [9,10], at
the Children’s Hospital Medical Center and Harvard Medical School.
Scientists tried for years to isolate a specific factor necessary for
new blood vessel formation that they could then try to block. They had
no problem finding candidate factors; they found a plethora of similar
factors that all stimulated new blood vessel formation. But blocking
just one of these factors never seemed to have much effect [7]. Like
many other important mechanisms in the body, redundancy had been
built-in. Attempting to simultaneously block all of the different
factors that could stimulate angiogenesis, seemed a daunting task.
At Genentech, Ferrara was still
working on relaxin as a potential drug to induce labor. Somewhat
unusually in the pharmaceutical industry, Genentech has always
encouraged its scientists to work on pet projects in their off-hours,
and Ferrara took the opportunity to study angiogenic factors [7,11,12].
Unlike most scientists hunting for anti-angiogenic factors, who were
cancer specialists, Ferrara was an expert in hormones involved in human
reproduction, some of which are produced in the pituitary gland. This
background may have given him the edge. Ferrara chose to look for
factors that stimulated new blood vessel formation in the pituitary
gland, a tissue that the cancer experts had not considered. And he soon
hit pay dirt.
In 1989, he published the first
paper describing the factor he found, which he dubbed “at least
provisionally” as vascular endothelial growth factor, or VEGF [11]. The
name stuck. And a key step towards a future miracle treatment for AMD
was taken.
Around this same time, Aunt
Maureen’s initial problems had resolved, her vision stabilized, and her
macular degeneration had not yet progressed to the wet form. Like a
ticking time bomb, though, she knew her vision could start to
deteriorate at any time.
During the next decade, much
work in Ferrara’s lab and others focused on learning both how VEGF
works and also how to stop it from working. One approach to stopping
VEGF was to make antibodies that would attack it. Antibodies are made
by an animal’s immune system as a way of deactivating foreign
substances that could be harmful when they enter the body. Each human
has an astounding number of different antibodies, perhaps as many as 10
billion [13], with each antibody specific to a particular foreign
substance or “antigen”. Antibodies work by binding very tightly to
their target antigen, taking the foreign substance out of commission.
Soon after VEGF was discovered,
Genentech started working on a VEGF antibody. Antibodies can be made in
animals like rabbits or mice, and they can also be made in animal cells
that grow in test tubes. Genentech had already developed antibodies
against other proteins to use as drugs, and they knew that a VEGF
antibody could be a blockbuster. Genentech was clearly developing the
anti-VEGF antibody to use as a cancer therapy, the holy grail of the
pharmaceutical industry. But Genentech was also, in parallel, trying to
block VEGF in other diseases where VEGF was known to be involved,
including wet AMD.
Antibodies administered orally
do not remain active in the body, as they are proteins that the
digestive system will break down just like a tiny bite of steak. For
cancer patients, then, Genentech was planning to bypass the
gastrointestinal tract by injecting the drug directly into the blood
stream, or intravenously. For cancer, it is not always known where
within the body cancer cells may lurk, so intravenous administration
makes sense since the drug goes everywhere blood goes. Giving a drug
intravenously, however, means there is a bigger chance of side effects
since the drug can go places where it should not be. Intravenous
administration also requires a lot more drug to ensure enough drug does
get to the parts of the body where it is needed. More drug makes
treatment more expensive.
To treat wet AMD, Genentech
decided to forego intravenous administration and inject the VEGF
antibodies right into the vitreous, which is the jelly-like part of the
eye. Getting injected into the vitreous of the eye, or intravitrealy,
sounds incredibly frightening. I asked Aunt Maureen about it.
“The first time I freaked. But honestly, it doesn’t even hurt”.
Local anesthetic is given
before the injection, and the needle used is very fine, a few times
thicker than a human hair. The volume delivered to the eye is about the
amount of a drop of water. Aunt Maureen reports her eyes feel tender
for about a day after the injection, and then everything is fine. She
has had at least eight Avastin injections now, about one per month, and
has had no side effects to date.
Because antibodies are such big
molecules, Genentech was concerned that the VEGF antibody would not be
able to move through the gelantinous layers of the eye to the retina,
where the drug needed to go to work. So they decided to test how well
the drug could move within the eye. Genentech used a
radioactively-labeled antibody. They also used a radioactively-labeled
fragment of the antibody. The fragment they chose was the part of the
antibody that actually was involved with binding VEGF, which is about a
third of the entire molecule. This fragment is called a Fab for
“Fragment Antigen Binding”.
Genentech injected either the
radioactive antibody or Fab into monkey eyes, and then looked to see
where the radioactivity went [14]. Sure enough, it looked like a
full-length antibody didn’t travel as well within the eye as the
shorter Fab fragment. However, they took a shortcut: they didn’t use
the actual full-length VEGF antibody, but a different antibody that was
about the same size that was easier to track within the animal. This
may have been a mistake.
At this point Genentech decided
to develop the smaller Fab antibody for wet AMD and the full-length
antibody for cancer. They called the full-length antibody bevacizumab,
and gave it the brand name of Avastin®. The small fragment version was
given the generic name of ranibizumab, with the brand name of
The true rationale behind
Genentech’s decision to develop Avastin and Lucentis as two separate
products may never be really known. The monkey study indicates they had
some scientific justification to develop the smaller antibody for use
in the eye. However, Genentech also certainly realized that having two
separate drugs could mean more profit.
Development of the VEGF
antibody for cancer proceeded rapidly, and in February of 2004,
Genentech received FDA approval to sell Avastin for colon cancer [7].
The development of Lucentis for wet AMD was going well, but slower. By
the following year, three clinical studies with Lucentis had been
completed. The results were spectacular. 95% of the subjects showed
stable or improved vision following one year of treatment with Lucentis
By this time, Aunt Maureen’s
AMD had progressed to the wet form. Her vision became so bad she had
trouble reading and was driving over sidewalks. Her doctor tried laser
therapy. He told Aunt Maureen she was lucky, as she was one of the 10%
of patients who responded well to it, at least initially.
Genentech announced the
Lucentis results at the meeting of the American Society of Retina
Specialists in Montreal of July 2005. It was intended to be the
springboard for Lucentis. However, to Genentech’s probable surprise, a
different Genentech drug stole the show [15].
That drug was Avastin. As word
starting leaking about the miraculous results with Lucentis, a handful
of trailblazing ophthalmologists, who couldn’t wait for FDA approval of
Lucentis, took matters into their own hands. Some began using
intravenous Avastin in patients with wet AMD. And a few brave doctors
began injecting the drug, approved only for colon cancer, into eyes of
patients who had wet AMD [16,17].
The Avastin results reported at
the Montreal meeting, although representing only 18 patients, of whom
only one received an intravitreal injection [15], were comparable to
the Lucentis results reported at the same meeting, according to an
article later that year in the Los Angeles Times [18]. The earlier
experiment in monkeys may have mislead Genentech into thinking Avastin
would not work in the eye, but these new results in humans showed that
it clearly could.
The Montreal meeting was
pivotal for Avastin use in AMD, according to Irv Arons, a long-time
consultant to the ophthalmology industry [19]. The excitement generated
among retinal specialists was tremendous.
“Word spread like a tsunami”
according to Lynne Peterson, writing in Trends-in Medicine after the
Montreal meeting [15]. Within 3 months more than 1000 wet AMD patients
had received intravitreal injections of Avastin, according to the Los
Angeles Times [18].
To understand the significance
of the use of Avastin in wet AMD at that time, it helps to understand a
little about the FDA approval process for drugs. When the FDA approves
a drug, it is always for a particular disease or “indication”. Approval
means that the FDA has reviewed all of the pertinent animal and human
studies of that drug and has agreed that the drug is both effective in
treating that disease and safe for use in that disease.
Although the FDA approves a
drug for a specific disease or “indication”, it is legal and not
unusual for a physician to prescribe and use the drug for other
indications. For example, a drug approved for breast cancer might be
tried in a patient with a different type of cancer. This type of
prescription for a disease other than the official approved FDA
indication is called “off-label” usage.
Because a drug used off-label
has not gone through the rigorous testing and FDA scrutiny for that
disease that the approved indication has, certain barriers exist to
help limit widespread off-label usage. The FDA puts strict gags on
companies to prevent them from advertising their drugs for unapproved
indications. Insurance companies may refuse to pay or reimburse for
off-label treatments.
According to Lynne Peterson,
writing just after the Montreal meeting, Genentech was alarmed about
the flood of off-label Avastin use. Officially, Genentech was concerned
about the possible safety problems associated with using Avastin in the
eye [15]. Avastin was not manufactured initially to meet the rigorous
requirements for use in the eye. In addition, unlike Lucentis, Avastin
has to be diluted before it is injected into the eye.
This dilution can only be done
by a special compounding pharmacy. There is no formal inspection or
quality control required after the dilution step, and errors in
dilution or contamination are therefore possible and probably more
likely than in the production of the carefully controlled, single-use
containers of Lucentis produced entirely within Genentech’s hands.
Genentech has no ability to control Avastin compounding once it is
sold, yet the company might still be held liable if a patient received
an eye infection, for example, after treatment with off-label Avastin.
Dr. Danis at the University of
Wisconsin-Madison was one of many caught by the wave of Avastin
excitement following the initial reports presented in Montreal prior to
the approval of Lucentis. His first experience using Avastin was in
Donna, his patient with the long history of AMD who had run out of
therapeutic options.
“She came to me waving this newspaper clipping,” said Danis. She demanded that he try Avastin on her. So he did.
She came back a week later. She
wanted a shot in the other eye, because she believed the drug was
working. Within six months of treatment, she was driving herself to the
clinic and seeing 20/40, which means she could read the 5th line down
from the top of an eye chart in a vision exam.
“She likes to say she had ‘Avastin’ improvement in both eyes”, chuckles Danis.
Besides possible safety
problems, Genentech also had commercial reasons to be concerned about
off-label Avastin use. Avastin could steal Lucentis’s market before
Lucentis was even officially launched. Genentech therefore raced to get
their product approved, seeking “fast track” status to expedite the
lengthy, cumbersome FDA review process, which generally takes a year.
They submitted their Lucentis data later that year, and Lucentis was
approved six months later, in June of 2006 [20].
As might be expected for a drug
that is only injected once a month and was expensive to develop and
manufacture, Genentech set a high price for Lucentis, around $2000 per
injection [21]. Even with Medicare coverage, the standard 20% co-pay
required by the patient was about $400 per month for Lucentis, which
was too much for some. Avastin, in contrast, is given to cancer
patients in doses 100 times greater than Lucentis, and is administered
twice per month instead of once. For cancer indications, Avastin is
still considered a very expensive drug (up to $100,000 annually per
patient [22]), but the cost of the amount needed for an intravitreal
injection ends up being very low, about $50, because the amount needed
in the eye is so tiny [21]. Avastin could therefore make a significant
dent in Lucentis’s profits.
Initially, Medicare and private
insurance companies did not reimburse for Avastin when used in AMD
because the drug was not approved for that indication, and no rigorous
clinical studies had been conducted with the drug to formally test its
effectiveness or safety. However, the full drug cost for Avastin
without any reimbursement was only about 10% of the cost of Lucentis
after reimbursement. So many physicians and patients opted for Avastin,
including Aunt Maureen’s eye doctor.
Doctors were split on the use
of Avastin or Lucentis [16,23]. Some, like Danis, preferred to use
Avastin because of its lower cost. Others questioned the ethics of
using Avastin for an unapproved indication after an FDA approved drug,
Lucentis, was on the market.
There was also concern that
safety problems might start showing up in the burgeoning number of
patients receiving Avastin. While several small clinical studies with
intravitreal Avastin for AMD were published at this time, no large
studies had been conducted, as would have been required prior to FDA
approval. Genentech, of course, had no desire to sponsor an
intravitreal Avastin study, and they certainly had no incentive to seek
approval for Avastin for AMD. Eye doctor associations argued that a
head-to-head comparison of Lucentis and Avastin was needed, and many
began lobbying for a government-sponsored study to do just that
During its first year on the
market, Lucentis made money, but probably not as much as Genentech had
hoped. The Wall Street Journal reported that during the first 6 months
of 2007, sales of Avastin in the US were $1.1 billion dollars, while
Lucentis sales were about a third of that at $420 million [24].
On October 11, 2007,
Genentech’s president sent a letter to members of the eye care
community announcing that effective November 30, 2007, Genentech would
no longer allow its distributors to sell Avastin to compounding
pharmacies [25]. Perhaps realizing the potential hardship this move
would make for patients of limited financial means, the communication
also discussed a financial support program designed to make Lucentis
available to patients who cannot afford Lucentis. This program is still
operational, and Danis reports that it has worked well for his patients
that qualify for it.
Genentech explained in the
letter that this move to block sales to compounding pharmacies was
triggered by two FDA inspections. One inspection, of a compounding
pharmacy in Massachusetts, took place in late 2004, prior to the
approval of Lucentis [26]. The pharmacy was specifically cited for
“repackaging” Avastin for use in eye indications. The FDA was
“particularly concerned” because Avastin as originally sold is a
sterile solution, meaning it contains no microorganisms that might
cause infection. By repackaging Avastin, it would be possible for
bacteria or other microbes to contaminate the product. The introduction
of microbes directly into they eye by intravitreal injection could
cause serious eye infections that could lead to blindness.
The other FDA inspection noted
in Genentech’s October letter was of Genentech itself. The FDA said
that Genentech’s manufacturing facility and quality standards for
Avastin were not adequate for making a drug designed for use in the eye
Some rationale beyond profit
appears to exist, therefore, for Genentech’s October 2007 decision to
block sale of Avastin to compounding pharmacies. Even so, Genentech
received considerable flack from the press regarding this decision. A
Wall Street Journal article published the day after the Genentech
letter was released pointed out that if patients were given Avastin
instead of Lucentis, the annual savings to the Medicare program (and
therefore US taxpayers) could be over $1 billion [27]. This caught the
attention of Senator Herb Kohl (D-Wisconsin), Chairman of the Senate’s
Special Committee on Aging. He asked that the Center for Medicare and
Medicaid Services look into the matter [28].
In response to the strong
criticism from physicians, patients, Congress and the press, Genentech
announced two weeks later that they would delay the restriction of
sales to compounding pharmacies until January 2008 [29]. In this second
announcement, Genentech explicitly stated that the decision to block
sales was “not motivated by a desire for increased profits”, a comment
that has been viewed with some skepticism in the media
In December of 2007, following
two months of intensive discussions between Genentech and several eye
doctors’ organizations to reach a compromise to the dilemma, Genentech
announced that it would allow sale of Avastin to physicians, who could
then direct the drug to a compounding pharmacy [35]. Genentech also
reported destroying more than $200 million worth of Avastin that would
not have been suited for use in the eye, presumably to address the
FDA’s concerns following their inspection [29].
In the meantime, the long-hoped
for head-to-head clinical study comparing Avastin and Lucentis began in
February 2008 and is still underway [36]. As expected, Genentech is not
involved in the study [37], which is sponsored by the National Eye
Institute and is called the CATT study (“Comparison of Age-related
Macular Degeneration Treatment Trials: Lucentis-Avastin”). Results from
this study, which involves 1208 participants in 59 locations throughout
the US, should be available in February of 2012 [36].
The results from this study
have important implications. It will at long last provide data
regarding the relative effectiveness and safety of Avastin and
Lucentis, which may improve treatment for patients with wet AMD. If the
Avastin results are promising, billions of tax-payers’ dollars could be
saved each year. The study will also address the optimal dosing
frequency for both Avastin and Lucentis, which has been the subject of
conflicting reports in the literature. If Avastin proves successful in
this study, many countries worldwide may more formally adopt Avastin
usage for wet AMD, particularly in those countries where Lucentis is
not currently available, according to Danis.
Pharmaceutical companies often
justify the high cost of their products by citing statistics about the
risks and high costs of developing drugs, or by explaining that a large
percentage of their revenues are used to fund research on the next
miracle cure. But pharmaceutical companies are for-profit enterprises,
and their public financial statements make it clear that if successful,
they make money well beyond expenses. Do pharmaceutical companies
deserve to earn money if it means making life saving or important
quality-of-life enhancing drugs more expensive? Is the high cost of
such drugs, reimbursed at least partly by Medicare and insurance
companies, a surreptitious scheme by drug companies to make the
taxpaying public support them? Should the public have access to drugs
that have not been approved by the FDA when FDA-approved drugs for that
disease exist? The ethical issues associated with the pharmaceutical
industry are complex and continually evolving, and the Avastin-Lucentis
debate highlights many of them.
No one outside of Genentech
will probably ever know the whole story behind the development and
marketing strategies for Avastin and Lucentis. When I asked a source at
Genentech if she could provide additional insight into this area, or
guide me to someone at Genentech who could, she was required to tell me
that Genentech employees were forbidden to discuss the Avastin/Lucentis
What is not disputed, however,
is that Genentech’s two drugs, Avastin and Lucentis, have helped many
people around the world retain or regain their eyesight, a truly
significant medical advance. In the words of Dr. Danis: “It’s almost
like a miracle”.
Last year Christmas I received
a beautiful lace-trimmed and embroidered dresser scarf that Aunt
Maureen made for me. I see the dresser scarf every morning when I first
get up and fumble for my eye-glasses, which I need to get me to the
bathroom where I put in my contact lenses. Aunt Maureen is now well
past the age of 60. And she can see.
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Wendy Bedale
biochemist by training, Wendy currently is the Director of Regulatory
Affairs for Deltanoid Pharmaceuticals and is an Assistant Scientist at
the University of Wisconsin-Madison. She enjoys reading and writing
about science and technology in her free time.
She can be contacted at: Wendy Bedale

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