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Lou-Ellen Barkan interviews Elemer Piros
Part II of our Reflections interview with Dr. Piros is featured in our Winter 09-2010 issue.
L OU-ELLEN BARKAN (LEB): Welcome Elemer and thank
you for joining us today. How did you become interested
in Alzheimer’s?
Elemer Piros (EP): I started off in neuroscience and
worked on addiction
for a decade. I wanted
to understand the molecular
mechanisms that
are in play once a drug is
hit by alcohol or opioid
substances. I learned a
great deal about neuronal
communication. I
read quite a bit about
Alzheimer’s research as
it was close to my field.
When I moved to Wall Street, Alzheimer’s research
kept me interested looking for companies that develop
Alzheimer’s drugs. I found quite a few and learned about
the rationale for their work, the targets and how the field
is changing. It changes every six months when there is
something new and more exciting that gives us a better
understanding of the underlying cause of the disease.
LEB: Why has there been such a large response from the
commercial research community?
EP: The market is extremely large. According to a National
Institute of Drug Abuse survey, society spends the most
money on addiction and Alzheimer’s disease. So there is
a large, unserved market opportunity and, while we have
four drugs on the market, these only alleviate symptoms.
They are not disease modifiers.
LEB: Is there equal focus on prevention, treatment and
cure?
EP: The most significant effort is in treatment. Prevention
is very difficult until we have a better understanding of
the underlying cause. We have ideas and hypotheses,
but at best we are still only attacking downstream events
from the root cause. And that leads to treatment of the
symptoms rather than the cause of the disease. What makes
it more complicated is that there could be more than one
underlying mechanism and my Alzheimer’s disease might
be very different from yours. There may be shared elements
in the mechanism, but the root cause may be different.
We also have to think about genetic predisposition and
environmental factors.
LEB: Can we assume that the stage at which you start
taking drugs is also a factor in the outcome?
EP: The earlier the better. But what makes it very
challenging from the drug-development perspective is that,
even in untreated patients, progression is very slow in the
early phases. It may take a long time before you see the
declining phase. If you want to show a difference between
treatment and placebo, you have to wait from a year and a
half to three years and the cost of clinical studies increases
tremendously. Companies try to catch the point before
there is a precipitous decline. Once we are at the end phase
of the disease, when so much damage has already been
done, it is not reasonable to expect to reverse the damage.
LEB: I find the complex path to drug approval both
reassuring and frustrating. Frustrating because it is such
a long process. Reassuring because we can assume that
when the drug finally gets to market, it’s been appropriately
tested for safety and efficacy. But look what happened
with Vioxx, which went through the approval process and
still turned out to be toxic. We want something quickly, but
we also want it to be safe.
EP: By the time a successful drug gets to market, dozens
of other drugs have died along the way for one reason or
another. It could be lack of efficacy or some potential
toxicity in animals that predicts a poor outcome in people.
Dozens of compounds are killed before they even get to
human testing. Once we arrive at the human trial, we still
have only a 10% chance that a drug will make it to the
market. The odds are against any compound, no matter
how good the rationale may be, because true toxicity
testing can only be done in human beings.
This is one of the reasons that pharmaceutical companies
give for why they charge so much for drugs. It is not only
the expense of developing the drug, but the expense of
the failed drugs. If they kill them early enough, they don’t
have to invest as much. Recent failures that got to Phase
III trials cost companies millions of dollars and there is no
return on investment.
LEB: Flurizan was a great hope until it failed this summer.
I understand that — just before the final results were
published — there was a $100 million investment by
the Danish company Lundbeck, and that money is not
refundable.
Can we talk a little about compassionate use of drugs?
EP: The FDA and the European agencies grant
compassionate use for drugs to be sold at a cost basis to
patients while the drugs are in clinical trials. Compassionate
use is usually granted in situations when there is limited
survival. For example, in pancreatic cancer — which
has a median survival rate of 6-9 months — or pediatric
indications where there is a genetic disorder that will run
its course within 5-10 years. In these cases, almost anything
should be tried if it’s not toxic for the individual. Therefore,
the FDA allows those drugs to be available even before
there is a formal approval.
For chronic diseases like Alzheimer’s, it’s a borderline
situation between acute and chronic. People tend to have
a long life once they are diagnosed, so the disease doesn’t
fall into the acute category.
LEB: Is the compassionate use integrated into clinical
trials, or is it something my internist can just prescribe?
EP: It could be separate and prescribed by anyone who has
access to the company, but the physician and the FDA must
set up the channel for the prescription.
LEB: So, for example, if I had pancreatic cancer, I might be
told that there’s no trial right now, but there is a drug being
produced — perhaps overseas — and we can try to get
that drug for you.
EP: You could get the drug that way, but the FDA is more
likely to get you approval to take a drug that is concurrently
being tested in clinical studies. In other words, if there
is a new drug in Portugal that has never been tested on
human beings, it is less likely that the FDA will approve
your taking it. There has to be some sort of evidence,
background information and preferably concurrent clinical
studies for the FDA to feel safe in approving the drug for
compassionate use.
LEB: I understand what you mean about Alzheimer’s
falling somewhere between chronic and acute. The
average length of the disease is eight years, but we
know it can last more than twenty years. I could make an
argument that for every person who is diagnosed in the
early stage, compassionate use would be appropriate. If
there was something out there, I certainly would want to
take it as long as the impact on my general health was not
a problem.
EP: That’s the problem. We have to be very conscious
about safety since these drugs will be taken for a long time.
The FDA, without safety information available on the
drug from dozens if not hundreds of subjects, would not
feel comfortable with uncontrolled experiments going on
around the world or the country. One important reason is
that if there is a tightly controlled protocol, the value of the
information is much more significant than if a report comes
in from a city like New York where someone took the drug
and developed a liver condition. In that example, it would
be very difficult to understand whether the condition was
caused by the drug or if the patient had another condition.
That’s why regulation for compassionate or long-term use
is stringent.
LEB: So it’s not likely that the FDA will approve
compassionate use for Alzheimer’s in the near term?
Maybe not until we know more about what causes the
disease and puts you on a faster track to the late stage.
But what if I had the disease and I was diagnosed as
someone who would go from the early stage to the late
stage in one year?
EP: The compassionate use program, at least to my
knowledge, is not based on a set of rules. It can be
negotiated on an individual basis and between the company,
the physician and the FDA.
LEB: At the 2008 Annual Meeting, we talked about
genetics and community-based studies. What is the
impact of the focus on genetics?
EP: We know that Alzheimer’s is not a purely genetic
disorder. There are some cases where there is an inheritance
of certain genes, but these cases are in the minority. However,
understanding which genes lead to the sporadic version
— that is, where it’s not caused by a genetic predisposition
— is very helpful because the cause or trigger mechanism
may be similar. Someone may be more predisposed to get
the disease early in life and others may be predisposed to
have a more precipitous course of the disease. It’s extremely
crucial to identify as many inherited genes and pathways as possible, because they could give us information on how
to treat the entire disease population and how to develop
new drugs.
LEB: You are reinforcing my opinion that we need
strong collaboration among the various enterprises:
small biotechs, large laboratories and pharmaceuticals,
hospitals and universities, research scientists working on
genetics and results from clinical trials. It’s a very complex
community. Is everyone cooperating?
EP: There’s increasing collaboration. At your Annual
Meeting, one of the speakers was talking about a study
in which they found new genes, and the information was
available immediately, free-of-charge, to anyone who needs
access for scientific purposes.
In the past there were isolated efforts on various
continents, and industry and academia went different ways.
Industry obviously has an interest to protect its intellectual
property until the patent is issued. In academia the goal
may not necessarily be to develop a drug, but rather to
understand how the brain works. In the past, connections
between industry and academia were usually made when
results were presented at a national or international
conference. Today, there is more and more collaboration,
because people realize that this is such a complex disease that
one scientist’s favorite hypothesis may not be the only one.
LEB: We’ve had an ongoing concern that there may be too
much investment in the amalyoid hypothesis. Is this the
right hypothesis? We’ve been looking for the renegades.
EP: It’s probably a reasonable hypothesis, but it shouldn’t be
the only one because we know how different the disease is
in different people, both in the age of onset and the length
and course of the disease. The manifestations of the disease
are also different. We should entertain other hypotheses.
The sad part of this story is that for decades, the
mavericks weren’t funded by the NIH because there was
a cult-like following of the amyloid theory. Everything
else was seen as unreasonable. There are still two groups that disagree about the pathway of the disease and I don’t
think they’ve come to a point where they each accept each
other’s ideas.
The remaining argument is a chicken or egg problem.
In other words, if the amyloid is at the root of the problem
and the tau follows, then it makes sense to inhibit the
amyloid and break plaque buildup. However, if we approach
the tau first, the amyloid problem may cause other issues,
which are not addressed. Tau treatment might only treat
the symptoms rather than the cause. Each one is a different
value proposition. What comes first? Nevertheless, it is
nice to see these opponents talking and acknowledging
that each has valid points.
LEB: Last summer one scientist suggested that there are
two kinds of amyloid, soluble and non-soluble. Why has
no one thought of this before? It seems so obvious.
EP: What we are actively working on is what’s harmful for
the brain versus what helps the brain’s functionality. You
could be too aggressive and clean up amyloid needed for
normal function. If we are too aggressive on one pathway,
it leads to severe side effects. One vaccine trial was halted
because the treatment may have been too aggressive. If
we were more refined in our thinking and could attack
multiple targets, that would be ideal.
LEB: Amyloid protein exists throughout the body. Have
we learned anything from
amyloidosis research?
EP: There are a number of common features, but we are
much more advanced in our understanding of Alzheimer’s
disease and we have more treatment options available. It’s
ironic that the same company that developed Alzhemed
(Neurochem), which failed to show efficacy for Alzheimer’s
disease, also failed with a similar approach for amyloidosis.
Amyloidosis is not as prevalent, so we haven’t spent that
much time and effort on it.
Elemer Piros, Ph.D., Senior Biotechnology Analyst — Previously, Dr. Piros was a buy-side biotechnology analyst at Spear, Leeds & Kellogg, now
a wholly-owned subsidiary of Goldman Sachs. From 1990 to 2000, Dr. Piros conducted academic research in the field of neuroscience, focusing on
understanding the molecular mechanism of communication in the nervous system. He has published his findings in peer-reviewed scientific journals.
Dr. Piros earned degrees in mathematics and biology, and a Ph.D. in neuroscience at the University of California at Los Angeles. He then completed
post-doctoral training at Cornell University Medical College in New York. Dr. Piros was named the #1 stock-picker in biotechnology in The Wall Street
Journal’s annual “Best on the Street” survey in 2007. In 2008, the Financial Times ranked Dr. Piros amongst the top three earnings estimators in the
pharmaceutical industry. Currently, Dr. Piros’ research universe includes emerging biotechnology companies that develop products addressing the
nervous system and cancer.
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