Unlocking Serendipity Is the Key to Life Science
Breakthroughs PART II
Siggelkow: What to me sets this book apart is that you have these
in-depth studies of individual diseases and where different solutions came
from. So let’s start with cardiovascular diseases and one of the key
discoveries in this arena has been statins. They were discovered in Japan by
Akira Endo who works for Sankyo, a Japanese company, but they were not brought
to market by them but by Merck. What were some of the lessons that we can draw?
Rea: Takira Endo was originally trained as an agriculture
biochemist … who came up with enzymes that clarified fruit juices. I think the
key play in that story is that he went and had a leave of absence of two years
… and he went to New York City.
And that is when he became cognizant of the
scale of cardiovascular disease in the west. Cardiovascular disease was
virtually unheard of in Japan at that time. And so then he went back to Japan
and engaged in this huge number of screens of fungal filtrates for agents that
interfere with … cholesterol biosynthesis.
What happened was one, he was operating in
Japan and Sankyo did not have the awareness of the extent of cardiovascular
disease at that time. Cardiovascular disease was relatively rare, and at that
point in time no one had considered the possibility of the identification of
therapeutic agents that could address the cholesterol matter, which came out of
the Framingham Heart Study in the U.S.
Because it had never been done before, the
thing that stalled that research program was the animal trials that sported a
cellular histology that looked like a pre-cancer. As it turns out that was not
the case, it was more a manifestation of elaboration of a membrane system that
is involved in cholesterol biosynthesis, a sort of compensate response to
statin therapy.
Merck at that time was aware that Sankyo had
a patent on statins and they were investigating the statins. In Merck’s case,
what was so wonderful was the leadership of research at that time — Roy Vagelos
— had trained as a cardiologist at Columbia. He had worked with very sick heart
patients, and he had also spent the bulk of his career as a fundamental
biochemist working on lipid metabolism.
So he was perfectly positioned to understand
this nascent technology and what its true significance might be. And as a
result Merck received a sample of the agent in question, it’s called
mevastatin, the very first statin to be discovered, and they started doing
trials, and on the basis of those trials, and on the basis of the advice they
were getting from some of the clinicians with whom they were interfacing, they
realized that they were on to something that could be huge, and of really
profound significance.
They realized that even if there were some
off-target effects of the statins, which as it turns out is probably not the
case, they felt that the benefit to individuals that would likely succumb to
cardiovascular disease in their 30s or their 40s without some sort of
therapeutic intervention far outweighed that risk. That was what seeded what
eventually happened, and Merck carried the product forward as you know. They
went forward with an alternate to mevastatin.
Singh: When you go forward in that you see the story of
Lipitor and Warner Lambert coming up with something that was very innovative,
the most successful drug in history. What are the lessons?
Rea: That is a wonderful example of serendipity. It was Warner
Lambert that started the Lipitor cascade before they were bought by Pfizer, and
that was thanks to the work of Bruce Roth, who was a very young postdoctoral
fellow … and he was adept at tinkering around with organic chemicals. And he
was the first guy to do an in vitro synthesis of a statin. He recapitulated the
synthesis of mevastatin, and Warner Lambert got wind of that and they hired
Bruce Roth.
What then drove the development of the statins
to eventually give rise to Lipitor, with one or two byways, was I think the
recognition that if Lipitor, or atorvastatin as it was called at the time, were
to enter the market it had to have a significant edge over pre-existent
statins.
That is when they pushed very hard … and
doubled the efficacy of the agent, meaning individuals could take far less of
the therapeutic to get even more benefit than they would get from the statins
currently on market. That is what really solved the case.
Burns: Phil’s comments basically show that you need to know the
science as well as the business to see how these products and companies emerge.
Siggelkow: Rob, you were involved in a chapter I think on balloon
angioplasty, and I think that was partly the kitchen table innovation story.
Most of the chapters are about drug discovery, and this was a chapter about
medical devices. So what were some of the new insights that came from looking
at medical devices?
Burns: Well I stumbled on that one. I was doing a study of all
of these medical device entrepreneurs, and I stumbled across someone who said
that balloon angioplasty was one of the 10 most significant medical innovations
of the 20th century. And I knew what it was but I didn’t really know how it
came about, and I didn’t fully appreciate why it was one of the 10 most.
So I hired three MBA’s, two of whom were
cardiac surgeons, to help me go back and dig up all of this information. And it
just turned out to be one serendipity after another. And I think that was
particularly interesting about this innovation is the fact that the pioneers
were experimenting on themselves.
And so they were basically cutting open their
veins and inserting things into their veins to see how this stuff would work,
and then they would fashion not only their own catheters but their own balloons
at the end of these catheters — using all kinds of wacky materials — just to
see if this stuff would work – to come up with what we call proof of concept.
So these were people who obviously believed
in what they were doing, because they were willing to risk their lives for it.
And they’re mavericks, that’s one of the things we teach about in innovation …
it sometimes takes mavericks to pull things off. That’s who these people were.
One of them actually got the Nobel Prize 20 years after being ridiculed for
what he was doing. That’s just how maverick some of these people are.
It’s a fascinating study. And then the guy,
Andres Grunzeg who is recognized as the pioneer, he was ridiculed by almost all
of his colleagues, and it took a couple of innovation champions, people who are
superior in the hierarchy who recognize that he may be on to something, to
support him, to protect him from all of the other colleagues who just wanted to
torpedo his research.
Siggelkow: Mark, coming back to this question of, “Is big Pharma
broken?” — now we hear the economist’s side of the story.
Mark Pauly: I think the correct statement is — it’s not any
more broken than it ever was. It’s not really correct to imagine there was some
kind of golden age that we’ve fallen from. We actually provide some empirical
evidence in the book on two things that are supposed to be indicators of
problems.
One is the flow of new innovative products,
and the actual empirical evidence suggests that that rate of introduction has
been pretty much stable, maybe even slightly increasing over time — if you look
at it over a long time period. There was a period in the late 1990’s when there
was a substantial growth in the introduction of new products, but that was because
the FDA changed its rules and allowed drug companies to pay for their own
randomized control trials. So they cleaned out the inventory of products they
were working on and put them on the market all at once.
But then after that blip was averaged out,
the rate of introduction of new products has been pretty stable over time. I do
think it is worthwhile to say that they are still turning out some wonderful
new products, and if anything, the effectiveness of the products that are
introduced … has actually improved a little bit.
So that’s good news. The bad news is that the
cost per new drug developed has increased substantially over time. There’s
actually quite an argument and a fuss people make about this, but at least some
estimates suggest it’s as high as $2 billion per new drug that actually makes
it to market. Now most of that money is not actually money that was spent on
the drug that made it to market. It’s payment for all of the dry holes and the
attempts that failed. And a big chunk of it also is the cost of capital,
because the time period between investment and return is so greatly delayed.
But what we found evidence for and conclude
is that the usual explanations for this, like scientists just want to get
grants and they don’t really want to make their products available to the
commercial market, or firms are just thick-headed when it comes to recognizing
wonderful new products, those may all be true actually, but we actually favor
an alternative explanation that says: As real income has grown and as insurance
coverage of drugs has grown, the revenue potential of a new product has
increased. And so if a new product can generate more revenue than was true 10
years ago, it’s going to make sense to invest in products with a lower chance
of success because the higher revenue is going to offset that.
So if you really want to know who is
responsible for the increasing cost of new products, I tell people to look in
the mirror. If only you were as poor or as poorly insured as you were 20 or 30
years ago … than it wouldn’t pay to bring these new drugs to market.
… So that is important. The other point I
would make is the big Pharma model used to be what we call screening dirt. They
come back with the latest set of things from Costa Rica, it would be dirt and
venom and bugs and things like that, and then actually a very efficient
technique was developed to have automated screening to see if there might be
some molecules there that were effective against some disease or other.
Discovery has moved away from that toward
what is called rational drug discovery. But one of the messages that we convey
in the book is that although it’s called rational drug discovery, there’s a lot
of irrationality and a lot of serendipity.
http://knowledge.wharton.upenn.edu/article/unlocking-the-creativity-or-serendipity-the-key-to-life-science-breakthroughs/?utm_source=kw_newsletter&utm_medium=email&utm_campaign=2018-04-26
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