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What Andy Grove and Michael Milken Have Taught Us
About Prostate Cancer
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04/20/2016
Solid tumors are typically managed with surgical resection, chemotherapy,
radiation and biologics, but it's the secondary tumor mass, the metastasis,
that kills patients. Dr. Stuart Holden of the UCLA Institute of Urologic
Oncology understands the importance of targeting metastatic disease, which
is driven by different genetic factors than the primary tumor from which it
arose—a fact that oncologists are just now coming to grips with. In this
interview with The Life Sciences Report , Dr. Holden describes an essential
target in aggressive prostate cancers, and a drug with the potential to address
that target and extend the lives of thousands of men.
Source: George S. Mack of The Life Sciences Report
The Life Sciences Report : You have had some noteworthy figures as patients in
your career. Among your prostate cancer patients are the late Andy Grove, former
chairman and CEO of Intel Corp. (INTC:NASDAQ), who passed away in late March
at age 79, and former investment banker Michael Milken, who continues to be
active as a supporter of prostate cancer research. You've had some very public
patients, haven't you?
Stuart Holden: I was involved with Dr. Grove when he was first diagnosed in 1998,
and I actually worked with him on the preparation of his now-famous article in
Fortune magazine. As a result of that, I got to know him, and became one of his
confidants on issues related to prostate cancer. As a matter of fact, I was
instrumental in convincing him to go on the board of the Prostate Cancer
Foundation, originally known as CaP CURE, which was started by Michael Milken
in 1993.
TLSR: Andy Grove was an engineer, and he approached his disease very
differently than most people, didn't he?
SH: Yes, he did. Dr. Grove had an
"I have put together an allincredibly analytical mind—the mind of an
star team of medical
engineer. Those of us who see patients
oncologists to help Arno
know that when you get to complex subject
Therapeutics Inc. both
matter like prostate cancer, different types of
design its clinical trials and
people process information in ways you
try to evaluate the science."
might predict from their backgrounds. As an
engineer he was extremely precise on
details, and was very quick to understand the nuances of his diagnosis, as well as
the vagaries and biases associated with treatment recommendations. He pointed
out a lot of the inconsistencies in our knowledge of treatment recommendations at
the time, and actually came to an excellent solution for his own disease. It was a
successful outcome. In fact, he actually died of complications of Parkinsonism, as I
understand it, and not from his prostate cancer, which had been well controlled by
the treatment he chose.
TLSR: What about Michael Milken?
SH: Michael is a brilliant guy as well, with a slightly different mind than Andy's, but
no less analytical. He came at it from both a financial and philanthropist
background. He was diagnosed in 1993 with a very aggressive form of prostate
cancer—and, I might add, with a very poor outlook—at the age 46. He had already
been active in writing checks to support cancer research when he was diagnosed,
but after his diagnosis he decided he needed to get more involved in the culture of
the world of prostate cancer, rather than just writing checks and hoping for the best.
He instructed me that we were going to start a foundation, now known as the
Prostate Cancer Foundation, and we have been working on this together since
then.
TLSR: Generally speaking, how did Milken approach the problem? He looked way
beyond the immediacy of his own disease, didn't he?
SH: Yes. Michael totally immersed himself into this work. He was quick to
understand that there was very little work being done in prostate cancer, and the
reason was that very little money was going to support research in the area. When
you would ask for funding from agencies like the National Cancer Institute, they
would say they didn't support work in this area because there was really no good
work to support. Then when you talked to the researchers, they'd say they didn't
work in the area because there was no money to support it.
"Michael Milken figured out right away that we needed to formulate a
strategy to get more money into the field."
Michael is a pretty smart fellow, and he figured out right away that we needed to
formulate a strategy to get more money into the field, and get more talented people
focused on this disease, both in his own interest and in the interest of every other
man who had prostate cancer or would have it in the future. He reckoned this was a
really big disease: the leading cause of cancer death in men, the second leading
cause of cancer diagnosis in men. There was virtually nothing going on in the
pharmaceutical industry, the biotech industry or even at the academic research
level. So we started a process in our foundation of granting money for research. We
made it a three-page application, we told people within 30 days whether they were
going to get funded, and we funded them. That created a tremendous dynamic in
the field.
TLSR: How much money has been granted by the Prostate Cancer Foundation?
SH: In the beginning, people didn't take us that seriously. Some people thought it
was a publicity stunt, but it clearly wasn't. We have been in business now for 23
years, and we have funded over $700 million ($700M) in research around the world.
I would say there has been almost no development in the treatment of advanced
prostate cancer that the Prostate Cancer Foundation hasn't had its fingerprint on at
some funding and support level.
TLSR: You've worked on the front lines of prostate cancer for more than 36 years.
What is the most dramatic change you've seen?
SH: I don't know if it's the most dramatic, but I would say the most game-changing
was the development of the prostate specific antigen (PSA) assay. It was
developed academically around 1977, and it was a true early biotechnology story. It
took until the mid- or late 1980s before the PSA started creeping into routine clinical
practice. It was a huge game changer in the sense that maybe 10% of my patient
population was devoted to prostate cancer patients before the PSA assay, but since
its introduction, I would say 80% of my patients fall into that category. I specialize in
that area as a genitourinary oncologist, so my experience is a little biased, but that's
the way it is today.
"At the end of the day, PSA is still the best biomarker in clinical
utilization."
The PSA has been both heralded and demonized. It's been used properly and
misused. But during the PSA era, the death rate from prostate cancer has gone
down 40%. The PSA has also led to overdiagnosis and overtreatment—all of that is
true. But at the end of the day, PSA is still the best biomarker in clinical utilization. I
believe the single greatest reason for that reduction in deaths was the introduction
of the PSA assay into routine urology practice.
TLSR: Immunotherapy is the rage right now. Do you see anything interesting in that
realm for prostate cancer?
SH: I would say, with some degree of pride, that the first vaccine ever been
successfully used to treat cancer of any kind, and approved by the FDA in 2010, is
Provenge (sipuleucel-T; developed by Dendreon Corp., which was acquired in
bankruptcy by Valeant Pharmaceuticals Intl Inc. [VRX:NYSE]). I use the word pride
because the Prostate Cancer Foundation provided critical philanthropic support to
UC San Francisco to support this work in its infancy.
It was also the first cell therapy ever approved to treat cancer. The data show that
Provenge extended life, compared to a placebo, by about four-odd months. While
that's not a huge, grand-slam home run, Provenge has energized lots of companies
to start looking into immunological therapies for cancer in many different areas.
There is a lot of work going on in that area right now.
In addition to the FDA-approved vaccine Provenge, and we have several others in
development. One is GVAX-PCa (Aduro Biotech Inc. [ADRO:NASDAQ]); the other
is a viral vector called ProstVac VF (Bavarian Nordic [BAVA:OMX]).
"In the next few years, immune therapy will find its way into the
armamentaria of those who treat prostate cancer."
All sorts of work is going on in immunotherapy for prostate cancer using vaccine
strategies or checkpoint inhibitor medications in conjunction with radiation and
chemotherapy. There are many diseases in which immunotherapy has shown itself
to be effective, but I would also say we're in the first inning of a nine-inning game on
immuno-oncology. In the next few years, immune therapy will find its way into the
armamentaria of those who treat prostate cancer. There is certainly a lot of interest
in it.
TLSR: Provenge was not successful financially because it had a very high
manufacturing cost burden, which could not be overcome by even the high price tag
for patients. On March 28, Medivation Inc. (MDVN:NASDAQ), which developed the
prostate cancer drug enzalutamide (Xtandi; partnered with Japanese big pharma
Astellas Pharma Inc. [ALPMF:OTCPK; 4503:TYO]), received a congressional letter
signed by six U.S. senators and six U.S. representatives calling for a public hearing
to question Medivation about the cost of enzalutamide, which has a selling price of
$129,000 ($129K) in the U.S., versus $39K in Japan and Sweden, and $30K in
Canada. Do you have any thoughts on this topic, generally?
SH: I'll give you some background first. One of the things we did in our initial work at
the Prostate Cancer Foundation was try to attract the best scientists at UCLA to
work on prostate cancer. As part of that process, we wound up funding a small
project at UCLA headed by Dr. Charles Sawyers and Dr. Michael Chung, who are
the inventors and developers of enzalutamide. That charitable donation led to the
data they eventually produced, which eventually was licensed and bought by
Medivation, and was ultimately approved by the FDA. What's interesting here is that
this started with a fairly small research grant of just $150K, and that led to the
development of this multibillion-dollar drug. UCLA recently got a fairly sizable
royalty on that enzalutamide invention.
"Dr. Andy Grove pointed out a lot of the inconsistencies in our
knowledge of treatment recommendations at the time."
As a practicing physician, I'm excited to have played some role in the development
of enzalutamide, but when you prescribe it for patients, it becomes very difficult
because you immediately start something of a battle with the patient's insurance
company to figure out how it's going to get paid for. It usually involves several
phone calls, and sometimes peer-to-peer conversations with oncologists at the
insurance companies. It's very difficult to get utilization of these new drugs at these
cost levels. I'm not an expert, and I wouldn't pretend to give you a cost analysis as
to why the drug costs so much in the U.S. But to your point about Japan or Canada,
it is obviously disturbing when you see that the drug has become available in other
countries at a much lower cost. I think this is a very worrisome thing from the
standpoint that lots of new drugs are coming online that will be very expensive to
patients in the U.S.
TLSR: You are chair of the Arno Therapeutics Inc. (ARNI:OTC.MKTS) prostate
cancer scientific advisory board (SAB) for onapristone, a progesterone receptor
antagonist that is being tested in prostate and breast cancers. By contrast,
Medivation's enzalutamide is an androgen receptor inhibitor. Both of these
receptors are constitutively activated. Could you tell me about onapristone and why
you want to be involved with it?
SH: The way this came about was through the Dream Teams—Stand Up To
Cancer research projects. It's a partnership of the Stand Up To Cancer and Prostate
Cancer Foundation to offer support in prostate cancer. There's a West Coast Dream
Team and an East Coast Dream Team. Basically, what they're doing is assaying
biopsies of metastases in patients with prostate cancer, and doing genetic analyses
of the tumors to see what pathways are activated in the metastases compared to
what pathways might be active in the primary tumors. That's because it's the
metastases that kill you, not the primary tumors.
One of the most remarkable discoveries that came about from the analysis of these
biopsies was that 20% of the patients with prostate cancer metastases in the study
showed abnormalities in their DNA repair genes. That would involve the whole
family of genes that encompasses the tumor suppressor genes, BRCA1 and
BRCA2, which can have abnormalities or mutations that lead to breast cancer.
Patients with these mutations could be potentially susceptible to PARP inhibitor
drugs, the main one being olaparib (AstraZeneca [AZN:NYSE]), which is a PARP-1
inhibitor. PARP-1 is a vital enzyme for repairing breakage in DNA strands, but you
don't want them repaired in tumor cells. You want the tumor cells to die. Second,
these are also potentially susceptible to platinum-based chemotherapy as well.
This was a startling discovery because now we have clinical trials going on with a
drug that was developed originally for ovarian cancer. It's being used primarily in
breast cancer, but it turns out to have potential utility in up to 20% of the men who
are dying of metastatic prostate cancer. That was totally unforeseen and it was
game changing.
"I would say there has been almost no development in the treatment of
advanced prostate cancer that the Prostate Cancer Foundation hasn't
had its fingerprint on."
When we treat patients who have had heavy targeting of their androgen receptors
with drugs like enzalutamide and abiraterone (Zytiga; Johnson & Johnson
[JNJ:NYSE]), so that they have started to become resistant to the therapy, the DNA
repair genes become upregulated. One of the genes that is upregulated in these
biopsies is the progesterone receptor, which is the target of Arno Therapeutics'
onapristone. A significant number of patients have elevated progesterone receptors,
and in the way that the PARP inhibitor drugs target the other genetic abnormality,
the progesterone receptor should be an effective target in the group of patients
display this abnormality. This would be a great application of "precision medicine,"
which everybody talks about.
TLSR: Does the prospect of working on Arno's SAB to study its progesterone
receptor inhibitor excite you?
SH: Yes. I became excited, and a number of my colleagues at the Prostate Cancer
Foundation and in the field of prostate cancer also see this as a significant potential
target that could address patients whose cancers have metastasized and who may
exhibit this particular abnormality. There are two Phase 1/2 clinical trials underway
now. Both are open-label and in progesterone receptor-expressing tumors. One is a
60-patient dose-escalation trial (NCT02052128), which is wrapping up soon. The
other, a 75-patient trial (NCT02049190), is in advanced castration-resistant
disease, and it will wrap up at the end of 2017.
TLSR: What's the next step?
SH: I have put together what I hope is an all-star team of good-thinking medical
oncologists from around the country and internationally to help Arno both design its
clinical trials and also try to evaluate the science. We are trying to understand the
biology of why and how this disease progresses and metastasizes. We have this
drug that is already in clinical trials, and it just required a shift in thinking. I know
they have been testing the drug in endometrial and other cancers, but because of
the findings from the Dream Teams' analysis of tumor biopsies, prostate cancer has
become a significant therapeutic window of opportunity. The SAB that I'm heading
up at Arno will attempt to evaluate what this opportunity is, and determine the
smartest way to design the clinical trials and evaluate the information to see
whether onapristone could be a new therapeutic entity.
TLSR: Many thanks to you. It was a pleasure.
Stuart Holden MD is a Health Sciences Clinical Professor in the Department of
Urology at the David Geffen School of Medicine at UCLA and Associate Director
of the UCLA Institute of Urologic Oncology. Serving as Prostate Cancer
Foundation's medical director since the inception of the foundation in 1993,
Holden directs the medical and scientific strategy of PCF and oversees its grant
award programs, consortia activities and scientific meetings. An internationally
respected urologic oncologist and surgeon who has worked on the frontlines of
prostate cancer for more than 36 years, Holden introduced radioactive seed
implantation to Los Angeles and was an early adopter of ultrasound-guided
prostate biopsy. He completed his medical degree and surgical training at New
York Hospital Cornell University Medical College; his urology residency at Emory
University; and fellowships in urology and developmental genetics at MemorialSloan Kettering Cancer Center. He also was awarded a clinical fellowship from the
American Cancer Society.
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