A Powerful New Paradigm in Drug Development

Insider AbstractsP E E R P E R S P E C T I V E S I N O N C O L O G Y

Context of Vulnerability:A Powerful New Paradigm for Targeted Drug Development

A Q&A with Daniel D. Von Hoff, M.D.

Insider AbstractsP E E R P E R S P E C T I V E S I N O N C O L O G Y

Overview

In Peer Perspectives in Oncology, Medelis

brings together some of the most respected

researchers to talk about the issues facing

Chief Medical Officers today. They’re issues

we all face on a daily basis:

! Rising costs.

! Optimum patient accrual.

! Targeted therapeutics.

! Patient safety.

! FDA regulations.

! Efficacy.

! Budgets.

! Timelines.

In this Q&A series, we’ll discuss these

challenges with leading experts who deliver

practical, frontline insights gleaned from

years of experience bringing new drugs to

market.

www.medelis.com | [email protected]

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Introduction

Success developing targeted therapies in oncology depends on the ability to identi-fy new targets and develop agents that hit those targets. Renowned cancerresearcher Dr. Daniel Von Hoff and his team at the Translational GenomicsResearch Institute in Phoenix and Scottsdale, Arizona have been using thisapproach to develop novel therapies for patients with pancreatic cancer. They areguided by a rationale dubbed the “context of vulnerability.” In this issue of PeerPerspectives in Oncology, Dr. Von Hoff explains how this powerful paradigm hasalready led to promising discoveries and is changing the future of oncology drugdevelopment.

About Dr. Daniel Von Hoff

Daniel D. Von Hoff, M.D. is Senior Investigator and Head ofTranslational Research at the Translational Genomics ResearchInstitute's (TGen) Translational Drug Development Division andHead, Pancreatic Cancer Research Program in Phoenix, Arizona.He also serves as Chief Scientific Officer for U.S. Oncology andthe Scottsdale Clinical Research Institute, and is a foundingshareholder and advisory board member of Medelis.

Dr. Von Hoff's major interest is in the development of new anticancer agents, both inthe clinic and in the laboratory. He and his colleagues were involved in the beginningof the development of many of the agents we now use routinely, including mitox-antrone, fludarabine, paclitaxel, docetaxel, gemcitabine, CPT-11, gefitinib and others.At present, he and his colleagues are concentrating on the development of molecularlytargeted therapies.

Dr. Von Hoff's laboratory interests and contributions have been in the area of in vitrodrug sensitivity testing to individualize treatment for the patient. He and his laboratoryare now concentrating on discovery of new targets in pancreatic cancer. Dr. Von Hoffhas published more than 529 papers, 129 book chapters, and more than 891 abstracts.

Dr. Von Hoff was appointed to President Bush's National Cancer Advisory Board fromJune 2004 - March 2010. He is the past President of the American Association forCancer Research, a Fellow of the American College of Physicians, and a member andpast board member of the American Society of Clinical Oncology. He is a founder ofILEX Oncology, Inc. (acquired by Genzyme). He is founder and Editor Emeritus ofInvestigational New Drugs - The Journal of New Anticancer Agents as well as theEditor-in-Chief of Molecular Cancer Therapeutics. He is also proud to have been amentor and teacher for multiple medical students, medical oncology fellows, graduatestudents, and post-doctoral fellows.

Context of Vulnerability: A Powerful New Paradigm for Targeted Drug DevelopmentA Q&A with Daniel D. Von Hoff, M.D.

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Medelis: Judging from trials coming online, more and more companiesappear to be positioning themselves as targeted therapeutic compa-nies. Are the days of shrinking tumors with cytotoxic agents num-bered?

Dr. Von Hoff: There aren’t many groups developing cytotoxic agents now, mostlybecause the therapeutic index is not as great as it is for some of thecytostatic agents such as Tarceva® or AVASTIN®. Cytostatic agents areassociated with less bone marrow suppression, and they’re usuallyoral agents, which may be preferable for daily regimens. Now thatdoesn’t mean there won’t be some big hits with cytotoxic agents again,but there just aren’t that many being brought forward any more.

Medelis: What’s the big research focus these days?

Dr. Von Hoff: Today, people are focused on identifying a biologic target, thendesigning a drug that hits that target by searching chemical spacewith supercomputers. It’s totally different from more empiric-basedcytotoxic drug development. With cytostatic agents, we say, “whatmakes the cancer cell a cancer cell versus a normal cell?” And if itis an exaggerated target, you characterize it, and then try to findsomething that hits it.

Medelis: You use a phrase, “context of vulnerability,” which you havedescribed as an important key to cytostatic, or targeted, drug devel-opment. Can you explain what this means?

Dr. Von Hoff: The term was coined by Spyro Mousses, Ph.D., Director ofPharmaceutical Genomics Division at the Translational GenomicsResearch Institute. It refers to the genetic configuration in a patient’stumor that makes it susceptible to a specific drug. In other words,“context of vulnerability” provides the genetic rationale for a targetedtherapy. Other people have described it as “oncogene addiction” —if we can take away the “heroin,” the cell dies.

Medelis: How do you establish a patient’s context of vulnerability?

Dr. Von Hoff: One way to establish the context of vulnerability is to work back-wards from the result. For instance, in a phase I or phase II trial, youtreat a certain number patients, and when someone responds, you

Context of Vulnerability: A Powerful New Paradigm for Targeted Drug DevelopmentA Q&A with Daniel D. Von Hoff, M.D.

Context of Vulnerability: A Q&A with Daniel D. Von Hoff, M.D.

have to ask yourself, “Why did that patient respond? What was thevulnerability in this specific tumor or patient?” The patient eitherhad a genetic lesion or tumor stroma that was susceptible to thedrug in some way.

It gets down to taking a good history and physical, both of whichprovide clues to the genetic underpinnings of the cancer. Forinstance, it’s well known that if a patient has an Ashkenazi Jewishbackground, you have to consider BRCA1 and BRCA2. The secondimportant piece of information comes from profiling patients’ tumors.For instance, if there is a mutation in epidermal growth factor recep-tor (EGFR) then that would warrant treatment with Tarceva.

Medelis: How does context of vulnerability change drug development?

Dr. Von Hoff: If you let context of vulnerability guide drug development, youwould put only those patients who have the appropriate susceptibili-ty to the drug on trial. This optimizes your chance of seeing efficacywith a much smaller n. It’s essentially how Herceptin® got approvedwith an n of 480. If they hadn’t pre-selected patients for the contextof vulnerability, estimates say that it would have taken about 23,000patients to get the drug approved.

Medelis: You have also described the context of vulnerability as the oncolo-gist’s sixth vital sign. Can you explain this concept?

Dr. Von Hoff: The five vital signs that oncologists already use are blood pressure,pulse, respiratory rate, temperature, and level of pain, which is arecent development. We proposed context of vulnerability as thesixth vital sign and believe it holds a key to optimizing therapy foran individual patient.

For instance, if an Asian woman presents with bronchoalveolar car-cinoma, you would put her on an epidermal growth factor-receptor(EGFR) antagonist such as Tarceva. Her genetic vulnerability givesher an 80% chance of experiencing tumor shrinkage.

On the other hand, if a patient has advanced stage colon cancer, it’smore challenging to determine the context of vulnerability. You needto study the tumor and the patient to determine what he or she hashad and whether there is, as an example, an enzyme deficiencyassociated with the cancer.

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Medelis: From the sounds of it, perhaps context of vulnerability should be thefirst vital sign — something you think about right from the outset.

Dr. Von Hoff: That would be ideal, but it can be challenging to implementbecause of the reality of treatment.

Here’s an example. It’s 4:30 on a Friday afternoon and you’re theonly partner left in the office. Your last patient of the day arrives – a thirty-year-old man with a gigantic tumor in his abdomen. Hispathology indicates a rare tumor, a myxoid liposarcoma. The NCNNguidelines say, “Treat the patient with Adriamycin® or Adriamycinplus ifosfamide.”

You check the five vital signs and then you remember some doc say-ing something about checking the sixth vital sign. By this point, it’snow 6:00 PM and the easiest thing to do would be to have thepatient return on Monday to implement the NCNN guidelines. Butinstead, you start thinking about the sixth vital sign — “Is there any-thing special about this patient and this tumor? Anything about thegenetics or pathology?”

Sure enough, a recent article in The Lancet showed a drug calledecteinascidin-743 (ET-743) resulted in dramatic responses in over50% of patients with myxoid liposarcoma because they havetranslocations involving chromosomes 12 and 16. So you send histumor for a 12, 16 translocation analysis and get busy trying tosecure ET-743 for this man.

That’s great care, and if you aren’t matching the context of vulnera-bility to available therapeutics, you aren’t doing the best you can foryour patients. It takes more time and thinking but you’re doing thebest thing for your patients and for new agent development.

Medelis: Is it further complicated by the fact that there may be more than onecontext of vulnerability?

Dr. Von Hoff: Yes. The rare tumors appear to have just a single vulnerability thatyou can exploit. But with the more common solid tumors, it takeslonger to find out what the multiple contexts, or pathways, arebecause there are so many backup systems.

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Medelis: What is the potential for context of vulnerability to dramatically trans-form oncology therapy in the immediate future? Or are we still limitedby the lack of genetic information about the targets themselves?

Dr. Von Hoff: That’s a limiting factor, but all the work that Dr. Mousses is doingwith Pharma teams is starting to yield results, and clinical trials arejust starting.

Medelis: Context of vulnerability is another way of saying mechanism ofaction. Often though, a CMO is putting a drug into developmentwithout knowing how or why it works.

Dr. Von Hoff: That’s why you try to get more of a patient mix and observe closelyfor the sixth vital sign during the phase I trial. The science is at apoint where it’s not purely empiric.

There’s almost always some hint in the phase I. If I get a responseduring the trial, I have learned to ask incessantly, “Why that specificperson? Is it because they have, for example, mesothelioma? Is itbecause they have mesothelioma with a certain genetic mutation?”

At that point, you start lining up animal models with differentmesotheliomas and then test your drug, looking for the specificgenetic lesion that explains the response you saw in some patients.

It seems obvious in some ways, but it’s not the usual approach. Mostpeople perform a phase I trial just to get through it. They take a doseand run with it without probing the hints of activity.

Medelis: Do we currently have adequate therapeutics for the different contextsof vulnerability that could potentially exist?

Dr. Von Hoff: No, not even close. It will probably take about five years to getenough therapeutics to address the known contexts of vulnerability.There are about 400 new therapeutics available now and probably150 known targets, and there is a high degree of mismatch betweenthose. We only have a rudimentary understanding of how these anti-cancer agents work.

Medelis: What’s the focus of your research now, in regards to context of vul-nerability?

Dr. Von Hoff: Dr. Mousses is looking at siRNA, trying to establish which genotypeincreases tumor sensitivity. I am concentrating on pancreatic cancer,trying to determine which patient population would be responsiveto various agents such as an aurora kinase inhibitor.

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Medelis: Context of vulnerability flips the drug development paradigm; youknow what you’re targeting, you just need to find the agent, thearrow. How can CMOs orient their thinking to accommodate thisnew approach?

Dr. Von Hoff: No matter how you cut it, the data always counts. The CMO’s job isto help identify the context of vulnerability through careful analysisof the preclinical data and observation of patients. It is then the clin-ician’s responsibility to match drugs to contexts of vulnerability.

This where the translational investigator comes in — the M.D., Ph.D.or M.D. with laboratory experience who is steeped in the preclinicalmilieu and will not stop asking “why?” They’re in big demand nowbecause they can dramatically shorten development time. They canalso make a watertight argument for reimbursement — insurers willpay if it works.

Medelis: Are targeted therapeutics the future of oncology?

Dr. Von Hoff: I think that every drug we have is targeted and that it’s only a matterof time before the target is found for a drug a CMO may have underdevelopment.

Adriamycin, a powerful cytotoxic, is a good example. It was usedacross the board until it was discovered that it works through topoi-somerase II. Studies show that if a woman’s tumor does not possesstopoisomerase II, there is no point to using Adriamycin. In the caseof basal cell carcinoma, we showed that patients who had muta-tions in the PATCHED gene would have a high response rate.

Targeted therapeutics are catching on first in the rare tumorsbecause they don’t have as much genetic diversification as the morecommon solid tumors. However, an important story emerging nowis that if a patient has BRCA1 or BRCA2 breast or ovarian cancer,she will respond to PARP (poly[ADP-ribose] polymerase-1)inhibitors.

Medelis: How has the FDA responded?

Dr. Von Hoff: I think they’re encouraging this. Frankly, everybody should beencouraging it, because it establishes criteria for patient selection,which in turn optimizes chances of success.

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Medelis: What kind of feedback are you getting from national and interna-tional groups?

Dr. Von Hoff: Obviously, we are not the only ones pursuing this strategy.

Medelis: What’s the real promise and potential of this approach? Can it helpwin the fight against cancer?

Dr. Von Hoff: People say we have lost the war on cancer and it is so discouragingto the people who deliver the care every day, the people who areseeing those curves turn around.

The fact is that the rising tide of cancer deaths hasn’t just beenstemmed – it’s been turned around. Mortality, in terms of absolutenumber of deaths, has been down for two years in a row. It shouldhave been going up like a rocket because we’re all aging.

Medelis: Are investors and sponsors starting to see big opportunity, then,because the field really has turned a corner?

Dr. Von Hoff: Yes, and I have direct evidence of this. The bottom line for me is I willnever take another drug into patients, ever, unless I know the geneticor genomic context of vulnerability. Why? Because I’ve tasted highsuccess.

We just need to keep working incredibly hard to find the contexts ofvulnerability in the more common tumors. This whole idea of findingthe context of vulnerability — it’s so gratifying. It’s a way of trulyhelping people who seemed to have reached a dead end.

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Peer Perspectives in Oncology is a Q&A series brought to you by Medelis, a single-source provider for oncology drug development services. Medelis provides a total solution for biotechnology and pharmaceutical companies seeking rapid drug development and approval. To learn more, visit www.medelis.com.

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A Powerful New Paradigm in Drug Development