Chapter 08: Furthering Research through Partnerships with Drug Companies

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Chapter 08: Furthering Research through Partnerships with Drug Companies

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In this chapter, Dr. Gutterman offers several examples of how he learned to work with drug companies to further his own research. He was approached, for example, to test GM-CSF [granulocyte macrophage colony-stimulating factor] to restore platelet counts in chemotherapy patients. He also learned to protect his intellectual property. He attended meetings at the emerging drug companies and describes the impact of "seeing the power of venture money." He also observed how the biotech companies set up creative environments, sensing a kinship with the imaginative work they were doing.

Identifier

GuttermanJ_02_20120413_C08

Publication Date

4-13-2012

Publisher

The Historical Resources Center, The Research Medical Library, The University of Texas MD Anderson Cancer Center

City

Houston, Texas

Topics Covered

The University of Texas MD Anderson Cancer Center - Industry Partnerships; The Researcher; Discovery, Creativity and Innovation; Faith, Values, Beliefs; Professional Practice; The Professional at Work; Overview; Definitions, Explanations, Translations; Character, Values, Beliefs, Talents; Industry Partnerships; On Pharmaceutical Companies and Industry

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Disciplines

History of Science, Technology, and Medicine | Oncology | Oral History

Transcript

Tacey Ann Rosolowski, PhD:

There wasn’t a lot. You talked about the way it was established, Leon Davis and Elaine coming to talk to you, the setting up of it. I think you mentioned a few companies that were involved. But really, that is where the story stopped.

Jordan Gutterman, MD:

Well, I will fill in the blanks, and there may be other things that one day when I go back and look at my own records I will have every meeting chronicled, whether it was Pennzoil or—and my impressions, the key people. I know some of their names. I have thought about this. So again, I think that we talked about, initially, two sessions—this is going to end up being multiple sessions because I want this right. And I want it documented because the more I talk about it, the more excited—it’s very difficult, but I have been able to shut off what is going on now to go back in time, and to take two hours out, once I calm down and get started—you know—once I warm up. So we will go back, because I’m afraid I left out—and I probably will leave out some ideas and names and key people until I look over my oral history. Let’s call it that.

Tacey Ann Rosolowski, PhD:

Well, and the other thing is, remember, that you will get a copy of the transcript and things can be filled in

Jordan Gutterman, MD:

Yeah. No, I understand. So I told you yesterday about the hairy cell leukemia and the excitement of seeing the platelets go up first and then the white cells and the red cells and seven of seven patients and the elation of The New England Journal of Medicine and McNeil/Lehrer and people who said that this was all made up and the lady—you know—Dom Perignon with the paper cup. Quite an experience. [redacted] And as I said, I told you the story yesterday how the company confirmed all this once we reported all this. And—you know—people ask me a lot, “Well, did you benefit?”—because this eventually became a billion dollar drug—“You must have benefited. You turned over the license. You got it approved.” The answer is no. We never patented anything—ideas or anything. We just—I was just doing clinical medicine. It never even occurred to me. There are a lot of people including one Nobel Laureate from Biogen who thanked me at dinner one night and said, “Thank you for making me wealthy.” Sometimes it does, but you know what? Life is that way. If somebody asked me—I asked my colleague yesterday, “If somebody offered you a million dollars but you couldn’t do science anymore, what would you choose?” She said, “That is not a complex decision. Forget about it. That is not going to make me happy. I mean, I will take the money, but I wouldn’t change my life for anything.” And I feel the same way. If someone says, “You can’t”— I mean, this is a challenge where I am working now with the plants as this was—as the interferon. This is really a challenge in terms of, again, the politics, the money, and the regulatory. It’s exciting and a challenge, but it’s tough sometimes. And there are some days I’m thinking, “Why am I doing this?” But you couldn’t—there is no price to pay. It’s so interesting. Anyways, now CML—so chronic myeloid leukemia is—most people who listen to this are aware that in the eighties, again, there was no effective treatment for the disease. In fact, when I first came here, Freireich and his colleagues were using the cell separator to take off the excess white cells. They would give those white cells to patients who needed them, but that’s all they did. There were a couple of drugs then that were used—mustard drugs—that would lower the count. There is one drug called hydroxyurea, which inhibits DNA proliferation—that will lower the count. But none of those drugs—none of the chemotherapy did absolutely anything to the prognosis. The early phase of it is called benign phase—is a single mutation—which at the time we knew a little bit about—a translocation called the Philadelphia chromosome, but then—

Tacey Ann Rosolowski, PhD:

I am sorry. I missed that. What is that?

Jordan Gutterman, MD:

It’s called the Philadelphia chromosome.

Tacey Ann Rosolowski, PhD:

Philadelphia chromosome.

Jordan Gutterman, MD:

Just the whole research on CML, the molecular aspect is very pioneering. We gave a Lasker Award out for the elucidation of the chromosome defect and the molecular aspects of that. So that was back several years ago. We gave a second award out for the treatment of CML, not with interferon but with this Gleevec, which is so-called targeted therapy. But at the time, in the ‘80s—’82, ‘83—there was no treatment. We could lower counts, but there would be nothing for the prognosis. And all the patients—there was an average survival of 3.2 years, and most patients would then convert to what is called blast crisis—acute leukemia—which is sort of like metastatic cancer. And patients would die very quickly.

Tacey Ann Rosolowski, PhD:

Why is it called blast crisis?

Jordan Gutterman, MD:

Because they get these undifferentiated cells called myeloblasts. They are blasts. They are very indifferent. They are the first primitive—one of the first primitive cells in the bone marrow. So my colleague Dr. Talpaz started using interferon, and he did a nice job of working on the dose. Right away we began to see the blood counts go down. That was nice. That was prerequisite for anything, but it didn’t say anything because a couple of the chemotherapeutic drugs could do the same thing. But the chemotherapy never had a sustained elimination of the leukemia cell—that is, the Philadelphia chromosome—the abnormal chromosome. It was described in Philadelphia by a guy named Peter Nowell many, many years ago. Now, I should mention just for completions sake that [E. Donnall] Don Thomas, who was in Seattle at the Fred Hutchinson, won a Nobel Prize for bone marrow transplantation. He showed you could cure people with CML if they had an identical twin and gave their—so you could wipe out the disease if you just blast them with radiation, the chemo, and you could replace the marrow with an identical twin. He won a Nobel Prize for that and related work. But that is pretty rare for an identical twin. Other than that chemo, you might be able to get transient elimination, but they come back. Well, with interferon we saw the blood counts go down. And I will never forget one day in late ’82, about the time we were starting to see these interesting responses in hairy cell—this was heavy time—very exciting time. I see Talpaz way down the hall. He comes up to me—he is an Israeli guy—and he said, “Jordan, we got a bone marrow report back on a patient who has 50% reduction in the Philadelphia chromosome.” I said, “Really?” I said—same thing I had said with the hairy cell—“Well, I’ve got to repeat that, first of all. Is this an artifact?” But—you know—we thought maybe it was a transient thing. I mean, I was very excited. The patient would come back a month later, and now it was down to fifteen percent or something. This thing was disappearing. And then we did it a second time. Now, it wasn’t like hairy cell, where every patient or virtually every patient responded. Getting some suppression occurred in maybe 30%, 40% of patients. Getting a complete suppression was uncommon, but still it was amazing. I mean, we saw a complete elimination in perhaps 8% to 10%. But nonetheless—and then we worked—some patients stayed on the interferon. Interferon you cannot stay on indefinitely because you are just fatigued all the time. So we had to work out various aspects. Some people we would stop. Sometimes the disease did not come back at all. So I would say that I don’t have the precise figure today, but I would say we probably, with interferon alone, cured a small fraction of these patients, maybe 5% to 8%. But nonetheless, for a disease that has, say, 4000 or 5000 patients, that is still some souls. That is some people. I personally think this has been missed—the importance of interferon—because it was the first demonstration outside of the bone marrow transplant in identical twins that with a compound—with a drug—you could—in some patients—not even close to 100%—nothing like hairy cell—you could get selective suppression of the malignant clone of cells and get, at the same time—which really shocked me—restoration of the normal cells. So while you are suppressing the malignant stuff, you are allowing the normal cells to come back. We saw the same thing with hairy cell leukemia, but we didn’t have that type of marker. We eliminated the hairy cells. Andin contrast to normal people—I mean—excuse me—people that didn’t have blood cancers, where we lowered the blood count, in this case, the normal cells were able to restore themselves. So I think from a scientific standpoint—but the one criticism of the work—and I agree with it—is scientists need to be precise. Nobody understood exactly why this was going on, and it’s hard to build on that. It’s wonderful. And we now have a new treatment. The first report was 1983, in Blood. And then in ’86, the year interferon was approved for hairy cell leukemia, we had a major paper in The New England Journal of Medicine where we showed this Philadelphia chromosome, and it got a lot of attention because this was historical. Ten years later, a drug called Gleevec was designed by Novartis with the push of Brian Druker, who shared a Lasker Award for this. So I was involved with both of those awards along with two other guys, where they targeted the Philadelphia chromosome. Ninety percent of patients achieve remissions. Most of them have suppression—partial and usually complete—of the Philadelphia chromosome, and it’s an oral drug. They stay on it indefinitely. And it is a controlled disease in the vast majority of patients. The only negative about Gleevec is it probably cures very few people. They just have to stay on it. But how many diseases do we cure outside of infectious diseases? We don’t cure diabetes, but we control it with insulin. There are a lot of diseases like that. So this was a major advance, and that is why Druker shared the—and he deserves the most credit. A guy named [Charles] Sawyers shared that with him. He worked on resistance. Studies are going on with interferon plus Gleevec. I’m not aware—there has been some inconsistency whether the two are additive in any way, because most cancers—like most complex microbial infections, like TB and so forth, you best use combinations of drugs to prevent emergence of resistant cells. But nonetheless, interferon was a major advance. And it took another ten years before the real major advance. But still, I am very proud of that work. And it really showed you how to get selected suppression. I still think there is probably going to be a role for interferon in CML. Hairy cell, too, was supplanted by drugs, which were easier to give, less toxic. It’s still used today, but that’s okay. I mean, it would be like—I’m not equating it necessarily—but it would be like sulfa. Most people think penicillin was the first antibiotic. Sulfa drugs were. They are still used too. But penicillin was better, and now we have some highly effective—obviously tons of effective—so interferon is used in CML. It is used in hairy cell, but probably better—not probably but definitely—better in less toxic compounds are being used. But now hairy cell was on the map, and CML is on the map. So that is pretty exciting stuff. I haven’t been staying on top of those fields, although there are advances in these diseases and others. I noticed just yesterday there has been a resurgence of interest in interferon as an immunotherapy that is enhancing the immune system, so I think we are going to see much more use of interferon. People have asked me, “Is it used in all these diseases that you started?” The answer is not as much. And I think part of the reason is there is no champion like myself, I think. I mean, I’ll push if I think there is a real reason to use it. I don’t know. I’ve been a little disappointed that the—for a while, the momentum of interferon—people, again, were doing the cleanup, you know? They are putting the ball in the green. But I think there’s going to be a resurgence of interferon in terms of the cancer—in terms of figuring out newer mechanisms. I think if you could figure out precisely how it works it would help, particularly today with targeted therapy. Oncology community, patients, doctors, FDA, and so forth want to understand how this drug works. I don’t think we can get along any further by just giving a drug that works without understanding. I think what is most important is that it works. If you understand it, that is better. But as far as being on top of the list of drugs, I think people want to understand how they work first, and I agree with that. If you take antihypertensive, if you take anticholesterol, we understand how those drugs work, and they are extremely effective. So if there is one major criticism I have—and I got out of the field because I said I like to open things up, and then after it was approved—and I will come back to this—I learned a lot about marketing and how this all does. We made a few more advances, but then there were so many people in the field; I really wanted to start a whole new thing. I thought we needed different answers. I haven’t stayed on top of this very much. And who knows what will happen, because what I am doing now—which we won’t talk about today—may have an interface with interferon and perhaps other things. Okay, so in 1986, as I mentioned yesterday, in June—mid-June—the drug was approved by the FDA. It was just a little notice in the Wall Street Journal, I remember, that it had been approved. But this was anticlimactic. We knew it was going to be approved. I mentioned that in a few months before we had gone—I had gone with Roche to the FDA, and Schering went. They were back-to-back presentations. It was almost a forgone conclusion, I mean, you could not deny the use of interferon for hairy cell leukemia. It was an incurable disease at the time—nothing worked—and 90% of patients would benefit. So it was a slam dunk, so to speak.

Tacey Ann Rosolowski, PhD:

Can I ask you just a quick clarification question? You have been mentioning Roche and Schering, and were you talking about agents of those companies or actually people by those names?

Jordan Gutterman, MD:

No, Roche is Hoffmann-La Roche, a Swiss company.

Tacey Ann Rosolowski, PhD:

Right.

Jordan Gutterman, MD:

And Schering is Schering-Plough.

Tacey Ann Rosolowski, PhD:

Okay, so there were agents of those that were coming to these meetings with you?

Jordan Gutterman, MD:

Yeah.

Tacey Ann Rosolowski, PhD:

Okay. I just wondered if it was actually a person who was named that. Okay.

Jordan Gutterman, MD:

No, no. I had mentioned yesterday a couple of the names that were at the FDA meeting. I worked with Hoffmann-La Roche because I had gone there. It should be on the earlier tapes with Lesley [Brunet]. I went there June 15, 1978. I think it was the same trip, if I am not mistaken—same week as—no, no. It was June 15, 1978. I had gone there, I believe—something like that—after we had seen these responses in breast cancer with the natural interferon to meet with Dr. [John] Burns and Dr. [Sidney] Pestka, who eventually played a key role in cloning interferon-alpha for Roche—Roche Genentech. And there was another group, Biogen—a Swiss company—a Dr. [Charles] Weissmann—that was working. And Schering-Plough licensed that compound. Those were very exciting days. I think I described them on the previous day, but if I see it is left out, we will fill all that stuff in. Those were interesting days. And I, for the first time again, understand the pharmaceutical industry and also the nascence of the biotech industry—you know—Genentech and Roche—because I went with Mary Lasker in the late seventies to Genentech. Then [Robert] Bob Swanson—and my guess is that that is on the previous tapes, but if they are not, that is going to be important to go through.

Tacey Ann Rosolowski, PhD:

I don’t remember the detail that you gave, but you did talk about the beginnings of the biotech industry with Lesley.

Jordan Gutterman, MD:

Yeah. So I think we are going to hold that. I don’t want to be redundant.

Tacey Ann Rosolowski, PhD:

Yeah, until we have a little bit more—yes

Jordan Gutterman, MD:

Okay, so interferon gets approved in June of ’86, and we’re starting to think about branching out to other, as I called them, cytokines. And the big push in the mid-eighties was a discovery originally from a guy named Don Metcalf who won a Lasker Award for this work on growth factors—proteins—that allowed red cells to mature. One of the first ones was erythropoietin, EPO, which stimulates red cell production. It is produced in the kidney. A company called Amgen developed that for anemias, especially with dialysis. There was a compound called GM-CSF. That was developed by two or three companies—Schering-Plough and a new biotech company at the time called Immunex, which was started in 1980 in Seattle.

Tacey Ann Rosolowski, PhD:

What was the name of that drug you mentioned before?

Jordan Gutterman, MD:

EPO?

Tacey Ann Rosolowski, PhD:

No, the one after that.

Jordan Gutterman, MD:

GM-CSF.

Tacey Ann Rosolowski, PhD:

Yes, GM-CSF. Thank you.

Jordan Gutterman, MD:

That stimulates white cell formation. The M is for macrophages because it kind of activates the immune system. The connection with Immunex is important, but it becomes particularly important in the story of the nineties and the 2000s. I won’t get into that, but that becomes—my connection with Immunex really has a huge impact on what I’m going to tell you at some point. So I met the two principles of Immunex, the company that was started by two immunologists out of the Fred Hutchison Cancer Center—Steve Gillis and Chris Henney. They started this in 1980. It was interesting, actually. Again, being here at—and I don’t want to lose track of talking about MD Anderson, but this was all going on as I was a professor here and responsible for seeing patients and doing this research and then meeting these people, because I could see a lot of the drugs were being produced not by government but by biotech and the big pharma. So we had to figure out a way of working with these people, and it’s still complex—conflicts of interest, money gets involved, and so forth. But I was approached by Dr. Henney and Dr. Gillis. They knew about the work with interferon. Could we—would we be the first to do a growth factor in human patients to restore blood counts in people who get chemotherapy primarily? That was the whole idea. And they produced a—called GM-CSF. I think their trade name was Leukine. I hope I am not making a mistake here—L-E-U-K-I-N-E. Anyway, in ‘86 we started the first study, as far as I know, as I remember—I think it was around June—around the time interferon was approved—the first study in giving a chemical—a protein GM-CSF to restore blood counts, white cells for sure, and maybe platelets in people getting chemotherapy or in people with diseases that had bone marrow failure, like a disease called aplastic anemia or a complex called MDS, or myelodysplastic syndrome. These people have very low blood counts, and they die of either infection—they either convert to leukemia or if not, before then, then they die of infection or bleeding. It was a very exciting time again, and we were not surprised to see the blood counts go up. I worked with a woman who originally—her family is from India—Dr. [Saroj] Vadhan-Raj, who is still at MD Anderson. She did the first studies with me. We had two New England Journal papers, which says we did some really interesting things. We treated patients—we restored some of the blood counts of this disease called aplastic anemia and also, surprisingly, in this myelodysplastic, which is a pre-leukemic syndrome. The best of the group is a drug called G-CSF, and the trade name is Neupogen. This was produced by Amgen. And that came just a little bit later. That has ended up being the drug because it has fewer side effects than the GM-CSF. It made Amgen. Those two drugs made Amgen. EPO for the red cells—you know—it is a huge, multi-billion dollar company. I remember going to Amgen in ‘83 because they were interested in interferon because we had just—we hadn’t reported the hairy cell yet. I thought this company has no clue what they are doing. They were an early recombinant cloning company. This was ‘83. I never—I missed it completely. I missed it completely that they would become a multi-billion dollar company. The head of that company, George Rathmann, was a great visionary. He was determined to use erythropoietin to restore red cells in dialysis patients. And Genentech, I understand, turned that opportunity down. That became a big seller. And it became—it is a whole story unto itself. Then they licensed a drug called pluripotin from Sloan-Kettering for, I think, around $40 million, and that became a multi-billion dollar drug. It definitely supplanted the GM-CSF that we were working on. But it wasn’t an area that I was passionate about. It was interesting. We got some nice science. We did a lot of studies. But it wasn’t—you know—it maybe allowed for more chemo patients to recover more quickly or certainly not die of infections. So it definitely has a clinical use. But it wasn’t my major interest in research. So we did a lot of studies. We published a lot of papers, but—

Chapter 08: Furthering Research through Partnerships with Drug Companies

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