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One of the things that we did, actually, was collect samples, freeze them down, and then look at a variety of assays to try to see whether the drug was working or not. We also figured that if it was really working, the immune system would have to get better. I remember tracking down [Dr. Ronald] Ron Gress–he had done some work in transplantation–and with him trying to figure out how long we would have to give a drug to get improvement in the immune system. He noted that if you get an animal depleted of CD4 cells, you start to get them back in about four months. So we decided that if a patient can go for ideally four months, or maybe two months, and you do not see some improvement in the immune system, probably you are not there. Again, there was just no template for what would happen.
Hannaway: It was empirical.
Yarchoan: It was a hypothesis. The irony is that suramin had been tested–and this was a story that I took as a little bit of a warning–suramin had been tested for onchocerciasis down in Africa. It was tested under very primitive bush conditions where the researchers would go, on bicycles, from village to village, and they would give the drug on Monday to village A, on Tuesday to village B, and then they probably rested on Sunday; then the next Monday they would go to village A again. They would give it over a six-week course. That is what we did: we gave it once a week based in part on this African schedule. As an aside, I believe suramin was actually first synthesized by [Dr.] Paul Ehrlich.
Hannaway: My goodness.
Yarchoan: But the researchers in Africa initially concluded that the drug did not work, because initially they did not see anyone with onchocerciasis, or river blindness, get better. They went back the next year to visit the same towns, and they found that they had cured the blindness in a number of the patients. What had happened was that when the blindness got better, the patients just stopped showing up at the clinics because they could now go back out in the fields. So it was actually a warning to us that you have to make sure that you don't miss beneficial changes. It was amazing to me that you could miss curing blindness in someone, but I understood that it could happen.
Hannaway: If the patient disappeared and did not come back, you did not know.
Yarchoan: But when the paper describing the in vitro activity of suramin got accepted in Science, at that time NPR [National Public Radio] picked it up. I remember I was down in Sam’s office, and Sam said, “There is some radio show, like National Physicians’ Radio or something like that, and they want to talk to us. Could you speak to them?” I said, “Sure.” I got on the phone and there were typewriters clicking in the office, and the interviewer said, “Could you go and find a quieter room, please. We’re trying to record this.” I said, “Okay.” So I went and got permission to go in Sam’s inner office, and I closed the door and gave the interview. At the end, I said, “By the way, can you tell me what this is? Sam said it was National Physicians’ Radio.” The interviewer said, “No, it is National Public Radio.” So this interview about the drug then appeared over NPR, and that was actually a very effective recruiting mechanism for patients.
But we wanted to make sure that the patients entered into the study had virus that was replicating, so the protocol required that they had to have virus that could be cultured. This was only done in a few laboratories, so as a practical matter we wound up getting referrals from other academic physician-researchers who were beginning to be able to handle this virus.
Harden: Moving from the in vitro studies to the actual trial, how long did it take before you realized that the drug was going to be too toxic?
Yarchoan: The main issue was not that it was too toxic. It just did not work at levels that could be tolerated–or we could not tell that it was working. If that drug had clearly worked, I think we would have done more to try to get around the toxicity.
Hannaway: So it was not inhibiting reverse transcriptase.
Yarchoan: It actually would be very interesting to go back and figure out what went on with those patients. What we found was that the first assay that we thought we could use never got developed. Then we thought we would look at lymph nodes, because a paper had come out suggesting there was more virus in lymph nodes than in peripheral blood. For this first patient, we took two lymph node biopsies before we treated him, and we had [Dr.] George Shaw in Bob Gallo’s laboratory look at them for HIV by Southern blot. He could see a fair amount of virus in one lymph node and not that much virus in another lymph node. So, it became apparent to us that there was a certain amount of variation even before treatment and this was going to be very hard to use. Also, the lymph node biopsies were invasive, and the patient was becoming resistant to having more biopsies.
Then we tried collaborating with Mika Popovic in culturing the virus, but the system really was not quantitative enough to do it. So we were looking at CD4 counts and basically freezing down specimens for later studies. Then [Dr.] Mary Harper in Bob Gallo’s laboratory developed a method for in situ hybridization, so we used that in a number of patients, but the number of HIV-infected cells that they could detect was about one in 100,000, or one in a million, and it was too low to see differences.
Then we found, collaborating with [Dr. Philip] Phil Markham, that some patients appeared to become culture-negative, or that it took longer and longer to culture the virus after they received suramin. This suggested that there was a decreasing viral load. And we wrote this up in the publication from the trial in the Lancet. So this actually suggested that the drug might be doing something. But we never saw the CD4 counts go up. On the one hand we were a little bit optimistic because we had the virologic data, but in our hearts we did not feel it was working. The patients did not feel any better. That could have been in part because of toxicity. But we did not see any immunologic reconstitution. We thought that it was worth looking at further, but we did not feel we were seeing what we wanted to see with this drug, and the thing to do was to try other drugs.
In fact, suramin then went on to be studied in cancers. One of the patients in our trial developed adrenal insufficiency. Other researchers found that suramin induced consistent adrenal insufficiency at high doses, and they thought that it might be useful for adrenal tumors. Snuffy Myers, [Dr.] Charles Myers–everyone calls him Snuffy–and [Dr. Seymour] Sy Stein, who is now, I think, at Columbia, started looking at this in people with adrenal carcinoma and then switched over to another hormonally sensitive tumor, prostate cancer But they have been doing a number of trials with this, so it is not too toxic to give to people. It just did not clearly work against HIV.
Harden: I was about to ask you. That is why I was looking for the paper.
Hannaway: Yes. This is the Lancet paper.
Harden: I was going to ask you if you were collaborating also with [Dr. Anthony] Tony Fauci’s group, and obviously you were because you all published together.
Yarchoan: We treated some patients, Tony’s group treated some patients, and then [Dr. Robert] Bob Redfield over in Walter Reed treated some patients with suramin, so it was really a joint effort of the three groups.
Harden: Was there a fair amount of collaboration across institutes in these efforts?
Yarchoan: Yes. There was some. Tony Fauci and [Dr. Clifford] Cliff [Lane] were focusing, as I recall at the time, on their IL-2 [interleukin-2] effort, which is now coming to fruition. They had a program of bringing in patients and testing them with IL-2, so we thought of linking up with them and doing this first study.
Harden: Is there anything else we ought to say about suramin before we move on to AZT?
Yarchoan: The one thing I will say is, just to give us sort of a chronological history, that Sam had organized a conference in December of 1984 on retroviruses that was published in a supplement of Cancer Research. At that time, we had the sense that maybe there was some virologic effect but that this drug was not going to be very useful for people unless we dramatically figured out different pharmacokinetics. I remember we were all a little bit down about it at that time and looking for other things to do.
Harden: I have often gone back to the diagram that Howard Temin made. I think it was in 1986. It was soon after the HIV virus was defined, and it showed the viral life cycle with the idea of the points at which it might be interrupted. Was this mechanism in your head when you started working on the AZT class of drugs and were looking for a drug, too, beyond suramin? Were you thinking theoretically at that point?
Yarchoan: The story of how AZT was settled on is somewhat complicated. From our perspective, Sam felt that drug discovery was a complex process; that there were a number of pharmaceutical firms out there that did it; and if he could link up with such a firm, it would help things along. We all had a sense of the urgency about the disease and wanted to move as fast as possible. By linking up, we could tie in with a group that had expertise in some of the important steps in drug development, and they could organize the large trials and quickly bring it to market. Sam sometimes said that the federal government is not in the business of selling drugs. My recollection, from what he told me, was that, in the late summer and fall, he went around trying to talk to anyone he could get interested in developing drugs. What he found when he spoke to a number of pharmaceutical firms was that they were not interested at that time. In effect, they said, “Look, it is an epidemic, but there are only 50,000 people with the disease, and we can’t justify a big program to our stockholders for 50,000 people.”
Yarchoan: We were focused on reverse transcriptase at that time. We had done some library research trying to look up reverse transcriptase inhibitors that had been studied in animal retroviruses, because this was a clearly unique viral enzyme, and it was an obvious target. The rifampin analogs that we had thought about earlier were reverse transcriptase inhibitors, and we had settled on suramin as a reverse transcriptase inhibitor.
There was literature indicating that some nucleoside analogs were reverse transcriptase inhibitors and/or some of them had antiviral activity. So there was an interest in nucleosides. How Sam had the contact down at Burroughs Wellcome, I do not know, maybe through Dani Bolognesi. What happened there has been subject to varying interpretations, but my understanding is, Sam went down there to find a firm that he could collaborate with, possibly because they also had some nucleoside expertise. He gave a talk at Burroughs and then met with David Barry, and they settled on a collaboration. My understanding is that Burroughs had been testing some drugs themselves and had murine retrovirus expertise but essentially no HIV expertise. We had the HIV expertise, and it looked like a nice match. So they agreed on a collaboration where Burroughs would send some compounds up for us to test. Sam took it very seriously and rededicated a lot of the laboratory effort to testing those drugs during that period of time.
Hannaway: This was in 1984 or 1985?
Yarchoan: No, we are talking about from October 1984 to March of 1985.
Harden: But clearly before the Technology Transfer Act of 1986.
Harden: Would the whole thing have been handled differently if that act had been in place, or not? Did the act itself dictate certain relationships?
Yarchoan: I never read the act from beginning to end. But my impression is that, as a result of the act, the whole process of collaborating with industry became much more formalized and required formal agreements before things could move forward. Before that time, a lot of stuff was done just on a handshake or signed boilerplate documents drawn up by a company.
Harden: That is the impression other people have given us. Because of the subsequent legal problems, I am, I suppose, in one sense just asking, would it have been less complicated if there had been a formal mechanism before the fact, before that handshake? It is an interpretive question. Could you comment?
Yarchoan: Your question is whether the lack of a formal process, and whether the Technology Transfer Act and the processes put in place in that may have affected the collaboration and avoided some of the complications and arguments that have happened since then. I would say, in a sense, yes, but one has to ask whether the collaboration would have occurred if all the agreements had to be brokered before we started doing it. Certainly negotiating any agreements takes time, and I think it is quite possible that the collaboration would not have taken place at all, or it would have been substantially delayed, if all this had to have been done ahead of time. Certainly, if the whole process was in transition and people were skittish about what the final outcome would be, that would have posed a major problem. So it would have solved one problem, but it could have introduced a much bigger one.
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