AGM-1470:Interview with Dr. Ingber

Donald Ingber, M. D., Ph.D., is assistant professor of pathology at Harvard Medical School, and also on the faculty at Children's Hospital and at Brigham and Women's Hospital, Boston. We interviewed him by phone on September 11.

JJ: What is happening now with cancer results in animals? What is new since the Nature paper which you, Dr. Folkman, and others published last December?

DI: In the Nature article, we showed that a variety of different mouse tumors responded to a synthetic analog of fumagillin. We called this class of fumagillin-related compounds "angioinhibins."

We now have found that the results we reported are not limited to mouse tumors; we have found similar effectiveness in inhibiting the growth of solid tumors in rats and rabbits. And we tested some human tumors in nude mice -- human cells growing in immunocompromised mice. In all these systems, we continue to find that a variety of different tumors, and now tumors in different species, are sensitive to the drug.

JJ: Have there been any failures, any solid tumors that this drug did not work on?

DI: Not to my knowledge. We haven't found any.

JJ: What about side effects? Has AGM-1470 been tested in larger doses than necessary to inhibit tumor growth?

DI: That is currently under way. We are doing the tests needed to bring the drug to phase I trials. I have not heard specific results yet; that work is being carried out in Japan.

In our studies, when we did dose ranging in the past and went to very high doses, we did see some weight loss; but that's far above the dose that we used normally. At the dosage at which the drug is very effective in inhibiting tumor growth, we still see weight gain. When there is significant toxicity, the animals usually lose weight -- and then it can be hard to tell if the tumors are shrinking due to a specific anti-cancer effect of the drug, or because of generalized toxicity. For this reason, we believe it is very significant that the animals continue to gain weight while the tumors remain small.

JJ: Do tumors shrink much, or just not continue to grow?

DI: The drug primarily inhibits further growth and expansion. Tumors stay small, or slightly decrease in size. In humans, one approach might be surgery to remove a tumor, then put the patient on an anti-angiogenesis drug for life. For example, in breast cancer, physicians have tools to see it when it is small. They can remove it surgically, and patients do fairly well. But many of the women come back with metastases a few years later. This is something that might be prevented with this drug.

Another example is colon cancer. Fifty percent of certain classes of colon cancer will come back with metastases after surgical removal; you don't know which patients will develop metastases, and there is no way to inhibit them. In theory, if AGM-1470 works in humans the way it works in animals, even if there are small nodules of tumor cells already implanted, which is what people think goes on with metastases, they will not grow at distant sites.

"Micrometastases" survive off diffusion of oxygen and nutrients. They can grow to approximately a cubic millimeter in size. In autopsies of people with cancer you find many of these small nodules. But they will not kill patients as long as they do not start growing. Once they start growing, often many begin to grow simultaneously, and then it's rampant.

JJ: What do you see as most important at this time?

DI: My own view is that if this agent does not work, there will be another one like it in the future. AGM-1470 is the first progenitor of a new class of anti-cancer drugs with a totally different mechanism than conventional chemotherapy, which means they may have to be used in a totally different way. It will be confusing not only for patients to think about, but also for doctors.

Patients think chemotherapy means toxic effects: you lose your hair, you vomit, and you lose your immune response and get infections. All three of those side effects of chemotherapy are due to drugs which inhibit the growth of every kind of rapidly proliferating cell. The most rapidly proliferating cells are your hair follicles, your intestines, and your immune cells, which is why you get those three side effects from chemotherapy.

Angiogenesis inhibitors do not work that way, so they should not have those types of side effects. They offer a new type of therapy that has to be viewed in a different way.

Doctors now think you have to kill the tumor cells. Angiogenesis inhibitors often have no effect on tumor cells at all; tumor cells in culture can grow as well in the presence of AGM-1470 as if the drug were not there. You're inhibiting the tumor cells indirectly by inhibiting the blood vessels; the lack of oxygen and nutrients inhibits tumor cell growth. So you might not use this treatment the same way as a cancer drug where you're trying to get tumor kill. In classic cancer drugs, you have concerns with tumor cell resistance; that should not be as big a problem with anti-angiogenesis drugs.

Doctors will have to try this drug recognizing that it may require a different type of administration or regimen than used before. For example, AGM-1470 might be useful as an adjunct. You might shrink the tumor using existing drugs, while preventing its regrowth using anti-angiogenic drugs. These ideas will need to be brought out again and again over the next few years.

JJ: Do tumors develop resistance to AGM-1470?

DI: We haven't seen any resistance yet. Dr. Folkman's lab is currently exploring whether resistance can develop, to see if this is a major advantage of the drug. So far it seems to be a major advantage.

If you stop the drug in a treated animal, the tumor starts growing, and if you restart the drug, the tumor stops growing again. Most conventional cancer drugs can shrink a tumor, but if you stop treatment the tumor comes back, and if you give the drug again there is often no effect.

The reason we do not expect resistance with anti- angiogenesis drugs, or would expect much less, is that the target cell is a normal endothelial cell, and there is much greater fidelity in its repair and replication processes. Tumor cells are much more inaccurate than normal cells; they have a higher rate of mutation, as each time they divide there are errors being made. That increases the chance that drug-resistant variations will develop. So we would expect to see much less resistance develop in animals that are treated with anti-angiogenesis drugs, than we see with conventional cancer chemotherapy. That's what we have seen in the animals, but again we don't know what will happen in humans.

The major advantage of this drug, and the reason we have seen low toxicity, I believe, is that AGM-1470 does not kill the endothelial cells (or any other cells). It stops growing endothelial cells from proliferating further, and stops non- growing endothelial cells from beginning to grow. For example, some of the cells in your intestine are growing all the time, with a replacement time of about three days. That's why if a cancer drug kills growing cells, you have problems with your digestive tract, such as nausea and vomiting.

Endothelial cells that line your blood vessels have turnover times of the order of once every thousand or ten thousand days. They normally don't grow, except when you have a wound, or in other special cases. So if you use a drug that only inhibits growing endothelial cells, it will not affect normal vessels. But if a capillary cell begins to grow because of a tumor, the drug will inhibit it. That's why we think we are getting specificity and low toxicity. In animals, at sites other than where the tumor is, the cells do not appear to be affected by this drug.

JJ: Has AGM-1470 been tested against KS in animals?

DI: This drug is going into phase I clinical trials, and to expedite the process we decided to do it through the National Cancer Institute, in cooperation with the National Institute of Allergy and Infectious Diseases. Patients with Kaposi's sarcoma would be among the first to receive the drug -- along with those with cancers, although it is not yet clear which types of tumors will be targeted first. Breast and colon cancers would be excellent candidates, for the reasons I described above.

Now we are doing the toxicology and other tests for pre- clinical development -- giving high doses and looking for side effects, studying pharmacokinetics, choosing the formulation, deciding how it will be administered and stored, making sure the drug is pure, etc. This is going quite well right now. We are ready to try AGM-1470 with patients once it has gone through those protocols.

This work will be done in the same way and at the same speed whether or not we test the drug against KS in animals. Recently we have had a limited drug supply for such animal tests, because we are using large amounts of it in the studies mentioned earlier.

JJ: In other words, the same steps have to be followed whether or not you run KS tests in animals?

DI: Yes. And the data is so good with other tumors, the FDA and NCI and NIAID all feel this drug could go into humans as soon as it meets the criteria for phase I. My own view is that whether it worked or did not work for KS in animals, we would probably try it for KS in humans anyway.

I've given two talks to AIDS meetings and both times people have asked why it is taking so long. It's not taking long at all. We went to the government people only at the end of last year. We need to get these final studies done; basically we have the OK to move to phase I when we do all the standard studies that are required for phase I. It's been very quick from the government end.

JJ: What support would make it possible to move faster?

DI: I think it's moving as fast as it can right now. We have had complete support from both the NCI and NIAID. Even representatives of the FDA came to some of the meetings, so everyone is talking on the same terms.

Also, manufacturing enough of the drug does not seem to be a problem. There were various problems that had to be worked through, like choosing how to stabilize and package the compound. These are classic pharmaceutical-company concerns. However, the Japanese company is working double time doing very impressive work; every time they hit a stumbling block they come up with a creative answer.

These studies take a certain amount of time -- sometimes weeks to months to test certain doses and regimens. You have to wait for this time to elapse. You do the next study based on that result. I think it is going very well.

JJ: Why was there so much scientific skepticism in the past?

DI: The concept of angiogenesis as a target for anti- cancer drugs was pioneered by Dr. Judah Folkman. When he first presented it in the early 1970s, because it was different, many people resisted the idea. When I read the AIDS media today, I feel that you are well informed about science and give a good critique, asking why people keep doing the same things. There are always people trying to do new things, but their voices are not always heard.

We published studies of many angiogenesis inhibitors in the past; this is the first one that we have felt comfortable going all the way with. Some groups might take the first drug that has any activity in an animal and try to quickly move it into the clinic. We did not want one to turn out to be just moderately effective, or questionable. That may be why AGM-1470 has not been in the media that much. If anything we have tried to minimize the media.

However, I think it is important to get accurate information out. We want patients to understand the opportunity, and doctors to understand that there's something different out there.


Note: Trials are not recruiting at this time. The first human study is unlikely to begin before winter, and it could be later than that, depending on results of further toxicity tests. The earliest human trials will probably be conducted at the U. S. National Cancer Institute. AGM-1470 will be called TNP-470 when it enters clinical trials.