Treatment Issues, Vol 11, No 2; February 1997
Gabriel Torres, M.D.

Treatment Issues talked to Prof. De Clercq shortly before the Fourth Conference on Retroviruses and Opportunistic Infections. Among other topics, he mentioned the difficulties encountered in developing some of the nonnucleoside reverse transcriptase inhibitors and HIV-cell fusion that he has helped discover. These new compounds would be very helpful in putting together innovative combination therapies to combat HIV. Prof. De Clercq also brought up his continued enthusiasm for the nucleotide analogs, which are very slowly wending their way down the developmental pipeline.

Creative Therapeutic Combinations

Treatment Issues: Is there a need for new kinds of HIV drugs beyond what we have now, and if so, what?

De Clercq: . . .We should keep in mind that monotherapy definitely belongs to the past, and that we should go for a combination of several compounds. That may include protease inhibitors, that's for sure, but it should also include nonnucleoside reverse transcriptase inhibitors [NNRTIs -- ed.], and nucleoside reverse transcriptase inhibitors [nucleoside analogs]. So a combination of at least these three. If you look at the present time to what has been done, I don't think that this kind of combination of a nucleoside RT [reverse transcriptase -- ed.] inhibitor and nonnucleoside RT inhibitor, and then a protease inhibitor, has even been tried so far. [Editor's note: but see Protease Inhibitors: Resistance, Resistance, Resistance in this issue.] It's always the same combination -- AZT, 3TC, and then they add a protease inhibitor to that, or they add nevirapine. It's only nevirapine that has so far been used in that combination.

As you probably know, my task is to develop new compounds and I think we have been, let's say, quite helpful in coming up with a number of nonnucleoside RT inhibitors, with which I have the most experience. So most of the remarks I would give are based on that experience with these nonnucleoside RT inhibitors.

First, they are all able to completely suppress the virus when they are given at sufficiently high doses, and that you probably can keep the virus completely suppressed with these compounds -- certainly when you give them in combination with each other, or combined with a nucleoside analog, or in combination with a protease inhibitor.

TI: Do you think it's a viable thing -- to put two NNRTIs together?

De Clercq: That's certainly possible, yes. In all the combinations that we have tried of two nonnucleosides together, we have found synergistic activity. So even with two compounds that are going to the same target, we can still have synergistic action.

We have already an example of the very nice interaction between two protease inhibitors -- saquinavir and ritonavir -- that potentiate, or at least, ritonavir potentiates the activity of saquinavir. They have a different resistance profile, and the metabolism of saquinavir is reduced or delayed in the presence of ritonavir. So you have two good reasons for a combination of these two compounds.

Apparently, they work synergistically in the patient, too. So there is, in my opinion, a possibility of combining two protease inhibitors, and at the same time, two NNRTIs could also be combined. Even if they work at the same target, if their resistance profiles are different, again, you have good reason for combining.

Second Generation NNRTIs

TI: Isn't there a lot of cross-resistance between the various NNRTIs?

De Clercq: That is not necessarily true. I mean, that has always been the perception from the outside, and some of the compounds do, but some of them have a totally different resistance profile. In fact, I would go even one step further. If you use these compounds from the beginning at sufficiently high concentrations, the resistance does not even develop, particularly some of the newer compounds that are only at the initial state of development. I would mention, for instance, the carboxanilide compounds. We have found that some of these compounds are quite active against HIV resistant to other nonnucleoside RT inhibitors.

We also have very good experience with HBY 097, which we have studied intensively. That is the Hoechst Bayer compound; it is a very powerful compound. In fact, in our ranking, it's really within the top one or two, within the top few compounds that we have analyzed ourselves. I hope it will be developed. It's certainly one of the compounds that I would advocate for being used in combinations in the future. It's one of the top compounds.

TI: What about the UC compounds? How potent are they?

De Clercq: The Uniroyal compounds. Yes, well, these are carboxanilides. These are the two best compounds in our hands, based on the experience we have had with these compounds. [Editor's note: On the now four UC compounds' potency and ability to overcome resistance, see abstracts 569 and 570 from this year's Conference on Retroviruses and Opportunistic Infections.]

TI: Are these compounds being developed?

De Clercq: First of all, the compounds belong to the company Uniroyal, and that is more of a chemical company. So they have to find a larger company, a more pharmaceutical one. They are in the process now of trying to set up an arrangement with a larger company to do this, but it has not been decided yet. So we still have to wait. These two sets of compounds turned out to be so much more active than nevirapine. So that's the reason why we would be in favor of their further development.

TI: It's kind of funny that Uniroyal discovered them in the first place.

De Clercq: Originally, these compounds were designed to be herbicides or insecticides. I forget -- one of the two. This happens all the time. It also proves that in terms of chemical synthesis, it must be rather easy. So here, we have another example of compounds that must be less expensive than the current protease inhibitors. I mean, you can already tell, from the structure.

HIV-Cell Fusion Inhibitors

TI: Something else I wanted to ask you about was about fusion inhibitors, which block HIV binding and entering cells.

De Clercq: Well, I would say there's a lot of progress on the mechanism of fusion. There are already fusion inhibitors, but we do not know whether they act on the so-called second receptor, on the chemokine receptor.

As you probably know, we have developed some of the compounds that affect fusion. We described a few years ago a very interesting class of compounds, which are called the bicyclams.

TI: Do you know how they act?

De Clercq: We believe that they somehow penetrate into the interior of gp120 [HIV's envelope molecule -- ed.] and then buckle the stems of the [V3 and V4 ] loops together, so that during the process of fusion, the gp120 cannot unwind and open as it normally does. The bicyclams probably do not work on the chemokine receptor. That would have been too nice, but they certainly work at the fusion process.

TI: What kind of concentrations inhibit HIV?

De Clercq: In vitro, that is down to the nanogram per milliliter range, so they're very potent, and no toxicity whatsoever, up to 500 micrograms per milliliter. So they have selectivity indexes of more than 100,000. It's in the same range as the protease inhibitors and as the nonnucleoside RT inhibitors -- in the range of the best ones.

TI: How did the bicyclams get discovered?

De Clercq: Oh, discovered, like most other compounds, by accident. The purpose was, in fact, to design [ringed] compounds that were partly organic, partly inorganic, that would have an organic surrounding and then, in the middle, a metal. In the first experiments that we did, we looked to the activity of several monocyclams without metals in it and we found that monocyclams had no activity -- as we expected -- because the purpose was to build in a metal to make them active.

So we tested the monocyclams and we did not see activity, except for one preparation coming from a company in England. Then, in our studies with the Johnson Matthey company, we found that it was the bicyclam contaminant, in which the two cyclam rings were tethered together, that was responsible for the activity. From then on -- from the lead compound -- we, of course, improved on the potency.

Our hypothesis is that the zinc, which is present in cells, makes the link between the cyclams and the bottom of the loops in the gp120 and freezes it in a kind of an immobilized form so that it cannot unwind.

TI: What is the status of bicyclams at this point?

De Clercq: We were a little unlucky in the development for the following reason -- we gave these compounds in a license agreement to Sandoz, and then Sandoz, on a blue Monday, decided not to develop any antiviral compounds.

That was just when we were ready to go in the clinic with these compounds. So we have not been able to get information in humans. These are very good compounds, I mean, very strong, potent fusion inhibitors, and these compounds still deserve a chance.

Sandoz has returned the rights to Johnson Matthey, but Johnson Matthey is essentially a metal company. It has now spun off a smaller company, which is called Inormed. It's going to operate in Vancouver.

We lost several years, but the people at Inormed are absolutely dedicated to putting these compounds forward.

TI: Several antiviral drugs have gotten lost or delayed at Sandoz. [Editor's note: Sandoz has recently merged with Ciba-Geigy to form the giant "Novartis," which describes itself as "the world's leading life sciences company."]

De Clercq: Well, we hope it's only delayed. These belong to the most potent compounds we have ever had a chance to look at.

The Nucleotide Analogs: Unexpected Activity

TI: I was fascinated by some of the nucleotides and the range of viruses. It seems like we're going from an era where there was almost no treatments for viruses, to things like acyclovir to a few treatments for HIV, to some compounds that are really broadly active against many viruses now. Can you say something about how that came about and why these compounds are so broadly active?

De Clercq: I would like to stress that the origin of this work goes back to 1985, when we wanted to make hybrids -- a molecule between acyclic nucleosides [like acyclovir or ganciclovir] and a phosphonate, like Foscavir. We kept the activity as we expected, against herpes viruses, and we found now all herpes viruses to be sensitive to [hybrid] compounds like cidofovir. It's active against all the herpes viruses, but in addition, we found it active against polyoma. That means that even diseases like PML become, now, in the realm of treatment.

We have a model that we can induce tumors with polyoma virus, in rats. They are also responsive to the compound. We have only limited experience with PML in patients, but based on the effect against polyoma, we can easily predict activity against PML, and we have some cases -- two cases [in PML patients]. There is a recent case, of which I do not know the full story, going on here in New York, apparently. Adenoviruses [mostly respiratory infections -- ed.] are sensitive too, but also, even the pox viruses. This is, of course, not such an important virus anymore, but molluscum contagiosum, for instance, it is also sensitive. Then we also showed the activity against papilloma virus [the cause of warts and possibly cervical cancer -- ed.], and this, I think is one of the major breakthroughs in that area.

We found all herpes viruses to be sensitive to cidofovir. There's no exception. At the present time, there is absolutely nothing against Epstein-Barr virus [associated with lymphoma, mononucleosis and OHL -- ed.]. But Epstein-Barr virus-related tumors would be susceptible to treatment with cidofovir.

TI: What about KSHV, the herpes virus thought to trigger Kaposi's Sarcoma?

De Clercq: At the present time, we're doing Kaposi's, first in a cell line, and one of my coworkers is trying to set up in the system for Kaposi's in mice. I'm very curious. I wonder whether doing all these studies with CMV retinitis, they have been able to see something on Kaposi's. [Editor's note: see abstract LB20 from the Fourth Conference on Retroviruses, which describes cidofovir's activity against KSHV in cell cultures. Acyclovir, ganciclovir and foscarnet had much less effect.]

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