Gay Men's Health Crisis "Treatment Issues", Vol. 8, No. 11 December 1994

In an effort to examine AIDS drug development and research issues and gain a better understanding of Roche itself, David Gold and Dave Gilden of Treatment Issues interviewed Jfrgen Drews, President of International Research and Development for Roche and Whaijen Soo, Hoffmann-La Roche Vice-President of Virology at the headquarters of Hoffmann-La Roche in Nutley, NJ.

Jfrgen Drews Treatment Issues

(TI): Can you give us an overview of Roche's HIV research program?

Jfrgen Drews: We have HIVID [ddC] on the market and we are developing saquinavir [a protease inhibitor], which is likely to be the first approved protease inhibitor. We also worked on tat inhibition which we gave up because of disappointing clinical results. After these, we do not have other anti-HIV drugs. But we have a broad antiviral program and a program on immuno-enhancing drugs. Our anti-viral program, which we are enlarging, focuses on herpes, hepatitis and papilloma viruses. In about one to two years, they will start entering new compounds into the development pipeline. And we also have an immunology program which is very broad. One immune product, IL-12, is presently slotted for oncology [cancer] studies. That may be an area where we decide to reenter the AIDS arena.

We are also studying agents for some of the opportunistic infections, like mycobacteria and pneumocystis carinii to see whether we can find a drug that inhibits several of these infections.

TI: But essentially, after saquinavir, is Roche out of the AIDS field?

Drews: We are not out. We are really putting a lot of energy in saquinavir and ddC and trying out all kinds of combinations. But for the time being, we haven't done much in AIDS because we don't see any compelling ideas that seem particularly rewarding. If the scientific or technical feasibility is not there, we would rather do something that is more compelling at this point.

TI: Last summer, TAG [Treatment Action Group, the New York- based advocacy organization] proposed a "large simple trial" to evaluate saquinavir and other protease inhibitors. How does the company view such proposals?

Drews: The controlled trials with several thousand patients that we have now in the works will give us better information than these large simple trials, the way they were envisaged. They really wanted to use the protease inhibitors against the background of anything that might be taken in a very, very large population. Now, that's not impossible. But you need many, many patients in order to power the study to be able to say something. This is particularly impractical in the case of protease because it is so difficult and expensive to make. You may be willing to think about it with a drug that you can provide in large amounts at reasonable cost, but with these particular compounds it is not feasible.

TI: But look at ddC: the data is controversial and ambiguous at best. People don't have much confidence in the drug.

Drews: It depends really on which parameters you use. If you use certain surrogate parameters, there is clearly an effect. If you use mortality/morbidity, we know very little. We are moving away from using such drugs as single agents. The combination studies are most likely to be able to show some benefit in terms of improving morbidity over the long range.

TI: What should be the standard for measuring whether a drug like saquinavir is ready for accelerated approval?

Drews: We all have become a little less optimistic about the meaning of CD4 cells. Of course, morbidity and mortality are what really matters, but I have confidence in viral loads. If I can reduce PCR-detectable virus by one or two orders of magnitude, I would feel pretty confident that that will eventually have an effect on the course of the disease.

TI: When does Roche plan to apply for approval of saquinavir?

Drews: We don't really have a time schedule. We now have two large studies ongoing. One started accruing patients this year, the other in 1993. The original plans were to seek approval in 1995, but we may have to postpone that somewhat depending on the availability of drug. We don't want to apply for approval and not have the material to launch it broadly.

TI: If the compound is so expensive to produce, is it a feasible drug to develop?

Drews: I think it can be done. There have been improvements in the manufacturing and the number of steps required. We now think we can produce the drug in sufficient quantities and at a price that is feasible.

TI: How do we encourage greater investment in HIV research by the private sector?

Drews: It's difficult to say. HIV is perceived as a technically difficult area of study. Scientifically, there are not yet many obvious and very promising targets of intervention. It is a bit like oncology looked ten to fifteen years ago, [when] the investment wasn't all that overwhelming either. Today, oncology looks much different, with new mechanisms and an understanding of how it is caused. New targets are evolving at a rather rapid pace, and companies are reentering the field.

The other thing is that people perceive HIV as a highly politicized field where you risk not being able to judge your programs and developmental compounds on the basis of medical, scientific and economic feasibility. You have to take into account many other factors. That is perceived by many people -- quite frankly -- as a negative. This is to some extent due to the activity of groups like yours. On the other hand, the same groups have done quite a few good things such as pushing accelerated approval.

Whether the interference was positive or negative, it is perceived as putting a constraint on those who invest resources, money and time in finding something. In terms of encouraging more investment, the community advocates have become more constructively involved instead of simply protesting the inability of science or of the industrial community to come up with something that makes a big therapeutic difference. So there has been a change which is slowly being perceived as helpful. But we need a little more time and perhaps some stronger signals.

TI: The last time I was at Roche's offices was during an ACT UP demonstration. Why do you think there was such tension between Roche and activists?

Drews: First, I think there is a tremendous tension in the community about treatment issues. That is understandable and everybody will respect that. Secondly, the relationship between Roche and the community may not always have been handled very well, on both sides. I think that Roche has not been terribly open and communicative. Sometimes too guarded, and perhaps too cautious in dealing with the community. That is my impression coming in as an outsider with an international perspective and seeing the situation as it is. When I came to Nutley, I thought the organization here was more guarded, cautious and secretive than at Basel. But to me, improvement along these lines with more open communication is possible.

TI: One of the things that struck me about Roche was that the people in Nutley did not seem capable of making decisions. Everything had to go through headquarters in Basel.

Drews: But, you see, your negative impressions may have come from a time when Roche was really in transition. We started a new organization in pharmaceuticals in 1990, and my coming over here was part of that reorganization. Until that time, decision-making was really not so clear. Basel and Nutley were kind of acting like almost autonomous centers. For someone from the outside, it must indeed have been very confusing, and very difficult to really trace decisions. Now, the decision-making mechanisms are very clear.

TI: Roche also owns the rights to PCR technologies. How do you see the impact of these tests in HIV?

Drews: They're going to have a very large impact. PCR allows for a quick and convenient way to quantify viral loads. I am quite optimistic that it would be possible to extend the present ways of measuring viral RNA to make separate assessments for intracellular virus, for virus in plasma, and for virus in several cell compartments -- and thereby gaining a picture of what is really happening in HIV infection. I really see a tremendous increase in understanding of what actually is going on and how you can modify that by various treatment regimens.

TI: Do you anticipate the price of the HIV PCR test going down?

Drews: It's very difficult to say. Since the technology is going to come up with even better ways of doing this, you can charge the higher prices for the newer generation tests. And the older technologies will probably become cheaper. But you should really discuss it with our diagnostic people.

TI: Since many people with HIV are using vitamin supplements, and Roche is one of the largest producers of vitamins, how can we get real answers about whether these are useful? Drews: Again I only have an oversight in R & D, not in this area. It is very difficult to find industrial responses for these kinds of studies. While we are quite interested in learning more about these products, nobody really wants to do the studies. We support several such studies in various fields, usually in oncology, but we don't want to do them all. They should be done by health organizations like the NIH and by other national health organizations.

Whaijen Soo

TI: How many people will you be able to provide saquinavir for on an expanded access program?

Whaijen Soo: We had hoped to have enough drug for up to 4,000 or 5,000 patients [starting next year]. Because of the formulation problem, we really can't say for sure. We believe that once we commit the drug supply to these patients, we can't just run out of drug and leave them unable to continue.

TI: What is the drug supply problem?

Soo: The drug supply problem is more related to the formulation of the drug itself, not the substance. The drug is extremely difficult to manufacture, requiring multiple steps and a long lead time type of synthesis.

TI: Are you certain that you will have drug for expanded access program?

Soo: We are hopeful. The scientists from the United Kingdom and Switzerland working on this say that this problem can be solved. So we are very hopeful that we will be able to initiate an expanded access program sometime in 1995.

TI: Has there been any toxicity associated with saquinavir at the dose that you are testing?

Soo: At the doses used in the Phase I/II studies, we have not run into any toxicities that can be directly associated with saquinavir. However, in the study we have now been working on with Tom Merigan at Stanford, with doses up to 7200 mg per day (which is 7.2 grams), we have now run into GI complaints. It is not clear if this is due to the drug per se or the fact that it is such large quantity of drug, and a material that is not well absorbed.

TI: How far are you away from a new, more bioavailable form?

Soo: We have a formulation that is being studied -- so far only in single dose availability studies. And in all volunteers, we have seen up to a three-fold increase in bioavailability. But it is still quite early in terms of the drug development stage. We have to run a number of studies to make sure that the formulation is the right one to take into further clinical trials.

TI: In the Merigan study, have you seen toxicities at 3,600 mg?

Soo: No, we only saw the toxicity at the 7,200. We have seen a mild elevation of liver function in both dose regimens, 3,600 and the 7,200, such as the SGOT [enzyme]. But not in bilirubin. Not any sort of obstructive liver damage. These are mild and based on very preliminary information.

TI: Is the 1,800 mg dose used in the [large Roche] trials a suboptimum dose?

Soo: If we had to increase the dose during our early dose range studies, we would have required a much larger quantity of the drug. That was not realistically possible from a business sense. And therefore our choice was to go in and study the 600 mg regimen based on the early phase research data showing a biological effect, primarily based on CD4, and some effect on HIV RNA and then immediately go into the combination therapy. [But] we have not stopped trying to maximize the potential of this drug. We believe that the only way we can really go beyond the current dose regimen is to provide a formulation with a better bioavailability.

TI: What type of HIV reductions are you seeing at the 3,600 and the 7,200 regimen?

Soo: The data are very preliminary, but I think it is comparable to what is being reported by Merck.

TI: So it is a greater reduction than the decrease seen at 1,800 mg?

Soo: Yes.

TI: As a virologist, what do you believe are antiviral targets beyond protease?

Soo: A number of transcription-related steps in the viral replication have been targeted in the past such as tat. People are also looking at rev. [tat and rev are HIV proteins that regulate virus production.] But in those cases, I don't think we have a very complete knowledge of how the virus actually works, and it looks like the virus might be able to bypass some of these mechanisms to replicate. So I am less enthusiastic towards those steps. Integration will be a step that would be virus-specific. Glycosylation [adding sugar units to HIV protein molecules] is another step that people have targeted, and actually, there are a couple of drugs now in development that target the glycosylation process. But you have to be careful to target only HIV-specific glycosylation, not cellular glycosylation processes. I certainly hope additional basic research on viral replication can help us lead to better targets.

TI: Are you concerned that after the protease inhibitors, there doesn't appear to be at this point many new antiviral classes that can be available in the reasonable future?

Soo: I am. That is why I agree with Bill Paul [director of the Office of AIDS Research at the National Institute of Health] that we have to go back and look at the virus more critically and not try to pretend that we know enough about this virus. We have to do detailed work on viral replication. We also need to develop a strategy to maximize the drugs that we have right now: the nucleoside analogs, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors. And we have some preliminary information that we might be able to combine some protease inhibitors. So in that sense, we might have enough agents to look for incremental gains in HIV therapy.

TI: Some labs have volunteered to do a small study using the combination of Roche's and Merck's protease inhibitors to see if resistance can be delayed. Would you be able to provide a small amount of drug to such a lab?

Soo: Yes, we would be very happy to provide drug for such a trial. I think such a combination certainly offers some hope.

TI: Does Roche still have the rights to IL-2?

Soo: Yes, we have studied the drug for ten years, but we discontinued the program due to the toxicity profile and also the fact that so far we have not seen any significant data suggesting the activity of IL-2.

TI: What about the increases in T-cells?

Soo: We have seen the jump in CD4 cells in our earlier studies. [But] our experience so far is that IL-2 has a lot of toxicity and its effect is not sustained long-term. I am also concerned about the short-term increases in HIV from IL- 2.

On the other hand, it is not clear if interleukin-12 [IL-12] would necessarily increase viral load. We certainly would like to have that information. IL-12 offers the potential to be an immunomodulator that might provide some benefit, perhaps more in earlier disease. With a little bit more data on toxicity and HIV replication and from renal cell carcinoma studies, we would be very enthusiastic in bringing IL-12 into the HIV development process.

We are also watching very carefully the antisense and gene therapy approaches, and Roche is involved, you know, in both technologies. So if any new approach demonstrates the opportunity to advance HIV therapy, we can move in, you know, actually very quickly.

TI: How do you validate that reducing viral load -- especially to the levels that current levels of drugs achieve -- is clinically a useful strategy?

Soo: This is, in my mind where we are going to make some watershed decisions between industry and the government. There might now be a separation of responsibilities. I see the government getting more involved in the kind of medical strategy where you have different regimens to be used at different times, depending on when you start to see a rebound of virus. So a drug from a particular company might only contribute to some extent to the success of that strategy. It will be very difficult for FDA to tease out if a drug worked in that way and should be approved. So government now has the ability to look at all of these drugs being developed and test if it is possible to suppress viral replication for years. That will be the only way you can truly validate the hypothesis that suppression of viral replication will lead to clinical benefit.

Right now we are looking at a four month suppression of viral replication with individual protease inhibitors or with AZT. And perhaps a transient effect on CD4. So it is no surprise that you end up with very debatable surrogate marker data. You need a much longer-term effect on the surrogate markers and viral load. And since I am a virologist, I will bet on suppression of viral replication as our main drive, and I think eventually we will be able to demonstrate that a patient will benefit.

TI: You've worked closely with the ACTG [AIDS Clinical Trials Group of the NIH] system in some trials. How can it function more effectively?

Soo: Well, I actually served as the chairperson of the pharmaceutical advisory panel to the ACTG.

TI: So you bear part of the responsibility?

Soo: I unfortunately have to admit that I have not been able to help them to change the process quickly enough. But I think the ACTG leadership right now is very serious in trying to reorganize the operation to be more useful and efficient.

TI: Why do you think that the ACTG's primary infection effort has been so mediocre?

Soo: I think in general we see the ACTG group designing their studies in the more traditional way. Perhaps it is time for the ACTG investigators overall to be more open-minded in designing studies of HIV drugs.

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