Analogues and Antagonists in Fertility and Infertility

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Dr. Hans van der Slikke: "We are in Geneva at the 6th International Symposium on GnRH Analogues in Cancer and Human Reproduction, and next to me is Dr. Peter Boerrigter who is Head of the Clinical Products in the Fertility Clinical Development Department of Organon in the Netherlands. Peter, this morning you had a presentation about analogues and antagonists in fertility and infertility, and your talk was about the antagonists you're developing with Organon. You told us that the common practice in infertility in IVF is stimulation starting with a period of analogues but now with these antagonists you're starting a new way. Why this new product?''

Dr. Peter Boerrigter: "The standard treatment that is currently being employed in infertility clinics is a stimulation protocol that includes a GnRH agonist. This is widely used and is pretty much the standard in what is called a long protocol. The idea of having a GnRH analogue in a stimulation protocol is to turn down the pituitary function in order to prevent the premature occurrence of LH rises. In the past, it turned out to be very helpful and very successful to suppress the pituitary and prevent premature LH rises because in the past premature LH rises were the reason for cancellation of up to 30% of the cycles. By doing so the IVF protocols and also the clinical results from IVF procedures have become much more successful in that the embryo quality was much better, oocyte quality was much better, and better pregnancy rates were accomplished. The problem with the agonist is that, as the word says, it is a compound that stimulates the GnRH receptor and we learned that by prolonged treatment with an agonist, in the long run, after one to two weeks the receptors of the pituitary are desensitized and down-regulated so that we get in a state of suppression of the pituitary. The problem is that it takes a few weeks before the patients are in the status that we want them to be. The big advantage of the antagonist is that the effect is immediate and that is because it really binds to the receptor without activating the receptor and, therefore, there is an immediate effect. Also, when you discontinue treatment the recovery of the pituitary is almost instantaneous, this means that you have a very flexible way of treating patients and you don't need any pretreatment phase, which is so typical for an agonist protocol. So by doing so, the current and the new type of stimulation protocols that can be developed by using this antagonist is that you start with the stimulation and that during the last days of the stimulation you administer this antagonist to suppress the pituitary. That's exactly what you're looking for - a suppression of the pituitary during the last days of the stimulation because these are the critical days that a premature LH rise may occur. So the exposure of patients to an analogue, and an analogue can be either an agonist or an antagonist, we're talking about exposure with an agonist is much, much longer than with an antagonist because you need it only for a few days. To give you an example, the total exposure to the agonist in the typical long protocol is on average twenty days whereas with an antagonist the exposure to the analogue is only for five days, which is much, much shorter. This has huge implications in terms of convenience for the patients because the total treatment of a stimulation protocol is much, much shorter than with an agonist because the overall treatment duration is determined by the stimulation rather than the agonist. On average, what we had in our trials is that the total stimulation in using an antagonist is around 8-9 days whereas the total treatment including the agonist is around 20-25 days so this is a huge, huge advantage for the patients."

Dr. Hans van der Slikke: "Yesterday you also presented some results of the first big clinical trials you did, what's the most striking result you can tell us about?"

Dr. Peter Boerrigter: "Yes, indeed, we conducted three major clinical trials comparing the classical stimulation protocol, the long protocol with an agonist, and this new protocol with the antagonist. The major finding was that it is very effective in terms of prevention of the LH rises and that is, of course, the major indication why we are giving the antagonist but it also turned out that this treatment is very short as compared to an agonist protocol. To give you an idea, the total treatment period of stimulation for the patients includes around 8-9 days in an antagonist protocol, whereas it takes 20 days or even more in an agonist protocol so it's easy to understand that this is much, much shorter for the patients for whom treatment for IVF is very bothersome, and so we believe this is really a major step forward in terms of patient convenience."

Dr. Hans van der Slikke: "So they like it very much."

Dr. Peter Boerrigter: "As a matter of fact, most patients say - we really love it, so if they have to give their vote, I'm pretty sure they'd choose the antagonist protocol."

Dr. Hans van der Slikke: "But for the patients there must be other advantages then just winning of some time?"

Dr. Peter Boerrigter: "Sure, there is also a substantial advantage in that there is no chance of estrogen deprivation symptoms, which can also be a burden to patients in terms of hot flashes and that sort of thing. That is due to the fact that in an agonist protocol you start with the agonist for a few weeks before you start stimulation so some patients may already reach the point where they are fully pituitary suppressed before they start the actual stimulation. During this period they may suffer from estrogen deprivation symptoms, like I said - hot flashes. That is the situation that you don't have with an antagonist so this is a major advantage also in terms of side effects."

Dr. Hans van der Slikke: "You told us about some of the advantages about the procedure, but how about the results?"

Dr. Peter Boerrigter: "The results have been very good. To be very honest, in the very first trial we didn't get the results that we expected but it turned out that there was also a learning curve on our part. In the last trial, we had excellent results with exactly the same implantation rates in the two study arms and excellent ongoing pregnancy rates so we are very happy with the overall results."

Dr. Hans van der Slikke: "How about hyperstimulation?"

Dr. Peter Boerrigter: "Hyperstimulation is, let's say, fortunately a complication that occurs very rarely but there is a tendency with an antagonist protocol of a slightly lower chance on this very serious complication. With such a low frequency it is very difficult to get to statistical differences so we need a lot more experience there, and we need much more data in order to come to a fair comparison there."

Dr. Hans van der Slikke: "How many patients do you have in your trials now?"

Dr. Peter Boerrigter: "Our clinical database includes over 1,300 patients overall, and I would say there are over 800 exposed to the antagonist versus 400-500 on an agonist so there's a substantial database."

Dr. Hans van der Slikke: "Is it already used in clinical practice?"

Dr. Peter Boerrigter: "The product that is launched by the Organon Company is under the name Orgalutran in Europe is currently being introduced in European countries because it was approved in May of last year. I believe there are five countries right now that have access to this product but all the other countries will follow very shortly. In the United States this product is on the market under the name Antagon and is very, very successful."

Dr. Hans van der Slikke: "Peter, thank you very much for this interview."

Dr. Peter Boerrigter: "You're more than welcome."