RESEARCH & DEVELOPMENT

·David Jack·

Interest in the application of gonadotropin.releasing hormone (GnRH) analogues has grown dramatically since GnRH was rtnt isolated in 1971, and the GnRH agonists bave now firmly established themselves in the treatment or 11 variety of cancers, endometriosis, and fertility disorders. The first GnRH antagonists, cdrorelix and ganirelix, are about to reach the market for the flI'St time. A number of the sessions at the 5th International Symposium on GnRH analogues in Cancer and Human Reproduction [Geneva. Swil1.erland; February 1999] dealt with the latest results on these antagonists, particularly cetrorelix and its therapeutic indications.

Professor GUnter Emons from the University cf Gtlttingen. Gennany, described the results of his study sponsored by Asta Medica. This was a phase III! trial involving daily SC injections of cetrorelix 10 mg/day; the high dose was intended to produce higher serum concentrations than would be achieved by standard GnRH agonists such as buserelin and goserelin. The patients were women with advanced ovarian cancer who had already undergone first-line therapy with either cisplatin or carboplatin and they were stratified into 2 groups; those who were platin-resistant and those who were potentially platin-sensitive. The tumour lesion, quality of life and adverse events were monitored every 2-4 weeks.

Agressive in progressive ovarian cancer To date, a total of 17 patients are considered eval­

uable and data were presented on 15. Three patients have undergone temporary partial remission (2 platin­resistant and 1 platin-sensitive) and 2 have remained unchanged (2 platin-resistant). The time to regression in these patients ranged from J25 to 196 days. compared with a median time of 59 days for all patients.

In Professor Emons' opinion, 'these results are encouraging when it is taken into account that all 15 patients had tumours with primary resistance 10 platinum and the majority were progressive on 3rd and 5th line regimens. Some even had up to a dozen previous courses of chemotherapy' .

Cetrorelix was well tolerated and there was only one case of an anaphylaxis-type reaction. This was attributed to histamine release and was easily controlled. The trial will continue until 36 patients are recruited into each of the 2 arms.

Reduces uterine fibroids Uterine fibroids are the most common form of benign

tumour affecting the female reproductive system and, since receptors for estrogen and progesterone have been found in fibroid tissue, sex steroids are thought to playa key role in the pathogenesis of the condition. Although GnRH agonists, such as leuprorelin, are the treatment of first choice, uterine fibroids can reform after stopping therapy and the fibroids may reach their previous size. In order to keep the size of uterine fibroids as small as possible, combination regimens such as a GnRH agonist and addback therapy are required.

However, the new GnRH antagonists are also effec­tive but in order to avoid 'flare up', daily administration for months is required. For this reason long-acting formulations have been developed; one such formula­tion is cetrorelix depot, a micro-particulate formulation of cetrorelix.

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Dr R Felberbaum from Frauenklinik Universit3t LUbeck. Germany. described his study of cetrorelix in the management of uterine fibroids. This was a prospective. randomised, open clinical trial in 20 pre­menopausal women with symptomatic uterine fibroids. Cetrorelix depot 60mg was given 1M at cycle day 2 and then patients were randomised to a second dose of cetrorelix depot 30 or 60mg administered at treatment day 21 or 28, according to the degree of estradiol suppression. Surgery was performed after 6 or 8 weeks and weekly transvaginal sonography and magnetic resonance imaging were carried out both before and after treat- ment to evaluate fibroid volume.

A total of 16 patients exhibited satisfactory and sustained gonadotropin suppression and sex-steroid secretion. avoiding any initial flare up. When suppres­sion could be maintained for 7-8 weeks, a mean reduction in uterine and single fibroid volume of about 38% was obtained. In one case the reduction achieved was as great as 50%.

Dr Felberbaum said that GnRH antagonists may offer significant advantages over GnRH agonists if better formulations can be developed. The safety and efficacy of these sustained-delivery systems need to be established by means of long-term studies.

Agonists vs antagonists in ART Dr Felberbaum also attempted to evaluate the

future role likely to be played by the new GnRH antagonists in assisted reproduction treatments (ART). In his opinion, 'we may be on the verge of a new era in ART, the era of the antagonist' .

Successful ovarian stimulation is fundamental to any ART, but when using urinary or recombinant gonadotropins. the surge seen in luteinising hormone (LH) during controlled ovarian hyperstimulation (COH) has proved a major drawback. The incorporation of GnRH agonists in stimulation protocols has been able to reduce the incidence of such LH surges to below 2%.

Three different ART protocols for GnRH agonist use have been developed: 'ultra short', 'short' and ' long'. According to Dr Felberbaum, the long protocol has now become the 'gold standard' in a number of countries. For example, in Germany 35 000 cycles per year involve the use of this protocol, and it has also proved very popular in France. In addition, satisfact­ory and reliable pituitary suppression can be obtained by any of the 3 formulations of GnRH agonists currently available: nasal spray (daily administration), SC injection (daily administration) or a depot preparation (monthly administration).

According to Dr Felberbaum, the new GnRH antagonists such as cetrorelix and ganirelix, which are structurally much more complex than the agonists,

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may offer a number of advantages over the latter in ART. For example. they produce instant suppression of GnRH release and so there is no initial hormone surge; the rate of cyst formation is also lower. In addition, support during the luteaJ phase will probably not be required.

However. he said that there are also a number of disadvantages associated with the use of GnRH antagonists. For example. daily administration will not be suitable for the ultra long protocols that may be needed for the treatment of endometriosis or uterine fibroids. Also, dose titration may have to be carried out in each patient. which will be time consuming. The new drugs are more expensive than the establ­ished agonists and most clinicians have as yet no experience with these new agents.

Dr Felberbaum described the use of a new long protocol that he and his group designed called the 'Lubeck' protocol. This new protocol involves menotropins and concomitant mid·cycle multiple doses of a GnRH antagonist. His group have used this protocol in a randomised, open-label comparison of cetrorelix with buserelin. In the cetrorelix group the incidence of premature luteinisation was only 0 .89%.

Safety of GnRH antagonists Demonstration of the long·term safety of GnRH

antagonists will be critical for their success and this type of data will only be forthcoming once they enter into routine clinical use. However, Dr Hilda RiethmUlIer· Winzen from Asta summarised the data they have collected to date on cetrorelix.

She summarised the safety data that are currently available from a series of phase II and III studies that have been carried out in patients around the world and on children born to women treated with this drug. To date, 122 centres in Europe, US, Mexico, lapan, Israel, Australia and Hong Kong have taken part in the testing of cetrorelix.

Single and multiple doses of cetrorelix were given ranging from 0.1 to 5mg. The minimum effective doses were found to be 3mgl3ml as a single dose and O.25mgllml as a multiple dose. For the indication COHIART, the normal dose was O.25mg/day for a mean of 6 days. The drug has also been given to some patients every 4 weeks for periods of up to 5 years.

The main adverse events reported in the II completed clinical trials in COH involved a reaction at the site of

injection. The incidence of this event was 1.6% at the O.25mgll ml dose but was much higher. 20.3%, at the 3mgl3ml dose. The only other adverse events reported were nausea (0.5% of patients) and vomiting (0.2%). As far as pregnancy and delivery were concerned, II studies have been completed in 28 centres showing that a total of 235 pregnancies resulted in 171 deliveries and 215 live births. A further 26 pregnancies were reported as ongoing while the rates of abortion and ectopic pregnancy were 16.5% and 3.8%, respectively. All babies were found to be healthy at birth.

From the data collected so far from patients under­going COH as part of ART, cetrorelix exhibits good local and systemic tolerability and no residual drug effects have been noted during and following transfer of embryos.

What will the future hold? According to Dr Felberbaum, GnRH antagonists

offer clinicians a new therapeutic option. Nevertheless, he warned delegates that experience with these new antagonists has only been obtained in so called 'normal' patients, and that use in a much wider patient popula­tion will be needed to provide clear evidence of any benefits. In his opinion, until such evidence is obtained GnRH agonists should remain the treatment of choice forCOH.

It is far too early to tell whether the new GnRH antagonists will be able to successfully compete with established agonists and several years will be needed before a definitive answer will be possible. There is certainly still a lot of mileage Jeft in the agonists, particularly in the management of infertility, endomet­riosis and benign prostatic hypertrophy. Safety issues will be paramount and a clear answer is unlikely before the next GnRH symposium. -,.. EdiJ(JriIll comment: Cetrorrlix is under development with Asta Medica and is awaiting registration in Europe for the trratment offemale infertility. it is also in phase 11 trials for the trrarment of benign prostatic hyperplasia, uterine fibroids, and prostate and ovarian cancer. Ganirrlix is under development with Hoffmann -fA Roche and Organon and is ire phase III trials for the trratmertt offemole infertility. phase If trials for the trrarment of brrast, prostate and uterine cancer; and clinical trialsfor the treatment of endometriosis.