Cetrorelix
AEterna Zentaris recently announced a decision to continue development of cetrorelix, an luteinizing hormone-releasing hormone antagonist, in Japan after making advances in Phase II studies in Germany and completing a broad Phase II program in endometriosis, benign prostatic hyperplasia, and uterine myoma in the United States. This agent is currently the most advanced of the gonadotropin modulators in development for treatment of benign prostatic hyperplasia. AEterna Zentaris’s Japanese partners, Shionogi and Nippon Kayaku, planned to begin a Phase Ha clinical trial in 2005. This multicenter, placebo-controlled, randomized study will attempt to extrapolate the results from European studies to the Japanese benign prostatic hyperplasia population.
Cetrorelix blocks luteinizing hormone-releasing hormone receptors on the pituitary gland to prevent the release of luteinizing hormone (luteinizing hormone), thereby reducing the production of testosterone.
Cetrorelix is different from other agents in the gonadotropin modulator class because of its unique, incomplete suppression of testosterone synthesis and sustained action. Without full hormone suppression, patients do not experience the side effects typically associated with gonadotropin modulators, such as depression, muscle weakness, and loss of libido. Furthermore, because cetrorelix has a longer half-life than other drugs in its class, fewer days of administration are required.
In May 2004, AEterna Zentaris presented data from Phase II trials of cetrorelix in European benign prostatic hyperplasia patients (conducted by its partner, Solvay) at the 18th World Congress of the International Federation of Fertility Societies (IFFS). Two hundred and fifty patients were randomized into five treatment groups: placebo, one single intramuscular injection of cetrorelix via depot (30 mg or 60 mg), and four weekly subcutaneous (SC) injections of cetrorelix (5mg or 10 mg). Following the last treatment day, patients were observed for four months. All active treatment groups showed a dose-dependent improvement in International Prostate Symptom Scores and Qmax, compared with placebo (p < 0.001); the therapeutic responses were maintained for three months beyond the last day of therapy. Serum testosterone decreased but did not reach castration level. Patients did not experience sexual dysfunction related to cetrorelix treatment. After clearance of the drug, patients recovered normal serum testosterone levels.
Researchers conducted an open Phase I/II study to test whether short-term administration of cetrorelix improves the treatment of benign prostatic hyperplasia. Thirteen patients with moderate to severe benign prostatic hyperplasia were treated twice daily with 5 mg cetrorelix SC for two days followed by 1 mg/day SC for two months. They were evaluated at baseline, during treatment, and up to 18 months after therapy. Cetrorelix treatment resulted in a 52.9% decline (p < 0.0001) in the International Prostate Symptom Scores, a 46% improvement in QoL based on a QoL index (p < 0.001), a reduction of 27% (p < 0.006) in prostatic volume, and an increase in peak urinary flow (Qmax) rate of 2.86 mL/s at the end of therapy. Most patients continued to show a progressive improvement in urinary symptoms during long-term follow-up, with a decline in International Prostate Symptom Scores of 67% and 72% at weeks 20 and 85, respectively. This study demonstrates that short-term administration of cetrorelix produces long-term improvement. However, randomized, double-blind, placebo-controlled studies are needed to confirm these preliminary findings.