Clinical development of two innovative pharmaceutical forms of leuprorelin acetate

Abstract

Objectives: Two innovative pharmaceutical forms of leuprorelin acetate have been developed as 1-month and 3-month implants for the treatment of advanced hormone-dependent prostate cancer. These products contain active substance dispersed homogeneously in a biodegradable polymer. Here we present the key results from the clinical development of these slow-release implant formulations of leuprorelin. Methods: Two therapeutic studies of the 1-month implant were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Enantone) as the active control; and a single-arm study of the leuprorelin implant. For the 3-month implant, four therapeutic studies were performed: a randomized, controlled study comparing the leuprorelin implant with leuprorelin prolonged-release microspheres (Trenantone) as the active control; a single-arm study of the leuprorelin implant; and two long-term studies with the 3-month implant administered twice, either 12 or 16 weeks apart. A pooled analysis of data from the comparator-controlled and single-arm studies of the 3-month implant was also conducted. The main inclusion criterion for all studies was histologically confirmed advanced prostate cancer, with primary endpoints based around successful testosterone suppression (≤0.5 ng/ml). Results: In the comparator-controlled studies, both implants were as effective as the microspheres for achieving successful testosterone suppression and normalization of prostate-specific antigen (PSA) levels. Data from the single-arm and long-term studies were consistent with those from the comparator-controlled studies. In the pooled analysis, significantly more patients treated with the 3-month implant achieved successful testosterone suppression compared with the comparator ( p ≤ 0.01). The safety profile of the implants in the comparator-controlled studies was similar to that of the prolonged-release microsphere formulation, and consistent with that of the luteinizing hormone-releasing hormone agonist class. Conclusions: The innovative 1-month and 3-month implants of leuprorelin acetate are at least as effective as leuprorelin acetate prolonged-release microspheres for achieving successful testosterone suppression and normalization of PSA in men with advanced hormone-dependent prostate cancer, with a comparable safety profile.

GnRH agonists and antagonists in prostate cancer

“…Studies comparing one and three months formulations showed no relevant differences concerning effects on testosterone levels and PSA [84][85][86][87]. This was also the case for a comparison of three and six months formulations in a mixed population [88].…”

“…It should be noted that the studies with leuprorelin were performed with various formulations, whereas this was not the case for the other medicines. A specifi cation of the applied formulation was only provided in a few studies: Lupron [17,83], Enantone [18] and Sandoz generic formulation [87]. The 16 other studies did not specify the formulation, although the vast majority of studies used a dose of 7.5 mg per 28 days or 22.5 mg…”

“…Acquisition cost plays a key role in the fi nal selection of the drug of choice. The recent introduction of a generic leuprorelin implant formulation, which does not need reconstitution and can be stored outside of a refrigerator [87], and which is at least as effective as previously used leuprorelin formulations and was well tolerated in a relatively large group of patients (n = 818) [103] may be a good starting point for a renewed discussion on drug selection for the treatment of prostate cancer. Major cost savings might be applicable, because the acquisition cost of the various drugs has always been quite high.…”

Einsparpotenziale für die medikamentöse Therapie des Prostatakrebs sind in der GKV regional unterschiedlich

“…Damit ist Leuprorelin seit über 30 Jahren das führende GnRH-Analogon und bildet die Grundlage für viele multimodale Therapiekonzepte [11]. Neben der langjährigen Erfahrung der Ärzte mit dem Wirkstoff unterstützen auch sehr umfassende Daten zur Wirksamkeit und Sicherheit von Leuprorelin dessen Einsatz [12,13,14].…”

“…Das Generikum steht ebenfalls als Fertigspritze zur Verfügung, enthält jedoch ein stäbchenförmiges Implantat, das ohne weitere Vorbereitung direkt injiziert wird. Darüber hinaus gibt es keine Hinweise auf relevante Unterschiede in Hinblick auf Wirksamkeit, Sicherheit, Bioverfügbarkeit oder Lagerung, welche die beobachtete Marktdominanz des Altoriginals erklären würden [13].…”