General Information

Supprelin LA is a GnRH agonist and an inhibitor of gonadotropin secretion when given continuously. It desensitizes responsiveness of the pituitary gonadotropin which, in turn causes a reduction in ovarian and testicular steroidogenesis.

Supprelin LA is specifically indicated for the treatment of children with central precocious puberty (CPP).

Supprelin LA is supplied as an implant for continuous release over the course of 12 months. The recommended initial dose of the drug is one implant every 12 months.

Clinical Results

FDA Approval
FDA approval of Supprelin LA is based on the results of two open-label, single arm clinical studies. Study 1 enrolled 11 pretreated female subjects, 3.7 to 11.0 years of age. Study 2 enrolled 36 subjects (33 females and 3 males), 4.5 to 11.6 years of age. Sixteen of these subjects were pretreated and 20 were treatment-naïve. Endpoints were similar in both trials and included measurements of the suppression of gonadotropins (luteinizing hormone and follicle stimulating hormone) and gonadal sex steroids (estrogen in girls and testosterone in boys, respectively). Additional assessments were clinical (evidence of stabilization or regression of signs of puberty) or gonadal steroid-dependent (bone age, linear growth). In study 2 the primary measure of efficacy was LH suppression (defined as a peak LH <4 mIU/mL following stimulation with the GnRH analog leuprolide acetate). In both trials the endpoints were achieved. In study 2, suppression of LH was induced in all treatment naïve subjects and maintained in all pretreated subjects one month after implantation and continued through month 12. Secondary efficacy assessments indicated stabilization of disease. In addition, in study 2 estradiol suppression was present in 100% of the females through month 9 and 97% at month 12. Testosterone suppression was maintained in the three pre-treated males.

Mechanism of Action

Supprelin LA is a GnRH agonist and an inhibitor of gonadotropin secretion when given continuously. It delivers approximately 65 mcg histrelin acetate per day. Following an initial stimulatory phase, chronic, subcutaneous administration of histrelin acetate desensitizes responsiveness of the pituitary gonadotropin which, in turn causes a reduction in ovarian and testicular steroidogenesis. Administration of histrelin acetate results in an initial increase in circulating levels of LH and FSH, leading to a transient increase in concentration of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of histrelin acetate causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH.

Literature References

Eugster EA, Clarke W, Kletter GB, Lee PA, Neely EK, Reiter EO, Saenger P, Shulman D, Silverman L, Flood L, Gray W, Tierney D. Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: a multicenter trial. The Journal of clinical endocrinology and metabolism 2007 May;92(5):1697-704.

Hirsch HJ, Gillis D, Strich D, Chertin B, Farkas A, Lindenberg T, Gelber H, Spitz IM. The histrelin implant: a novel treatment for central precocious puberty. Pediatrics 2005 Dec;116(6):e798-802

Weise M, Flor A, Barnes KM, Cutler GB Jr, Baron J. Determinants of growth during gonadotropin-releasing hormone analog therapy for precocious puberty. The Journal of clinical endocrinology and metabolism 2004 Jan;89(1):103-7

Feuillan PP, Jones JV, Barnes K, Klein KO, Cutler GB Jr Follow-up of children and young adults after GnRH-agonist therapy or central precocious puberty. Journal of endocrinological investigation 2001 Oct;24(9):734-6.

Barradell LB, McTavish D Histrelin. A review of its pharmacological properties and therapeutic role in central precocious puberty. Drugs 1993 Apr;45(4):570-88.