Histrelin for Precocious Puberty Effective in 6-Year Study

Marlene Busko

April 09, 2015

In an extended phase 3 study of 36 children with central precocious puberty, up to six successive yearly implants that delivered histrelin (Supprelin LA, Endo Pharmaceuticals) for 12 months was safe and effective.

The study was published online March 24 in the Journal of Clinical Endocrinology & Metabolism.

Twenty-two children (71%) received three successive implants that delivered this gonadotropin-releasing hormone analog (GnRHa) to temporarily halt the progression of early puberty, and two children received six successive implants.

This study is "the last word on [the] original phase 3 trial" in the same 36 patients, which led to the approval of this drug in 2007, senior author Dr Erica A Eugster (Riley Hospital for Children at Indiana University Health, Indianapolis) told Medscape Medical News.

It demonstrates that a once-yearly 50-mg depot of histrelin implanted subcutaneously in a child's arm is a viable treatment option for children with central precocious puberty, with the advantage of not needing frequent intramuscular injections, she noted. The only other depot GnRHa approved for the treatment of central precocious puberty in the United States, leuprolide (Lupron, AbbVie), is given as intramuscular injections every month (at three different doses) or every 3 months (at two different doses).

The current study showed that while the children received the histrelin implants pubertal development stopped, which was confirmed by diminished follicle-stimulating–hormone [FSH] and luteinizing-hormone [LH] levels. Moreover, the abnormally rapid rate of maturation of bones slowed, and the major treatment goal — the child's predicted height — increased, Dr Eugster noted.

Within 6 months of stopping the histrelin-implant therapy, LH and FSH levels increased to pubertal levels, indicating the ability of the hypothalamic-pituitary-gonadal (HPG) axis to recover after long-term gonadotropin suppression.

The main side effects from histrelin implants were injection-site reactions and scars, and the implants sometimes became brittle and broke during removal.

Temporarily Halting Puberty in 6- to 8-Year-Old Girls

Central precocious puberty can occur as early as age 2, but is mostly found in 6- to 8-year-old girls, who enter puberty at least 2 years before the "lower end of normal," Dr Eugster explained. It is 10 to 28 times more common in girls than in boys. Some children may have a slowly progressive form that does not benefit from intervention, she noted

With precocious puberty, children may initially be tall for their age but then stop growing and do not reach their potential full adult height. Like other GnRHas, histrelin suppresses the release of FSH and LH from the pituitary gland. Children with central precocious puberty may require 3 or more years of treatment before they reach a "typical" age for puberty.

The researchers enrolled 13 girls and three boys with a mean age of 8.9 who had already been receiving GnRHa therapy and 20 girls with a mean age of 7.1 who were treatment–naive for the 1-year initial study. All 36 children had central precocious puberty, based on their pretreatment bone age compared with other children of the same age (determined by an X ray of the hand and wrist) and confirmed by LH and FSH levels following stimulation with a GnRHa.

After the initial 12-month trial in these 36 children, the majority continued on for subsequent treatment, with the following number of children receiving successive implants:

  • 31 received two.

  • 22 received three.

  • 13 received four.

  • 11 received five.

  • Two received six.

Hormonal suppression was maintained throughout the study in all patients. From baseline to 4 years, the mean ratio of bone age to chronological age decreased from 1.42 to 1.18. From baseline to 5 years, the mean predicted adult height in girls increased from 151.9 cm to 166.5 cm.

There were no adverse effects on growth or on recovery of the HPG axis after the hormonal suppression was stopped. The histrelin implant was generally well tolerated.

The most frequent treatment-emergent adverse effects, reported by 19 patients (52.8%), were mild to moderate site reactions such as discomfort or pain that resolved. The implant broke during 25 (22.1%) of 113 explantation procedures, but complete removal was achieved in all but two cases.

Most patients (92%) who chose not to receive a subsequent year of histrelin therapy were considered to be an appropriate age to enter puberty or they had completed the study.

Although the study implants were explanted after 1 year, other research has demonstrated a duration of action of at least 2 years, which would decrease costs and reduce the number of surgical procedures a child would receive, Dr Eugster noted.

The study was funded by Endo Pharmaceuticals. Dr Eugster has received grant and research support funding from Endo Pharmaceuticals and Abbott. Disclosures for the coauthors are listed in the article.

J Clin Endocrinol Metab. Published online March 24, 2015. Article

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