Merck Serono is optimistic that early data from a pharmacogenomics study with Saizen, a pediatric growth hormone therapy, will enable it to identify and validate response markers in order to develop a predictive dosing model for the drug.
At the European Society of Pediatric Endocrinology’s annual meeting in September, Merck Serono presented one-month results of the Phase IV PREDICT study, which aims to identify potential genetic markers and serum biomarkers that can predict which children will respond to the treatment for growth hormone deficiency, or Turner syndrome.
“Results will be used in the development of a novel pharmaco-prediction model to optimize growth hormone therapy,” the company said in a statement.
A Merck Serono spokesperson told Pharmacogenomics Reporter this week that to date the PREDICT study accuracely determined the predictive value of genetic markers on IGF-1 levels following one month of GH treatment.
The company has already initiated a follow-up trial to collect long-term outcome data and validate the genetic and serum markers, and the predictive value of its tests after treatment with Saizen for one year and then for up to five years.
“This may ultimately lead to a predictive model that may aid the choice of starting dose of GH treatment to maximize response, yet minimizing adverse events,” the spokesperson said.
Merck Serono’s Saizen was approved in the EU for pediatric GHD in 1989 and for Turner syndrome in 1991. Saizen was approved in the US for pediatric GHD in 1996, but is not approved for Turner syndrome.
Merck Serono estimates that between one in 4,000 and one in 10,000 children in the US have been diagnosed with GHD, a condition characterized by slow growth. More than 50,000 adults in the US are growth-hormone deficient, and there are 6,000 new cases of GHD annually nationwide. TS is a growth disorder that causes short stature in girls born with a missing, incomplete, or damaged X chromosome
“This may ultimately lead to a predictive model that may aid the choice of starting dose of GH treatment to maximize response, yet minimizing adverse events.”
The PREDICT study, initiated in 2002, was conducted at 42 sites in 15 countries. The study enrolled 318 prepubertal previously GH-treatment naïve children, 169 GHD patients and 149 TS patients, and then treated them with Saizen for four weeks.
Researchers looked at more than 1,500 genetic markers and 98 candidate genes associated with growth and metabolism pathways and analyzed these markers’ association with IGF-1. Based on study participants’ IGF-1 levels, genome-wide analysis was performed using Illumina’s GoldenGate Genotyping platform.
One-month results showed that levels of all biomarkers studied changed “significantly” between baseline and one-month in children with TS and GHD. Merck Serono would not provide more detailed results from the study ahead of formal publication in peer-reviewed journals.
The company is currently preparing three articles on the PREDICT study results, specifically discussing biomarkers, genotyping, and gene expression profiling, and will submit these to peer-reviewed journals in the coming months.
According to Merck Serono, these one-month results identified genetic markers that have been associated with GH pathways in previously published studies.
“It was extremely satisfactory to see that, indeed, some of the genetic markers identified had been previously shown to be associated with pathways modulated by GH, such as PIK3 in GHD children,” the spokesperson said. “Moreover the genes associated with change in IGF-I differ in GHD and TS children, also indicative of disease-specific gene associations in relation to GH treatment.”
However, Merck Serono did identify new genetic markers associated with GHD. The spokesperson did not say what these new markers were.
Currently, doctors dose GH treatments in the pediatric population by weight. This method yields variable response in patients, who may experience sup-optimal efficacy following short- and long-term treatment.
“Many physicians utilize auxological parameters (e.g. height or height velocity), biochemical measures (e.g. IGF-I levels), and other clinical observations to adjust and attempt to optimize GH dosing for individual patients during routine clinical evaluations,” the Merck Serono spokesperson said in an e-mail. “However, specific practice guidelines for this approach are not available ... [and] current data related to prediction of GH response are very limited.”
In the past, researchers have attempted to correlate growth with single baseline measures of auxological and demographic characteristics, or biomarkers such as levels of GH, IGF-1, insulin-like growth factor binding protein 3 (IGFBP-3) acid-labile subunit and C-terminal propeptide of type I procollagen (PICP) or amino-terminal propeptide of type III procollagen (PIIINP). However, these studies have yielded variable results, and existing predictive dosing formula have not been validated against final adult height, according to the spokesperson.
This correlation with adult height “is the primary long-term endpoint of childhood GH therapy,” the spokesperson noted, adding that “pharmacogenomics provides an innovative and potentially valuable approach toward increasing our knowledge of human variability in GH treatment response and has important implications for the treatment of childhood short stature and related healthcare delivery.”