Pharmacodynamics of C-Type Natriuretic Peptide (CNP) and its Amino-Terminal Propeptide (NTproCNP) during Recombinant Human Growth Hormone Treatment in Children: A Potential Biomarker of Efficacy

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 624-646-Growth: Clinical Trials & Observational Studies
Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-631
Parisa Salehi*1, Mitchell E. Geffner2, John Lima3, Eric A Espiner4, Timothy C Prickett5, Kaitlin Sikes6 and Robert Caldwell Olney6
1Children's Hospital of Los Angeles, Los Angeles, CA, 2Children's Hospital Los Angeles, Los Angeles, CA, 3University of Florida Health Science Center, Jacksonville, FL, 4University of Otago, Christchurch, Christchurch, New Zealand, 5Christchurch School of Medicine, Christchurch, New Zealand, 6Nemours Children's Clinic, Jacksonville, FL
Background: Treatment of short stature with rhGH is common practice, but is burdensome and costly. Response to treatment can be variable and there is no effective biomarker to predict efficacy. C-type natriuretic peptide (CNP), a small single-chain peptide produced by growth plate chondrocytes, plays an essential role in growth plate expansion and hence linear growth.  Circulating levels of the amino-terminal propeptide of CNP (NTproCNP) reflects production of CNP, and is more easily measured. Plasma NTproCNP is strongly correlated with height velocity in healthy children and in children treated with recombinant human growth hormone (rhGH), and is a potential biomarker of rhGH responsiveness.

Objective: To describe the pharmacodynamic response of CNP and NTproCNP to rhGH in previously untreated short children.

Methods: Twenty prepubertal subjects with either idiopathic short stature (ISS) or GH deficiency (GHD) were recruited for a prospective, longitudinal pharmacodynamic study.  Subjects were started on rhGH (Norditropin, Novo Nordisk, Princeton NJ) at 0.05 mg/kg/day and followed for one year. Subjects were seen 12 times during the study for determination of height and plasma levels of CNP and NTproCNP. Data are presented as medians with intra-quartile ranges (25th–75thpercentile).

Results: Preliminary analyses showed no differences in CNP and NTproCNP levels between the ISS and GHD groups (Mann-Whitney U tests), so the groups were combined. For both CNP and NTproCNP, plasma levels increased after two days of treatment and remained above baseline for six months (P<0.0005 for both, ANOVA with repeated measures and Holm’s post-hoc pairwise analysis). CNP levels peaked at 14 days (7-28 days) at a concentration of 2.0 pM (1.7-2.3 pM), increasing 77.8% (43.1-107%) over baseline. Levels of NTproCNP also peaked at 14 days (12-28 days) at 43.7 pM (39.7-50.0 pM), increasing 47.9% (31.4-65.4%) over baseline. There was a positive correlation between day 14 NTproCNP levels and six-month height velocity (R2=0.22, P<0.05, n=18).

Conclusion: In children with either ISS or GHD, levels of CNP and NTproCNP increase rapidly following initiation of rhGH treatment. Levels peak between 7 and 28 days, indicating that this is the optimal interval in which to measure these peptides.While there was a correlation between 14-day NTproCNP levels and height velocity at six months, a larger study is needed to determine the clinical value of measuring this biomarker in predicting responsiveness to rhGH treatment.

Disclosure: MEG: Coinvestigator, Research contract, Coinvestigator, Genentech, Inc., Advisory Group Member, EMD Serono, , Ipsen, Coinvestigator, Consulting fee, Coinvestigator, Eli Lilly & Company. Nothing to Disclose: PS, JL, EAE, TCP, KS, RCO

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Novo Nordisk Inc.; NIH NCRR CTSI GRANT 1UL1RR031986