Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children

Abstract

Corticosteroids are extensively used in pediatrics, yet the burden of side effects is significant. Availability of a simple, fast, and reliable biochemical read out of steroidal drug pharmacodynamics could enable a rapid and objective assessment of safety and efficacy of corticosteroids and aid development of corticosteroid replacement drugs. To identify potential corticosteroid responsive biomarkers we performed proteome profiling of serum samples from DMD and IBD patients with and without corticosteroid treatment using SOMAscan aptamer panel testing 1,129 proteins in <0.1 cc of sera. Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG). These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids. Known safety concerns were validated, including elevated non-fasting insulin (insulin resistance), and elevated angiotensinogen (salt retention). These were extended by new candidates for metabolism disturbances (leptin, afamin), stunting of growth (growth hormone binding protein), and connective tissue remodeling (MMP3). Significant suppression of multiple adrenal steroid hormones was also seen in treated children (reductions of 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol and testosterone). A panel of new pharmacodynamic biomarkers for corticosteroids in children was defined. Future studies will need to bridge specific biomarkers to mechanism of drug action, and specific clinical outcomes.

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

“…Adrenal suppression can be seen both acutely (hours after a single dose of pharmacological glucocorticoids), and chronically. Chronic treatment with glucocorticoids leads to chronic deficiencies in multiple steroidal hormones, including cortisol, testosterone, 17-hydroxyprogesterone, corticosterone, and 11-deoxycortisol [26]. The resulting hormonal imbalance puts patients at increased risk for a series of safety concerns.…”

Tracking disease progression non‐invasively in Duchenne and Becker muscular dystrophies

“…It is not clear to which extent the observed changes are caused by the disease itself or to the inability of the patients to use the affected muscles. There are only a few papers reporting the association of blood derived adipose markers such as leptin with DMD . The increase in leptin levels has been associated with fat mass and treatment with corticosteroids in DMD patients; an increase in leptin has however been reported in steroid naïve DMD patients together with other markers of metabolic syndrome such as hypertriglyceridemia, hyperinsulinemia and insulin resistance.…”

“…Published studies often used age as a proxy for disease severity, due to the unavailability of longitudinal samples that would enable modelling the intra‐individual variation and that represent a better simulation of evolving pathologic processes. There is only one recent report showing how a restricted number of proteins and steroid hormones can monitor safety and efficacy of glucocorticoids treatment in a longitudinal setup …”

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

“…An alternative approach that is increasingly used is molecular biomarkers (proteins, RNA) as a PD outcome measure. As an example, a set of serum proteins involved in inflammation and responsive to corticosteroids was defined in 3 pediatric disease states (Duchenne muscular dystrophy, pediatric inflammatory bowel disease, juvenile dermatomyositis) and 1 disease in adults (Antineutrophil antibody‐associated vasculitis) . These were then used to test the anti‐inflammatory effects of a new drug, vamorolone, in Duchenne muscular dystrophy .…”

“…As an example, a set of serum proteins involved in inflammation and responsive to corticosteroids was defined in 3 pediatric disease states (Duchenne muscular dystrophy, pediatric inflammatory bowel disease, juvenile dermatomyositis) and 1 disease in adults (Antineutrophil antibody-associated vasculitis). [33][34][35] These were then used to test the anti-inflammatory effects of a new drug, vamorolone, in Duchenne muscular dystrophy. 36 Initial dose-ranging pediatric trials in Duchenne muscular dystrophy studied a 24-fold dose range (0.25-6.0 mg/kg/day), in which the serum pharmacodynamics biomarkers helped to establish the likely efficacious doses with only a 2-week exposure study.…”