Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys
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Journal of Personalized Medicine Article Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys Shefa Tawalbeh 1,2 , Alison Samsel 2, Heather Gordish-Dressman 3, Yetrib Hathout 2,*, 4, CINRG-DNHS Investigators y and Utkarsh J. Dang * 1 Department of Biomedical Engineering, Binghamton University, Binghamton, NY 13902, USA; [email protected] 2 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA; [email protected] 3 Division of Biostatistics, Children’s National Hospital, Washington, DC 20010, USA; [email protected] 4 Department of Health Outcomes and Administrative Sciences, School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY 13902, USA * Correspondence: [email protected] (Y.H.); [email protected] (U.J.D.) Names and affiliations of the CINRG-DNHS Investigators are provided in the Acknowledgments. y Received: 7 August 2020; Accepted: 10 October 2020; Published: 12 October 2020 Abstract: Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g., weight gain, growth stunting, loss of bone density, etc. Here, we use the CINRG Duchenne natural history study to gain insight into comparative safety of Pred versus Dfz treatment through GC-responsive pharmacodynamic (PD) biomarkers. Longitudinal trajectories of SOMAscan® protein data obtained on serum of DMD boys aged 4 to 10 (Pred: n = 7; Dfz: n = 8) were analyzed after accounting for age and time on treatment. Out of the pre-specified biomarkers, seventeen candidate proteins were differentially altered between the two drugs (p < 0.05). These include IGFBP-2 and AGER associated with diabetes complications, and MMP-3 associated with extracellular remodeling. As a follow-up, IGFBP-2, MMP-3, and IGF-I were quantified with an ELISA using a larger sample size of DMD biosamples (Dfz: n = 17, Pred: n = 12; up to 76 sera samples) over a longer treatment duration. MMP-3 and IGFBP-2 validated the SOMAscan® signal, however, IGF-I did not. This study identified GC-responsive biomarkers, some associated with safety, that highlight differential PD response between Dfz and Pred. Keywords: Duchenne muscular dystrophy; pharmacodynamic biomarkers; prednisone; deflazacort; glucocorticoids; corticosteroids; safety 1. Introduction Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder affecting the expression of dystrophin protein, an essential protein that maintains muscle fiber integrity and function [1]. The lack of dystrophin expression leads to muscle inflammation at an early stage of the disease, followed by progressive muscle degeneration and wasting [2]. While there are promising gene therapy and exon-skipping treatments, some of which have received conditional approval from the EMA [3] and FDA [4–7], these are mutation-specific and only restore a partial amount of truncated dystrophin protein [8]. Hence, DMD patients will continue to need combination therapy using the current standard J. Pers. Med. 2020, 10, 164; doi:10.3390/jpm10040164 www.mdpi.com/journal/jpm J. Pers. Med. 2020, 10, 164 2 of 15 J. Pers. Med. 2020, 10, x FOR PEER REVIEW 2 of 17 of motor abilities [9], delay loss of independent ambulation, improve pulmonary function, and delay of care: glucocorticoids (GCs). GC use helps reduce muscle inflammation and delay the loss of motor the onset of cardiomyopathy [10–12]. However, a GC regimen can have many side effects, such as abilities [9], delay loss of independent ambulation, improve pulmonary function, and delay the onset weight gain, growth stunting, loss of bone density, hirsutism, Cushingoid features, osteoporosis, of cardiomyopathy [10–12]. However, a GC regimen can have many side effects, such as weight gain, hypertension, diabetes, behavioral disturbances, and difficulty in sleeping [12–14]. Commonly used growth stunting, loss of bone density, hirsutism, Cushingoid features, osteoporosis, hypertension, steroidal drugs for DMD are prednisone (Pred) and deflazacort (Dfz). Prednisone has been used to diabetes, behavioral disturbances, and difficulty in sleeping [12–14]. Commonly used steroidal drugs treat DMD patients in the USA since the seventies [15]. In February 2017, the FDA approved for DMD are prednisone (Pred) and deflazacort (Dfz). Prednisone has been used to treat DMD patients deflazacort to treat DMD patients aged five years and older [16] although this same drug has been in the USA since the seventies [15]. In February 2017, the FDA approved deflazacort to treat DMD widely used in Europe to treat DMD patients for years. Figure 1 shows structures of prednisone and patients aged five years and older [16] although this same drug has been widely used in Europe to deflazacort along with their respective active metabolites: prednisolone and 21-desacetyl deflazacort, treat DMD patients for years. Figure1 shows structures of prednisone and deflazacort along with their respectively. Both drugs are given to patients in their prodrug forms, which are then metabolized to respective active metabolites: prednisolone and 21-desacetyl deflazacort, respectively. Both drugs are their active forms in the liver. The active metabolite prednisolone has a hydroxyl group at carbon 17, given to patients in their prodrug forms, which are then metabolized to their active forms in the liver. while the active 21-desacertyl deflazacort has an oxazoline structure at that same position (red arrow The active metabolite prednisolone has a hydroxyl group at carbon 17, while the active 21-desacertyl in Figure 1). deflazacort has an oxazoline structure at that same position (red arrow in Figure1). Figure 1. 2D structures of Prednisone and Deflazacort (top panels) and their active drugs: prednisolone and 21-desacetyl deflazacort. The similarities are clear. The red arrows point to the structural differences Figure 1. 2D structures of Prednisone and Deflazacort (top panels) and their active drugs: between the active drugs. prednisolone and 21-desacetyl deflazacort. The similarities are clear. The red arrows point to the structuralMany e differencesfforts have between been undertaken the active drugs to investigate. the use of biomarkers in DMD [17–19] and the efficacy and safety of Pred versus Dfz [10–12,20,21]. Both drugs are known to be efficacious in prolongingMany efforts ambulation have been [10 un,11dertaken,14,22]. Forto investigate our purposes the use here, of webiomarkers provide in a smallDMD review[17–19] onand safety the efficacycomparisons and safety from of the Pred literature. versus TheseDfz [10 studies–12,20,21 were]. Both compared drugs toare clinical known outcome to be efficacious measures likein prolongingchanges in ambulation height, weight, [10,11,14,22 Cushingoid]. For features, our purposes and erythema, here, we among provide others a small to evaluate review di ffonerences safety in comparisonssafety. A comparison from the ofliterature high dose. These Dfz and studies Pred were in 70 systemiccompared lupus to clinical patients outcome concluded measure that Preds like was changeassociateds in height with a, significantweight, Cushingoid increase in features, weight gain, and Cushingoiderythema, among severity others index, to and evaluate hirsutism differences compared into safety Dfz [.23 A]. comparison In a double-blind, of high randomizeddose Dfz and study Pred on in 196 70 systemic DMD subjects, lupus Predpatients was concluded found to be that associated Pred waswith associated more weight with a gain significant than Dfz increase [10]. Inin anotherweight gain, randomized Cushingoid study severity (18 DMD index, patients), and hirsutism patients comparedtreated with to Dfz Pred [23] showed. In a double higher-blind, weight randomized gain compared study toon Dfz-treated196 DMD subjects, patients Pred [13]. wa Ass found compared to beto associated other studies with [ 10more,14], weight a comparison gain than of Dfz prednisone [10]. In a/prednisolonenother randomized versus study Dfz treated (18 DMD patients patients using), patients340 participants treated with from Pred the Cooperative showed higher International weight gain Neuromuscular compared Researchto Dfz-treated Group patients Duchenne [13] Natural. As comparedHistory Studyto other (CINRG-DNHS) studies [10,14] showed, a comparison that participants of prednisone/prednis treated with Dfzolone had versus increased Dfz frequency treated patientsof Cushingoid using 340 appearance, participants cataracts, from the andCooperative growth delay. International Another Neuromuscular study [13] reported Research that theGroup time Duchenneof initiating, Natural dosing, History and durationStudy (CINRG of treatments-DNHS) wereshowed associated that participants with side etreatedffects; longerwith Dfz duration had increasedand increased frequency Dfz dosageof Cushingoid predicted appearance, growth stunting cataracts and, and Dfz growth was reported delay. toAnother be associated study [13] with reported that the time of initiating, dosing, and duration of treatments were associated with side effects; longer duration and increased Dfz dosage predicted growth stunting and Dfz was reported J. Pers. Med. 2020, 10, 164 3 of 15 lighter weight and shorter heights compared to Pred [13]. To summarize, these studies suggest that treatment