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Relative bioavailability of 21-desacetyldeflazacort after oral administration of various deflazacort formulations and dosing conditions in healthy volunteer subjects
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Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
appeared to favor deflazacort over prednisone, well-powered clinical studies are needed to better assess these differences. http://dx.doi.org/10.1016/j.nmd.2016.06.339
P.311 Integrated prospective results from the deflazacort clinical program suggest less severe psychiatric adverse events with deflazacort versus prednisone in Duchenne muscular dystrophy J. Dubow, P. Sazani, T. Cunniff, S. Wanaski, J. Meyer Marathon Pharmaceuticals, Northbrook, USA Glucocorticoids (GCs) are first line therapy for the treatment of Duchenne muscular dystrophy (DMD). In the United States the most common regimens are prednisone 0.75 mg/kg/day (Pred) or deflazacort (DFZ) 0.9 mg/kg/day. Both Pred and DFZ have been demonstrated to improve muscle strength, prolong ambulation, decrease scoliosis, improve pulmonary function and possible delay cardiomyopathy in DMD patients. Weight gain and psychiatric adverse events (AEs) are the most common reasons for discontinuing GCs. DFZ demonstrated less weight gain than Pred in controlled clinical trials. We present psychiatric AEs from the US DFZ clinical program submitted to the FDA including prospective data from a 1 year double-blind, placebo controlled study with DFZ 0.9 mg/kg/day, DFZ 1.2 mg/kg/day, Pred 0.75 mg/kg/day and placebo, a 2 year study with DFZ 2.0 mg/kg/QOD vs placebo, an open-label PK study of DFZ 0.9 mg/kg/day its open label extension study. AEs were analyzed using the hostility/aggression standard MedDRA query. Overall, 21.6% of DFZ-treated patients (n = 176) experienced psychiatric AEs compared to 25.4% of Pred-treated patients (n = 63). AEs of abnormal behavior (14.3 vs 6.8%), aggression (7.9 vs 4.0%), psychomotor hyperactivity (4.8 vs 4.0%) were higher with Pred compared to DFZ. AEs of affect liability (2.3 vs 0%), laceration (0.6 vs 0%), mania (0.6 vs 0%) and substance-induced psychotic disorder (0.6 vs 0%) were higher with DFZ compared to Pred. Of the DFZ patients with psychiatric AEs, 24 subjects (13.6%) had mild, 13 subjects (7.4%) had moderate, and 1 subject (0.6%) had severe events. Of the 16 patients in the Pred 0.75 mg/kg/day group, 6 subjects (9.5%) had mild, 5 subjects (7.9%) had moderate, and 5 subjects (7.9%) had severe events. One subject discontinued treatment with DFZ compared to no subjects with Pred. Overall, psychiatric AEs were generally comparable between DFZ and Pred; however, the AEs appeared to be slightly less severe with DFZ compared to Pred. http://dx.doi.org/10.1016/j.nmd.2016.06.340
P.312 Effect of deflazacort and prednisone on muscle enzymes in the treatment of Duchenne muscular dystrophy J. Dubow, T. Cunniff, S. Wanaski, J. Meyer Marathon Pharmaceuticals, Northbrook, USA Duchenne muscular dystrophy (DMD) is an X-linked disease that affects approximately 1 in 5000 live male births. Corticosteroids (deflazacort and prednisone) have been shown to prolong independent ambulation, improve pulmonary function, delay the onset of cardiomyopathy and reduce the incidence of scoliosis. This randomized, double-blind, placebo-controlled, active comparator, Phase 3 study evaluated the efficacy of two deflazacort doses (0.9 and 1.2 mg/kg/day) compared to prednisone (0.75 mg/kg/day) and placebo for treatment of boys with DMD. The first segment compared deflazacort and prednisone to placebo over 12 weeks. The second segment compared the two doses of deflazacort to prednisone from 12 to 52 weeks of treatment. Creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were measured at baseline and 6, 24, and 52 weeks on treatment (in U/L). Here, we describe the effects of deflazacort and prednisone on these muscle enzymes over 1 year of treatment. A total of 196 participants from 9 centers were randomized to the 4 treatment groups. Baseline CK, LDH and AST were comparable between the groups. At Week 6, AST, CK and LDH
significantly decreased with 0.9 and 1.2 mg/kg/day of deflazacort and prednisone treatment compared to placebo (AST: −30, −51, −49, +14 respectively; CK: −3529, −2895, −3748, +840 respectively; LDH: −226, −207, −196, +92 respectively; p < 0.05). From Baseline to Week 52, deflazacort 0.9 mg/kg/day had greater but not statistically significant decreases in AST, CK, and LDH than deflazacort 1.2 mg/kg/day and prednisone (AST: −15.8, +13.1, −10 respectively; CK: −3638, −1015, −2737 respectively; LDH: −270, −162, −157 respectively). Deflazacort and prednisone improve biomarkers of muscle breakdown compared to placebo in patients with DMD. Continued improvement over 1 year was realized in the treatment groups with increased numeric improvements demonstrated with deflazacort 0.9 mg/kg/day compared to prednisone. http://dx.doi.org/10.1016/j.nmd.2016.06.341
P.313 Relative bioavailability of 21-desacetyldeflazacort after oral administration of various deflazacort formulations and dosing conditions in healthy volunteer subjects S. Wanaski 1, S. Brantley 2, L. Grasfeder 2, J. Dubow 1, B. Beers 1, E. Kernbauer 1, C. Wells 1, T. Cunniff 1 1 Marathon Pharmaceuticals, LLC, Northbrook, USA; 2 Nuventra, Inc., Durham, USA To support the clinical development program of deflazacort (DFZ) for the treatment of patients with Duchenne muscular dystrophy (DMD), we conducted two relative bioavailability studies to characterize the pharmacokinetics (PK) of 21-desacetyldeflazacort (21-desDFZ) after oral administration of DFZ across a range of dosing conditions in healthy volunteer subjects. DFZ is a heterocyclic glucocorticoid with anti-inflammatory and immunosuppressive properties; it is an ester pro-drug rapidly metabolized to the active moiety 21-desDFZ in plasma. The first study was a phase 1, single-center, open-label, randomized 5-period cross-over design in 45 subjects which assessed the relative bioavailability of the commercial tablet formulation (MP-104) compared to a research tablet formulation and a suspension formulation. Additionally, this study assessed the effects of food and the effects of crushing tablets on the PK of 21-desDFZ. The second study was a phase 1, single-center, single-dose, randomized, 2-period crossover design in 50 subjects which assessed the relative bioavailability of MP-104 compared to the Calcort® (DFZ tablet formulation approved in the UK). Healthy volunteers in both studies received 36 mg single oral doses of the various formulations and conditions with a 7-day washout between periods. DFZ and relevant metabolites were quantified in plasma samples using validated LC-MS/MS methods. Concentration data were analyzed using noncompartmental PK methods. Descriptive statistics were provided for all reportable PK parameters; Cmax and AUC were compared using mixed-model methods of the ln-transformed parameters using standard FDA bioequivalence criteria. MP-104 was bioequivalent to all formulations under all conditions tested save for subtle differences in Cmax. An increased Cmax was seen with MP-104 compared to the research tablet formulation and the Cmax was decreased when administered with a high-fat meal. MP-104 was bioequivalent to Calcort®. http://dx.doi.org/10.1016/j.nmd.2016.06.342
P.314 Pharmacokinetics of 21-desacetyldeflazacort and the safety of deflazacort after oral administration to children and adolescents with Duchenne muscular dystrophy S. Wanaski 1, P. Shieh 2, N. Kuntz 3, E. Ciafaloni 4, R. Butterfield 5, S. Brantley 6, L. Grasfeder 6, J. Dubow 1, B. Beers 1, E. Kernbauer 1, C. Wells 1, T. Cunniff 1, R. Griggs 4 1 Marathon Pharmaceuticals, LLC, Northbrook, USA; 2 UCLA Medical Center, Los Angeles, USA; 3 Northwestern University, Chicago, USA; 4 University of
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
appeared to favor deflazacort over prednisone, well-powered clinical studies are needed to better assess these differences. http://dx.doi.org/10.1016/j.nmd.2016.06.339
P.311 Integrated prospective results from the deflazacort clinical program suggest less severe psychiatric adverse events with deflazacort versus prednisone in Duchenne muscular dystrophy J. Dubow, P. Sazani, T. Cunniff, S. Wanaski, J. Meyer Marathon Pharmaceuticals, Northbrook, USA Glucocorticoids (GCs) are first line therapy for the treatment of Duchenne muscular dystrophy (DMD). In the United States the most common regimens are prednisone 0.75 mg/kg/day (Pred) or deflazacort (DFZ) 0.9 mg/kg/day. Both Pred and DFZ have been demonstrated to improve muscle strength, prolong ambulation, decrease scoliosis, improve pulmonary function and possible delay cardiomyopathy in DMD patients. Weight gain and psychiatric adverse events (AEs) are the most common reasons for discontinuing GCs. DFZ demonstrated less weight gain than Pred in controlled clinical trials. We present psychiatric AEs from the US DFZ clinical program submitted to the FDA including prospective data from a 1 year double-blind, placebo controlled study with DFZ 0.9 mg/kg/day, DFZ 1.2 mg/kg/day, Pred 0.75 mg/kg/day and placebo, a 2 year study with DFZ 2.0 mg/kg/QOD vs placebo, an open-label PK study of DFZ 0.9 mg/kg/day its open label extension study. AEs were analyzed using the hostility/aggression standard MedDRA query. Overall, 21.6% of DFZ-treated patients (n = 176) experienced psychiatric AEs compared to 25.4% of Pred-treated patients (n = 63). AEs of abnormal behavior (14.3 vs 6.8%), aggression (7.9 vs 4.0%), psychomotor hyperactivity (4.8 vs 4.0%) were higher with Pred compared to DFZ. AEs of affect liability (2.3 vs 0%), laceration (0.6 vs 0%), mania (0.6 vs 0%) and substance-induced psychotic disorder (0.6 vs 0%) were higher with DFZ compared to Pred. Of the DFZ patients with psychiatric AEs, 24 subjects (13.6%) had mild, 13 subjects (7.4%) had moderate, and 1 subject (0.6%) had severe events. Of the 16 patients in the Pred 0.75 mg/kg/day group, 6 subjects (9.5%) had mild, 5 subjects (7.9%) had moderate, and 5 subjects (7.9%) had severe events. One subject discontinued treatment with DFZ compared to no subjects with Pred. Overall, psychiatric AEs were generally comparable between DFZ and Pred; however, the AEs appeared to be slightly less severe with DFZ compared to Pred. http://dx.doi.org/10.1016/j.nmd.2016.06.340
P.312 Effect of deflazacort and prednisone on muscle enzymes in the treatment of Duchenne muscular dystrophy J. Dubow, T. Cunniff, S. Wanaski, J. Meyer Marathon Pharmaceuticals, Northbrook, USA Duchenne muscular dystrophy (DMD) is an X-linked disease that affects approximately 1 in 5000 live male births. Corticosteroids (deflazacort and prednisone) have been shown to prolong independent ambulation, improve pulmonary function, delay the onset of cardiomyopathy and reduce the incidence of scoliosis. This randomized, double-blind, placebo-controlled, active comparator, Phase 3 study evaluated the efficacy of two deflazacort doses (0.9 and 1.2 mg/kg/day) compared to prednisone (0.75 mg/kg/day) and placebo for treatment of boys with DMD. The first segment compared deflazacort and prednisone to placebo over 12 weeks. The second segment compared the two doses of deflazacort to prednisone from 12 to 52 weeks of treatment. Creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were measured at baseline and 6, 24, and 52 weeks on treatment (in U/L). Here, we describe the effects of deflazacort and prednisone on these muscle enzymes over 1 year of treatment. A total of 196 participants from 9 centers were randomized to the 4 treatment groups. Baseline CK, LDH and AST were comparable between the groups. At Week 6, AST, CK and LDH
significantly decreased with 0.9 and 1.2 mg/kg/day of deflazacort and prednisone treatment compared to placebo (AST: −30, −51, −49, +14 respectively; CK: −3529, −2895, −3748, +840 respectively; LDH: −226, −207, −196, +92 respectively; p < 0.05). From Baseline to Week 52, deflazacort 0.9 mg/kg/day had greater but not statistically significant decreases in AST, CK, and LDH than deflazacort 1.2 mg/kg/day and prednisone (AST: −15.8, +13.1, −10 respectively; CK: −3638, −1015, −2737 respectively; LDH: −270, −162, −157 respectively). Deflazacort and prednisone improve biomarkers of muscle breakdown compared to placebo in patients with DMD. Continued improvement over 1 year was realized in the treatment groups with increased numeric improvements demonstrated with deflazacort 0.9 mg/kg/day compared to prednisone. http://dx.doi.org/10.1016/j.nmd.2016.06.341
P.313 Relative bioavailability of 21-desacetyldeflazacort after oral administration of various deflazacort formulations and dosing conditions in healthy volunteer subjects S. Wanaski 1, S. Brantley 2, L. Grasfeder 2, J. Dubow 1, B. Beers 1, E. Kernbauer 1, C. Wells 1, T. Cunniff 1 1 Marathon Pharmaceuticals, LLC, Northbrook, USA; 2 Nuventra, Inc., Durham, USA To support the clinical development program of deflazacort (DFZ) for the treatment of patients with Duchenne muscular dystrophy (DMD), we conducted two relative bioavailability studies to characterize the pharmacokinetics (PK) of 21-desacetyldeflazacort (21-desDFZ) after oral administration of DFZ across a range of dosing conditions in healthy volunteer subjects. DFZ is a heterocyclic glucocorticoid with anti-inflammatory and immunosuppressive properties; it is an ester pro-drug rapidly metabolized to the active moiety 21-desDFZ in plasma. The first study was a phase 1, single-center, open-label, randomized 5-period cross-over design in 45 subjects which assessed the relative bioavailability of the commercial tablet formulation (MP-104) compared to a research tablet formulation and a suspension formulation. Additionally, this study assessed the effects of food and the effects of crushing tablets on the PK of 21-desDFZ. The second study was a phase 1, single-center, single-dose, randomized, 2-period crossover design in 50 subjects which assessed the relative bioavailability of MP-104 compared to the Calcort® (DFZ tablet formulation approved in the UK). Healthy volunteers in both studies received 36 mg single oral doses of the various formulations and conditions with a 7-day washout between periods. DFZ and relevant metabolites were quantified in plasma samples using validated LC-MS/MS methods. Concentration data were analyzed using noncompartmental PK methods. Descriptive statistics were provided for all reportable PK parameters; Cmax and AUC were compared using mixed-model methods of the ln-transformed parameters using standard FDA bioequivalence criteria. MP-104 was bioequivalent to all formulations under all conditions tested save for subtle differences in Cmax. An increased Cmax was seen with MP-104 compared to the research tablet formulation and the Cmax was decreased when administered with a high-fat meal. MP-104 was bioequivalent to Calcort®. http://dx.doi.org/10.1016/j.nmd.2016.06.342
P.314 Pharmacokinetics of 21-desacetyldeflazacort and the safety of deflazacort after oral administration to children and adolescents with Duchenne muscular dystrophy S. Wanaski 1, P. Shieh 2, N. Kuntz 3, E. Ciafaloni 4, R. Butterfield 5, S. Brantley 6, L. Grasfeder 6, J. Dubow 1, B. Beers 1, E. Kernbauer 1, C. Wells 1, T. Cunniff 1, R. Griggs 4 1 Marathon Pharmaceuticals, LLC, Northbrook, USA; 2 UCLA Medical Center, Los Angeles, USA; 3 Northwestern University, Chicago, USA; 4 University of