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Glucocorticoids deflazacort and prednisone show muscle strength effects versus placebo in boys with Duchenne muscular dystrophy ages 5–7
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212 5
S181
Rochester, Rochester, USA; University of Utah, Salt Lake City, USA; 6 Nuventra, Inc., Durham, USA
appeared to have some benefits compared to prednisone in certain motor functions.
Marathon is developing deflazacort (DFZ) for the treatment of patients with Duchenne muscular dystrophy (DMD). DFZ is a heterocyclic glucocorticoid with anti-inflammatory and immunosuppressive properties; it is an ester prodrug rapidly metabolized to the active moiety 21-desacetyldeflazacort (21desDFZ) in plasma. Despite extensive clinical experience, the pharmacokinetics (PK) of 21-desDFZ after oral administration of DFZ has not been characterized in DMD patients. We conducted an open label, single period study in 16 children (ages 4–11) and 8 adolescents (ages 12–16) with DMD which characterized the single-dose and steady-state PK of 21-desDFZ after oral administration of DFZ tablets. The secondary objective of the study was to assess the safety and tolerability of DFZ. The study duration was 8 days consisting of DFZ administration (0.9 mg/kg, QD) on day 1–8 with PK sampling on days 1 and 8. All patients enrolled into an open-label extension study. DFZ and relevant metabolites were quantified in patient plasma samples using validated methods. Concentration data were analyzed using noncompartmental pharmacokinetic methods and descriptive statistics were provided for all reportable PK parameters. On days 1 and 8, geometric mean 21-desDFZ exposure parameters (Cmax and AUC) were slightly higher (1.5– 2.0-fold) in adolescents compared to children. However, the geometric mean terminal elimination half-life values were similar between study populations (1.17 hours in children and 1.34 hours in adolescents on day 1). The dosenormalized exposure parameters and the dose-dependent parameters (CL/F and Vd/F) were consistent between study populations. Multiple oral doses of deflazacort (0.9 mg/kg/day) were well tolerated. In conclusion, the pharmacokinetics of 21-desDFZ after oral administration of DFZ were well characterized in this study. There was a trend toward increasing exposure with increasing age, possibly a function of total dose received.
http://dx.doi.org/10.1016/j.nmd.2016.06.344
http://dx.doi.org/10.1016/j.nmd.2016.06.343
P.315 A comparison of the effects of deflazacort and prednisone versus placebo on timed functional tests in boys with Duchenne muscular dystrophy J. Meyer, J. Dubow, T. Cunniff, S. Wanaski Marathon Pharmaceuticals, LLC, Northbrook, USA The measurement of timed functional tests (TFTs) is commonly used to evaluate children with Duchenne muscular dystrophy (DMD). As muscle weakness progresses, compensatory movements are used to perform the tasks, resulting in higher measured times. Corticosteroids have demonstrated clinical benefit in the treatment of DMD including performance in timed function tests. In a randomized, double-blind, placebo-controlled, active comparator, Phase 3 study, the efficacy of two doses of deflazacort (0.9 mg/kg/day and 1.2 mg/kg/ day) was compared to prednisone (0.75 mg/kg/day) and placebo for the 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. We conducted an analysis of timed functional tests (standing from lying position, climbing 4 stairs, and running or walking 30 feet) between deflazacort, prednisone and placebo groups. TFTs showed statistically significant differences between active treatments and placebo in times from supine to standing, climbing 4 stairs, and time to run/walk 30 feet at 12 weeks (p < 0.002). At 12 weeks there was a trend toward significant improvement with deflazacort 0.9 mg/kg/day vs. prednisone in time to climb 4 stairs (p = 0.066). From baseline to 52 weeks, both doses of deflazacort had numerically greater improvement in TFTs compared to prednisone. However, only time to climb 4 stairs reached significance with deflazacort 0.9 mg/kg/day (p < 0.05) and time to run/walk 30 feet trended toward significance with deflazacort 1.2 mg/kg/day (p = 0.07) vs. prednisone. Both deflazacort and prednisone demonstrated significant improvement versus placebo in timed functional testing. Benefits were sustained over 52 weeks with both deflazacort and prednisone, but deflazacort
P.316 Potential mechanisms for prolonged loss of ambulation with deflazacort in Duchenne muscular dystrophy – Tolerability profile and effects on growth J. Meyer, T. Cunniff, S. Wanaski, J. Dubow Marathon Pharmaceuticals, LLC, Northbrook, USA DMD is an X-linked disease that affects approximately 1 in 5000 live male births. Without treatment, boys lose ambulation in their pre-teens due to deterioration of muscle strength and eventually succumb to respiratory, orthopedic, and/or cardiac complications at a mean age ~19 years. Deflazacort has demonstrated profound clinical benefit on the course of the disease. Here we summarize published data demonstrating deflazacort delays time to loss of ambulation in DMD patients compared to non-steroid treated boys and compared to prednisone and use growth and weight gain data from a randomized, controlled, double-blind, placebo-controlled and active comparator, 52-week study for the treatment of DMD as a possible explanation for the difference in efficacy seen between deflazacort and prednisone (deflazacort 0.9 mg/kg/day and 1.2 mg/kg/day vs. prednisone 0.75 mg/kg/day) Previously published studies established that treatment with deflazacort prolongs ambulation compared to no-treatment. Additional published clinical investigations demonstrated that deflazacort prolongs ambulation compared to prednisone. One study found that deflazacort-treated boys maintained a chronic therapeutic dose compared to prednisone. The current randomized study demonstrated that forearm length (p < 0.005), length percentile (p < 0.05) and height percentile (p < 0.002) were significantly less with deflazacort than prednisone over 52 weeks of treatment. It also showed that deflazacort-treated boys had significantly less weight gain (p < 0.001) compared to prednisone. Data demonstrate deflazacort prolongs LoA in DMD patients. This may in part be due to the shorter stature and decreased weight gain with deflazacort compared to prednisone, which allows for a biomechanical advantage. Better tolerability of deflazacort compared to prednisone could also account for an improved efficacy profile in DMD patients. Additional studies are warranted to help elucidate the mechanism behind these effects. http://dx.doi.org/10.1016/j.nmd.2016.06.345
P.317 Glucocorticoids deflazacort and prednisone show muscle strength effects versus placebo in boys with Duchenne muscular dystrophy ages 5–7 P. Sazani, T. Cunniff, S. Wanaski, J. Dubow, J. Meyer Marathon Pharmaceuticals, LLC, Northbrook, USA Glucocorticoids (GCs) are a key component in the standard of care of Duchenne muscular dystrophy (DMD) patients, and have been shown to positively affect muscle strength. The objective of this post-hoc analysis was to assess the effects of deflazacort (DFZ) and prednisone (Pred) on muscle strength in ambulant DMD patients ages 5–7. This analysis is derived from a larger 52 week randomized, double-blind, placebo-controlled, active comparator, Phase 3 study that evaluated the efficacy of two DFZ doses (0.9 mg/kg/day and 1.2 mg/kg/day) compared to Pred (0.75 mg/kg/day) and placebo in DMD patients ages 5–15. Participants (N = 196, ages 5–15 were randomized to the 4 treatment groups; of those, 73 patients were ages of 5–7. The data show a positive response to GCs in muscle strength (using a modified 11-point medical research council scale, mMRC) in children ages 5–7, for both DFZ and Pred, while placebo patients worsened. However, only the prednisone group reached significance versus placebo. Over 52 weeks of treatment both DFZ and Pred-treated patients continued to improve in mMRC with no statistical differences between DFZ and Pred but a greater numerical
S182
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
improvement with DFZ. Similar benefits were also seen in the Supine-toStanding, Climbing 4 Stairs, and 30 Feet Run/Walk tests where both doses of DFZ and Pred demonstrated significant benefit versus placebo. Over 52 weeks of treatment, both DFZ groups and Pred continued to show numerical improvement in all timed functional tests but there was no statistical differences between DFZ and Pred. The prednisone group consistently showed less improvement compared to DFZ in these analyses. Overall, subset analysis from a Phase 3 study of GC administration in DMD patients demonstrates improvements in both muscle strength and timed functional tests over 52 weeks of treatment, in boys ages 5–7. These data support the notion that initiation of GC can have a beneficial effect on motor function at ages as young as 5. http://dx.doi.org/10.1016/j.nmd.2016.06.346
P.318 Effect of deflazacort and prednisone versus placebo on muscle strength in boys with Duchenne muscular dystrophy who have lost ambulation: Results from the deflazacort clinical trial program T. Cunniff, S. Wanaski, J. Dubow, J. Meyer Marathon Pharmaceuticals, LLC, Northbrook, USA Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy. Glucocorticoids are the mainstay of treatment in ambulatory patients, but often discontinued after boys have lost ambulation. This was a randomized, double-blind, placebo-controlled, active comparator, Phase 3 study which evaluated the efficacy of two deflazacort doses (0.9 mg/kg/day 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. We conducted a post-hoc subgroup analysis analyzing the effects of deflazacort and prednisone on muscle strength (using a modified 11-point medical research council scale) in patients who were nonambulatory at baseline. A total of 196 participants were randomized to the 4 treatment groups; 45 patients were non-ambulatory at baseline. At 12 weeks, both doses of deflazacort and prednisone had numerical improvement in muscle strength while placebo patients worsened. Deflazacort at 1.2 mg/kg/day reached significance over placebo at 12 weeks (LS mean change of 0.49; p < 0.05). Over 52 weeks of treatment, both deflazacort groups showed numerical improvement in muscle strength while the prednisone group worsened [LS mean change vs. prednisone of 0.27 for deflazacort 0.9 mg/kg/day (p = 0.387) and 0.45 for deflazacort 1.2 mg/kg/day (p = 0.088)]. This is the first prospective, randomized, blinded study to demonstrate the effects of deflazacort and prednisone on muscle strength in non-ambulatory boys with DMD. In this small, sub-set analysis, deflazacort demonstrated trends in improving muscle strength in boys who had lost ambulation. Although the recommended dose of deflazacort is 0.9 mg/kg/ day, increased doses may be required to preserve motor function in postambulatory boys; these data merit further investigation. http://dx.doi.org/10.1016/j.nmd.2016.06.347
managed with rigorous and standardized management of GC side effects. JE was diagnosed with DMD at age 5.8 years after he presented with gross motor difficulties and gait abnormality. Initial CPK level was 18106. Genetic testing showed a deletion of exons 45–57 of the dystrophin gene. Muscle immunoblot studies showed absent dystrophin. Daily deflazacort was started at age 9.7 years. JE lost independent ambulation at age 13 years. Deflazacort dose was increased to 52.5 mg at age 15 years. JE has continued on 52.5 mg of daily deflazacort (currently dosed at 0.7 mg/kg/day) with a total duration of daily deflazacort treatment of 22 years 9 months. At age 32.5 years, JE had an EK2-R score of 34 and a PUL(2.0) score of 15/42. He drives a hand controlled car and feeds himself with Wilmington Robotic Exoskeleton arms. JE has normal cardiac function without myocardial fibrosis on cardiac MRI. He is on prophylactic lisinopril since age 23 years and carvedilol since age 27 years. JE uses night time BiPAP since age 23 years. The side effects of osteoporosis were managed with bisphosphonates and teriparatide. JE had successful cataract surgery at age 16 years. Pubertal delay was managed with long term testosterone therapy. JE has a normal facies with no side effects pertaining to height and weight. This case highlights the feasibility of long term dosing of daily deflazacort to treat DMD with rigorous and standardized management of the predictable side effects of GC to maximize its potential benefit. http://dx.doi.org/10.1016/j.nmd.2016.06.348
P.320 Bone health in steroid treated Duchenne muscular dystrophy: A regional case series from the Southwest of the UK P. Dawson 1, K. Vijyakumar 2, A. Majumdar 2 1 University of Bristol, Bristol, UK; 2 University Hospital Bristol, Bristol, UK Duchenne Muscular Dystrophy (DMD), the commonest form of muscular dystrophy, progresses to loss of ambulation and premature death. Since treatment with corticosteroids has become the ‘standard of care’ there have been increasing reports of painful and debilitating long-bone and vertebral fractures, thought to be associated with steroid-induced osteoporosis. This project aims to describe the screening and management of bone health in a cohort of steroid treated DMD patients. The data of forty-four patients undergoing treatment for DMD over a 12 year period (2004–2016) in the South-West region of England were analysed and recorded. 67% of boys, with a mean age of 6 years, initiated a steroid regime before the study period. All had measurements of their bone biochemistry. 41% of boys have received a DEXA scan to date, of whom 8 were osteoporotic. 8 boys have sustained a fracture. All received a prescription of vitamin D and calcium supplementation. 3 boys have received bisphosphonate therapy, with 2 self-reporting a reduction in bone pain and all showing remission of osteoporosis on DEXA. This cohort is consistent with recent findings of a low BMD and high fracture rate in steroid-treated DMD patients. Proactive management of bone health is imperative to optimize quality of life in these patients. A central database would facilitate the production of evidence based guidelines for the optimal timing of DEXA screening and response to bisphosphonate treatment. http://dx.doi.org/10.1016/j.nmd.2016.06.349
P.319 Clinical outcome of 22 years of daily deflazacort treatment in a 32-year-old patient with Duchenne muscular dystrophy C. Tian 1, K. Shellenbarger 1, J. Jefferies 1, H. Sawnani 1, M. McMahon 1, N. Watts 2, B. Wong 1 1 Cincinnati Children’s Hospital, Cincinnati, USA; 2 Mercy Health, Cincinnati, USA Long term efficacy of daily prednisone or deflazacort treatment in patients with Duchenne muscular dystrophy (DMD) has been demonstrated in natural history and cohort studies. However, the predictable side effects of long term daily glucocorticoids (GC) have resulted in the use of alternative intermittent dosing regimes. We would like to report the positive clinical outcome of 22 years of daily deflazacort treatment in a 32-year-old patient with DMD
DMD CLINICAL ASPECTS II P.321 Development of a prognostic model for 1-year change in 6-minute walk distance (6MWD) in patients with Duchenne muscular dystrophy (DMD) N. Goemans 1, J. Signorovitch 2, E. Swallow 2, J. Song 2, S. Ward 3 1 University Hospitals Leuven, Leuven, Belgium; 2 Analysis Group, Inc, Boston, USA; 3 The TAP Collaboration, Cambridge, MA, USA Disease progression is inherently heterogeneous among individuals with DMD. The resulting variation in outcome measures can complicate the
S181
Rochester, Rochester, USA; University of Utah, Salt Lake City, USA; 6 Nuventra, Inc., Durham, USA
appeared to have some benefits compared to prednisone in certain motor functions.
Marathon is developing deflazacort (DFZ) for the treatment of patients with Duchenne muscular dystrophy (DMD). DFZ is a heterocyclic glucocorticoid with anti-inflammatory and immunosuppressive properties; it is an ester prodrug rapidly metabolized to the active moiety 21-desacetyldeflazacort (21desDFZ) in plasma. Despite extensive clinical experience, the pharmacokinetics (PK) of 21-desDFZ after oral administration of DFZ has not been characterized in DMD patients. We conducted an open label, single period study in 16 children (ages 4–11) and 8 adolescents (ages 12–16) with DMD which characterized the single-dose and steady-state PK of 21-desDFZ after oral administration of DFZ tablets. The secondary objective of the study was to assess the safety and tolerability of DFZ. The study duration was 8 days consisting of DFZ administration (0.9 mg/kg, QD) on day 1–8 with PK sampling on days 1 and 8. All patients enrolled into an open-label extension study. DFZ and relevant metabolites were quantified in patient plasma samples using validated methods. Concentration data were analyzed using noncompartmental pharmacokinetic methods and descriptive statistics were provided for all reportable PK parameters. On days 1 and 8, geometric mean 21-desDFZ exposure parameters (Cmax and AUC) were slightly higher (1.5– 2.0-fold) in adolescents compared to children. However, the geometric mean terminal elimination half-life values were similar between study populations (1.17 hours in children and 1.34 hours in adolescents on day 1). The dosenormalized exposure parameters and the dose-dependent parameters (CL/F and Vd/F) were consistent between study populations. Multiple oral doses of deflazacort (0.9 mg/kg/day) were well tolerated. In conclusion, the pharmacokinetics of 21-desDFZ after oral administration of DFZ were well characterized in this study. There was a trend toward increasing exposure with increasing age, possibly a function of total dose received.
http://dx.doi.org/10.1016/j.nmd.2016.06.344
http://dx.doi.org/10.1016/j.nmd.2016.06.343
P.315 A comparison of the effects of deflazacort and prednisone versus placebo on timed functional tests in boys with Duchenne muscular dystrophy J. Meyer, J. Dubow, T. Cunniff, S. Wanaski Marathon Pharmaceuticals, LLC, Northbrook, USA The measurement of timed functional tests (TFTs) is commonly used to evaluate children with Duchenne muscular dystrophy (DMD). As muscle weakness progresses, compensatory movements are used to perform the tasks, resulting in higher measured times. Corticosteroids have demonstrated clinical benefit in the treatment of DMD including performance in timed function tests. In a randomized, double-blind, placebo-controlled, active comparator, Phase 3 study, the efficacy of two doses of deflazacort (0.9 mg/kg/day and 1.2 mg/kg/ day) was compared to prednisone (0.75 mg/kg/day) and placebo for the 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. We conducted an analysis of timed functional tests (standing from lying position, climbing 4 stairs, and running or walking 30 feet) between deflazacort, prednisone and placebo groups. TFTs showed statistically significant differences between active treatments and placebo in times from supine to standing, climbing 4 stairs, and time to run/walk 30 feet at 12 weeks (p < 0.002). At 12 weeks there was a trend toward significant improvement with deflazacort 0.9 mg/kg/day vs. prednisone in time to climb 4 stairs (p = 0.066). From baseline to 52 weeks, both doses of deflazacort had numerically greater improvement in TFTs compared to prednisone. However, only time to climb 4 stairs reached significance with deflazacort 0.9 mg/kg/day (p < 0.05) and time to run/walk 30 feet trended toward significance with deflazacort 1.2 mg/kg/day (p = 0.07) vs. prednisone. Both deflazacort and prednisone demonstrated significant improvement versus placebo in timed functional testing. Benefits were sustained over 52 weeks with both deflazacort and prednisone, but deflazacort
P.316 Potential mechanisms for prolonged loss of ambulation with deflazacort in Duchenne muscular dystrophy – Tolerability profile and effects on growth J. Meyer, T. Cunniff, S. Wanaski, J. Dubow Marathon Pharmaceuticals, LLC, Northbrook, USA DMD is an X-linked disease that affects approximately 1 in 5000 live male births. Without treatment, boys lose ambulation in their pre-teens due to deterioration of muscle strength and eventually succumb to respiratory, orthopedic, and/or cardiac complications at a mean age ~19 years. Deflazacort has demonstrated profound clinical benefit on the course of the disease. Here we summarize published data demonstrating deflazacort delays time to loss of ambulation in DMD patients compared to non-steroid treated boys and compared to prednisone and use growth and weight gain data from a randomized, controlled, double-blind, placebo-controlled and active comparator, 52-week study for the treatment of DMD as a possible explanation for the difference in efficacy seen between deflazacort and prednisone (deflazacort 0.9 mg/kg/day and 1.2 mg/kg/day vs. prednisone 0.75 mg/kg/day) Previously published studies established that treatment with deflazacort prolongs ambulation compared to no-treatment. Additional published clinical investigations demonstrated that deflazacort prolongs ambulation compared to prednisone. One study found that deflazacort-treated boys maintained a chronic therapeutic dose compared to prednisone. The current randomized study demonstrated that forearm length (p < 0.005), length percentile (p < 0.05) and height percentile (p < 0.002) were significantly less with deflazacort than prednisone over 52 weeks of treatment. It also showed that deflazacort-treated boys had significantly less weight gain (p < 0.001) compared to prednisone. Data demonstrate deflazacort prolongs LoA in DMD patients. This may in part be due to the shorter stature and decreased weight gain with deflazacort compared to prednisone, which allows for a biomechanical advantage. Better tolerability of deflazacort compared to prednisone could also account for an improved efficacy profile in DMD patients. Additional studies are warranted to help elucidate the mechanism behind these effects. http://dx.doi.org/10.1016/j.nmd.2016.06.345
P.317 Glucocorticoids deflazacort and prednisone show muscle strength effects versus placebo in boys with Duchenne muscular dystrophy ages 5–7 P. Sazani, T. Cunniff, S. Wanaski, J. Dubow, J. Meyer Marathon Pharmaceuticals, LLC, Northbrook, USA Glucocorticoids (GCs) are a key component in the standard of care of Duchenne muscular dystrophy (DMD) patients, and have been shown to positively affect muscle strength. The objective of this post-hoc analysis was to assess the effects of deflazacort (DFZ) and prednisone (Pred) on muscle strength in ambulant DMD patients ages 5–7. This analysis is derived from a larger 52 week randomized, double-blind, placebo-controlled, active comparator, Phase 3 study that evaluated the efficacy of two DFZ doses (0.9 mg/kg/day and 1.2 mg/kg/day) compared to Pred (0.75 mg/kg/day) and placebo in DMD patients ages 5–15. Participants (N = 196, ages 5–15 were randomized to the 4 treatment groups; of those, 73 patients were ages of 5–7. The data show a positive response to GCs in muscle strength (using a modified 11-point medical research council scale, mMRC) in children ages 5–7, for both DFZ and Pred, while placebo patients worsened. However, only the prednisone group reached significance versus placebo. Over 52 weeks of treatment both DFZ and Pred-treated patients continued to improve in mMRC with no statistical differences between DFZ and Pred but a greater numerical
S182
Abstracts 2016 / Neuromuscular Disorders 26 (2016) S88–S212
improvement with DFZ. Similar benefits were also seen in the Supine-toStanding, Climbing 4 Stairs, and 30 Feet Run/Walk tests where both doses of DFZ and Pred demonstrated significant benefit versus placebo. Over 52 weeks of treatment, both DFZ groups and Pred continued to show numerical improvement in all timed functional tests but there was no statistical differences between DFZ and Pred. The prednisone group consistently showed less improvement compared to DFZ in these analyses. Overall, subset analysis from a Phase 3 study of GC administration in DMD patients demonstrates improvements in both muscle strength and timed functional tests over 52 weeks of treatment, in boys ages 5–7. These data support the notion that initiation of GC can have a beneficial effect on motor function at ages as young as 5. http://dx.doi.org/10.1016/j.nmd.2016.06.346
P.318 Effect of deflazacort and prednisone versus placebo on muscle strength in boys with Duchenne muscular dystrophy who have lost ambulation: Results from the deflazacort clinical trial program T. Cunniff, S. Wanaski, J. Dubow, J. Meyer Marathon Pharmaceuticals, LLC, Northbrook, USA Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy. Glucocorticoids are the mainstay of treatment in ambulatory patients, but often discontinued after boys have lost ambulation. This was a randomized, double-blind, placebo-controlled, active comparator, Phase 3 study which evaluated the efficacy of two deflazacort doses (0.9 mg/kg/day 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. We conducted a post-hoc subgroup analysis analyzing the effects of deflazacort and prednisone on muscle strength (using a modified 11-point medical research council scale) in patients who were nonambulatory at baseline. A total of 196 participants were randomized to the 4 treatment groups; 45 patients were non-ambulatory at baseline. At 12 weeks, both doses of deflazacort and prednisone had numerical improvement in muscle strength while placebo patients worsened. Deflazacort at 1.2 mg/kg/day reached significance over placebo at 12 weeks (LS mean change of 0.49; p < 0.05). Over 52 weeks of treatment, both deflazacort groups showed numerical improvement in muscle strength while the prednisone group worsened [LS mean change vs. prednisone of 0.27 for deflazacort 0.9 mg/kg/day (p = 0.387) and 0.45 for deflazacort 1.2 mg/kg/day (p = 0.088)]. This is the first prospective, randomized, blinded study to demonstrate the effects of deflazacort and prednisone on muscle strength in non-ambulatory boys with DMD. In this small, sub-set analysis, deflazacort demonstrated trends in improving muscle strength in boys who had lost ambulation. Although the recommended dose of deflazacort is 0.9 mg/kg/ day, increased doses may be required to preserve motor function in postambulatory boys; these data merit further investigation. http://dx.doi.org/10.1016/j.nmd.2016.06.347
managed with rigorous and standardized management of GC side effects. JE was diagnosed with DMD at age 5.8 years after he presented with gross motor difficulties and gait abnormality. Initial CPK level was 18106. Genetic testing showed a deletion of exons 45–57 of the dystrophin gene. Muscle immunoblot studies showed absent dystrophin. Daily deflazacort was started at age 9.7 years. JE lost independent ambulation at age 13 years. Deflazacort dose was increased to 52.5 mg at age 15 years. JE has continued on 52.5 mg of daily deflazacort (currently dosed at 0.7 mg/kg/day) with a total duration of daily deflazacort treatment of 22 years 9 months. At age 32.5 years, JE had an EK2-R score of 34 and a PUL(2.0) score of 15/42. He drives a hand controlled car and feeds himself with Wilmington Robotic Exoskeleton arms. JE has normal cardiac function without myocardial fibrosis on cardiac MRI. He is on prophylactic lisinopril since age 23 years and carvedilol since age 27 years. JE uses night time BiPAP since age 23 years. The side effects of osteoporosis were managed with bisphosphonates and teriparatide. JE had successful cataract surgery at age 16 years. Pubertal delay was managed with long term testosterone therapy. JE has a normal facies with no side effects pertaining to height and weight. This case highlights the feasibility of long term dosing of daily deflazacort to treat DMD with rigorous and standardized management of the predictable side effects of GC to maximize its potential benefit. http://dx.doi.org/10.1016/j.nmd.2016.06.348
P.320 Bone health in steroid treated Duchenne muscular dystrophy: A regional case series from the Southwest of the UK P. Dawson 1, K. Vijyakumar 2, A. Majumdar 2 1 University of Bristol, Bristol, UK; 2 University Hospital Bristol, Bristol, UK Duchenne Muscular Dystrophy (DMD), the commonest form of muscular dystrophy, progresses to loss of ambulation and premature death. Since treatment with corticosteroids has become the ‘standard of care’ there have been increasing reports of painful and debilitating long-bone and vertebral fractures, thought to be associated with steroid-induced osteoporosis. This project aims to describe the screening and management of bone health in a cohort of steroid treated DMD patients. The data of forty-four patients undergoing treatment for DMD over a 12 year period (2004–2016) in the South-West region of England were analysed and recorded. 67% of boys, with a mean age of 6 years, initiated a steroid regime before the study period. All had measurements of their bone biochemistry. 41% of boys have received a DEXA scan to date, of whom 8 were osteoporotic. 8 boys have sustained a fracture. All received a prescription of vitamin D and calcium supplementation. 3 boys have received bisphosphonate therapy, with 2 self-reporting a reduction in bone pain and all showing remission of osteoporosis on DEXA. This cohort is consistent with recent findings of a low BMD and high fracture rate in steroid-treated DMD patients. Proactive management of bone health is imperative to optimize quality of life in these patients. A central database would facilitate the production of evidence based guidelines for the optimal timing of DEXA screening and response to bisphosphonate treatment. http://dx.doi.org/10.1016/j.nmd.2016.06.349
P.319 Clinical outcome of 22 years of daily deflazacort treatment in a 32-year-old patient with Duchenne muscular dystrophy C. Tian 1, K. Shellenbarger 1, J. Jefferies 1, H. Sawnani 1, M. McMahon 1, N. Watts 2, B. Wong 1 1 Cincinnati Children’s Hospital, Cincinnati, USA; 2 Mercy Health, Cincinnati, USA Long term efficacy of daily prednisone or deflazacort treatment in patients with Duchenne muscular dystrophy (DMD) has been demonstrated in natural history and cohort studies. However, the predictable side effects of long term daily glucocorticoids (GC) have resulted in the use of alternative intermittent dosing regimes. We would like to report the positive clinical outcome of 22 years of daily deflazacort treatment in a 32-year-old patient with DMD
DMD CLINICAL ASPECTS II P.321 Development of a prognostic model for 1-year change in 6-minute walk distance (6MWD) in patients with Duchenne muscular dystrophy (DMD) N. Goemans 1, J. Signorovitch 2, E. Swallow 2, J. Song 2, S. Ward 3 1 University Hospitals Leuven, Leuven, Belgium; 2 Analysis Group, Inc, Boston, USA; 3 The TAP Collaboration, Cambridge, MA, USA Disease progression is inherently heterogeneous among individuals with DMD. The resulting variation in outcome measures can complicate the