2 REAL-WORLD STUDIES.
2 YEARS+ PROLONGED AMBULATION vs PREDNISONE.^1,2

In 2 separate real-world studies, adolescents treated with deflazacort showed prolonged ambulation compared to those treated with prednisone.^1,2

Median age at loss of ambulation^1,2

A natural history observational prospective study evaluating age at loss of independent ambulation (LoA) and side-effect profiles associated with different corticosteroid regimens in DMD. The study included 340 DMD participants, aged 2-28 years, who were enrolled in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). LoA was defined as continuous wheelchair use, confirmed by inability to walk 10 minutes unaided. Effects of prednisone or prednisolone (PRED)/deflazacort (DFZ), administration frequency, and dose were analyzed by time-varying Cox regression. Average dose of daily PRED administered while ambulatory (n=94) was 75% ± 17% of recommended, which was lower than daily DFZ (83% ± 15%, n=80).¹

Bello 2015 Study Summary

Prednisone/prednisolone and deflazacort regimens in CINRG Duchenne Natural
History Study

A natural history observational prospective study evaluating age at LoA and side-effect profiles associated with different glucocorticoid corticosteroid regimens in DMD. The study included 340 DMD participants, aged 2-28 years, who were enrolled in the CINRG-DNHS. LoA was defined as continuous wheelchair use, confirmed by inability to walk 10 minutes unaided. Effects of prednisone or PRED/DFZ, administration frequency, and dose were analyzed by time-varying Cox regression. Side-effect frequencies were compared using the chi-square test. Average dose of daily PRED administered while ambulatory (n=94) was 75% ± 17% of recommended, which was lower than daily DFZ (83% ± 15%, n=80).
Participants treated ≥1 year while ambulatory (n=252/340) showed a 3-year median delay in LoA. Fourteen different regimens were observed. Nondaily treatment was common for PRED (37%) and rare for DFZ (3%). DFZ was associated with later LoA than PRED (hazard ratio 0.294 ± 0.053 vs 0.490 ± 0.08; 2-year difference in median LoA with daily administration). Average dose was lower for daily PRED (0.56 mg/kg/day, 75% of recommended) than daily DFZ (0.75 mg/kg/day, 83% of recommended). DFZ showed higher frequencies of growth delay, Cushingoid appearance, and cataracts, but not weight gain.
For comparisons of median LoA between glucocorticoid corticosteroid-treated and untreated participants, “glucocorticoid corticosteroid-treated” only included those patients who had been administered glucocorticoid corticosteroids for ≥1 year, starting 1≥ year before LoA. Side-effect frequency was calculated in 277 participants (86.2%) with any treatment duration while ambulatory. Weight gain (65%), Cushingoid appearance (55%), growth delay (37%), behavior changes (37%), low bone mass density and/or fracture (22%), cataracts (15%), and skin abnormalities (13%) were most frequently reported. Some frequencies might be underestimated because side effects were recorded for only the 3 most recent glucocorticoid corticosteroid regimens before study baseline. Weight gain frequency was similar for daily DFZ and daily PRED, but daily DFZ showed higher incidence of Cushingoid appearance (72% vs 50%), growth delay (60% vs 27%), and cataracts (29% vs 5%).

Study Limitations

Based upon the study design and enrollment, the following limitations should be considered:

Steroid use was not randomized as might be in a controlled clinical trial
Comparisons between DFZ and PRED are not included in the approved Prescribing Information for DFZ, as PRED is not an approved treatment for DMD
The analyses included a comparison of multiple glucocorticoid agents and regimens (such as daily vs intermittent dosing)

— Fourteen distinct regimens of PRED or DFZ were observed

— An in-depth analysis of specific doses or schedules was not feasible in a long-term, prospective, observational study

A “historical” improvement in care was noted, showing a parallel increase in the frequency of glucocorticoid prescriptions for DMD and implementation of other standards of care such as physical therapy, management of joint contractures, and bone fracture prevention
DFZ and PRED utilized in this study were from various manufacturers in and outside the United States
Potential differences were noted in socioeconomic status of patients and caregivers—DFZ was not commercially available in the United States at the time of the study

Financial Disclosures of Study Sponsors

This project was funded through the Italian Ministry of Education PhD grant awarded to L.B. for the 28th Cycle of the Doctorate School of Medical, Clinical, and Experimental Science at the University of Padova, Italy; and grants from the NIH (U54HD053177, R24HD050846, UL1RR031988, UL1RR024992, U54RR026139, G12RR003051, 1R01AR061875, RO1AR062380), the US Department of Education/NIDRR (H133B031118, H133B090001), the US Department of Defense (W81XWH-09-1-0592).

Bello L, Gordish-Dressman H, Morgenroth LP, et al; CINRG Investigators. Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study. Neurology. 2015;85(12):1048-1055.

A single-center, retrospective cohort analysis of 435 boys with DMD at Cincinnati Children’s Hospital Medical Center (CCHMC) from 2004 to March 2017. Outcomes assessed included: age at clinical events, including loss of ambulation (defined as functional mobility scale >4), and scoliosis; ambulatory, pulmonary, and cardiac function; and weight, lean body mass, and bone health. Average age at steroid initiation was 6.4 years for patients taking prednisone and 5.7 years for those taking deflazacort.²

Marden 2020 Study Summary

Real-world outcomes of long-term prednisone and deflazacort use in patients with Duchenne muscular dystrophy: experience at a single, large care center

A retrospective study assessing outcomes among patients with DMD receiving deflazacort or prednisone in real-world practice. 435 DMD patients, aged 4 years and older, who attended the CCHMC from 2004 to March 2017 were studied retrospectively using time-to-event and regression analyses. Loss of ambulation was identified as functional mobility scale (FMS) score >4, which is indicative of patients’ full-time use of a wheelchair for mobility in DMD. Age at onset of scoliosis was defined as the first recorded clinical diagnosis of scoliosis in the patient’s medical record. Age at first occurrence of FMS >4 and first diagnosis of scoliosis were studied in time-to-event analyses, with age as the time variable, and censoring at the end of data availability. Kaplan-Meier curves and log-rank tests were calculated to compare these outcomes between steroid initiation groups. Cox proportional hazards analyses were used to estimate the association between steroid type and age at event while adjusting for age at steroid initiation, the calendar year during which the patient had initiated steroid use, and whether the patient had initiated steroids prior to or after their first clinic visit at CCHMC. The adjusted analyses thus accounted for differences in the duration of steroid exposure, potential temporal trends that might impact outcomes across groups, and potential differences in care received prior to CCHMC. Sensitivity analyses were conducted distinguishing between patients who received daily versus other regimens of prednisone and, separately, distinguishing those who maintained prednisone versus those who switched to deflazacort after initiation.

Among n = 600 total boys in the CCHMC database, n = 559 had their date of steroid initiation recorded and n = 500 had a steroid type recorded at some point during their follow-up history at CCHMC. A further
n = 435 of these patients had at least one assessment of FMS or an assessment for scoliosis. The overall average follow-up included in the time-to-event analyses was 11.2 years in the FMS analyses and 11.9 years in the scoliosis analyses. The follow-up time was similar across prednisone- and deflazacort-initiated patients (<6 months difference in mean follow-up time). At first clinic visit at CCHMC with functional data recorded, deflazacort-initiated patients were on average younger, shorter and weighed less, compared with prednisone-initiated patients. The deflazacort-initiated group was also younger on average at steroid initiation compared with the prednisone-initiated group (5.7 vs 6.4 years, respectively). Across measures of ambulatory, pulmonary and cardiac function at the first clinic visit at CCHMC, deflazacort-treated patients tended to have better or similar function compared with prednisone-treated patients.

Study Limitations

Steroid use was not randomized as might be in a controlled clinical trial. Therefore:

Differences in outcomes between steroid groups could be confounded by factors that differ between these groups
It could also be hypothesized that differences in care received prior to CCHMC, including potential differences in steroid dosing or supportive care, could have impacted outcomes
A higher proportion of patients initiating prednisone did so prior to CCHMC compared with those initiating deflazacort it is possible that unobserved differences are present
Cost has been a factor for most families at CCHMC who opt for prednisone instead of out-of-pocket, imported deflazacort
The impact of different dosing regimens is a plausible contributor to the differences in outcomes observed in the present study between patients receiving prednisone and deflazacort
Ambulatory test results were not available from patients who were unable or unwilling to complete the assessments

This study was facilitated by cTAP with funding from PTC. cTAP is a pre-competitive coalition of academic clinicians, drug developers and patient foundations formed in 2015 to overcome challenges affecting clinical trials in DMD. cTAP has received sponsorship from Astellas Pharma (Mitobridge), BioMarin, Biophytis, Bristol-Myers Squibb, Catabasis, FibroGen, Inc., Italfarmaco SpA, Marathon Pharmaceuticals, Pfizer, Inc., PTC Therapeutics, Roche, Sarepta Therapeutics, Shire plc, Solid Biosciences, Summit Plc., Wave Life Sciences, Parent Project Muscular Dystrophy, Charley’s Fund and CureDuchenne, a founding patient advocacy partner and provider of initial seed funding to cTAP.

Marden JR, Freimark J, Yao Z, Signorovitch J, Tian C, Wong BL. Real-world outcomes of long-term prednisone and deflazacort use in patients with Duchenne muscular dystrophy: experience at a single, large care center. J Comp Eff Res. 2020;9(3):177-189.

Real-world outcomes. Real-life impact.²

2020
Long-Term
Real-World Study

Scoliosis developed later in patients taking deflazacort than those taking prednisone.²

7.9% of deflazacort-initiated patients and 17.9% of prednisone-initiated patients developed scoliosis by the end of the study.²

Marden 2020 Study Summary

Real-world outcomes of long-term prednisone and deflazacort use in patients with Duchenne muscular dystrophy: experience at a single, large care center

Study Limitations

Steroid use was not randomized as might be in a controlled clinical trial. Therefore:

Differences in outcomes between steroid groups could be confounded by factors that differ between these groups
It could also be hypothesized that differences in care received prior to CCHMC, including potential differences in steroid dosing or supportive care, could have impacted outcomes
A higher proportion of patients initiating prednisone did so prior to CCHMC compared with those initiating deflazacort it is possible that unobserved differences are present
Cost has been a factor for most families at CCHMC who opt for prednisone instead of out-of-pocket, imported deflazacort
The impact of different dosing regimens is a plausible contributor to the differences in outcomes observed in the present study between patients receiving prednisone and deflazacort
Ambulatory test results were not available from patients who were unable or unwilling to complete the assessments

Daily deflazacort delayed loss of ambulation longer vs daily, weekend, and intermittent prednisone¹

Age at Loss of Ambulation with
deflazacort vs prednisone¹

Bello 2015 Study Summary

Prednisone/prednisolone and deflazacort regimens in CINRG Duchenne Natural
History Study

Participants treated ≥1 year while ambulatory (n=252/340) showed a 3-year median delay in LoA. Fourteen different regimens were observed. Nondaily treatment was common for PRED (37%) and rare for DFZ (3%). DFZ was associated with later LoA than PRED (hazard ratio 0.294 ± 0.053 vs 0.490 ± 0.08, 2-year difference in median LoA with daily administration). Average dose was lower for daily PRED (0.56 mg/kg/day, 75% of recommended) than daily DFZ (0.75 mg/kg/day, 83% of recommended). DFZ showed higher frequencies of growth delay, Cushingoid appearance, and cataracts, but not weight gain.

For comparisons of median LoA between glucocorticoid corticosteroid-treated and untreated participants, “glucocorticoid corticosteroid-treated” only included those patients who had been administered glucocorticoid corticosteroids for ≥1 year, starting 1≥ year before LoA. Side-effect frequency was calculated in 277 participants (86.2%) with any treatment duration while ambulatory. Weight gain (65%), Cushingoid appearance (55%), growth delay (37%), behavior changes (37%), low bone mass density and/or fracture (22%), cataracts (15%), and skin abnormalities (13%) were most frequently reported. Some frequencies might be underestimated because side effects were recorded for only the 3 most recent glucocorticoid corticosteroid regimens before study baseline. Weight gain frequency was similar for daily DFZ and daily PRED, but daily DFZ showed higher incidence of Cushingoid appearance (72% vs 50%), growth delay (60% vs 27%), and cataracts (29% vs 5%).

Study Limitations

Based upon the study design and enrollment, the following limitations should be considered:

Steroid use was not randomized as might be in a controlled clinical trial
Comparisons between DFZ and PRED are not included in the approved Prescribing Information for DFZ, as PRED is not an approved treatment for DMD
The analyses included a comparison of multiple glucocorticoid agents and regimens (such as daily vs intermittent dosing)

— Fourteen distinct regimens of PRED or DFZ were observed

— An in-depth analysis of specific doses or schedules was not feasible in a long-term, prospective,
observational, natural history study

A “historical” improvement in care was noted, showing a parallel increase in the frequency of glucocorticoid prescriptions for DMD and implementation of other standards of care such as physical therapy, management of joint contractures, and bone fracture prevention
DFZ and PRED utilized in this study were from various manufacturers in and outside the United States
Potential differences were noted in socioeconomic status of patients and caregivers—DFZ was not commercially available in the United States at the time of the study

Financial Disclosures of Study Sponsors

Study Limitations

Comparisons between deflazacort and prednisone are not included in the Prescribing Information for deflazacort because prednisone is not an approved treatment for DMD.