Resumos que serão apresentados no Congresso da Academia Americana de Neurologia em abril de 2016

Effect of Deflazacort and Prednisone Versus Placebo on Pulmonary Function in Boys with Duchenne Muscular Dystrophy Who Have Lost Ambulation

Jordan Dubow, Timothy Cunniff, Stephen P. Wanaski, James Meyer
Northbrook, IL, USA
Abstract
Objective: To prospectively assess the effects of deflazacort and prednisone on pulmonary function in boys with DMD who have lost ambulation
Background: Duchenne Muscular Dystrophy (DMD) is the most common type of muscular dystrophy. As the disease progresses, weakness of respiratory muscles results into restrictive pulmonary disease, pulmonary complications and increased morbidity and mortality.
Methods: This randomized, double-blind, placebo-controlled, active comparator, Phase 3 study 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 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 a post-hoc subgroup analysis of pulmonary function (FVC, MVV) in patients who were non-ambulatory at baseline.
Results: A total of 196 participants from 9 centers were randomized to the 4 treatment groups; 45 patients were non-ambulatory at baseline. At 12 weeks, both doses of deflazacort demonstrated improvement over placebo on FVC and MVV (p=0.065 for 0.9 mg/kg/day on FVC and p=0.02 for 1.2 mg/kg/day on MVV) while prednisone had larger numerical declines than placebo in both measures. Over 52 weeks of treatment deflazacort at 0.9 mg/kg/day had a 0.128 L improvement in FVC and an 11.1 L/min improvement in MVV compared to prednisone (NS) while deflazacort at 1.2 mg/kg/day demonstrated a 13.6 L/min improvement in MVV over prednisone (p=0.065). More patients on deflazacort showed improvement from baseline in pulmonary function compared to prednisone.
Conclusions: This is the first prospective, randomized, blinded study to demonstrate the benefits of deflazacort and prednisone on pulmonary function in non-ambulatory boys with DMD. Although some measures appeared to favor deflazacort
over prednisone, well-powered clinical studies are needed to better assess these differences.

Effect of Deflazacort and Prednisone on Muscle Enzymes in the Treatment of Duchenne Muscular Dystrophy

Jordan Dubow, Stephen P. Wanaski, Timothy Cunniff, James Meyer
Northbrook, IL, USA
Abstract
Objective: To describe the effects of deflazacort and prednisone on muscle enzymes over 1 year during the treatment of boys with Duchenne muscular dystrophy (DMD).
Background: DMD is an X-linked disease that affects approximately 1 in 5,000 live male births. Corticosteroids (deflazacort and prednisone) are shown to prolong independent ambulation, improve pulmonary function, delay the onset of cardiomyopathy and reduce the incidence of scoliosis.
Methods: 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).
Results: 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).
Conclusions: 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.

Potential Mechanisms for Prolonged Loss of Ambulation with Deflazacort in Duchenne Muscular Dystrophy - Tolerability Profile and Effects on Growth

Timothy Cunniff,1Stephen Wanaski,1Jordan Dubow,2James Meyer2
1Chicago, IL, USA, 2Northbrook, IL, USA
Abstract
Objective: To summarize prolonged loss of ambulation (LoA) data for Deflazacort in Duchenne Muscular Dystrophy (DMD) patients and propose a mechanism for this finding based on randomized, controlled clinical trial data
Background: DMD is an X-linked disease that affects approximately 1 in 5,000 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.
Design/Methods: We summarized published data demonstrating deflazacort delays time to LoA in DMD patients compared to non-steroid treated boys and compared to prednisone. Growth and weight gain data from a randomized, controlled, double-blind, placebo-controlled and active comparator, 52-week study for the treatment of DMD may help explain the difference in efficacy (deflazacort 0.9 mg/kg/day and 1.2 mg/kg/day vs. prednisone 0.75 mg/kg/day)
Results: 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.
Conclusions: 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

Results of North Star Ambulatory Assessments (NSAA) in the Phase 3 Ataluren Confirmatory Trial in Patients with Nonsense Mutation Duchenne Muscular Dystrophy (ACT DMD)

Katharine Bushby,1Jan Kirschner,2Xiaohui Luo,3Gary Elfring,3Hans Kroger,3Peter Riebling,3Tuyen Ong,3Robert Spiegel,3Stuart W. Peltz,3Francesco Muntoni,4for the Ataluren DMD Study Steering Committee
1Newcastle upon Tyne, United Kingdom, 2Freiburg, Germany, 3South Plainfield, NJ, USA, 4London, United Kingdom
Abstract
Objective: Examine the efficacy of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) as assessed by the NSAA.
Background: Results of the Phase 3, randomized, double-blind, placebo-controlled ACT DMD trial have been reported. The NSAA is a validated functional scale to measure disease progression specifically in ambulant boys with DMD.
Design/Methods: ACT DMD enrolled males aged 7-16 years with nmDMD and baseline six-minute walk distance (6MWD) ≥150m and ≤80%-predicted. Eligible patients were randomized 1:1 to receive ataluren 10, 10, 20 mg/kg or placebo orally three times daily for 48 weeks. A subgroup analysis of patients with baseline 6MWD of 300-400m was pre-specified. The NSAA consists of 17 activities ranging from standing from a chair to jumping. Each activity is scored as 0, 1, or 2; the sum of these 17 scores forms the total score, which is linearized to a 0 (worst)-100 (best) score.
Results: The intent-to-treat population of ACT DMD consisted of 228 patients (ataluren, n=114; placebo, n=114). Overall, patients who received ataluren gained a 1.5-point advantage in NSAA observed score compared with patients who received placebo (mean NSAA scores, ataluren: -7.0; placebo: -8.5; p=0.270). In the pre-specified subgroup of 99 patients with baseline 6MWD 300-400m, the advantage conferred by ataluren over placebo increased to 4.5 points (mean observed NSAA scores, ataluren: -5.7; placebo: -10.2; p=0.030).
Conclusions: Ataluren is the first drug to demonstrate a benefit to patients with nmDMD compared with placebo as assessed by NSAA scores; this benefit was especially pronounced in the subgroup of patients with baseline 6MWD 300-400m. NSAA results when combined with 6MWD results, provide complementary information on different aspects of motor function in nmDMD patients and further demonstrate the efficacy of ataluren in this patient population. More detailed analysis of NSAA domains will be presented.

Ataluren: An Overview of Clinical Trial Results in Nonsense Mutation Duchenne Muscular Dystrophy

Craig McDonald,1Katharine Bushby,2Mar Tulinius,3Richard Finkel,4Haluk Topaloglu,5John W. Day,6Kevin Flanigan,7Linda Lowes,7Michelle Eagle,8Xiaohui Luo,9Gary Elfring,9Hans Kroger,9Peter Riebling,9Tuyen Ong,9Robert Spiegel,9Stuart W. Peltz,9Jan Kirschner,10for the Ataluren DMD Study Steering Committee
1Sacramento, CA, USA, 2Newcastle Upon Tyne, United Kingdom, 3Gothenburg, Sweden, 4Orlando, FL, USA, 5Cayyolu, Ankara, Turkey, 6Stanford, CA, USA, 7Columbus, OH, USA, 8Tyne and Wear, United Kingdom, 9South Plainfield, NJ, USA,10Freiburg, Germany
Abstract
Objective: Provide an overview of ataluren clinical trial results in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD).
Background: Ataluren is the first drug to treat the underlying cause of nmDMD. It enables ribosomal readthrough of a premature stop codon to produce full-length functional dystrophin, without affecting normal stop codons.
Design/Methods: Phase 2 and 3 trials of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized.
Results: Clinical trials of ataluren in nmDMD include: a Phase 2a proof-of-concept study (N=38) whose primary endpoint was muscle dystrophin expression following 28 days of treatment; a Phase 2b randomized controlled trial (RCT) (N=174), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks; an ongoing US-based open-label extension (N=108) evaluating long-term safety; an ongoing non-US-based open-label extension (N=94) evaluating long-term safety and efficacy; and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in 6MWD over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, with larger treatment effects observed in patients at higher risk of ambulatory decline. This study was the basis for ataluren’s approval in the European Union. The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail.
Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression in patients with nmDMD.

ACT DMD: Effect of Ataluren on Timed Function Tests (TFTs) in Nonsense Mutation Duchenne Muscular Dystrophy

Nathalie Goemans,1Craig Campbell,2Craig M. McDonald,3Thomas Voit,4Xiaohui Luo,5Gary Elfring,5Hans Kroger,5Peter Riebling,5Tuyen Ong,5Robert Spiegel,5Stuart W. Peltz,5Katharine Bushby,6for the Ataluren DMD Study Steering Committee
1Belgium, 2London, ON, Canada, 3Sacramento, CA, USA, 4London, United Kingdom, 5South Plainfield, NJ, USA,6Newcastle Upon Tyne, United Kingdom
Abstract
Objective: Determine the effects of ataluren on motor function in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) using TFTs.
Background: Ataluren is the first drug to treat the underlying cause of nmDMD by promoting readthrough of a premature stop codon to produce full-length functional dystrophin. It is approved in Europe for the treatment of nmDMD in ambulatory patients aged ≥5 years.
Design/Methods: ACT DMD (Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy) is a Phase 3, randomized, double-blind, placebo-controlled study. Males 7-16 years of age with nmDMD and a screening six-minute walk distance (6MWD) ≥150m and <80%-predicted were randomized 1:1 to ataluren 40 mg/kg/day or placebo for 48 weeks. A pre-specified subgroup included patients whose baseline 6MWD was 300-400m. Secondary endpoints included TFTs: 10-meter walk/run; 4-stair climb; 4-stair descend. A meta-analysis of the overall ACT DMD population and the ‘ambulatory decline phase’ subgroup of the Phase 2b study (ie, those patients meeting ACT DMD entry criteria) was pre-specified in the ACT DMD statistical plan.
Results: In the overall ACT DMD population (N=228), changes in the three TFTs presented below, favored ataluren over placebo: 10-meter walk/run, -1.2s (p=0.117); 4-stair climb, -1.8s (p=0.058); 4-stair descend, -1.8s (p=0.012). In the pre-specified subgroup (n=99), these differences increased to -2.1s, -3.6s, and -4.3s, respectively, and were statistically significant for the 4-stair climb (p=0.003) and 4-stair descend (p<0.001), and approached significance for 10-meter walk/run (p=0.066). Results are supported by the meta-analysis (N=291), which demonstrated significant differences in all three TFTs: 10-meter walk/run, -1.4s (p=0.025); 4-stair climb, -1.6s (p=0.018); 4-stair descend, -2.0s (p=0.004).
Conclusions: TFT results showed a benefit for ataluren in ACT DMD, and a larger treatment effect in the pre-specified baseline 6MWD 300-400m subgroup as well as the pre-specified meta-analysis of ACT DMD and the Phase 2b study decline subgroup.

Safety and Tolerability of Ataluren in a Phase 3 Study of Patients with Nonsense Mutation Duchenne Muscular Dystrophy

Craig Campbell,1Perry Shieh,2Thomas Sejersen,3Xiaohui Luo,4Gary Elfring,4Hans Kroger,4Peter Riebling,4Tuyen Ong,4Robert Spiegel,4Stuart W. Peltz,4Brenda Wong,5for the Ataluren DMD Study Steering Committee
1London, ON, Canada, 2Los Angeles, CA, USA, 3Stockholm, Sweden, 4South Plainfield, NJ, USA, 5Cincinnati, OH, USA
Abstract
Objective: Examine the safety/tolerability of ataluren in the Ataluren Confirmatory Trial in Duchenne Muscular Dystrophy (ACT DMD), a randomized, double-blind, placebo-controlled Phase 3 study of patients with nonsense mutation DMD (nmDMD).
Background: A randomized, double-blind, placebo-controlled Phase 2b study of ataluren in patients with nmDMD reported that ataluren was generally well tolerated.
Design/Methods: In this Phase 3, ACT DMD, multicenter study, males aged 7-16 years with nmDMD, baseline six-minute walk distance (6MWD) ≥150m and ≤80% of predicted, and steroid use ≥6 months were randomized 1:1 to ataluren 10, 10, 20 mg/kg or placebo orally 3 times daily for 48 weeks.
Results: 230 patients were randomized (ataluren, n=115; placebo, n=115). Demographics were well balanced across treatment arms. Overall, 96.1% of patients completed the 48-week trial, and 97% of those chose to continue in the extension study. 103 (89.6%) patients on ataluren and 100 (87.0%) patients on placebo experienced treatment-emergent adverse events (TEAEs). The most common TEAEs in the ataluren and placebo arms, respectively, were vomiting (22.6% and 18.3%), nasopharyngitis (20.9% and 19.1%), fall (19.1% and 17.4%), headache (18.3% for both), and cough (16.5% and 11.3%). Four patients in each arm had at least 1 serious adverse event (SAEs). In the ataluren arm, these SAEs were pneumonia and bronchiolitis in 1 patient, pneumonia and post-traumatic pain in 1 patient, tendon disorder in 1 patient, and adenoidal and nasal turbinate hypertrophy in 1 patient; none were considered ataluren-related by the investigator. Only 1 patient in each arm discontinued treatment due to TEAEs: 1 patient discontinued ataluren due to Grade 2 constipation considered possibly related to treatment, and 1 patient discontinued placebo due to loss of ambulation.
Conclusions: Ataluren was generally well-tolerated by patients with nmDMD, and the spectrum and severity of adverse 

Ataluren Confirmatory Trial in DMD: Effect of Ataluren on Activities of Daily Living in Nonsense Mutation Duchenne Muscular Dystrophy

Ros Quinlivan,1Xiaohui Luo,2G. Elfring,3Hans Kroger,2Peter Riebling,3Tuyen Ong,3Robert Spiegel,3Stuart Peltz,3Jan Kirschner,4for the Ataluren DMD Study Steering Committee
1London, United Kingdom, 2South Plainsfield, NJ, USA, 3South Plainfield, NJ, USA, 4Freiburg, Germany
Abstract
Objective:
Evaluate the effect of ataluren on ambulatory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Change in activities of daily living (ADL) was investigated as a secondary endpoint.
Background:
Ataluren is the first drug to target the underlying cause of nmDMD, by promoting readthrough of a premature stop codon to produce full-length functional dystrophin.
Methods:
ACT DMD was a randomized (1:1), double-blind, placebo-controlled Phase 3 study that evaluated ataluren 40 mg/kg/day, administered over 3 doses, vs placebo over 48 weeks. Inclusion/exclusion criteria were designed to enrich for a population with the greatest opportunity to detect a clinical benefit over a 48-week study, while being inclusive enough to enroll an appropriate number of subjects over a feasible time period for an orphan disease. Participants were males 7-16 years of age with a screening six-minute walk distance (6MWD) ≥150m and ≤80%-predicted. Patients or parents/caregivers reported changes from baseline in physical functioning, general energy level, cognition/school function, emotional/social functioning, and sleep, rated on a Likert scale from 1 (much worse) to 5 (much better), using a DMD-specific survey developed for this study.
Results:
230 patients were randomized to ataluren (n=115) or placebo (n=115). Changes in ADL/disease symptoms trended in favor of ataluren versus placebo across all physical functioning categories, including lower- and upper-extremity muscle function. At Week 48, more ataluren- than placebo-treated patients reported improvement (22.2% vs 16.1%, respectively) or lack of progression (55.6% vs 50.9%) in walking and fewer ataluren-treated patients reported worsening in walking (22.2% vs 33.0%). These effects did not reach statistical significance. The same pattern of changes (with smaller group differences) was observed for stair-climbing and upper extremity activities of self-care.
Conclusions:
Results indicate a positive clinical effect of ataluren on ADL in boys with nmDMD, expanding the benefit beyond ambulation.
.

Eteplirsen, a Phosphorodiamidate Morpholino Oligomer (PMO) for Duchenne Muscular Dystrophy (DMD): Clinical Update and Longitudinal Comparison to External Controls on Six-Minute Walk Test (6MWT)

J. R. Mendell,1Nathalie Goemans,2Louise Rodino-Klapac,1Zarife Sahenk,1Linda Lowes,1Lindsay Alfano,1K. Berry,1E. Peterson,1S. Lewis,1Kim Shontz,1J. Shao,3P. Duda,3C. Donoghue,3F. Schnell,3J. Dworzak,3Bruce Wentworth,4,3E. M. Kaye,3E. Mercuri,5DMD Italian Network6
1Columbus, OH, USA, 2Leuven, Belgium, 3Cambridge, MA, USA, 45Rome, Italy, 6Italian Network, Italy
Abstract
Objective:
DMD, a rare, degenerative, X-linked genetic disease results in progressive muscle loss and premature death, occurring in ~1:3500-5000 males worldwide. DMD is primarily caused by frameshift-causing whole-exon mRNA deletions that prevent production of dystrophin protein. Eteplirsen, a PMO, is designed to induce production of internally-shortened dystrophin in patients amenable to exon 51-skipping.
Methods:
In a 24-week double-blind placebo-controlled study, twelve 12 boys aged 7-13 years were randomized to weekly intravenous infusions of 30/50 mg/kg eteplirsen or placebo, rolling-over to an ongoing open-label extension study (1:1 30/50 mg/kg). Clinical outcome measures included 6MWT and dystrophin expression. Routine safety assessments and cardiac monitoring were conducted.
External control (EC) data were obtained from the DMD Italian Network and the Leuven Neuromuscular Research Center. A cohort (N=13) comparable to the eteplirsen-treated boys was defined based on age at baseline, corticosteroid use, and genotype. 3 year longitudinal data were used for comparative analysis of 6MWT performance.
Results:
At Year 3, a statistically-significant treatment benefit of 151 meters on 6MWT was observed in eteplirsen-treated patients compared with EC (p<0.01). 2/12 (16.6%) eteplirsen patients lost ambulation by Year 1 with no additional losses observed, compared with 6/13 (46%) EC at Year 3.
Muscle biopsy analysis demonstrated exon 51-skipping in consented eteplirsen-treated patients (N=11) by RT-PCR and statistically significant increases (p<0.001) of dystrophin intensity and % dystrophin-positive fibers by immunohistochemistry over untreated DMD controls (N=9). Western blot confirmed dystrophin production in 9/11 patients.
No deaths, discontinuations due to AEs, or treatment-related SAEs were reported. LVEF on ECHO was stable over 3 years. AEs were generally mild and unrelated to study-drug.
Conclusions:
After 3 years of eteplirsen-treatment, DMD patients had a mean 6MWT that was 151m higher (p<0.01) than the comparable external cohort and de novo dystrophin was detected using 3 complementary methods in nearly all eteplirsen-treated patients.

Electrical Impedance Myography and Quantitative Ultrasound Detect Steroid Related Improvements in Duchenne Muscular Dystrophy

Seward Rutkove,1Craig Zaidman,2Jim Wu,1Amy Pasternak,1Lavanya Madabusi,1Heather Szelag,1Tim Harrington,1Adam Pacheck,1Sung Yim,1Kush Kapur,1Basil Darras1
1Boston, MA, USA, 2Saint Louis, MO, USA
Abstract
OBJECTIVE: To determine whether electrical impedance myography (EIM) and quantitative ultrasound (QUS) can detect the beneficial effect of corticosteroids in boys with Duchenne muscular dystrophy (DMD).
BACKGROUND: We recently completed a 2-year natural history study of EIM and QUS in boys with DMD; a small subset of boys was initiated corticosteroids during the study. Given the beneficial impact of corticosteroids in DMD, these boys’ data were analyzed separately to determine if EIM and QUS could detect a steroid effect.
DESIGN/METHODS: Of the boys with DMD who were enrolled, 4 who had at least one visit before starting steroids and at least 2 visits after were identified. For each, the EIM and QUS data for multiple muscles was analyzed. In addition, the Northstar Ambulatory Assessment (NSAA) was performed. Data for both EIM and QUS were collected on 6 different muscles unilaterally including, deltoid, biceps, forearm flexors, quadriceps, tibialis anterior, and medial gastrocnemius). Given the small number of subjects, formal statistical analysis was not performed. The data are presented as mean (range).
RESULTS: Both EIM and QUS showed improvement in the months following initiation of corticosteroids. Specifically, the 6-muscle average EIM reactance ratio increased by 20.5% (11%-31.5%) and the 6-muscle QUS grays scale level decreased by 12.2% (6.9%-15%). These improvements were consistent with those observed in NSAA, which improved by 17.5% (3.2%-40%) for three patients on whom it was performed.
CONCLUSIONS: These data suggest that EIM and QUS appear to be sensitive to corticosteroid effects in boys with DMD, mirroring the functional improvements that are typically observed in the months following corticosteroid initiation. More importantly, it suggests that both of these approaches to muscle assessment could play useful roles as pharmacodynamic biomarkers in future early phase clinical therapeutic trials.

Use of the Six-Minute Walk Distance (6MWD) Across Duchenne Muscular Dystrophy (DMD) Studies

Craig M. McDonald,1H. Lee Sweeney,2Xiaohui Luo,3Gary Elfring,3Hans Kroger,3Peter Riebling,3Tuyen Ong,3Robert Spiegel,3Stuart W. Peltz,3Eugenio Mercuri,4for the Ataluren DMD Study Steering Committee
1Sacramento, CA, USA, 2Gainesville, FL, USA, 3South Plainfield, NJ, USA, 4Roma, Italy
Abstract
Objective: Evaluate optimal ranges of 6MWD for inclusion in ambulatory DMD trials.
Background: 6MWD is a validated clinical outcome for ambulatory DMD studies and the primary endpoint in trials of ataluren, drisapersen, tadalafil, and eteplirsen. Decline in 6MWD is predictive of disease progression, time to loss of ambulation, and subsequent onset of disease milestones. Over time, there has been an effort to tighten 6MWT inclusion criteria, thereby excluding ambulatory patients with near-normal walking ability and those with severely impaired ambulation.
Design/Methods: Recent DMD studies were reviewed to determine how the 6MWT has evolved as a sensitive clinical endpoint.
Results: 6MWT inclusion criteria for DMD clinical trials have evolved since 2008 from the original criteria of 75m with no ceiling value for the first two trials which used the 6MWT as a clinical endpoint. These baseline 6MWT criteria have narrowed to a floor value as high as 300m for the eteplirsen open-label Phase 3 study (Sarepta 4658-301 initiated 2015) and ceiling values as low as 400m in the tadalafil Phase 3 trial (Eli Lilly H6D-MC-LVJJ initiated 2013). The Phase 3 ataluren study (ACT DMD; initiated 2013) included patients with a baseline ≥150m and <80% predicted, with a pre-specified subgroup of 300-400m baseline. In the ACT DMD study, the benefit of ataluren over placebo observed in the overall population (48-week difference=15m; p=0.213) was enhanced in the pre-specified 300-400m subgroup (47m; p=0.007). Sensitivity analyses confirmed an ataluren effect with 6MWD ≥250 to <400m (29.5m; p=0.035); ≥200 to <400m (26.6m; p=0.0501); and ≥300 to <450m (24.4m; p=0.0504).
Conclusions: When evaluating drugs expected to slow progression in DMD, narrower 6MWD ranges are being used as inclusion criteria. For ataluren, a pre-specified range of 300-400m demonstrated the greatest treatment effect. Meaningful effects were seen with 6MWD from 200-450m.

A Pilot Study to Evaluate Adherence to the 2010 Care Considerations for Duchenne Muscular Dystrophy at Selected Clinics Identified by the Muscular Dystrophy Surveillance Tracking and Research Network (MDSTARnet) Sites. Phase 2: Data from Medical Record Abstraction

Shree Pandya,1Kristin Caspers Conway,2Christina Trout,2Christina Westfield,3Deborah Fox3
1Rochester, NY, USA, 2Iowa City, IA, USA, 3Albany, NY, USA
Abstract
Objective:To evaluate through abstraction of medical records adherence to current DMD care recommendations by a group of clinics associated with MDSTARnet.
Background:Care recommendations for the management of patients with Duchenne Muscular Dystrophy (DMD) were developed by an international panel of experts convened and supported by the Centers for Disease Control and Prevention (CDC) and published in 2010. In 2013, the CDC funded a pilot study to adherence to these recommendations by selected clinics treating dystrophinopathy patients.
Methods:The pilot study included two phases. In the first phase, a survey was distributed to 9 clinic directors identified by the MD STARnet sites in Arizona, Colorado, Iowa and western New York. The second phase involves abstraction of medical records for dystrophinopathy cases birth through age 21 identified by the same
sites and followed from 1/1/ 2012 through 12/31/2014. Information being abstracted includes medical providers and frequency of visits to these providers; diagnostic assessments; corticosteroid use; and assessment and management of neuromuscular, orthopedic, rehabilitation, pulmonary, cardiac, gastrointestinal/nutritional, endocrine, and neurocognitive /psychosocial problems.
Results:Medical record abstraction is currently ongoing and expected to be completed by the end of 2015. Preliminary findings describing adherence to care recommendations will be presented at the meeting. To complement these results, the results from the clinic director survey will also be presented.
Conclusions:Based on the findings from phase 1 -Clinic Director Survey - a majority of the clinics seem to have adopted most of the care recommendations in their management practices. Results from phase 2 - Medical Record Abstraction- will provide additional information about current practices at the provider and case level. The availability of data from a clinic director survey and medical record abstraction data afford a unique perspective on assessing the use of best practice, as prescribed in the care recommendations, for dystrophinopathy patients.

A Pilot Study to Evaluate Adherence to the 2010 Care Considerations for Duchenne Muscular Dystrophy (DMD) at Selected Clinics Identified by the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) Sites. Phase 1:Clinic Director Survey

Shree Pandya,1Kristin Caspers-Conway,2Christina Trout,2Christina Westfield,3Deborah Fox3
1Rochester, NY, USA, 2Iowa City, IA, USA, 3Albany, NY, USA
Abstract
Objective:To evaluate adoption of the Care Considerations for DMD through a pilot survey of clinic directors identified by the MD STARnet sites.
Background: Care recommendations for the management of patients with Duchenne Muscular Dystrophy (DMD) were developed by an international panel of experts convened and supported by the Centers for Disease Control and Prevention (CDC) and published in 2010. In 2013, the CDC funded a pilot study to evaluate adherence to these recommendations by selected clinics treating dystrophinopathy patients.
Methods:The pilot study included two-phases. In the first phase, a survey was distributed to 9 clinic directors identifiedby the MD STARnet sites in Arizona,Colorado, Iowa and western New York. The survey was comprised of questions about interdisciplinary management and perceived barriers to care at the patient, system, and provider levels.Item response categories were included to reflect recommended care practices and alternative approaches to patient management. The second phase includes medical record abstraction of patient records.
Results: Completed surveyswere received from six clinics. Findings suggest all clinics offer multidisciplinary care, examine patients biannually, and offer all patients corticosteroidtreatment. Monitoring of pulmonary health was consistent with recommendations for non-ambulatory, asymptomatic patients. Monitoring of scoliosis and cardiac health consistent with recommendations were reported by 80% of clinic directors and over one-half reported neurocognitive/ neuropsychological evaluations.Prominent system barriers were funding for ancillary staff and care coordination. Barriers for families included distance to care, lack of resources and out-of-pocket expenses.
Conclusions:A majority of surveyed clinics reported adherence to most of the care recommendations in their management practices. The next phase of the project includes medical record abstraction. The availability of both clinic surveys and medical record abstraction afford a unique perspective on assessing the use
of the care recommendations when treating dystrophinopathy patients.

Muscle MRI in Becker Muscular Dystrophy and Correlation with DMD Mutations and Outcome Measures

Andrea Barp,1Luca Bello,2Paola Campadello,2Claudio Semplicini,2Paolo Ortolan,2Riccardo Zanato,2Roberto Stramare,2Elena Pegoraro2
12Padova, Italy
Abstract
OBJECTIVE: Evaluation with Magnetic Resonance (MRI) of fatty replacement and edematous involvement in skeletal muscle in patients with Becker Muscular Dystrophy (BMD) and correlations with DMD mutations and the main outcome measures, North Star Ambulatory Assessment (NSAA) and 6 minute walk test (6MWT);
BACKGROUND: Muscle MRI in patients with Becker Muscular Dystrophy has a distinct pattern of involvement, possibly related to specific DMD mutations and disease progression;
DESIGN/METHODS: 55 molecularly confirmed BMD patients (aged 7-69 yrs) were evaluated at baseline with MRI to ascertain the degree of fat infiltration at the lower limbs (T1W sequences) according to the Mercuri scale, and edema score (STIR sequence); all patients were evaluated with functional scales (NSAA and 6MWT) at baseline, and subsequently after one year;
RESULTS: Fat infiltration and edema mainly affect specific muscle groups, in particular gluteus maximus (32/55), vastus lateralis (36/55), biceps femoris (39/54) and gastrocnemius medialis (39/55). Severity of muscle involvement was significantly correlated with DMD mutation: patients with single deletion of exon 48 or with deletions including exon 51 showed a milder muscular involvement at MRI when compared with other deletions or mutation classes. NSAA and 6MWT are strongly correlates with MRI muscular involvement at baseline (p<0.001). Vastus lateralis fat infiltration scores correlate significantly at baseline with 6MWT (rho = -0.61, p<0.001) and NSAA (rho = -0.91, p<0.001) and predict functional changes after 1 year (6MWT rho = -0.42, p = 0.004, NSAA rho = -0.67, p<0.001). These findings were confirmed also in biceps femoris and gastrocnemius medialis.
CONCLUSIONS: Severity of muscular involvement at muscle MRI is strongly correlated to specific DMD mutations and with clinically meaningful outcome measures. Muscle MRI seems also predictive of disease progression.

Quantitative Ultrasound Detects Disease Progression in Duchenne Muscular Dystrophy

Craig Zaidman,1Kush Kapur,2Jim Wu,2Amy Pasternak,3Lavanya Madabusi,2Heather Szelag,2Tim Harrington,4Adam Pacheck,2Sung Yim,2Basil Darras,4Seward Rutkove4
1Saint Louis, MO, USA, 23Boston, MA, 4Boston, MA, USA
Abstract
Objective:
Quantitative muscle ultrasound could serve as a biomarker in clinical trials in Duchenne muscular dystrophy (DMD).
Background:
Grayscale pixel levels from the muscle image (GSL) are reliably measured, are increased in DMD, and relate to function. We measured changes in GSL over time in DMD compared to healthy controls.
Methods:
We measured GSL from serial ultrasound images obtained over a period of up to 24 months from unilateral proximal (deltoid, biceps brachii, quadriceps) and distal (anterior forearm, tibialis anterior, and medial gastrocnemius) muscles in 30 boys with DMD age 7 (2-13) years and 29 healthy males age 7 (2-15) years. We used a linear mixed-effects model to compare trajectories of GSL from individual muscles and of GSL averaged from groups of muscles. We grouped subjects by disease and age (younger/older than 8 years).
Results:
GSL were higher in DMD than controls at all ages from all muscles (p<0.001). Age impacted which dystrophic muscles showed the greatest increase over time in GSL. Over the 24-month period, GSL increased most in the upper limb and forearm muscles in older children with DMD (p<0.001), whereas in younger children, GSL increased most in the proximal and quadriceps muscles (p<0.02). GSL increased most in older boys with DMD. A 24-month clinical trial would need only 9 older boys with DMD to detect normalization of the GSL slope in upper limb muscles but would need 69 younger boys to detect the same effect in proximal muscles.
Conclusions:
Ultrasound image based outcomes in DMD perform differently depending on the age of the subjects and body region studied. GSL could be used as an outcome measure in clinical trials in older boys with DMD but is less sensitive to changes over time in younger boys. Future analysis will compare changes over time in GSL to functional measures.

The Relationship between Bone Mineral Density and Cardiovascular Function in Duchenne Muscular Dystrophy: A Retrospective Cohort Study

Tara A. Kervin,1,2Mathula Thangarajh2
12Washington, DC, USA
Abstract
Objective: The objective of this retrospective cohort study is to examine the relationship between bone mineral density (BMD) and cardiovascular health in patients with Duchenne muscular dystrophy (DMD).
Background: DMD is a genetic disorder, affecting boys that cause progressive muscle weakness. Cardiac dysfunction is a frequent cause of death in DMD. The long-term use of oral corticosteroids to delay the progression of muscle weakness in DMD is complicated by poor bone health. Epidemiological studies have suggested a biological link between the loss of BMD and cardiovascular disease, including coronary artery disease and cerebrovascular events. Whether an association between low BMD and cardiac dysfunction occurs in DMD boys has not yet been studied.
Methods: Data on DMD patients was collected retrospectively from patient records dated 2010 2014 at Children's National Medical Center in Washington, D.C. Whole body BMD was measured using DEXA scan and left ventricular ejection fraction (LVEF) was measured using echocardiogram. Linear regression was used to evaluate the relationship between BMD and LVEF.
Results: This analysis included 32 boys with DMD who had BMD baseline measurements at a mean age of 11±3 (SD) years with the worst LVEF measured a mean 23.7±21.8 (SD) months after baseline. The final adjusted linear regression of the relationship between baseline BMD Z-score and worst LVEF was not statistically significant (R2=0.1460, ß=0.41,p-value=0.6455).
Conclusions: In this cohort of boys with DMD, BMD was not associated with LVEF dysfunction up to 79 months later. Future research with more longitudinal follow-up is suggested.

Intravenous Trehalose Improves Dysphagia and Muscle Function in Oculopharyngeal Muscular Dystrophy (OPMD): Preliminary Results of 24 Weeks Open Label Phase 2 Trial

Zohar Argov,1,2Irit Gliko-Kabir,2Bernard Brais,3Yoseph Caraco,1Dalia Megiddo2
1Jerusalem, Israel, 2Tel Aviv, Israel, 3Montreal, QC, Canada
Abstract
Objective: To assess the safety and efficacy of weekly IV administration of Cabaletta (trehalose 9% solution) in OPMD after a 24 week open label phase 2 trial.
Background: Trehalose showed efficacy in reducing PABPN1 muscle aggregation and improving muscle function in a transgenic OPMD mouse model.
Methods:25 genetically-confirmed OPMD patients received weekly infusion of 300 cc Cabaletta. Swallowing, muscle power and functional tests, and swallowing quality of life report (SWAL-QOL) were assessed at baseline and after 24 weeks.
Results: No serious drug-related adverse effects were noted. Time to swallow 80cc cold water (an OPMD validated dysphagia test) improved by 35.3% (p<0.0001). This was correlated with improvement in patient reported symptom severity (p=0.05). Validated swallowing related patient questionnaire (SWAL-QOL) score improved progressively from 54.0 points to 58.8 after 12 weeks to 61.4 after 24 weeks (12.1% improvement p=0.0448). Muscle strength measured in Kg by a hand-held dynamometer showed an increased power in all 5 tested muscle actions, and reached significance for knee and foot extension. When a lower limb composite (combining hip flexion, knee extension, foot dorsiflexion) power was calculated the percent increase in strength was 13.4% (p=0.0059). Arm lift test improved by 17.6% (p=0.019), while the improvement in sit-to-stand (14.1%) and 4-stairs climb tests showed an improvement trend which did not reach significance.
Conclusions: Preliminary findings show that IV trehalose is safe and improves swallowing and muscle power that are major disabilities in OPMD. The objective measured improvement in drinking time is matched by the QOL reports. This is the first time in OPMD that a pharmacotherapy shows early improvement of multiple recorded end points. A phase 3 placebo controlled study is soon to be launched.

Reliability and Validity of the 6 Minute Walk Test in Individuals with Facioscapulohumeral Dystrophy

Katy Eichinger,1Chad Heatwole,1Susanne Heininger,1Nikia Stinson,2Kathryn Wagner,2Alrabi Tawil,1Jeffrey Statland3
1Rochester, NY, USA, 2Baltimore, MD, USA, 3Kansas City, KS, USA
Abstract
Objective: To determine the reliability, relationship measures of disease, and consistency across sites of the 6 minute walk test (6MWT) in patients with facioscapulohumeral muscular dystrophy (FSHD).
Background: With the potential for targeted treatment in FSHD in the near future, establishment of relevant outcome measures is crucial. The 6MWT is a measure of sub-maximal exercise capacity that incorporates strength and endurance into a single test, and has become a standard outcome in various neuromuscular diseases.
Methods: Genetically defined and clinically affected FSHD participants at the University of Rochester and Kennedy Krieger Institute performed measures of mobility and strength. The 6MWT, the Timed Up and Go (TUG) and the 30 foot go/Timed 10 meter test (10MT) were performed as measures of mobility at both sites using standard procedures. Strength was assessed using standard manual muscle testing.
Results: 91 participants (57% male) with a mean age of 48.6 years (range= 18-84) performed mobility measures. The mean distanced walked during the 6MWT was 412.3 meters (range 61.3-653.7; standard deviation 127.4). The interclass correlation coefficient for test-retest reliability of the 6MWT was 0.99 (n=36). The 6MWT was correlated with lower extremity strength (n= 36; r=0.789; p<0.0001), the FSHD Clinical Score (n=76; r=0.585; p<0.001), and the 10MT (n=89; r= 0.775; p<0.0001). There were significant differences between sites with regard to age, TUG, and 10MT, however no significant differences were noted between sites in distance walked during the 6MWT or the FSHD clinical score.
Conclusions: The 6MWT is a reliable measure of functional capacity for individuals with FSHD. No significant differences were noted in the mean distance walked during the 6MWT between sites. Assessing the sensitivity of the 6MWT will be important in determining its utility of as an outcome measure for future trials.

Study Design of a Phase 1/2a Trial with ISIS-DMPKRx for the Treatment of Myotonic Dystrophy Type 1

Charles Thornton,1Richard Moxley,1John Day,2Tetsuo Ashizawa,3Richard Barohn,4Doris Leung,5John Kissel,6Nicholas Johnson,7Katy Eichinger,1Jason Hardage,2Donovan Lott,8Melissa Currence,4Nikia Stinson,5Wendy King,9Heather Hayes,10Frank Bennett,11Kathie Bishop,11Laurence Mignon,11ISIS-DMPKRX Team
1Rochester, NY, USA, 2Stanford, CA, USA, 3Gainesville, FL, USA, 4Kansas City, KS, USA, 5Baltimore, MD, USA, 6Columbus, OH, USA, 7Salt Lake City, UT, USA, 8Gainseville, FL, USA, 9Worthington, OH, USA, 10Salt Lake,, UT, USA, 11Carlsbad, CA, USA
Abstract
Objective:
To assess the safety, tolerability, and pharmacokinetics of ISIS-DMPKRx, a Gen 2.5 antisense oligonucleotide (ASO) drug targeted to DMPK mRNA associated with myotonic dystrophy type 1 (DM1).
Background:
DM1 is a multi-systemic disorder caused by the expansion of CTG tandem repeats on the 3ʹ untranslated region of the DMPK gene. The resulting toxic mRNA containing a CUG expanded region is aberrantly retained in the nucleus of cells and accumulates in subnuclear foci, sequestering or interfering with the normal functioning of two families of RNA-binding splice regulators: muscleblind-like (MBNL) proteins and CUG binding protein 1. Preclinical studies have shown that ASOs can reduce toxic RNA through an RNase H1 mechanism, thereby re-establishing splicing patterns and reducing myotonia in mice. A Phase 1 single-ascending dose study of ISIS-DMPKRx has been completed in healthy adult subjects with data supportive of ISIS-DMPKRx advancing into DM1 patients.
Methods:
This is an ongoing multi-center Phase 1/2a, placebo-controlled study to assess the safety, tolerability and pharmacokinetics of multiple-ascending doses of ISIS-DMPKRx given subcutaneously to adult DM1 patients aged between 20 and 55 years. Multiple dosing cohorts are anticipated, with patients receiving 8 injections over 6 weeks in the low dose cohorts, or 14 injections over 12 weeks in the high dose cohort. In addition to safety and tolerability, a battery of outcome measures is being conducted to measure muscle function and molecular endpoints from repeat muscle biopsies.
Results and Conclusions:
To date, ISIS-DMPKRx has been generally well-tolerated and supports continued evaluation. No clinically significant or negative findings in laboratory evaluations, vital signs, ECGs or physical examinations have been noted. The pharmacokinetic profile is similar to other ASOs. Functional outcomes measures show good intra-rater reliability and consistency among the different centers, further supporting the use of these measures in clinical trials.

Wireless Sensors to Measure Walking in Patients with Facioscapulohumeral Muscular Dystrophy (FSHD)

Jessie Huisinga, Adam Bruetsch, Melissa Currence, Laura Herbelin, Omar Jawdat, Mamatha Pasnoor, Mazen Dimachkie, Richard Barohn, Jeffrey Statland
Kansas City, KS, USA
Abstract
Objective: The purpose of this study to was to examine walking characteristics in persons with FSHD using objective, quantitative metrics obtained with commercially available wireless sensors.
Background: Timed functional tasks, which measure the time to complete activities, are not necessarily sensitive to disease progression in FSHD. Quantifying functional motor tasks using objective metrics may reveal a continuum of motor disability in persons with FSHD that predicts future motor dysfunction.
Methods: This is part of an ongoing pilot study of 20 persons with FSHD. Subjects performed the timed up and go test, a standardized test of walking that requires the patient to rise from a seated position, walk a defined distance, turn 180 degrees, walk back to a chair and sit down, while outfitted with 6 wireless sensors containing a tri-axial accelerometer and gyroscope. Parameters of movement assessed during walking including temporal and spatial parameters, limb range of motion, and trunk motion. Subjects returned within 2 weeks to repeat testing to determine test-retest reliability. Temporal and spatial parameters of gait were compared to clinical severity score and the 6 minute walk test.
Results: We present preliminary data on 8 participants (3 men/5 women; 4 mild-moderate/4 moderate-severe), with reliability testing for 5 participants. Temporal gait parameters were reduced compared to normative values, and there was a trend towards decreasing performance with increasing disease severity. Reliability was good to excellent for most gait metrics (ICC 0.85-0.99). Range of motion in arms and legs showed asymmetry in FSHD compared. Primary gait metrics had moderate to strong correlations to 6 minute walk test distances (Pearson correlation: r=0.76-0.96).
Conclusions: Instrumented timed functional tasks using portable wireless sensors are simple and quick to perform, appear to be reliable, are abnormal in FSHD, and appear to be able to distinguish between FSHD participants with differing disease severities.