Extension Study of NS-065/NCNP-01 in Boys With Duchenne Muscular Dystrophy (DMD)

This is a Phase II, multicenter, open-label, extension study of NS-065/NCNP-01 administered intravenously once weekly for an additional 192 weeks to boys with DMD who complete Study NS-065/NCNP-01-201. This study will evaluate the safety, tolerability, and clinical efficacy of NS-065/NCNP-01 at dose levels of up to 80 mg/kg/week administered by weekly IV infusion over an additional treatment period of 192 weeks or until enrollment in a separate long-term follow up program of NS-065/NCNP-01, whichever is earlier.

Patients who complete the Phase II Dose-finding Study NS-065/NCNP-01-201 are eligible to enroll.

• NS-065/NCNP-01 (Drug): Received during weekly intravenous infusions

Primary outcomes

• Change From Baseline in Time to Stand (TTSTAND) Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A primary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Time to Stand (TTSTAND)
• Change From Baseline in Time to Stand (TTSTAND) Velocity Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A primary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Time to Stand (TTSTAND) Velocity
• Number of Participants With Treatment Related Adverse Events as Assessed by CTCAE v4.0. [Up to 192 weeks of treatment]: For adverse events (AEs) starting in study 201 (NCT02740972) which are not resolved at the time of enrollment into this study 202, any change in outcome or relatedness were reported in study 201. For AEs starting in study 201 which increase in severity or becomes serious after enrollment in this study 202, a new AE was reported in this study. Treatment-emergent AEs (TEAEs) were summarized by dose level. Coding was done by system organ class and preferred term (using the Medical Dictionary for Regulatory Activities (MedDRA)). Level of severity was assessed using the CTCAE grading system.

Secondary outcomes

• Change From Baseline in Time to Run/Walk 10 Meters Test (TTRW) Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Time to Run/Walk 10 meters test (TTRW)
• Change From Baseline in Time to Run/Walk 10 Meters Test (TTRW) Velocity Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Time to Run/Walk 10 meters test (TTRW) Velocity. The results were converted into velocity (meter/time).
• Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Time to Climb 4 stairs (TTCLIMB)
• Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Time to Climb 4 stairs (TTCLIMB) Velocity. The results were converted into velocity (meter/time).
• Change From Baseline in North Star Ambulatory Assessment (NSAA) Score Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): North Star Ambulatory Assessment (NSAA) score The NSAA is a functional scale devised for use in ambulant children with Duchenne muscular dystrophy (DMD). It consists of 17 activities graded 0 (unable to perform), 1 (performs with modifications), 2 (normal movement). It assesses abilities necessary to remain ambulant that have been found to progressively deteriorate in untreated DMD patients, as well as in other muscular dystrophies such as Becker Muscular Dystrophy. NSAA Total Score ranges from 0 to 34, with a score of 34 implying normal function.
• Change From Baseline in Six-Minute Walk Test (6MWT) Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Six-Minute Walk Test (6MWT)
• Change From Baseline in Quantitative Muscle Testing (QMT) for Handgrip Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Quantitative Muscle Testing (QMT) for Handgrip For QMT tests, the higher of each of the bilateral scores recorded for each muscle group at each visit were analyzed. QMT tests were analyzed by dominant/non-dominant side. QMT is a well-established method for measuring muscle weakness in neuromuscular disease. Patients will be placed on an examination table with a back-support system to eliminate the need for manual back stabilization. Following a single practice administration, each patient will complete a scored QMT evaluation (perform 2 tests; with the higher of the 2 values used for data analysis). QMT will be performed by recording force in pounds through a direct computer interface with a strain gauge.
• Change From Baseline in Quantitative Muscle Testing (QMT) for Elbow Flexors Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Quantitative Muscle Testing (QMT) for Elbow Flexors For QMT tests, the higher of each of the bilateral scores recorded for each muscle group at each visit were analyzed. QMT tests were analyzed by dominant/non-dominant side. QMT is a well-established method for measuring muscle weakness in neuromuscular disease. Patients will be placed on an examination table with a back-support system to eliminate the need for manual back stabilization. Following a single practice administration, each patient will complete a scored QMT evaluation (perform 2 tests; with the higher of the 2 values used for data analysis). QMT will be performed by recording force in pounds through a direct computer interface with a strain gauge.
• Change From Baseline in Quantitative Muscle Testing (QMT) for Elbow Extensors Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Quantitative Muscle Testing (QMT) for Elbow Extensors For QMT tests, the higher of each of the bilateral scores recorded for each muscle group at each visit were analyzed. QMT tests were analyzed by dominant/non-dominant side. QMT is a well-established method for measuring muscle weakness in neuromuscular disease. Patients will be placed on an examination table with a back-support system to eliminate the need for manual back stabilization. Following a single practice administration, each patient will complete a scored QMT evaluation (perform 2 tests; with the higher of the 2 values used for data analysis). QMT will be performed by recording force in pounds through a direct computer interface with a strain gauge.
• Change From Baseline in Quantitative Muscle Testing (QMT) for Knee Flexors Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Quantitative Muscle Testing (QMT) for Knee Flexors For QMT tests, the higher of each of the bilateral scores recorded for each muscle group at each visit were analyzed. QMT tests were analyzed by dominant/non-dominant side. QMT is a well-established method for measuring muscle weakness in neuromuscular disease. Patients will be placed on an examination table with a back-support system to eliminate the need for manual back stabilization. Following a single practice administration, each patient will complete a scored QMT evaluation (perform 2 tests; with the higher of the 2 values used for data analysis). QMT will be performed by recording force in pounds through a direct computer interface with a strain gauge.
• Change From Baseline in Quantitative Muscle Testing (QMT) for Knee Extensors Versus Matched Historical Controls [Baseline 201, Weeks 37, 49, 73, 109, 157, 205 in Study 202]: A secondary efficacy endpoint was compared to Baseline of Study 201 (NCT02740972): Quantitative Muscle Testing (QMT) for Knee Extensors For QMT tests, the higher of each of the bilateral scores recorded for each muscle group at each visit were analyzed. QMT tests were analyzed by dominant/non-dominant side. QMT is a well-established method for measuring muscle weakness in neuromuscular disease. Patients will be placed on an examination table with a back-support system to eliminate the need for manual back stabilization. Following a single practice administration, each patient will complete a scored QMT evaluation (perform 2 tests; with the higher of the 2 values used for data analysis). QMT will be performed by recording force in pounds through a direct computer interface with a strain gauge.

Sex: Male, ages: 4 Years to 10 Years

Inclusion Criteria:

1. Completed Study NS-065/NCNP-01-201 through Week 25.
2. Willing and able to comply with scheduled visits, investigational product administration plan, and study procedures.
3. Stable dose of glucocorticoid (GC), and is expected to remain on the stable dose for the duration of the study.

Exclusion Criteria:

1. Serious or severe adverse event in Study NS-065/NCNP-01-201 that precludes safe use of NS-065/NCNP-01.
2. Patient had a treatment which was made for the purpose of dystrophin or its related protein induction after completion of Study NS-065/NCNP-01-201.
3. Patient took any other investigational drugs after completion of Study NS-065/NCNP-01-201.
4. Patient was judged by the investigator and/or the Sponsor that it was not appropriate to participate in the extension study for other reasons.

Participant flow

Outcome results

• Change From Baseline in Time to Stand (TTSTAND) Versus Matched Historical Controls (Primary), Least squares mean, seconds: NS-065/NCNP-01 40mg/kg 0.17 +/- 1.60; NS-065/NCNP-01 80mg/kg -0.38 +/- 1.59; Total NS-065/NCNP-01 Group -0.11 +/- 1.12
• Change From Baseline in Time to Stand (TTSTAND) Velocity Versus Matched Historical Controls (Primary), Least squares mean, rise/s: NS-065/NCNP-01 40mg/kg 0.03 +/- 0.03; NS-065/NCNP-01 80mg/kg 0.04 +/- 0.03; Total NS-065/NCNP-01 Group 0.04 +/- 0.02
• Number of Participants With Treatment Related Adverse Events as Assessed by CTCAE v4.0. (Primary), Count of participants, Participants: NS-065/NCNP-01 40mg/kg 8; NS-065/NCNP-01 80mg/kg 8; Total NS-065/NCNP-01 Group 16
• Change From Baseline in Time to Run/Walk 10 Meters Test (TTRW) Versus Matched Historical Controls (Secondary), Least squares mean, seconds: NS-065/NCNP-01 40mg/kg -0.41 +/- 1.06; NS-065/NCNP-01 80mg/kg -1.35 +/- 1.05; Total NS-065/NCNP-01 Group -0.88 +/- 0.75
• Change From Baseline in Time to Run/Walk 10 Meters Test (TTRW) Velocity Versus Matched Historical Controls (Secondary), Least squares mean, m/s: NS-065/NCNP-01 40mg/kg 0.15 +/- 0.17; NS-065/NCNP-01 80mg/kg 0.53 +/- 0.17; Total NS-065/NCNP-01 Group 0.34 +/- 0.12
• Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Versus Matched Historical Controls (Secondary), Least squares mean, seconds: NS-065/NCNP-01 40mg/kg -0.37 +/- 1.54; NS-065/NCNP-01 80mg/kg 0.38 +/- 1.54; Total NS-065/NCNP-01 Group 0.01 +/- 1.09
• Change From Baseline in Time to Climb 4 Stairs (TTCLIMB) Velocity Versus Matched Historical Controls (Secondary), Least squares mean, m/s: NS-065/NCNP-01 40mg/kg 0.04 +/- 0.04; NS-065/NCNP-01 80mg/kg 0.01 +/- 0.04; Total NS-065/NCNP-01 Group 0.02 +/- 0.03
• Change From Baseline in North Star Ambulatory Assessment (NSAA) Score Versus Matched Historical Controls (Secondary), Least squares mean, score on a scale: NS-065/NCNP-01 40mg/kg 2.53 +/- 1.83; NS-065/NCNP-01 80mg/kg -0.02 +/- 1.83; Total NS-065/NCNP-01 Group 1.27 +/- 1.29
• Change From Baseline in Six-Minute Walk Test (6MWT) Versus Matched Historical Controls (Secondary), Least squares mean, m: NS-065/NCNP-01 40mg/kg 15.15 +/- 26.84; NS-065/NCNP-01 80mg/kg 13.03 +/- 28.15; Total NS-065/NCNP-01 Group 14.30 +/- 19.29
• Change From Baseline in Quantitative Muscle Testing (QMT) for Handgrip Versus Matched Historical Controls (Secondary), Least squares mean, lb: NS-065/NCNP-01 40mg/kg 0.56 +/- 1.28; NS-065/NCNP-01 80mg/kg 1.86 +/- 1.42; Total NS-065/NCNP-01 Group 1.09 +/- 0.94
• Change From Baseline in Quantitative Muscle Testing (QMT) for Elbow Flexors Versus Matched Historical Controls (Secondary), Least squares mean, lb: NS-065/NCNP-01 40mg/kg -0.11 +/- 0.72; NS-065/NCNP-01 80mg/kg 0.57 +/- 0.78; Total NS-065/NCNP-01 Group 0.21 +/- 0.53
• Change From Baseline in Quantitative Muscle Testing (QMT) for Elbow Extensors Versus Matched Historical Controls (Secondary), Least squares mean, lb: NS-065/NCNP-01 40mg/kg 0.55 +/- 0.73; NS-065/NCNP-01 80mg/kg 0.88 +/- 0.78; Total NS-065/NCNP-01 Group 0.70 +/- 0.53
• Change From Baseline in Quantitative Muscle Testing (QMT) for Knee Flexors Versus Matched Historical Controls (Secondary), Least squares mean, lb: NS-065/NCNP-01 40mg/kg -0.35 +/- 1.48; NS-065/NCNP-01 80mg/kg 2.04 +/- 1.56; Total NS-065/NCNP-01 Group 0.82 +/- 1.10
• Change From Baseline in Quantitative Muscle Testing (QMT) for Knee Extensors Versus Matched Historical Controls (Secondary), Least squares mean, lb: NS-065/NCNP-01 40mg/kg 1.25 +/- 1.93; NS-065/NCNP-01 80mg/kg 1.10 +/- 1.97; Total NS-065/NCNP-01 Group 1.15 +/- 1.38

Adverse events

Time frame: Up to 192 weeks

Serious adverse events by term

Other adverse events by term

40 more terms not shown.

• Study Protocol and Statistical Analysis Plan (PDF, 2020-07-21)

• Paula R. Clemens, MD, Study chair, University of Pittsburgh