A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate The Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 In Ambulatory Boys With Duchenne Muscular Dystrophy

INTERVENTION: Product Code: PF‐06252616 Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: PF‐06252616 Current Sponsor code: PF‐06252616 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Solution for injection/infusion Route of administration of the placebo: Intravenous use Product Code: PF‐06252616 Pharmaceutical Form: Powder for solution for infusion INN or Proposed INN: PF‐06252616 Current Sponsor code: PF‐06252616 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 260‐ Pharmaceutical form of the placebo: Solution for injection/infusion Route of administration of the placebo: Intravenous use CONDITION: Duchenne's Muscular Dystrophy ; MedDRA version: 20.0 Level: PT Classification code 10013801 Term: Duchenne muscular dystrophy System Organ Class: 10010331 ‐ Congenital, familial and genetic disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] SECONDARY OUTCOME: Secondary end point(s): Strength and Function: ; ‐ Mean change from baseline as compared to placebo on function tests ; including, Forced Vital Capacity (FVC), Northstar Ambulatory Assessment ; (NSAA), range of ; motion (ROM), Performance of Upper Limb (PUL), 6MWD at Week 17, 33 ; and 49. Mean change from baseline as compared to placebo on the 4 SC ; at Week 17 and 33. ; ‐ Mean change from baseline as compared to placebo on muscle strength ; by myometry at Week 17, 33 and 49. ; ‐ In subject randomized to sequence 1, mean change from baseline as ; compared to historical control on functional tests including, 4SC, FVC, ; NSAA, PUL, 6MWD at Week 97. ; ‐ In a pre‐specified subset of subjects who may demonstrate a rapid ; disease decline and with relatively low variability, the mean change from ; baseline as compared to placebo on function testes including, 4SC, FVC, ; NSAA, PUL, 6MWD at Week 17, 33 and 49. The definition of this ; subgroup will be detailed in the Statistical Analysis Plan (SAP). ; ‐ In a pre‐specified subset of subjects who may demonstrate a rapid ; disease decline, the mean change from baseline as compared to placebo ; on muscle strength at Week 17, 33 and 49. ; Pharmacodynamic: ; ‐ Mean percent change as compared to placebo in muscle volume as ; measured on MRI by Week 17, 33 and 49. Within subject change from ; baseline in thigh muscle volume through week 97. ; ‐ Noncompartmental GDF‐8 parameters such as AUCt(GDF‐8), ; AUCt,ss(GDF‐8), CGDF‐8(0), Cmax,ss(GDF‐8), Tmax(GDF‐8), ; Ctrough,ss(GDF‐8), and Css,av (GDF‐8), may be determined. ; ; Pharmacokinetic: ; ‐ All subjects receiving active drug: Cmax, Tmax, and Ctrough for all visits with PF‐06252616 dosing. ; ‐ All subjects receiving active drug in Period 1 followed by placebo in Period 2 (Sequence 2): terminal t½ for Visit 19 (last dose in Period 1) using concentration data from samples collected during placebo treatment in Period 2. ; ‐ Subjects with additional PK sampling receiving active drug in Period 1: AUCt and Cav for Visits 3, 9, and 15 (first dose of each dose escalation level); AUCt, Cav, and CL for Visits 7, 13, and 19 (last dose of each dose escalation level); for subjects in Sequence 2, also Vss for Visit 19. ; ; Immunogenicity: ; Incidence of ADA and neutralizing antibody (NAb) development by Week 97. Timepoint(s) of evaluation of this end point: Week 17, 33, 49 through 97. 2. Subjects who are able to perform the 4 stair climb in =0.33 but =1.6 stairs/second at screening.* 4. Subjects and their legal guardians who are willing and able to comply with scheduled visits, t PRIMARY OUTCOME: Main Objective: ‐ To determine the safety and tolerability of multiple ascending repeat IV doses of PF‐06252616 in ambulatory boys with DMD.; ‐ To demonstrate the efficacy of treatment with IV doses of PF‐06252616 based on an observed mean change from baseline on function (4 Stair Climb) as compared to placebo following 49 weeks of treatment. Primary end point(s): Safety:; ‐ Incidence of dose limiting or intolerability treatment related AEs by Week 49.; ‐ Incidence, severity and causal relationship of treatment emergent AEs (TEAEs) and withdrawals due to TEAEs by Week 49.; ‐ Incidence and magnitude of abnormal laboratory findings (clinical laboratory tests [hematology, chemistry, GGT, PT, aPTT, creatine kinase, amylase, serum ferritin,; serum iron, Total Iron Binding Capacity (TIBC), % transferrin saturation, hormone [luteinizing hormone [LH], follicle stimulating hormone [FSH], thyroxine [T4],; thyroid stimulating hormone [TSH], fecal occult and urinalysis) by Week 49.; ‐ Abnormal and clinically relevant changes in liver MRI by Week 45 and physical examinations (including nose and throat mucosal exam and Tanner stage), weight, vital signs, ECG, cardiac MRI or echocardiogram measured LVEF (and other exploratory cardiac endpoints), DXA (bone mineral density), x‐ray (bone age) and C‐SSRS parameters by Week 49. Cardiac MRI with gadolinium is the preferred method for cardiac imaging. If the subject has a; contraindication to gadolinium, cardiac MRI without gadolinium will be acceptable. Echocardiogram may be substituted if it is not possible to perform cardiac MRI or if; use of echocardiogram is dictated by the local standard of care.; ; Efficacy: ; ‐ Mean change from baseline on the 4 stair climb (4SC) as compared to placebo by Week 49. Secondary Objective: ‐ To characterize the effects of PF‐06252616 on muscle strength and; other functional assessments compared to placebo; ‐ To evaluate the PD activity of PF‐06252616 based on the percent; change of muscle volume from baseline as compared to placebo; ‐ To evaluate the PD profile of PF‐06252616 based on GDF‐8 (myostatin); modulation in serum; ‐ To characterize the PK profile of PF‐06252616; ‐ To evaluate the immunogenicity of PF‐06252616; ‐ To characterize the long‐term effects following approximately 2‐years; of treatment with PF‐06252616 on functional assessments compared to; historical control.; ‐ To characterize the effects of PF‐06252616 on muscle strength and; functional assessments compared to placebo in subset of subjects who; may demonstrate a rapid disease decline and with relatively low; variability over a one‐year period. Timepoint(s) of evaluation of this end point: Week 49 INCLUSION CRITERIA: 1. Ambulatory boys age 6 to <16 years old (at the time of randomization), diagnosed with DMD. Diagnosis must be confirmed in subject’s medical history and by genetic testing obtained during routine clinical care for diagnostic purposes as reported from an appropriate regulated laboratory using a clinically validated genetic test (genetic testing is not provided by the sponsor). Results must confirm the presence of a mutation in the dystrophin gene(s) which is clinically consistent with the diagnosis of DMD. 3. Evidence of a personally signed and dated informed consent and assent (where appropriate) document indicating that the subject and a legally acceptable representative/parent(s)/legal guardian have been informed of all pertinent aspects of the study.