A Trial of PF-06252616 in Ambulatory Participants With LGMD2I

Study Overview
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Brief Summary
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The investigational product PF 06252616, a humanized anti myostatin monoclonal antibody that neutralizes myostatin (GDF8) is in development for the treatment of Limb Girdle Muscular Dystrophy 2I (LGMD2I) to preserve and/or improve muscle function. This study will provide the clinical assessment of the safety, tolerability, Pharmacokinetics and Pharmacodynamics of PF 06252616 following repeat IV doses in ambulatory adults with LGMD2I.

Detailed Description
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This study is a Phase 1b/2, open-label multiple ascending dose escalation study to evaluate the safety, tolerability, efficacy, PK and PD of PF 06252616 in ambulatory adults with LGMD2I. The study design is intended to determine the optimal safe and pharmacologically active dose of PF 06252616 in LGMD2I while providing an opportunity for all subjects to receive active drug for a rare and disabling disorder. The study will be conducted in three periods: Lead-In, Treatment and Follow-up periods. The Lead-In and Follow-up periods will each be 16 weeks to allow an assessment of the change of various outcome measures of this period of time and comparison of change in function before, during and after treatment. The Treatment period will be 32 weeks. Three cohorts of participants will be enrolled and receive escalating doses of PF 06252616. The first cohort will have the option to crossover to the highest dose.

Official Title
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A Phase 1b/2, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Participants With LGMD2I

Conditions
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LGMD2I

Intervention / Treatment
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* Drug: PF 06252616


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients age ≥ 18 Diagnosis of LGMD2I as defined by clinical presentation consistent with LGMD2I and FKRP gene testing showing biallelic alterations known or likely to be pathogenic. 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). Ability to walk/run 10m Ability to rise from chair Adequate hepatic and renal function on screening laboratory assessments Iron content estimate on the screening liver MRI within the normal range as determined by R2* value (R2* ≤ 139 Hz at 3.0T). Participant must provide written informed consent for participating in study. Participant must possess the ability, per the Principal Investigator (PI), to understand and comply with protocol instruction for the entire duration of the study. Exclusion Criteria: Known cognitive impairment or behavioral issues that would impede the ability to provide informed consent or to follow study instructions. History of major surgical procedure within 6 weeks of signing the informed consent or planned surgery during the study. Any injury which may impact functional testing. Previous injuries must be fully healed prior to consent. Prior lower limb fractures must be fully healed and at least 3 months from injury dates. Previous treatment with another investigational product within 30 days or 5 half-lives, (whichever is longer) prior to consenting. Corticosteroid treatment within 3 months prior to consenting. Compromised cardiac function (left ventricular ejection fraction <50%). Unwilling or unable (e.g. metal implants, requires sedation) to undergo examination with closed MRI without sedation. History of allergic or anaphylactic reaction to a therapeutic or diagnostic protein. Female subjects who are pregnant or nursing. Subjects who, are biologically capable of having children who are unwilling or unable to use highly effective methods of contraception (as outlined in this protocol) during sexual activity for the duration of the study and through completion of final study visit. Predisposition to iron accumulation. (Serum iron >1.2 X ULN, serum ferritin >1.2 ULNN). Underlying disposition for bleeding disorder on screening laboratory assessment (PT/INR>1.25 X ULN, aPTT > 1.25 ULN, fecal occult blood is positive) Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurologic, or allergic disease. Unwillingness or inability to comply with the requirements of this protocol (in the opinion of the PI) including, but not limited to, the presence of any condition (physical, mental, or social) that is likely to affect the participant's ability to return for study visits or adhere to the visit schedule.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Dose, Cohort 1<br>4 subjects will be enrolled in cohort 1 and will receive an initial dose of 5mg/kg PF 06252616 IV every 4 weeks. Following 32 weeks of treatment and a safety review, if no stopping rules have been met, subjects will be receive an additional 32 weeks of treatment with 40 mg/kg PF 06252616 IV every 4 weeks. | Drug: PF 06252616<br> <br> |
| Active Comparator: Middle dose, Cohort 2<br>8 subjects will be enrolled in cohort 2 and receive 20 mg/kg of PF 06252616 IV every 4 weeks for 32 weeks. | Drug: PF 06252616<br> <br> |
| Active Comparator: High dose, Cohort 3<br>8 subjects will be enrolled in cohort 3 and receive 40 mg/kg of PF06252616 IV every 4 weeks for 32 weeks. | Drug: PF 06252616<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events | Adverse events include subject-reported symptoms as well as clinically-significant changes in laboratory testing, vital signs, and suicide screening (based on the Columbia Suicide Severity Rating Scale). | Baseline through 64 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Serum Concentration at Steady State (Cmax, ss) of GDF-8 | The concentration of myostatin (GDF-8) was measured in serum 2 hours after dose administration at two visits (Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3)where drug concentration had reached steady state. The highest concentration from these two time points was averaged for each cohort. | Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3 | 
| Minimum Observed Serum Trough Concentration at Steady State (Ctrough,ss) of GDF-8 | The concentration of myostatin (GDF-8) was measured in serum prior to dose administration at two time points (Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3) where drug concentration had reached steady state. The lowest concentration from these two time points was averaged for each cohort. | Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3 | 
| Maximum Observed Serum Concentration (Cmax) of PF-06252616 | The peak concentration of study drug (PF-06252616) was measured in serum following dose administration at two time points (Day 113 and Day 169) where drug concentration had reached steady state. The higher concentration from these two time points was averaged for each cohort. | Day 113 and Day 169 | 
| Minimum Observed Serum Trough Concentration (Ctrough) of PF-06252616 | The peak concentration of study drug (PF-06252616) was measured in serum prior to dose administration at two time points (Day 113 and Day 169) where drug concentration had reached steady state. The lower concentration from these two time points was averaged for each cohort. | Day 113 and Day 169 | 
| Immunogenicity: Incidence of Anti-drug Antibody | Blood samples were tested for the presence of anti-drug antibodies prior to the initiation of study drug, at dose escalation (Cohort 1 only), and at 3 separate time points after the last dose was given. | Baseline through 96 weeks | 
| Mean Change From Baseline in 10 Meter Walk/Run Time in Seconds | Subjects are asked to run or walk as quickly as possible for 10 meters from a standing position. The total time to traverse 10 meters is recorded in seconds. | Baseline through 32 weeks | 
| Mean Change From Baseline of Forced Vital Capacity in Liters | The total forced vital capacity was measured using a bedside spirometer. The best of 3 trials was recorded. | Baseline through 32 weeks | 
| Mean Change From Baseline in 2MWD in Meters | Average change in distance (in meters) walked in 2 minutes. | Baseline through 32 weeks | 
| Mean Change From Baseline in TUG in Seconds | The timed-up-and-go test (TUG) is the total time it takes the subject to rise from a seated position, walk to a marker 3 meters away, return to the chair, and sit. | Baseline through 32 weeks | 
| Mean Change From Baseline in Muscle Strength as Measured by Modified MRC Scale | Twenty-two muscle groups were measured on a modified MRC scale ranging from 1 through 12. The total scores from all 22 muscle groups were added to generate a summary score ranging from 12 to 264 with higher scores signifying greater strength. The change in summary score was calculated over the first 32 weeks of treatment. | Baseline through 32 weeks |