A Trial of PF-06252616 in Ambulatory Participants With LGMD2I

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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02841267

Enrollment

Registered

2016-07-22

Start date

2016-07-31

Completion date

2019-01-31

Last updated

2020-10-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

LGMD2I

Brief summary

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

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.

Interventions

DRUGPF 06252616

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 99 Years

Healthy volunteers

Inclusion criteria

1. Male and female patients age ≥ 18 2. 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). 3. Ability to walk/run 10m 4. Ability to rise from chair 5. Adequate hepatic and renal function on screening laboratory assessments 6. Iron content estimate on the screening liver MRI within the normal range as determined by R2\* value (R2\* ≤ 139 Hz at 3.0T). 7. Participant must provide written informed consent for participating in study. 8. 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

1. Known cognitive impairment or behavioral issues that would impede the ability to provide informed consent or to follow study instructions. 2. History of major surgical procedure within 6 weeks of signing the informed consent or planned surgery during the study. 3. 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. 4. Previous treatment with another investigational product within 30 days or 5 half-lives, (whichever is longer) prior to consenting. 5. Corticosteroid treatment within 3 months prior to consenting. 6. Compromised cardiac function (left ventricular ejection fraction \<50%). 7. Unwilling or unable (e.g. metal implants, requires sedation) to undergo examination with closed MRI without sedation. 8. History of allergic or anaphylactic reaction to a therapeutic or diagnostic protein. 9. Female subjects who are pregnant or nursing. 10. 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. 11. Predisposition to iron accumulation. (Serum iron \>1.2 X ULN, serum ferritin \>1.2 ULNN). 12. Underlying disposition for bleeding disorder on screening laboratory assessment (PT/INR\>1.25 X ULN, aPTT \> 1.25 ULN, fecal occult blood is positive) 13. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, neurologic, or allergic disease. 14. 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.

Design outcomes

Primary

Measure	Time frame	Description
Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events	Baseline through 64 weeks	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).

Secondary

Measure	Time frame	Description
Minimum Observed Serum Trough Concentration at Steady State (Ctrough,ss) of GDF-8	Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3	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.
Maximum Observed Serum Concentration (Cmax) of PF-06252616	Day 113 and Day 169	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.
Minimum Observed Serum Trough Concentration (Ctrough) of PF-06252616	Day 113 and Day 169	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.
Immunogenicity: Incidence of Anti-drug Antibody	Baseline through 96 weeks	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.
Maximum Observed Serum Concentration at Steady State (Cmax, ss) of GDF-8	Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3	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.
Mean Change From Baseline of Forced Vital Capacity in Liters	Baseline through 32 weeks	The total forced vital capacity was measured using a bedside spirometer. The best of 3 trials was recorded.
Mean Change From Baseline in 2MWD in Meters	Baseline through 32 weeks	Average change in distance (in meters) walked in 2 minutes.
Mean Change From Baseline in TUG in Seconds	Baseline through 32 weeks	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.
Mean Change From Baseline in Muscle Strength as Measured by Modified MRC Scale	Baseline through 32 weeks	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.
Mean Change From Baseline in 10 Meter Walk/Run Time in Seconds	Baseline through 32 weeks	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.

Countries

United States

Participant flow

Pre-assignment details

One participant in Cohort 2 was consented, but elected to withdraw from the study prior to assignment to a treatment arm.

Participants by arm

Arm	Count
Cohort 1 - Low Dose 4 subjects were enrolled in cohort 1 and received an initial dose of 5mg/kg PF 06252616 IV every 4 weeks. Following 32 weeks of treatment, subjects received an additional 32 weeks of treatment with 40 mg/kg PF 06252616 IV every 4 weeks.	4
Cohort 2 - Middle Dose 7 subjects were enrolled in cohort 2 and received 20 mg/kg of PF 06252616 IV every 4 weeks for 32 weeks.	7
Cohort 3 - High Dose 8 subjects were enrolled in cohort 3 and received 40 mg/kg of PF06252616 IV every 4 weeks for 32 weeks.	8
Total	19

Baseline characteristics

Characteristic	Cohort 1 - Low Dose	Cohort 2 - Middle Dose	Cohort 3 - High Dose	Total
Age, Continuous	45 years STANDARD_DEVIATION 8	41 years STANDARD_DEVIATION 18	34 years STANDARD_DEVIATION 9.9	39 years STANDARD_DEVIATION 13
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	4 Participants	7 Participants	8 Participants	19 Participants
Sex: Female, Male Female	3 Participants	4 Participants	5 Participants	12 Participants
Sex: Female, Male Male	1 Participants	3 Participants	3 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk
deaths Total, all-cause mortality	0 / 19	0 / 4	0 / 4	0 / 4	0 / 7	0 / 6	0 / 8	0 / 6
other Total, other adverse events	9 / 19	4 / 4	4 / 4	4 / 4	6 / 7	4 / 6	7 / 8	6 / 6
serious Total, serious adverse events	1 / 19	0 / 4	0 / 4	0 / 4	0 / 7	1 / 6	0 / 8	0 / 6

Outcome results

Primary

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).

Time frame: Baseline through 64 weeks

Population: All enrolled subjects are included in the analysis.

Arm	Measure	Group	Value (NUMBER)
Cohort 1	Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events	Any adverse event	45 events
Cohort 1	Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events	Serious adverse event	0 events
Cohort 2, Middle Dose	Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events	Any adverse event	21 events
Cohort 2, Middle Dose	Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events	Serious adverse event	0 events
Cohort 3, High Dose	Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events	Any adverse event	40 events
Cohort 3, High Dose	Incidence of Dose Limiting or Intolerability Treatment Related Adverse Events	Serious adverse event	0 events

Secondary

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.

Time frame: Baseline through 96 weeks

Population: All enrolled subjects were included in the analysis.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Cohort 1	Immunogenicity: Incidence of Anti-drug Antibody	0 Participants
Cohort 2, Middle Dose	Immunogenicity: Incidence of Anti-drug Antibody	0 Participants
Cohort 3, High Dose	Immunogenicity: Incidence of Anti-drug Antibody	0 Participants

Secondary

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.

Time frame: Day 337 and Day 393 for Cohort 1; Day 113 and 169 for Cohorts 2 and 3

Population: All enrolled participants were analyzed. For Cohort 1, measurements are provided for the 40mg/kg dosing period.

Arm	Measure	Value (MEAN)	Dispersion
Cohort 1	Maximum Observed Serum Concentration at Steady State (Cmax, ss) of GDF-8	9.02 ng/ml	Standard Deviation 3.2
Cohort 2, Middle Dose	Maximum Observed Serum Concentration at Steady State (Cmax, ss) of GDF-8	8.96 ng/ml	Standard Deviation 3.02
Cohort 3, High Dose	Maximum Observed Serum Concentration at Steady State (Cmax, ss) of GDF-8	9.67 ng/ml	Standard Deviation 6.45

Secondary

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.

Time frame: Day 113 and Day 169

Population: All enrolled participants were analyzed. For Cohort 1, measurements are provided for 5mg/kg dosing period.

Arm	Measure	Value (MEAN)	Dispersion
Cohort 1	Maximum Observed Serum Concentration (Cmax) of PF-06252616	215306.5 ng/ml	Standard Deviation 29490.4
Cohort 2, Middle Dose	Maximum Observed Serum Concentration (Cmax) of PF-06252616	779015.7 ng/ml	Standard Deviation 115450
Cohort 3, High Dose	Maximum Observed Serum Concentration (Cmax) of PF-06252616	1625203 ng/ml	Standard Deviation 271159.6

Secondary

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.