a trial of pf-06252616 in ambulatory participants with lgmd2i

Conditions: LGMD2I

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.

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.

Eligibility criteria:
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.