A Study to Evaluate the Safety and Tolerability of PF-06939926 Gene Therapy in Duchenne Muscular Dystrophy

Study Overview
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Brief Summary
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This is a first-in-human/first-in-patient, multi-center, open-label, non-randomized, ascending dose, safety and tolerability study of a single intravenous infusion of PF-06939926 in ambulatory and non-ambulatory subjects with Duchenne muscular dystrophy (DMD). Other objectives include measurement of dystrophin expression and distribution, and assessments of muscle strength, quality, and function. A total of approximately 22 subjects will receive PF-06939926, and these will include both ambulatory and non-ambulatory subjects. Up to 13 subjects may be included in a cohort that includes the concomitant medication, sirolimus. In order to mitigate unanticipated risks to subject safety, enrollment will be staggered within and between two planned dose-levels and will include a formal review by an external data monitoring committee (E-DMC) prior to dose progression.

Official Title
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A PHASE 1B MULTICENTER, OPEN-LABEL, SINGLE ASCENDING DOSE STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF PF-06939926 IN AMBULATORY AND NON-AMBULATORY SUBJECTS WITH DUCHENNE MUSCULAR DYSTROPHY

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Genetic: PF-06939926


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age as follows, based on ambulatory status: FOR AMBULATORY PARTICIPANTS, defined as the ability to walk at least 10 meters unassisted: Between 4 and 12 years, inclusive, FOR NON-AMBULATORY PARTICIPANTS, defined as the inability to walk at least 10 meters unassisted: No age restrictions so long as loss of ambulation occurs prior to the subject's 17th birthday; Diagnosis of Duchenne muscular dystrophy confirmed by medical history and genetic testing; Receipt of glucocorticoids for 6 months and a stable daily dose for at least 3 months prior to study entry; Ability to tolerate magnetic resonance imaging (MRI) without sedation and with no contraindications to these procedures; Ability to tolerate muscle biopsies under anesthesia with no contraindications to these procedures; Body weights as follows, based on ambulatory status: FOR AMBULATORY PARTICIPANTS: Between 15 kg and 50 kg, FOR NON-AMBULATORY PARTICIPANTS: Less than 75 kg, but which may be managed or adjusted to a lower limit, especially to ensure participant safety; Functional performance as follows, based on ambulatory status: FOR AMBULATORY PARTICIPANTS: Ability to rise from floor within seven (7) seconds, FOR NON-AMBULATORY PARTICIPANTS: Percent predicted forced vital capacity greater than 40% as part of pulmonary function tests, as well as adequate upper limb function. Exclusion Criteria: Receipt of live attenuated vaccination within 3 months prior to receiving PF-06939926 or exposure to an influenza (or other inactivated) vaccination or systemic antiviral and/or interferon therapy within 30 days prior to receipt of PF-06939926; Prior exposure to any gene therapy agent, including exon-skipping agents; Exposure to other investigational drugs within 30 days or 5 half-lives, whichever is longer; Neutralizing antibodies (NAb) against adeno-associated virus, serotype 9 (AAV9); Compromised cardiac function as indicated by left ventricular ejection fraction on cardiac MRI, as follows, based on ambulatory status: FOR AMBULATORY PARTICIPANTS: Less than 55%, FOR NON-AMBULATORY PARTICIPANTS: Less than 35%; Inadequate hepatic or renal function or risk factors for autoimmune disease on screening laboratory assessments. The following genetic abnormalities in the dystrophin gene as confirmed by the investigator based on the review of the DMD genetic testing: Any mutation (exon deletion, exon duplication, insertion, or point mutation) affecting any exon between exon 9 and exon 13, inclusive; OR A deletion that affects both exon 29 and exon 30. Sirolimus Cohort Inclusion Criteria > 8 years of age Exclusion Criteria Hypersensitivity to sirolimus or intolerance to soy, including a history of angioedema Concomitant use with strong CYP3A4/P-gp inducers or inhibitors

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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Male

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06939926<br> | Genetic: PF-06939926<br>* Recombinant adeno-associated virus, serotype 9 (AAV9) carrying a truncated human dystrophin gene (mini-dystrophin) under the control of a muscle-specific promoter. Subjects will receive a single intravenous infusion of one of 2 dose levels.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting safety or intolerability, as measured by treatment-related adverse events |  | through 1 year post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evidence of mini-dystrophin expression and distribution assessed by immunohistochemistry, western blot, and/or LC-MS using muscle biopsies |  | at baseline, 2 months and 1 year post-treatment | 
| Incidence, severity and causal relationship of treatment-emergent adverse events |  | through 5 years post-treatment | 
| Incidence and magnitude of abnormal laboratory findings |  | through 5 years post-treatment | 
| Incidence and severity of abnormal and clinical relevant changes in physical and neurological examinations |  | through 5 years post-treatment | 
| Incidence and severity of abnormal and clinical relevant changes in body weight |  | through 5 years post-treatment | 
| Incidence and severity of abnormal and clinical relevant changes in vital signs |  | through 5 years post-treatment | 
| Incidence and severity of abnormal and clinical relevant changes on electrocardiogram (ECG) |  | through 5 years post-treatment | 
| Incidence and severity of abnormal and clinical relevant changes in body weight and vital signs |  | through 5 years post-treatment | 
| Incidence and severity of abnormal and clinical relevant changes in cardiac MRI-measured left ventricular ejection fraction (LVEF) |  | through 5 years post-treatment | 
| Incidence and severity of abnormal and clinical relevant changes in Columbia Suicide Severity Rating Scale (C-SSRS) |  | through 5 years post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene therapy, mini-dystrophin, AAV, fordadistrogene movaparvovec