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

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ClinicalTrials.gov Identifier: NCT03362502
Recruitment Status : Active, not recruiting
First Posted : December 5, 2017
Last Update Posted : December 13, 2022
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Description
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Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Genetic: PF-06939926 Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 23, 2018
Actual Primary Completion Date : March 28, 2022
Estimated Study Completion Date : March 30, 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: PF-06939926 Genetic: PF-06939926

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.


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of dose-limiting safety or intolerability, as measured by treatment-related adverse events [ Time Frame: through 1 year post-treatment ]

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

Other Outcome Measures:
  1. Percent change from baseline of nadir in C4 levels [ Time Frame: through day 30 post-treatment ]
  2. Percent change from baseline of nadir in platelet levels [ Time Frame: through day 30 post-treatment ]
  3. Percent change from baseline of NAb antibody titers [ Time Frame: through day 30 post-treatment ]

Eligibility Criteria
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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

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:

    1. Any mutation (exon deletion, exon duplication, insertion, or point mutation) affecting any exon between exon 9 and exon 13, inclusive; OR
    2. 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03362502


Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
More Information
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Additional Information:

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT03362502    
Other Study ID Numbers: C3391001
First Posted: December 5, 2017    Key Record Dates
Last Update Posted: December 13, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
gene therapy
mini-dystrophin
AAV
fordadistrogene movaparvovec
Additional relevant MeSH terms:
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Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
 Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked