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

Phase 1

Active, not recruiting

• Conditions: Duchenne Muscular Dystrophy
• Interventions: Genetic: PF-06939926

• Registration Number: NCT03362502
• Lead Sponsor: Pfizer

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2017-11-29
• Study First Submitted QC: 2017-11-29
• Study First Posted: 2017-12-05
• Study Start: 2018-01-23
• Primary Completion: 2022-03-28
• Status Verified: 2022-12
• Last Update Submitted: 2022-12-12
• Last Update Posted: 2022-12-13
• Study Completion: 2026-03-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: Male
• Target Recruitment: 23

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
PF-06939926	PF-06939926	-

Primary Outcome Measures

Name	Time	Method
Number of Participants With All-Causality Treatment-Emergent Adverse Events (TEAEs) for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Any AE that started following start of treatment of PF-06939926 was counted as a treatment-emergent AE (TEAE). A serious AE (SAE) was an untoward medical occurrence that resulted in death, was life-threatening (immediate risk of death), required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly/birth defect, or was considered to be an important medical event. Severe AE=an event that prevents normal everyday activities.
Number of Participants With All-Causality TEAEs by System Organ Class (SOC) and Preferred Term (PT) for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Any AE that started following start of treatment of PF-06939926 was counted as a TEAE. For this outcome measure, TEAEs were reported according to Medical Dictionary for Regulatory Activities (MedDRA) version 25.0 SOC and PT.
Number of Participants With Treatment-Related TEAEs for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Any AE that started following start of treatment of PF-06939926 was counted as a TEAE. An SAE was an untoward medical occurrence that resulted in death, was life-threatening (immediate risk of death), required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly/birth defect, or was considered to be an important medical event. Severe AE=an event that prevents normal everyday activities. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Treatment-related AEs and SAEs were determined by the investigator.
Number of Participants With Treatment-Related TEAEs by SOC and PT for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Any AE that started following start of treatment of PF-06939926 was counted as a TEAE. For this outcome measure, TEAEs were reported according to MedDRA version 25.0 SOC and PT. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Treatment-related AEs were determined by the investigator.
Number of Participants With All-Causality SAEs by SOC and PT for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Any AE that started following start of treatment of PF-06939926 was counted as a TEAE. An SAE was an untoward medical occurrence that resulted in death, was life-threatening (immediate risk of death), required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly/birth defect, or was considered to be an important medical event. For this outcome measure, TEAEs were reported according to MedDRA version 25.0 SOC and PT.
Number of Participants With Treatment-Related SAEs by SOC and PT for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Any AE that started following start of treatment of PF-06939926 was counted as a TEAE. An SAE was an untoward medical occurrence that resulted in death, was life-threatening (immediate risk of death), required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in congenital anomaly/birth defect, or was considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Treatment-related AEs and SAEs were determined by the investigator. For this outcome measure, TEAEs were reported according to MedDRA version 25.0 SOC and PT.
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality for 1-Year Follow-Up - Hematology	Baseline up to 1 year post dose of PF-06939926	Following hematologic parameters were analyzed for laboratory examination: hemoglobin, hematocrit, red blood cell (RBC) count, platelet count, white blood cell count, total neutrophils, absolute neutrophils (ANC), eosinophils, monocytes, basophils, lymphocytes, red blood cell indices, and haptoglobin. Laboratory abnormalities with occurrence in at least 1 participant are reported for this outcome measure. Baseline was defined as the last pre-dose measurement.
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality for 1-Year Follow-Up - Clinical Chemistry	Baseline up to 1 year post dose of PF-06939926	Following parameters for clinical chemistry were analyzed for laboratory examination: blood urea nitrogen (BUN) and creatinine, glucose, calcium, sodium, potassium, chloride, total CO2 (bicarbonate), aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (direct and indirect bilirubin), alkaline phosphatase, uric acid, albumin, total protein, serum phosphorus, cystatin C, creatine kinase, creatine kinase myocardial b fraction (CK-MB), amylase, lipase, gamma-glutamyl transferase (GGT), C-reactive protein (CRP), and cardiac troponin I. Laboratory abnormalities with occurrence in at least 1 participant are reported for this outcome measure. Baseline was defined as the last pre-dose measurement.
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality for 1-Year Follow-Up - Urinalysis	Baseline up to 1 year post dose of PF-06939926	Following parameters for urinalysis were analyzed for laboratory examination: pH, glucose, protein, blood, ketones, nitrites, leukocyte esterase, and microscopy. Laboratory abnormalities with occurrence in at least 1 participant are reported for this outcome measure. Baseline was defined as the last pre-dose measurement.
Change From Baseline on Left Ventricular Ejection Fraction as Measured by Cardiac Magnetic Resonance Imaging (MRI) for 1-Year Follow-Up	Baseline, 1 year post dose of PF-06839926 (Day 360)	Cardiac MRI was performed after thigh and upper limb MRI or on separate days within the required visit window. Change in LVEF is presented as percentages, and was calculated as \[(stroke volume) / (end-diastolic volume)\]\*100%. Baseline is defined as the last pre-dose measurement. Change from baseline on Day 360 (ie, 1 year post dose) was reported for this outcome measure.
Number of Participants With Electrocardiograms (ECGs) Meeting the Pre-Defined Categorical Criteria for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	Triplicate ECG was performed after the participant had rested quietly for at least 10 minutes in a supine position. The pre-defined categorical criteria include PR interval aggregate (msec): value\>=300, baseline\>200 and percent change\>=25%, baseline\<=200 and percent change\>=50%; QRS duration aggregate (msec): value\>=140, percent change\>=50%; QTcF interval aggregate (msec): 450\<=value\<480, 480\<=value\<500, value\>=500, 30\<=change\<60, change\>=60. Only the category(ies) with at least 1 participant meeting the pre-defined criterion is/are reported for this outcome measure. Baseline for ECG was defined as the measurement before the Day 1 study drug administration.
Number of Participants With Positive Responses on Columbia-Suicide Severity Rating Scale (C-SSRS) According to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) Categories	Baseline, Day 7, Day 14, Day 180, and Day 360	C-SSRS is a participant rated questionnaire to assess whether participant experienced the following: completed suicide(1), suicide attempt(2)("Yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior(3)("Yes" on "preparatory acts or behavior"), suicidal ideation(4)("Yes" on "wish to be dead","non-specific active suicidal thoughts","active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior(7)("Yes" on "Has subject engaged in non-suicidal self-injurious behavior"). Yes/No responses are mapped to C-CASA categories. C-SSRS was conducted with the participant's care giver/legal guardian on the participant's behalf throughout the study for participants\<=12 years of age at screening. Baseline is defined as the last predose measurement. Number of participants with responses of "Yes" is reported for this outcome measure.
Number of Participants With Vital Signs Meeting the Pre-Defined Categorical Criteria for 1-Year Follow-Up	Baseline up to 1 year post dose of PF-06939926	Vital signs consisted of blood pressure, respiratory rate, and heart rate, was obtained with these measurements at the following timepoints: within 30 minutes before and approximately 30 minutes, 1, 2, 4, 8, and 24 hours after the start of the infusion, and on Days 4, 7, 10, 14, 30, 90, 180, and 360. Baseline was defined as the last pre-dose recording. Number of participants who had at least 1 vital sign measurement at the specified timepoints meeting the pre-defined criteria from baseline up to the end of 1-year follow-up is reported for this outcome measure.

Trial Locations

Locations (22)

Primary Children's Hospital; 🇺🇸 Salt Lake City, Utah, United States

University of Utah Clinical Neurosciences Center; 🇺🇸 Salt Lake City, Utah, United States

Ronald Reagan UCLA Medical Center - Interventional Radiology; 🇺🇸 Los Angeles, California, United States

UCLA Children's Heart Center; 🇺🇸 Los Angeles, California, United States

MRI Research Center; 🇺🇸 Los Angeles, California, United States

Reed Neurological Research Center; 🇺🇸 Los Angeles, California, United States

Ronald Reagan UCLA Medical Center (Investigational Drug Section); 🇺🇸 Los Angeles, California, United States

Ronald Reagan UCLA Medical Center Drug Information Center; 🇺🇸 Los Angeles, California, United States

UCLA (David Geffen School of Medicine); 🇺🇸 Los Angeles, California, United States

UCLA Mattel Children's Hospital; 🇺🇸 Los Angeles, California, United States

UCLA Medical Center; 🇺🇸 Los Angeles, California, United States

UCLA Outpatient Surgery Center; 🇺🇸 Los Angeles, California, United States

Duke Neurology; 🇺🇸 Durham, North Carolina, United States

Duke University Medical Center, Lenox Baker Children's Hospital; 🇺🇸 Durham, North Carolina, United States

Biospecimen Repository & Processing Core - BPRC; 🇺🇸 Durham, North Carolina, United States

Duke Cardiovascular Magnetic Resonance Center; 🇺🇸 Durham, North Carolina, United States

Duke Children's Hospital & Health Center; 🇺🇸 Durham, North Carolina, United States

Duke University Hospital Investigational Drug Services (IDS) Pharmacy; 🇺🇸 Durham, North Carolina, United States

CCTS Clinical Research Center; 🇺🇸 Salt Lake City, Utah, United States

University of Utah Imaging and Neurosciences Center; 🇺🇸 Salt Lake City, Utah, United States

University of Utah Hospital & Clinics Investigational Drug Services; 🇺🇸 Salt Lake City, Utah, United States

University of Utah Hospital; 🇺🇸 Salt Lake City, Utah, United States