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

Duchenne Muscular Dystrophy Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03362502
• Other study ID #: C3391001
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 23, 2018
• Est. completion date: March 30, 2026

Study information

• Verified date: December 2022
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 23
• Est. completion date: March 30, 2026
• Est. primary completion date: March 28, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 4 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

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.

Locations

Country	Name	City	State
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 Neurology	Durham	North Carolina
United States	Duke University Hospital Investigational Drug Services (IDS) Pharmacy	Durham	North Carolina
United States	Duke University Medical Center, Lenox Baker Children's Hospital	Durham	North Carolina
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	CCTS Clinical Research Center	Salt Lake City	Utah
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	University of Utah Clinical Neurosciences Center	Salt Lake City	Utah
United States	University of Utah Hospital	Salt Lake City	Utah
United States	University of Utah Hospital & Clinics Investigational Drug Services	Salt Lake City	Utah
United States	University of Utah Imaging and Neurosciences Center	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent change from baseline of nadir in C4 levels		through day 30 post-treatment
Other	Percent change from baseline of nadir in platelet levels		through day 30 post-treatment
Other	Percent change from baseline of NAb antibody titers		through day 30 post-treatment
Primary	Incidence of dose-limiting safety or intolerability, as measured by treatment-related adverse events		through 1 year post-treatment
Secondary	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
Secondary	Incidence, severity and causal relationship of treatment-emergent adverse events		through 5 years post-treatment
Secondary	Incidence and magnitude of abnormal laboratory findings		through 5 years post-treatment
Secondary	Incidence and severity of abnormal and clinical relevant changes in physical and neurological examinations		through 5 years post-treatment
Secondary	Incidence and severity of abnormal and clinical relevant changes in body weight		through 5 years post-treatment
Secondary	Incidence and severity of abnormal and clinical relevant changes in vital signs		through 5 years post-treatment
Secondary	Incidence and severity of abnormal and clinical relevant changes on electrocardiogram (ECG)		through 5 years post-treatment
Secondary	Incidence and severity of abnormal and clinical relevant changes in body weight and vital signs		through 5 years post-treatment
Secondary	Incidence and severity of abnormal and clinical relevant changes in cardiac MRI-measured left ventricular ejection fraction (LVEF)		through 5 years post-treatment
Secondary	Incidence and severity of abnormal and clinical relevant changes in Columbia Suicide Severity Rating Scale (C-SSRS)		through 5 years post-treatment

External Links

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