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

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.


Eligibility 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