a study to evaluate the safety and tolerability of pf-06939926 gene therapy in duchenne muscular dystrophy

Conditions: Duchenne Muscular Dystrophy

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.


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

Keywords: gene therapy mini-dystrophin aav fordadistrogene movaparvovec