PF-06939926 Gene Therapy for Duchenne Muscular Dystrophy

Recruiting at 24 trial locations

Age: Any Age

Sex: Male

Trial Phase: Phase 1

Sponsor: Pfizer

Must be taking: Glucocorticoids

Must not be taking: Gene therapy agents

Disqualifiers: Live vaccines, Cardiac dysfunction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 7

Duration: 1 day

23 Participants Needed

Trial Summary

Do I need to stop my current medications for this trial?

The trial does not specify if you need to stop your current medications, but you must have been on a stable dose of glucocorticoids for at least 3 months before joining. If you are part of the sirolimus cohort, you cannot use certain other medications that interact with it.

What data supports the effectiveness of the treatment PF-06939926 for Duchenne Muscular Dystrophy?

Research shows that gene therapy using viral vectors, like adeno-associated viruses (AAV), has made significant progress in treating Duchenne Muscular Dystrophy by delivering a functional version of the dystrophin gene, which is crucial for muscle stability. Studies in animal models and early human trials have demonstrated promising results in improving muscle function and reducing symptoms. ^{1 2 3 4 5}

How does the PF-06939926 treatment for Duchenne Muscular Dystrophy differ from other treatments?

PF-06939926 is a gene therapy that uses a modified virus to deliver a mini-dystrophin gene specifically to muscle cells, aiming to restore the missing dystrophin protein in Duchenne Muscular Dystrophy patients. This approach is unique because it targets the root cause of the disease by attempting to replace the defective gene, unlike traditional treatments that mainly focus on managing symptoms. ^{1 4 6 7 8}

What is the purpose of this trial?

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.

Research Team

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Eligibility Criteria

This trial is for boys with Duchenne muscular dystrophy (DMD), both walking and non-walking, who can handle MRI scans without sedation. Participants must meet specific genetic criteria, have a certain level of muscle function, and be on stable glucocorticoids. Boys should weigh under 50 kg if walking or under 75 kg if not. Those in the Sirolimus Cohort must be over 8 years old.

Inclusion Criteria

Age as follows, based on ambulatory status: FOR AMBULATORY PARTICIPANTS: Between 4 and 12 years, FOR NON-AMBULATORY PARTICIPANTS: 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; Ability to tolerate muscle biopsies under anesthesia with no contraindications; 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; 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; > 8 years of age for Sirolimus Cohort

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, 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; Hypersensitivity to sirolimus or intolerance to soy, including a history of angioedema; Concomitant use with strong CYP3A4/P-gp inducers or inhibitors.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous infusion of PF-06939926

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Multiple visits including Day 7, Day 14, Day 180, and Day 360

Treatment Details

Interventions

• PF-06939926

Trial Overview The study tests PF-06939926 gene therapy's safety in DMD patients by giving a single IV dose to about 22 participants. It includes staggered enrollment and reviews by an external committee before increasing doses. The trial also measures dystrophin levels, muscle strength, quality, and function.

Participant Groups

Group I: PF-06939926 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

Gene therapy using a 6.3 kb minidystrophin cDNA delivered via adenovirus was effective in treating muscular dystrophy in neonatal mdx mice, suggesting a potential approach for Duchenne muscular dystrophy (DMD).

However, adult mice experienced strong immune reactions to the adenovirus, indicating that using a modified adenovirus with dystrophin cDNA or upregulating endogenous utrophin could be safer and more effective strategies for treating DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene therapy to muscle diseases: perspective and issues on basic research]. Takeda, S.[2012]

The micro-dystrophin gene transfer using rAAVrh74.MHCK7 was found to be well tolerated in a phase 1/2a trial with four young patients, showing only mild to moderate adverse events and no serious complications over one year.

All patients demonstrated significant expression of micro-dystrophin in muscle fibers and improvements in functional measures, such as North Star Ambulatory Assessment scores and reduced creatine kinase levels, indicating potential benefits beyond standard care for Duchenne muscular dystrophy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. Mendell, JR., Sahenk, Z., Lehman, K., et al.[2021]

Duchenne muscular dystrophy (DMD) is a rare genetic disease affecting young boys, caused by defects in the dystrophin gene, which is essential for muscle stability, and currently has no cure.

Two promising therapeutic strategies being explored are AAV-mediated gene augmentation to provide a functional dystrophin and AON-mediated exon skipping to correct the gene's defects, with ongoing preclinical and clinical trials assessing their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-Associated Virus (AAV) Mediated Dystrophin Gene Transfer Studies and Exon Skipping Strategies for Duchenne Muscular Dystrophy (DMD). Kawecka, K., Theodoulides, M., Hasoglu, Y., et al.[2019]

The first-in-human study of DEC cell therapy for Duchenne Muscular Dystrophy (DMD) showed no adverse events in the first 3 patients over 14 months, indicating a strong safety profile for this novel treatment.

Patients receiving DEC therapy demonstrated significant improvements in muscle function and strength, as measured by various functional tests, suggesting that this therapy could effectively enhance quality of life for DMD patients without the need for immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dystrophin Expressing Chimeric (DEC) Cell Therapy for Duchenne Muscular Dystrophy: A First-in-Human Study with Minimum 6 Months Follow-up. Heydemann, A., Bieganski, G., Wachowiak, J., et al.[2023]

Gene therapy for Duchenne muscular dystrophy (DMD) is being actively researched, with promising results from using modified adeno-associated viruses to deliver a mini-gene of dystrophin into muscle cells, which is expected to enter clinical trials soon.

Various methods, including viral and nonviral delivery systems, have been tested in biological models, highlighting the need for collaboration among Russian laboratories to advance these gene therapy experiments towards clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current state and prospects for gene therapy of Duchenne muscular dystrophy in the world and in Russia]. Baranov, VS., Baranov, AN., Zelenin, AV.[2014]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Gene therapy to muscle diseases: perspective and issues on basic research]. [2012]

2. England pubmed.ncbi.nlm.nih.gov

Gene therapy research for Duchenne and Becker muscular dystrophies. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Viral vector-mediated gene therapies. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. [2021]

5. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Adeno-Associated Virus (AAV) Mediated Dystrophin Gene Transfer Studies and Exon Skipping Strategies for Duchenne Muscular Dystrophy (DMD). [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Dystrophin Expressing Chimeric (DEC) Cell Therapy for Duchenne Muscular Dystrophy: A First-in-Human Study with Minimum 6 Months Follow-up. [2023]

7. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Current state and prospects for gene therapy of Duchenne muscular dystrophy in the world and in Russia]. [2014]

8. United States pubmed.ncbi.nlm.nih.gov

Dystrophin delivery in dystrophin-deficient DMDmdx skeletal muscle by isogenic muscle-derived stem cell transplantation. [2012]