A Phase 1/2 Study of the Safety and Efficacy of MVX-220 in Angelman Syndrome

A Multi-Center, Open-label, Phase 1/2 Trial of the Safety and Efficacy of MVX-220 Gene Therapy Administered by Intra-Cisterna Magna Injection to Participants With Angelman Syndrome

The purpose of this study is to evaluate the safety and efficacy of MVX-220 gene therapy in children and adults with Angelman syndrome with UBE3A gene deletion, uniparental disomy, or imprinting center defect genotypes.

MVX-220 is an investigational gene replacement therapy intended to provide a functional copy of the UBE3A gene to individuals with Angelman syndrome. This study is designed to evaluate the safety, tolerability and efficacy of MVX-220 in participants with Angelman syndrome who have deletion, uniparental disomy, or imprinting center disorder genotypes. The study has 2 primary cohorts: Cohort 1 that includes adults followed by Cohort 2 that includes children. All patients will receive a single dose of MVX-220 administered by injection into the cisterna magna. There is no control group and all individuals will receive the gene therapy. An independent data safety monitoring board will review the safety information from Cohort 1 before individuals can be enrolled in Cohort 2. An optional cohort of adults and/or children (Cohort 3) may be enrolled based on a review of data from Cohorts 1 and 2. All patients will be required to take steroids before and for a brief period during the study to help mitigate the risk of immune response to the gene therapy. Patients will be followed for safety and efficacy for an initial 2-year period post-treatment and then transition to less frequent monitoring schedule for an additional 3 years. The total duration of follow up in the study is 5 years.

Key Inclusion Criteria:

1. The participant's parent/legal guardian must provide written informed consent.

2. Symptoms consistent with AS and documented genetic confirmation of one of the following genotypes resulting in a diagnosis of AS:

   1. Full maternal UBE3A gene deletion causing AS in the region of 15q11.2-q13
   2. Uniparental disomy
   3. Imprinting center defect

3. The participant must be 18 to 50 years of age, inclusive (for adult participants), or 4 to 8 years of age, inclusive (for pediatric participants), at Screening.

4. The participant must have the ability to ambulate independently.

5. The participant must be on stable antiepileptic medications (with no changes within 1 month prior to the Screening visit, except for weight associated dose adjustments).

Key Exclusion Criteria:

1. Clinically significant medical finding other than AS, that, in the judgment of the Investigator would make the participant unsuitable for participation.

2. Laboratory abnormalities including but not limited to:

   1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > upper limit of normal (ULN)
   2. Total and/or fractionated bilirubin (direct and/or indirect) > ULN
   3. Gamma-glutamyl transferase (GGT) > ULN
   4. Estimated glomerular filtration rate (eGFR) below the lower limit of normal (LLN) for age
   5. Hemoglobin < 8 g/dL
   6. White blood cell (WBC) count outside the normal range for age
   7. Platelet count < LLN
   8. Partial thromboplastin time (PTT) outside the reference range
   9. PT/International normalized ratio (INR) outside the reference range

3. Any known history and/or family history of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) or multisystem inflammatory syndrome (MIS).

4. Any known history and/or family history of disordered complement function and/or complement gene mutation(s).

5. History of systemic lupus erythematous, Still's disease, rheumatoid arthritis, and/or other severe autoimmune conditions per judgment of the Investigator.

6. Any known history of thrombotic microangiopathy (TMA)/microangiopathic hemolytic anemia, or hypercoagulable conditions including, but not limited to, disseminated intravascular coagulation (DIC), deep venous thrombosis, and pulmonary embolism.

7. Current therapy with high dose immunosuppressants.

8. Prior or current treatment with an investigational drug within 6 months or 5-half-lives of the hospital admission whichever is longer.

9. Prior treatment with an antisense oligonucleotide within 1 year of hospital admission.

10. A history of gene therapy administration.

11. Any contraindication to ICM administration procedure, including contraindications to imaging, contrast use, anesthesia, or any condition that would increase the risk of adverse outcomes from the ICM procedure.

12. Any contraindication to glucocorticoid use