Gene Transfer Clinical Trial for Mucopolysaccharidosis (MPS) IIIB

NCT03315182 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: ABT-002
• Study Type: interventional
• Target: 11
• Locations: 4 countries
• Sites: 4

Brief Summary

Open-label, dose-escalation clinical trial of rAAV9.CMV.hNAGLU injected intravenously through a peripheral limb vein

Conditions

Mucopolysaccharidosis Type 3 B

Keywords

MPS IIIB; Sanfilippo Syndrome B

Outcome Measures

Primary Outcomes (2)

• Change from baseline in the Age Equivalent Developmental score (calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children Second Edition, based on developmental age) compared with Natural History Study data

  24 months

• Product safety as defined by the incidence, type and severity of treatment-related adverse events and serious adverse events

  24 Months

Secondary Outcomes (11)

• Change from baseline of central spinal fluid heparan sulfate after treatment

  24 months

• Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment

  24 Months

• Change from baseline in CSF or plasma NAGLU enzyme activity levels after treatment

  24 Months

• Change from baseline in liver and/or spleen volumes after treatment, as measured by magnetic resonance imaging

  24 Months

• Change from baseline in brain volumes after treatment, as measured by magnetic resonance imaging

  24 Months

Study Arms (3)

Cohort 1 (Low Dose) rAAV9.CMV.hNAGLU

EXPERIMENTAL

Subjects will receive a single infusion: • Cohort 1 (Low Dose): 2 X 10E13 vg/kg (n=2 participants)

Biological: rAAV9.CMV.hNAGLU

Cohort 2 (Med Dose) rAAV9.CMV.hNAGLU

EXPERIMENTAL

Subjects will receive a single infusion: • Cohort 2 (Med Dose): 5 X 10E13 vg/kg (n=4-5 participants)

Biological: rAAV9.CMV.hNAGLU

Cohort 3 (High Dose) rAAV9.CMV.hNAGLU

EXPERIMENTAL

Subjects will receive a single infusion: • Cohort 3 (High Dose): 1 X 10E14 vg/kg (n=4-8 participants)

Biological: rAAV9.CMV.hNAGLU

Interventions

rAAV9.CMV.hNAGLU BIOLOGICAL

Adeno-associated virus serotype 9 carrying the human NAGLU gene under the control of a CMV enhancer/promoter (rAAV9.CMV.hNAGLU) will be delivered one-time through a venous catheter inserted into a peripheral limb vein.

Cohort 1 (Low Dose) rAAV9.CMV.hNAGLU; Cohort 2 (Med Dose) rAAV9.CMV.hNAGLU; Cohort 3 (High Dose) rAAV9.CMV.hNAGLU

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Confirmed diagnosis of MPSIIIB by both of the following two methods:
• No detectable or significantly reduced NAGLU enzyme activity by plasma.
• Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the NAGLU gene
• Age: From Birth to 2 years or children older than 2 years with a minimum cognitive Development Quotient (DQ) of 60 or above (calculated by Bayley Scales of Infant and Toddler Development - Third Edition)

You may not qualify if:

• Inability to participate in the clinical evaluation as determined by Principal Investigator
• Identification of two nonsense or null variants on genetic testing of the NAGLU gene
• Has evidence of an attenuated phenotype of MPS IIIB
• Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
• Active viral infection based on clinical observations as infections by Adenoviruses, Epstein-Barr Virus, Cytomegalovirus, Respiratory Syncytial Virus
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer , or precludes the child from participating in the protocol assessments and follow up as autoimmune diseases requiring immunosuppression, such as juvenile rheumatoid arthritis or idiopathic thrombocytopenia purpura
• Subjects with total anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
• Subjects with a positive response for the ELISPOT for T-cell responses to AAV9
• Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection
• Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy
• Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
• Uncontrolled seizure disorder
• Any item (braces, etc.) which would exclude the subject from being able to undergo MRI according to local institutional policy
• Any other situation that precludes the subject from undergoing procedures required in this study
• Subjects with cardiomyopathy or significant congenital heart abnormalities

Sponsors & Collaborators

• Abeona Therapeutics, Inc: lead

Study Sites (4)

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Armand-Trousseau Hospital

Paris, France

Location

University Hospital Hamburg-Eppendorf

Hamburg, Germany

Location

Hospital Clinico Universitario de Santiago

Santiago de Compostela, 15706, Spain

Location

Related Publications (17)

• Fu H, Dirosario J, Killedar S, Zaraspe K, McCarty DM. Correction of neurological disease of mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain barrier gene delivery. Mol Ther. 2011 Jun;19(6):1025-33. doi: 10.1038/mt.2011.34. Epub 2011 Mar 8.

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• Truxal KV, Fu H, McCarty DM, McNally KA, Kunkler KL, Zumberge NA, Martin L, Aylward SC, Alfano LN, Berry KM, Lowes LP, Corridore M, McKee C, McBride KL, Flanigan KM. A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design. Mol Genet Metab. 2016 Nov;119(3):239-248. doi: 10.1016/j.ymgme.2016.08.002. Epub 2016 Aug 18.

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• Neufeld EF, Cantz MJ. Corrective factors for inborn errors of mucopolysaccharide metabolism. Ann N Y Acad Sci. 1971 Jul 6;179:580-7. doi: 10.1111/j.1749-6632.1971.tb46934.x. No abstract available.

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• Weber B, Guo XH, Kleijer WJ, van de Kamp JJ, Poorthuis BJ, Hopwood JJ. Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. Eur J Hum Genet. 1999 Jan;7(1):34-44. doi: 10.1038/sj.ejhg.5200242.

  PMID: 10094189 BACKGROUND

• Wijburg FA, Wegrzyn G, Burton BK, Tylki-Szymanska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013 May;102(5):462-70. doi: 10.1111/apa.12169. Epub 2013 Feb 6.

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• de Ruijter J, Valstar MJ, Wijburg FA. Mucopolysaccharidosis type III (Sanfilippo Syndrome): emerging treatment strategies. Curr Pharm Biotechnol. 2011 Jun;12(6):923-30. doi: 10.2174/138920111795542651.

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• Murrey DA, Naughton BJ, Duncan FJ, Meadows AS, Ware TA, Campbell KJ, Bremer WG, Walker CM, Goodchild L, Bolon B, La Perle K, Flanigan KM, McBride KL, McCarty DM, Fu H. Feasibility and safety of systemic rAAV9-hNAGLU delivery for treating mucopolysaccharidosis IIIB: toxicology, biodistribution, and immunological assessments in primates. Hum Gene Ther Clin Dev. 2014 Jun;25(2):72-84. doi: 10.1089/humc.2013.208. Epub 2014 Apr 10.

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• Ribera A, Haurigot V, Garcia M, Marco S, Motas S, Villacampa P, Maggioni L, Leon X, Molas M, Sanchez V, Munoz S, Leborgne C, Moll X, Pumarola M, Mingozzi F, Ruberte J, Anor S, Bosch F. Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy. Hum Mol Genet. 2015 Apr 1;24(7):2078-95. doi: 10.1093/hmg/ddu727. Epub 2014 Dec 18.

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• Hamano K, Hayashi M, Shioda K, Fukatsu R, Mizutani S. Mechanisms of neurodegeneration in mucopolysaccharidoses II and IIIB: analysis of human brain tissue. Acta Neuropathol. 2008 May;115(5):547-59. doi: 10.1007/s00401-007-0325-3. Epub 2007 Dec 4.

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• Tamagawa K, Morimatsu Y, Fujisawa K, Hara A, Taketomi T. Neuropathological study and chemico-pathological correlation in sibling cases of Sanfilippo syndrome type B. Brain Dev. 1985;7(6):599-609. doi: 10.1016/s0387-7604(85)80008-5.

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• Schlesinger AE, Edgar KA, Boxer LA. Volume of the spleen in children as measured on CT scans: normal standards as a function of body weight. AJR Am J Roentgenol. 1993 May;160(5):1107-9. doi: 10.2214/ajr.160.5.8470587.

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• Malm G, Mansson JE. Mucopolysaccharidosis type III (Sanfilippo disease) in Sweden: clinical presentation of 22 children diagnosed during a 30-year period. Acta Paediatr. 2010 Aug;99(8):1253-7. doi: 10.1111/j.1651-2227.2010.01800.x. Epub 2010 Mar 14.

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• McCurdy VJ, Johnson AK, Gray-Edwards HL, Randle AN, Bradbury AM, Morrison NE, Hwang M, Baker HJ, Cox NR, Sena-Esteves M, Martin DR. Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease. Gene Ther. 2021 Apr;28(3-4):142-154. doi: 10.1038/s41434-020-00190-1. Epub 2020 Sep 3.

  PMID: 32884151 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis III

Condition Hierarchy (Ancestors)

Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.

Study Record Dates

• First Submitted: October 10, 2017
• First Posted: October 20, 2017
• Study Start: October 16, 2017
• Primary Completion: April 7, 2022
• Study Completion: April 7, 2022
• Last Updated: May 5, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1); FR (1); DE (1); ES (1)