A Clinical Trial of Gene Therapy for Mucopolysaccharidosis VI,a Severe Lysosomal Storage Disorder (MeuSIX)

Abstract

Contract No.: 304999; EU contribution: € 5,995,041; Total costs: € 7,877,621.40; Starting date: 01/12/2012; Duration: 60 months

Background and Objectives

Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal storage disease caused by deficient arylsulfatase B (ARSB) activity. Clinical manifestations include hydrocephalus, spinal cord compression, corneal clouding, hearing loss, coarse facial features, macroglossia, heart valve disease, cardiomyopathy, respiratory insufficiency, hepatosplenomegaly, inguinal and abdominal hernias, dwarfism/growth retardation, skeletal dysplasia, and joint stiffness. Cognitive functions are usually normal, although physical and visual impairment may limit psychomotor performance.

The Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved enzyme replacement therapy (ERT) with recombinant ARSB (galsulphase; Naglazyme; BioMarin Pharmaceutical Inc.) for the treatment of MPS VI. However, current clinical evidence shows that ERT has limitations: (1) efficacy is very limited in some tissue types, (2) weekly intravenous infusions are needed to achieve disease amelioration, and (3) elevated costs make treatment inaccessible for many patients.

Gene therapy has the potential to provide a more effective, long-term solution for MPS VI: a single administration of adeno-associated viral (AAV) vectors targeting the liver can provide a lifelong source of ARSB.

Nonclinical studies in rodent and feline models of MPS VI showed that a single administration of AAV vector serotype 8 (AAV2/8) encoding ARSB converts the liver into a factory organ, which provides enzyme for systemic distribution, and results in biochemical, pathological, skeletal, and functional improvements.^1–6 Treated MPS VI cats showed stable, within the normal range, levels of circulating ARSB activity, up to 6 years postinjection without immune responses (Ferla and Auricchio, unpublished data).

Encouraged by these ground-breaking nonclinical results, the MeuSIX consortium will conduct a multicenter phase I/II clinical trial to investigate the safety and efficacy of AAV-mediated gene therapy in patients with MPS VI. Orphan drug designation for the use of MPS VI therapeutic AAV vector has been obtained from both the EMA and the U.S. FDA.

To achieve this goal, MeuSIX has the following objectives:

1. to produce AAV2/8.TBG.hARSB vector for a gene therapy human clinical trial, according to Good Manufacturing Practice (GMP);

2. to perform nonclinical pharmacological and toxicological studies using the AAV2/8.TBG.hARSB vector;

3. to design a phase I/II clinical trial, in which the GMP vector is tested in MPS VI patients, to generate data related to pharmacokinetics, pharmacodynamics, safety, and efficacy;

4. to produce and file the documents required to obtain authorization from regulatory authorities to execute a phase I/II clinical trial; and

5. to perform a multicenter phase I/II clinical trial to investigate the safety and efficacy of AAV2/8.TBG.hARSB gene therapy for MPS VI.

In conclusion, MeuSIX has been designed to investigate the safety and efficacy of intravascular administrations of AAV2/8 in MPS VI patients. Positive results from this phase I/II study will support an eventual licensure of AAV2/8.TBG.hARSB for the treatment of MPS VI.

Approach and Methodology

The approach initially focuses on the production of GMP AAV2/8.TBG.hARSB vector and on investigation of the safety and efficacy of the vector in animals. In parallel, the consortium will generate all the necessary paperwork for the production and filing of the required regulatory documents for authorization to perform the trial, including request for protocol assistance to the EMA to appropriately develop strategies regarding the clinical aspects of the study; request for the authorization of the clinical sites to the clinical use of genetically modified organisms; preparation of the Investigational Medicinal Product Dossier, Investigator's Brochure, and Clinical Trial Application.

Once approval from the competent authorities is received, the consortium will proceed with the multicenter phase I/II MPS VI clinical trial. All patients included in the trial will be appropriately characterized at the molecular and clinical levels before entering the trial. We aim at enrolling MPS VI patients from three different sites: Federico II University Hospital (Italy), Hacettepe University (Turkey), and Erasmus MC (The Netherlands). The vector will be administered at Federico II University, where also the baseline and key follow-up visits to the patients will be performed; the other two sites will perform additional visits on the patients they will contribute.

An ethics committee, the Ethics Advisory Group, will advise on all ethics aspects of patient treatment and care. The project has also developed appropriate plans to engage with patient organizations, including the Italian, French, Dutch, Turkish, Spanish, British, and American MPS societies, including a program through the project website to disseminate results and to update on the progress of the project.

In addition, an independent ad hoc Data and Drug Safety Monitoring Board has been established; it includes qualified clinicians, biostatisticians, and ethics experts assessing the progress, safety data, and critical efficacy endpoints of the study.

Main Findings

The main findings of MeuSIX to date are presented below:

1. Preliminary meeting with the Italian Regulatory Authority, which resulted in advice from the agency related to chemistry, manufacturing, and controls issues.

2. The partners evaluated and selected contract research organizations (CROs) and contract manufacturing organizations (CMOs) to produce and test the investigational medicinal product (IMP); they successfully delivered manufacturing processes and product-specific test methods to the selected CMO and CROs, and worked to develop and optimize the ARSB gene therapy vector production process. The manufacturing process has now been established, and the IMP production is in process.

3. While the manufacturing of clinical vector proceeds, nonclinical studies, under good laboratory practice (GLP) conditions, are being performed to test toxicity, biodistribution, and expression of the vector in animals. The studies in animals are performed with material produced with a GMP-comparable process. Partners developed the related analytical methods and assays, established the standard operating procedures, and evaluated power analysis of this study. At the present time, GLP vector administration in animals has been completed, and later phases of the investigation are underway.

4. The consortium's clinical members have drafted a study protocol including the inclusion/exclusion criteria and the primary and secondary endpoints of safety and efficacy.

5. The Ethics Advisory Group is overseeing the development of guidelines for the consent forms and ensuring uniformity of operations in all participating centers.

6. The MeuSIX consortium is performing molecular and clinical characterizations of MPS VI patients that will lead to the identification of potential candidates to be included on the trial from the Erasmus MC, Hacettepe University, and Federico II University Hospitals.

Expected Outcome

The MPS VI gene therapy trial will be the first gene therapy clinical trial in which AAV2/8 is used to treat a metabolic disease. Given its innovative approach, it may serve as a pioneering framework for clinical trials for other diseases caused by lysosomal enzyme deficiency, and in general for inborn errors of liver metabolism. The results from this study may indicate that the liver, converted into a factory organ via administration of viral vectors, supports production and secretion of therapeutic proteins, in an efficient and safe manner.

Footnotes

Website: meusix.tigem.it

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10.

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