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Periodic Report Summary 2 - MEUSIX (Clinical trial of gene therapy for MPS VI - a severe lysosomal storage disorder)

Project Context and Objectives:
Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal storage disease caused by deficient arylsulfatase B (ARSB) activity. Clinical manifestations of MPS VI 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., CA) for the treatment of MPS VI. However, current clinical evidence shows that ERT has its limitations: its efficacy is limited in terms of the range of affected tissue types that it can treat; the enzyme’s plasma half-life is short, and weekly intravenous infusions are needed to achieve disease amelioration; elevated costs make treatment inaccessible for many patients.
Gene therapy has the potential to provide a more effective, long-term solution to MPS VI: a single administration of adeno-associated viral (AAV) vectors targeting the liver can likely provide a lifelong source of ARSB.
Partner 1 has investigated this approach in small and large animal models of MPS VI. The Partner found that a single intravascular administration of AAV2/8 encoding ARSB results in efficient transduction of MPS VI rat and cat liver and in significant levels of therapeutic ARSB expression for at least 4 years post-injection. In addition, significant improvement in biochemical, pathological, and skeletal features in a large animal model of MPS VI was observed during this study.
Encouraged by these groundbreaking preclinical results, the MeuSIX consortium has to 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 (ODD) has been obtained from both the EMA and the US FDA for approval of MPS VI therapeutic AAV vector use.
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 due to 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.
To achieve this goal, the Partners have identified five main milestones, which are the overall objectives of MeuSIX proposal:
1. to produce AAV2/8.TBG.hARSB vector for a gene therapy human clinical trial, according to Good Manufacturing Practice (GMP) (clinical-grade);
2. to perform pre-clinical pharmacological and toxicological studies using the AAV2/8.TBG.hARSB vector;
3. to design a Phase I/II clinical trial, in which the GMP AAV2/8.TBG.hARSB vector is tested in MPS VI patients, to generate data related to pharmokinetics, pharmacodynamics, safety, and efficacy;
4. to produce and file the documents required to obtain authorization from Italian, Turkish and Dutch regulatory agencies to execute a Phase I/II clinical trial;
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.

Project Results:
As a preliminary step of the project, the Partners planned the production of AAV2/8.TBG.hARSB clinical vector under GMP conditions for use as an investigational medicinal product (IMP) and provide a safety report for regulatory authorities.
To discuss the project, Partners met with the Italian Regulatory Authority (ISS), which gave them advice related to chemistry, manufacturing, and controls (CMCs) issues. Partner 2 evaluated and selected contract research organizations (CROs) and contract manufacturing organizations (CMOs) to produce and test the IMP. Partner 2 successfully delivered well-established 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.
Partners 1 and 2 have chosen a company that will provide the qualified person (QP), which will give approval for the IMP. Partner 1 engaged the company, which conducted an audit of the selected CMOs and CROs. The audit identified issues with the CMO, which is responsible for manufacturing the IMP; Partner 2 and the CMO have implemented corrective actions to address the audit findings; the process has been established, and Partner 2 is ready to begin IMP manufacture.
During the course of the project, additional deliverables were requested. The ISS has stated that GMP-like material could be used in non-clinical studies, and thus Partner 2 has provided vector for use in non-clinical work during tech transfer. The Partner has also provided data on vector stability in the medium used for infusion in animals during the non-clinical studies. Since long-term stability data are requested as part of the investigational medicinal product dossier (IMPD), additional material was also produced for a long-term stability study.
The corrective actions, designed to address the audit findings, resulted in significant delays in IMP manufacturing. Nevertheless, use of GMP-like material in non-clinical studies has allowed them to begin on time according to the original project timeline and to test toxicity, biodistribution and expression of the vector. Partner 1 and Partner 3 developed the related analytical methods and assays, establishing the standard operating procedures (SOPs); Partner 7 evaluated power analysis of this study. Vector administration in animals has been completed, and later phases of the investigation are underway.
Appropriate design of the multicenter trial is crucial to generate data that are indicative of both the safety and efficacy of the treatment. 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.
Partners have established an independent Data and Drug Safety Monitoring Board, which will assess the progress, safety data and critical efficacy endpoints of the study.
Partners have also established an Ethics Advisory Group (EAG), composed of medical ethicists and members of patient organizations that give guidance on the ethical aspects of patient treatment and care. The EAG oversees the development of guidelines for the consent forms and ensure uniformity of operations in all participating centres.
Partners 1, 2, 4, 5 and 6 reported the molecular and clinical characterizations of MPS VI patients. These characterizations will contribute to identification of possible treatment candidates from the Erasmus MC, Hacettepe University and Federico II University Hospitals.
The project also oversees the production and filing of the required regulatory documents; the following actions have been taken in order to fulfil this process: preparation of the pre-submission meeting with ISS, request for authorization of the clinical site for the use of vector, and preparation of the IMPD. A pre-submission meeting at EMA (European Medicine Agency) has also been completed. Scientific advice has been asked on clinical aspects of the proposed trial design, including age inclusion criteria, enrolment of patients based on genotype, vector doses and dose-escalation design, endpoints, and patients return to enzyme replacement therapy.
In summary, although the release of the IMP for the clinical trial has been delayed, at the present time the vector is ready and the QC testing is at its final steps. The QP certification is almost ready, as the QP inspected all the facilities involved in manufacturing and testing, and documented the compliance with GMPs. Once the QC testing will be completed and certified, the documents related to Quality of vector will be added to the draft of IMPD (that already includes the non-clinical studies report, the clinical protocol and drafts of vector quality sections), and the final documents will be submitted to ISS for final approval.

Potential Impact:
The MeuSIX program has responded to the call, HEALTH.2012.2.4.4-1, which has been established to develop “pre-clinical studies of EU designated orphan medicinal products”. MeuSIX has assembled a consortium, consisting of leading basic scientists, expert clinicians and SME’s, to develop a unique program to specifically respond to this call and develop a novel gene therapy trial for the rare genetic disorder MPS VI. The programme aims to develop new improved therapy for patients affected with rare diseases, “to alleviate the disease’s negative impacts on the quality of life of such patients and their families”. MeuSIX directly addresses this objective by developing a one-in-a-life-time treatment for MPS VI, which will improve the life of patients and their families and lift the significant economic burden that current treatments have on national health care systems.
The major expected impacts of MeuSIX are:
1. Decreased limitations of ERT for MPS VI.
ERT with recombinant rhARSB (Naglazyme) has been approved by the FDA and the EMA and is currently recommended as a therapy strategy for MPS VI (Giugliani et al., 2007). However, ERT has several limitations. First, rhARSB has a short plasma half-life (Crawley et al., 1996; Harmatz et al., 2005), requiring weekly intravenous infusions that carry a risk of allergic reaction and often require a central venous access point, which in turn carries risks of sepsis. Second, some organs and tissues like bone, cartilage and cornea are not corrected by such treatment (Harmatz et al., 2008), likely because of limited biodistribution, resulting in a certain range of treatable tissues. Third, the cost of ERT is extremely high (Schlander and Beck, 2009), thus becoming an inaccessible solution for many patients, especially in underdeveloped countries that do not offer reasonable health care options. Our pre-clinical data in MPS VI animal models suggest that gene therapy based on a single intravascular administration of AAV2/8 expressing ARSB has the potential to overcome each of these ERT limitations.
Following the positive results observed in the AAV2/8 hemophilia B trial, it has been hypothesized that the single gene therapy administration may reduce the costs of treatment/patient from, currently, $400˙000 per year (FIX prophylaxis/therapy), to $30˙000 (single AAV2/8 administration) (Ponder, 2011). For MPS VI the increment of cost decrease would be even higher, considering that ERT costs 150˙000-450˙000 euro/patient/year. Thus, overall gene therapy may provide a significant improvement in the treatment of MPS VI.

2. Exploitation of data for future marketing authorization requests to develop a drug accessible to MPSVI patients.
The clinical trial is the result of collaboration between academic sites, industry and expert CROs (for non-clinical studies and monitoring of the clinical multicenter study), with the objective of moving AAV2/8-mediated gene transfer into the first phases of clinical development. This collaboration will ensure that the quality of the data produced within this trial will comply with the standards required to obtain market authorization.

3. Establishment of a platform for stable secretion of systemic proteins for other rare diseases.
If proven safe and effective, the approach may be extended to other LSDs without CNS involvement, which rely on ERT as the current therapeutic option, and thus are impacted by the same treatment limitations: these LSDs include Hunter, Fabry, Pompe and Gaucher Diseases. More generally, AAV2/8-mediated gene transfer to liver may be applicable to several other rare diseases, including conditions that like LSDs require sustained release of therapeutic proteins (i.e. alpha1-antitrypsin deficiency or hemophilias), or liver-specific conditions, like urea cycle disorders, organic acidemias, familial hypercholesterolemia or inherited hyperbilirubinemias.

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