Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Periodic Report Summary 2 - NET4CGD (Gene Therapy for X-linked Chronic Granulomatous Disease (CGD))

Project Context and Objectives:
The Net4CGD project is focused on the clinical development of a new orphan drug that can rapidly become a new treatment option for patients with the X-linked form of chronic granulomatous disease (X-CGD). This rare immunodeficiency is a severe monogenic disorder of the phagocytes causing intractable infections and granulomas. Several members of the consortium have already attempted gene correction of X-GCD using gammaretroviral vectors but with unsatisfactory results. Net4CGD proposes to conduct studies that will achieve effective transduction of hematopoietic cells, long-term engraftment of gene modified cells aiming to benefit patient health by effective and safe treatment of the disease. This will be achieved with state-of-the art technology and knowledge in expert centers. Encouraging preclinical results have been obtained with an advanced generation-lentiviral vector capable of expressing the transgene in phagocytes.

The main objective is to conduct a multi-centric gene therapy study for X-CGD to generate high quality data that could facilitate future product registration.

The Net4CGD consortium includes 7 scientific and clinical partners, 3 small and medium enterprises (SMEs) in the biotechnological and service sector and 1 partner fully dedicated to the management of the consortium. The main tasks for the Consortium over the next 4 years include i) Manufacturing clinical grade vector to support clinical studies, ii) Conducting a multi-center phase I/II trial in eligible X-CGD patients, with lentiviral gene-modified autologous hematopoietic stem cells to evaluate the safety and efficacy of the procedure iii) Ensuring high-quality and harmonization of products and procedure to facilitate future product registration iv) obtaining state-of the art information on biological efficacy and safety in patients by assessing immune restoration and large-scale integrome data. In addition, the consortium aims to communicate effectively the results of its efforts towards the scientific community, patients, families and the general public.

Project Results:
Since the beginning of the project, the consortium has successfully developed a new vector, the G1XCGD vector, which is a latest-generation lentiviral vector allowing strong expression of the transgene in myeloid cells and capable of correcting the GCD defect in phagocytes. The process for the large-scale manufacture of clinical-grade G1XCGD lentiviral vector has been implemented in compliance with Good Manufacturing Practice (GMP). Three lots of clinical-grade G1XCGD lentiviral vector have been manufactured for the clinical trials. The production of a fourth lot has been postponed for the last period of the project due to the slow recruitment of patients in the trial. Analytical procedures were developed for the vector testing and improved, in particular to reduce the costs of testing.

The partners of the consortium have worked together to harmonize the preparation of the investigational medicinal product (IMP) in GMP. The IMP is the patient’s autologous cells transduced with the vector. A first IMP was manufactured for a patient enrolled in the clinical trial and met the release criteria, greatly exceeding the minimum specification for cell dose and cell viability.

To request approval for a European multi-centric gene therapy trial for X-CGD a unique Investigational Medicinal Product Dossier (IMPD) was submitted to the different competent national regulatory authorities. The clinical trial has been registered at the European Medicines Agency (EMA) under EudraC/T: 2012-000242-35. In the UK, the trial was approved in January, 2013. The UCL center was opened in March, 2013. In Germany and Switzerland, the trial was initially approved respectively in November 2013 and September 2014. The centers were opened in October 2014 and January 2015 respectively. The French site participation was delayed due to changes in local manufacturing regulation, providing an opportunity to conduct a separate study to generate supportive data. The French study was conditionally approved as of Dec 2015. With 3 open clinical centers in 3 European states, the current multi-center trial will allow the treatment of 15 patients.

An initial assessment of the risk benefit of the clinical study was made at the beginning of the project and approved by an independent ethics expert. This initial assessment concluded that there is a clear benefit to conduct the clinical trial using the G1XCGD lentiviral viral to treat patients suffering from CGD and who have no treatment option. All ethical and regulatory aspects of such a project have been taken into consideration and are included in the management of the project. Regular ethical monitoring updates are included in the periodic report plan to the European Commission. A Data Safety Monitoring Board (DSMB) has been assembled by the sponsor of the trial.

The multicentric trial is currently actively recruiting. One patient has been treated in London, showing that cells could be collected in sufficient amounts and transduced at high levels with the vector. The IMP was safe. After gene therapy, the patient recovered normal blood counts and peripheral blood neutrophils were transduced over time. The levels of marking were consistent with the restoration of biochemical activity to therapeutic levels. Neutrophil oxidative function was detected in neutrophils after gene therapy. The patient died after 9 weeks but during the evaluable period, results in this patient confirmed that gene therapy can provide significant levels of gene correction in the myeloid cell compartment leading to clinical benefit. No new patient has been treated yet but several new patients have been identified. Efforts are ongoing to increase patient recruitment.

In parallel efforts with the trial, studies in a murine model of CGD suggest that hematopoiesis is affected by the high levels of inflammation characteristic of the disease. The impact of these recent findings on patients treatment is unknown. The separate French trial will provide an opportunity to explore this question.

A website on the consortium is regularly updated ( and a first public newsletter was issued. The Consortium has been represented at several international meetings in particular through the attendance of several partners at important international meetings in Gene Therapy (ESGCT) or Rare Diseases (IRDIRC). The Consortium has published several articles on their project.

In conclusion, the Net4CGD Consortium is progressing successfully towards its goals and maintains an excellent core of activities mainly focused on the conduct of a multicentric trial while generating new knowledge.

Potential Impact:
Results of the study are expected to permit the registration of a new medicinal product which is expected not only to improve patient quality of life but also to reduce the economic burden associated with this rare disease. As of M36, the project has successfully established a network of expert investigating centers in gene therapy, unique in Europe and worldwide. However, the delay in patient recruitment for this trial will probably postpone the interim analysis of the study beyond the end of the funding period. An extension of the project would enable us to capitalize on the major investment that has been put in place to contribute to iRDIRC objectives.

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