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

Periodic Report Summary 2 - DEVELOPAKURE (Clinical Development of Nitisinone for Alkaptonuria)

Project Context and Objectives:
The main objective of this proposal is to study the efficacy and safety of an orphan designated drug, nitisinone, in order to obtain its marketing authorisation for the treatment of patients with Alkaptonuria (AKU), a rare and debilitating Mendelian disease for which there is no licensed treatment. A second objective is to improve the current knowledge of the natural history of AKU, especially in young people. Thanks to our existing successful non-clinical and clinical research (cell and tissue models, animal models, natural history studies), we are now in a position to complete the clinical development of nitisinone for AKU. This will involve a dose-response study (SONIA 1), an efficacy study (SONIA 2) to demonstrate improved clinical parameters, and a cross-sectional study (SOFIA) in children and young adults to provide information on the age at which it might be most beneficial to begin treatment. The results of DevelopAKUre, if positive, will allow us to make a European Marketing Authorisation Application for nitisinone for the treatment of AKU, thereby contributing to the goal of the International Rare Disease Research Consortium of 200 new therapies by 2020. AKU, also known as Black Bone Disease, is caused by a deficient enzyme, homogentisate 1,2-dioxygenase (HGD), leading to the accumulation of a substance called homogentisic acid (HGA). Some of this HGA is oxidised into a black pigment polymer in a process called ochronosis. The black pigment polymer is deposited in connective tissues, particularly cartilage, leading to early onset, severe arthritis, heart disease and disability. Nitisinone is an enzyme inhibitor that reduces the accumulation of HGA and should prevent or slow the damage from AKU. The dose of nitisinone to be used in AKU has not been adequately studied and described. Before the efficacy of nitisinone can be determined in the 4-year outcomes study (SONIA 2), a study to determine the most appropriate dose in AKU was carried out in SONIA 1. This is the main basis of the 18-month report. The dose of nitisinone for AKU has been found to be the 8 mg dose. Since the closest available formulation of nitisinone is 10 mg, the dose that is being used in SONIA 2 is 10 mg nitisinone oral daily. The project is complex and required the co-operation of the large consortium that has come together to deliver DevelopAKUre. They include the Royal Liverpool University Hospital as the Coordinator, the AKU Society (UK) and ALCAP (France) patient groups for communications/dissemination and help with patient recruitment, three SMEs (Nordic Biosciences (Denmark) for biomarker analysis, PSR (Netherlands) for clinical trial coordination and Cudos (Netherlands) for medical monitoring), a mid-sized pharma company Sobi (Swedish Orphan Biovitrum International) supplying the drug and regulatory advice, three universities (Liverpool, Siena and the Slovak Institute of Molecular Physiology and Genetics) for the analysis and interpretation of data, and three clinical trial centres (Liverpool, Hôpital Necker (Paris), National Institute of Rheumatic Diseases (Slovakia)) to recruit sufficient participants. This project can only be achieved through a Europe-wide collaboration, as it allows us to recruit enough patients for an adequately powered trial and gives us access to the elite among AKU researchers.

Project Results:
The research carried out so far can be classed into
(i) Project management activities: Determination of the most appropriate dose suitable for most patients with AKU and demonstrating efficacy and safety in a cohort of AKU patients has been completed in SONIA 1, and required co-operation and co-ordination of activities. Commencing and carrying out SONIA 2 and SOFIA

Potential Impact:
Expected final results and their potential impact 1 Expected final results of the project: The expected final result in DevelopAKUre is the successful determination of the appropriate nitisinone dose for AKU patients, confirm by clinical study that nitisinone is efficacious and safe in long term use of nitisinone and finally to show when ochronosis (the process leading to the morbidity of AKU) begins during the human life cycle. 2 Potential impact and use: (i) The Project should deliver appropriate information to improve care of rare diseases patients. Successful completion of DevelopAKUre will change the landscape in research and clinical management of AKU. It will provide a disease-modifying treatment for the very first time. (ii) This project will tell us how to monitor nitisinone therapy long-term and is expected to prevent progressive morbidity through effective treatment if nitisinone is shown to alter the progression of pathological changes in AKU. Improved AKU patient health, quality of life and empowerment in the EU and worldwide also meets the wider goals of the Health Work programme 2012. (iii) The natural history of AKU will be more completely understood. This will allow better approaches to treatment. (iv) Paediatric dimension by addressing the health of youth and children fulfils a key strategy of EU 2020. (v) Collected data should be of sufficient quality to be exploited in marketing authorisation requests. (vi) The projects should contribute to the IRDiRC goals and mission of fostering international collaborative research on rare diseases. IRDiRC Goal of 200 therapies for rare diseases by 2020 (if successful, DevelopAKUre will lead to the approval of a therapy for AKU, a rare disease, by 2020) and develop diagnostic tests for most rare diseases.

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Reported by

United Kingdom