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Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment
  1. Lakshminarayan R Ranganath1,2,
  2. Anna M Milan1,2,
  3. Andrew T Hughes1,2,
  4. John J Dutton1,
  5. Richard Fitzgerald3,
  6. Michael C Briggs4,
  7. Helen Bygott1,
  8. Eftychia E Psarelli5,
  9. Trevor F Cox5,
  10. James A Gallagher2,
  11. Jonathan C Jarvis6,
  12. Christa van Kan7,
  13. Anthony K Hall8,
  14. Dinny Laan7,
  15. Birgitta Olsson9,
  16. Johan Szamosi9,
  17. Mattias Rudebeck9,
  18. Torbjörn Kullenberg9,
  19. Arvid Cronlund9,
  20. Lennart Svensson9,
  21. Carin Junestrand9,
  22. Hana Ayoob10,
  23. Oliver G Timmis10,
  24. Nicolas Sireau10,
  25. Kim-Hanh Le Quan Sang11,
  26. Federica Genovese12,
  27. Daniela Braconi13,
  28. Annalisa Santucci13,
  29. Martina Nemethova14,
  30. Andrea Zatkova14,
  31. Judith McCaffrey15,
  32. Peter Christensen16,
  33. Gordon Ross16,
  34. Richard Imrich17,
  35. Jozef Rovensky18
  1. 1Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Liverpool, UK
  2. 2Department of Musculoskeletal Biology, University of Liverpool, Liverpool, UK
  3. 3Department of Clinical Pharmacology, Royal Liverpool University Hospital, Liverpool, UK
  4. 4Department of Ophthalmology, Royal Liverpool University Hospital, Liverpool, UK
  5. 5Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
  6. 6School of Sport and Exercise Science, Liverpool John Moores University, Liverpool, UK
  7. 7PSR group B.V., Hoofddorp, Netherlands
  8. 8Cudos BV, Hoofddorp, Netherlands
  9. 9Swedish Orphan Biovitrum AB (publ), Stockholm, Sweden
  10. 10AKU Society, Cambridge, UK
  11. 11Hôpital Necker-Enfants Malades, Paris Cedex 15, France
  12. 12Nordic Bioscience, Herlev, Denmark
  13. 13Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy
  14. 14Laboratory of Genetics, Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia
  15. 15Agilent Technologies Ireland, Cork, Ireland
  16. 16Agilent Technologies, Stockport, UK
  17. 17Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
  18. 18National Institute of Rheumatic Diseases, Piešťany, Slovakia
  1. Correspondence to Professor Lakshminarayan R Ranganath, Department of Clinical Biochemistry and Metabolism, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK; lrang{at}liv.ac.uk

Abstract

Background Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied.

Methods Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone.

Findings A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy.

Conclusions In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range.

Trial registration number EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.

  • Arthritis
  • Spondyloarthritis
  • Osteoarthritis

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