Australian Public Assessment Report for Nitisinone Proprietary Product Name: Orfadin Sponsor: Orphan Australia Pty Ltd January 2011 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The TGA is a division of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices. · TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website. About AusPARs · An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. · An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2011 This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General’s Department, National Circuit, Barton ACT 2600 or posted at http://www.ag.gov.au/cca AusPAR Orfadin Nitisinone Orphan Australia Pty Ltd PM-2009-02266-3-3 Page 2 of 86 Date of Finalisation 15 October 2010 Therapeutic Goods Administration Contents I. Introduction to Product Submission .............................................................. 4 Submission Details........................................................................................................ 4 Product Background ..................................................................................................... 4 Regulatory Status .......................................................................................................... 6 Product Information ...................................................................................................... 6 II. Quality Findings .................................................................................................. 6 Drug Substance (active ingredient)............................................................................ 6 Drug Product .................................................................................................................. 7 Biopharmaceutics .......................................................................................................... 7 PSC Consideration ........................................................................................................ 8 Quality Summary and Conclusions............................................................................ 8 III. Nonclinical Findings .......................................................................................... 9 Introduction..................................................................................................................... 9 Pharmacology .............................................................................................................. 10 Pharmacokinetics ........................................................................................................ 10 Toxicology ..................................................................................................................... 11 Nonclinical Summary and Conclusions .................................................................. 18 IV. Clinical Findings ............................................................................................... 19 Introduction................................................................................................................... 19 Pharmacokinetics ........................................................................................................ 20 Pharmacodynamics ..................................................................................................... 31 Efficacy .......................................................................................................................... 33 Safety ............................................................................................................................. 50 Clinical Summary and Conclusions ......................................................................... 59 V. Pharmacovigilance Findings .......................................................................... 64 VI. Overall Conclusion and Risk/Benefit Assessment .................................... 66 Quality ............................................................................................................................ 66 Nonclinical .................................................................................................................... 66 Clinical ........................................................................................................................... 67 Risk Management Plan ............................................................................................... 72 Risk-Benefit Analysis .................................................................................................. 73 Outcome ........................................................................................................................ 76 Attachment 1. Product Information ...................................................................... 76 AusPAR Orfadin Nitisinone Orphan Australia Pty Ltd PM-2009-02266-3-3 Page 3 of 86 Date of Finalisation 15 October 2010 Therapeutic Goods Administration I. Introduction to Product Submission Submission Details Type of Submission New Chemical Entity Decision: Approved Date of Decision: 15 October 2010 Active ingredient(s): Nitisinone Product Name(s): Orfadin Sponsor’s Name and Orphan Australia Pty Ltd Address: 300 Frankston-Dandenong Road Dandenong Vic 3175 Dose form(s): Capsule Strength(s): 2 mg, 5 mg and 10 mg Container(s): High density polyethylene bottle with a tamper proof low density polyethylene cap Pack size(s): 60 Approved Therapeutic use: For the treatment of patients with hereditary tyrosinaemia type 1 in combination with dietary restriction of tyrosine and phenylalanine. Route(s) of administration: Oral Dosage: The dose of nitisinone should be adjusted individually. The recommended initial dose is 1 mg/kg body weight/day divided in 2 doses administered orally. The capsule may be opened and the content suspended in a small amount of water or formula diet immediately before intake. ARTG Numbers: 164163, 164173, 164174 Product Background This is an application from Orphan Australia to register nitisinone (Orfadin) for the treatment of hereditary tyrosinaemia type I (HT-1) in capsule strengths 2 mg, 5 mg, and 10 mg. HT-1 (also known as hepatorenal tyrosinaemia) is an autosomal recessive inherited disease of tyrosine metabolism resulting from a deficiency of the enzyme fumarylacetoacetate (FAH) which is the final enzyme in the tyrosine catabolic pathway (Figure 1). This deficiency leads to accumulation of the toxic intermediates maleylacetoacetate and fumarylacetoacetate and their toxic metabolites succinylacetone and succinylacetoacetate. Succinylacetone causes systemic inhibition of porphobilinogen (PBG) synthase, resulting in increased concentrations of δ-aminolevulinate. Detection of urinary succinylacetone and PBG-synthase inhibition in the blood are important diagnostic tests for HT-1 [Arora et al., 2006] and the detection of 1,2 urinary succinylacetone is considered to be “pathognomic” [McKeirnan 2006]. The 1 Arora N et al. Cardiomyopathy in tyrosinemia type I is common but usually benign. J Inherit Metab Dis 2006; 29: 54-57. AusPAR Orfadin Nitisinone Orphan Australia Pty Ltd PM-2009-02266-3-3 Page 4 of 86 Date of Finalisation 15 October 2010 Therapeutic Goods Administration diagnosis is confirmed by measuring FAH activity in fibroblasts or lymphocytes or by demonstrating the presence of pathogenic mutations in FAH [McKeirnan, 2006].2 Figure 1: Catabolic pathway of tyrosine and its association with porphyrin synthesis in HT-1. The clinical features of the condition include severe liver dysfunction, impaired coagulation, painful neurological crises, renal tubular dysfunction, rickets, failure to thrive, increased risk of hepatocellular carcinoma, and “boiled cabbage” odour.3 The dominant feature of the condition is liver disease (both acute and chronic). The severity of the disease is related to the age of onset. The acute form usually