Australian Public Assessment Report for Abatacept (rch) Proprietary Product Name: Orencia Sponsor: Bristol-Myers Squibb Australia Pty Ltd April 2010 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 Orencia Abatacept (rch) Bristol-Myers Squibb Australia Pty Ltd PM-2008-03683-3-3 Page 2 of 75 Date of Finalisation 4 March 2010 Therapeutic Goods Administration Contents I. Introduction to Product Submission .............................................................. 4 Submission Details........................................................................................................ 4 Product Background ..................................................................................................... 4 Regulatory Status .......................................................................................................... 6 Product Information ...................................................................................................... 7 II. Quality Findings .................................................................................................. 7 Drug Substance (active ingredient)............................................................................ 7 Drug Product .................................................................................................................. 7 Quality Summary and Conclusions............................................................................ 7 III. Nonclinical Findings .......................................................................................... 7 Introduction..................................................................................................................... 7 Pharmacology ................................................................................................................ 8 Pharmacokinetics .......................................................................................................... 8 Toxicology ....................................................................................................................... 8 Nonclinical Summary and Conclusions .................................................................. 12 IV. Clinical Findings ............................................................................................... 13 Introduction................................................................................................................... 13 Pharmacokinetics ........................................................................................................ 15 Pharmacodynamics ..................................................................................................... 17 Efficacy .......................................................................................................................... 18 Safety ............................................................................................................................. 37 Clinical Summary and Conclusions ......................................................................... 45 V. Pharmacovigilance Findings .......................................................................... 46 VI. Overall Conclusion and Risk/Benefit Assessment .................................... 46 Quality ............................................................................................................................ 46 Nonclinical .................................................................................................................... 46 Clinical ........................................................................................................................... 47 Risk-Benefit Analysis .................................................................................................. 49 Outcome ........................................................................................................................ 52 AusPAR Orencia Abatacept (rch) Bristol-Myers Squibb Australia Pty Ltd PM-2008-03683-3-3 Page 3 of 75 Date of Finalisation 4 March 2010 Therapeutic Goods Administration I. Introduction to Product Submission Submission Details Type of Submission Extension of Indications Decision: Approved Date of Decision: 4 March 2010 Active ingredient(s): Abatacept (rch) Product Name(s): Orencia Sponsor’s Name and Bristol-Myers Squibb Australia Pty Ltd Address: 556 Princes Highway Noble Park Vic 3174 Dose form(s): Powder for IV infusion Strength(s): 250 mg Container(s): Single-use vial with a silicone-free disposable syringe Pack size(s): Individually packaged Approved Therapeutic use: Orencia in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate or tumour necrosis factor (TNF) blocking agents. A reduction in the progression of joint damage and improvement in physical function have been demonstrated during combination treatment with Orencia and methotrexate. Orencia is indicated for reducing signs and symptoms in paediatric patients 6 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis who had an inadequate response to one or more disease-modifying anti- rheumatic drugs (DMARDS). Orencia may be used as monotherapy or concomitantly with methotrexate (MTX). Orencia should not be administered concurrently with other biological DMARDs (eg, TNF inhibitors, rituximab, or anakinra). Route(s) of administration: IV infusion Dosage: Following the initial administration, Orencia should be given at 2 and 4 weeks after the first infusion, then every 4 weeks thereafter, 500 mg, 750 mg or 1 g, depending on body weight. Product Background Juvenile Rheumatoid Arthritis (JRA), also known as Juvenile Idiopathic Arthritis (JIA), represents a major clinical and societal problem with significant unmet needs. The common sequelae of failed medical therapy include chronic pain, diminution of quality-of-life, significant debility and economic hardship, which persist life-long. Recent adult trials of abatacept suggest it has a more favourable risk-benefit profile than other disease modifying AusPAR Orencia Abatacept (rch) Bristol-Myers Squibb Australia Pty Ltd PM-2008-03683-3-3 Page 4 of 75 Date of Finalisation 4 March 2010 Therapeutic Goods Administration agents. The clinical efficacy of abatacept in RA suggests that the same approach may be successful in JRA/JIA. Hence, numerous reasons for extending the use of Orencia to paediatric patients with JRA/JIA were drawn from the fact that: · JRA/JIA is the most prevalent paediatric rheumatic illness and one of the most common chronic diseases of childhood. Nearly 50% of children with JRA/JIA suffer from recurrent or persistent disease. This eventually leads to active arthritis and ongoing joint destruction in adulthood. · Significantly increased mortality has been described especially when active synovitis persists into adulthood. Even during childhood, JRA/JIA is associated with increased mortality. Polyarticular JRA/JIA, accounting for about 40% of all JRA/JIA cases, has the poorest prognosis, with only a 15% probability of disease remission within 10 years. Over 60% of these children will have significant joint damage, often within the first 2 years of disease onset. · Current medical treatments, including disease modifying