Australian Public Assessment Report for Degarelix Proprietary Product Name: Firmagon Sponsor: Ferring Pharmaceuticals Pty Ltd May 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 2010 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 Firmagon Degarelix Ferring Pharmaceuticals Pty Ltd PM-2008-2254-4 Page 2 of 84 Date of Finalisation 16 February 2010 Therapeutic Goods Administration Contents I. Introduction to Product Submission ..................................................................... 4 Submission Details ................................................................................................. 4 Product Background ............................................................................................. 4 Regulatory Status .................................................................................................. 7 Product Information.............................................................................................. 8 II. Quality Findings .................................................................................................... 8 Drug Substance (active ingredient) ....................................................................... 8 Drug Product ......................................................................................................... 8 Bioavailability ........................................................................................................ 9 Quality Summary and Conclusions ...................................................................... 9 III. Nonclinical Findings .............................................................................................. 9 Introduction ........................................................................................................... 9 Pharmacology ........................................................................................................ 9 Pharmacokinetics ................................................................................................ 11 Toxicology ............................................................................................................ 13 Nonclinical Summary and Conclusions .............................................................. 17 IV. Clinical Findings .................................................................................................. 18 Introduction ......................................................................................................... 18 Pharmacodynamics ............................................................................................. 20 Pharmacokinetics ................................................................................................ 20 Drug Interactions ................................................................................................ 33 Efficacy ................................................................................................................ 33 Safety .................................................................................................................... 53 Clinical Summary and Conclusions .................................................................... 67 V. Pharmacovigilance Findings ............................................................................... 69 VI. Overall Conclusion and Risk/Benefit Assessment .............................................. 69 Quality ................................................................................................................. 69 Nonclinical ........................................................................................................... 69 Clinical ................................................................................................................. 69 Risk-Benefit Analysis .......................................................................................... 71 Outcome ............................................................................................................... 71 Attachment 1. Product Information......................................................................... 71 AusPAR Firmagon Degarelix Ferring Pharmaceuticals Pty Ltd PM-2008-2254-4 Page 3 of 84 Date of Finalisation 16 February 2010 Therapeutic Goods Administration I. Introduction to Product Submission Submission Details Type of Submission New Chemical Entity Decision: Approved Date of Decision: 16 February 2010 Active ingredient(s): Degarelix Product Name(s): Firmagon Sponsor’s Name and Ferring Pharmaceuticals Pty Ltd Address: PO Box 1014 Gordon NSW 2072 Dose form(s): Powder for injection with diluent Strength(s): 80 mg and 120 mg Container(s): Vial Pack size(s): One or Two Vials with Diluent Approved Therapeutic use: Treatment of patients with prostate cancer in whom androgen deprivation therapy is warranted. Route(s) of administration: Subcutaneous Dosage: 240 mg initially (2x 120 mg vials), followed by 80 mg (1x 80 mg vial) at monthly intervals. Product Background In Australia, prostate cancer is the second most common cancer in males after non melanoma skin cancer, and the second most common cause of male cancer death after lung cancer [AIHW, 2007]. In 2003, there were 13,526 new cases of prostate cancer and 2,837 deaths due to the disease [AIHW, 2007]. Of the new cases, 84% occurred in men aged 60 years and over, while 84% of the deaths occurred in men aged 70 years and older. The aged- standardised incidence rate was 144.2 [95% confidence interval [CI]: 141.7, 146.6] per 100,000 males, and the age-standardised mortality rate was 34.1 [95% CI: 32.8, 35.4] per 100,000 males. The incidence of prostate cancer increases with age with the rate in 2003 being 86 per 100,000 in men aged 50-54 years and 999 per 100,000 in men aged 85 years and older. In 2003, the risk of diagnosis of prostate cancer was 1 in 9 by age 75, and 1 in 5 by age 85, with the respective figures for risk of death due to prostate cancer being 1 in 84 and 1 in 22. The incidence of new cases of prostate cancer diagnosed in 2003 (144 per 100,000 males) was less than the 1994 peak incidence (184 per 100,000 males) over the period 1982 to 2003. Degarelix is a third generation gonadotrophin releasing hormone (GnRH) antagonist, which acts through binding to pituitary GnRH receptors. It is a linear decapeptide amide containing seven artificial amino acids, five of which are D-amino acids. The drug produces a rapid decrease in circulating levels of testosterone, luteinising hormone (LH), and follicle stimulation hormone (FSH). The sponsor claims that degarelix has the potential to offer additional therapeutic benefits to those of GnRH agonists for the treatment of patients with prostate cancer as it is not associated with an initial testosterone surge and flare of clinical AusPAR Firmagon Degarelix Ferring Pharmaceuticals Pty Ltd PM-2008-2254-4 Page 4 of 84 Date of Finalisation 16 February 2010 Therapeutic Goods Administration symptoms. The initial testosterone surge after treatment with GnRH receptor agonists has been reported to worsen the clinical status of some patients with prostate cancer (for example increased bone pain, spinal cord compression, ureteric obstruction). Australian registered drugs providing androgen deprivation therapy (ADT) for advanced prostate cancer include GnRH agonists (leuprorelin acetate, goserelin acetate) and anti-androgens (nilutamide, bicalutamide, flutamide, cyproterone acetate). The US National Comprehensive Cancer Network