(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/052204 A l 16 April 2015 (16.04.2015) P C T (51) International Patent Classification: Pennyfoot Street, Nottingham Nottinghamshire NG1 IGF A61K 38/09 (2006.01) A61K 9/16 (2006.01) (GB). (21) International Application Number: (74) Agent: BATES, Philip, Ian; Reddie & Grose LLP, 16 PCT/EP2014/071474 Theobalds Road, London Greater London WC1X 8PL (GB). (22) International Filing Date: 7 October 2014 (07. 10.2014) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (26) Publication Language: English BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (30) Priority Data: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 13 187665.8 8 October 201 3 (08. 10.2013) EP KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (71) Applicant: FERRING BV [NL/NL]; Polaris Avenue 144, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, NL-2132 JX Hoofddorp (NL). PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (72) Inventors: SCHWACH, Gregoire Charles Joseph; Gam- TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. mel Kongevej 25, 2tv, DK-1610 Copenhagen V (DK). SCHIEFELBEIN, Lars; Davidsbodenstrasse 9, CH-4056 (84) Designated States (unless otherwise indicated, for every Basel (CH). NAYLOR, Andrew; Critical Pharmaceuticals kind of regional protection available): ARIPO (BW, GH, Ltd, Pennyfoot Street, BioCity Pennyfoot Street, Notting GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, ham Nottinghamshire NG1 IGF (GB). WHITAKER, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (AL, BG, Mark Andrew; Critical Pharmaceuticals Ltd, Pennyfoot TM), European AT, BE, CH, CY, CZ, DE, Street, BioCity Pennyfoot Street, Nottingham Nottingham DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, shire NG1 IGF (GB). ARROWSMITH, Nicholas John; Critical Pharmaceuticals Ltd, Pennyfoot Street, BioCity SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). [Continued on nextpage] (54) Title: MICROPARTICLES COMPRISING GNRH MADE BY PGSS 101-075 1 1 :f g o [h] o Fig. 3 © (57) Abstract: A pharmaceutical formulation comprising a solid matrix of one or more biodegradable polymers, the solid matrix in o cluding a pharmaceutically active substance or a pharmaceutically acceptable salt thereof distributed homogeneously or substantially homogeneously within the matrix; wherein the pharmaceutically active substance is, for example, a gonadotropin releasing hormone (GnRH), a GnRH agonist or a GnRH antagonist. WO 2015/052204 Al llll II II 11III II Published: MICROPARTICL.ES COMPRISING GNRH MADE BY PGSS The present invention relates to formulations for sustained, extended, and/or delayed (or otherwise controlled) release of a pharmaceutically active substance such as a peptide. The formulations may be for use in the treatment of disease, for example the formulations may be used for the treatment and/or prevention of prostate cancer. Prostate cancer is a leading cause of mortality and morbidity for men in the industrialized world. The majority of prostate cancers are dependent on testosterone for growth, and the current medical approach in the management of advanced prostate cancer involves androgen deprivation. The aim is to reduce serum testosterone (T) to below castrate level (T < 0.5 ng/mL). This may be achieved by, for example, bilateral orchiectomy or by the administration of gonadotrophin releasing hormone (GnRH) receptor agonists. Gonadotrophin releasing hormone (GnRH) is a natural hormone produced by the hypothalamus that interacts with a receptor in the pituitary to stimulate production of luteinising hormone (LH). To decrease LH production, agonists of the GnRH receptor (GnRH-R), such as leuprolide (Lupron) and goserelin, have been developed. Such GnRH- R agonists initially act to stimulate LH release and only after prolonged treatment act to desensitize GnRH-R such that LH is no longer produced, ultimately causing suppression of testosterone production by the testes. However, the initial stimulation of LH production by the agonist leads to an initial surge in the production of male sex hormones. This phenomenon, known as the "testosterone surge" or "flare reaction," can last for as long as two to four weeks, and may stimulate the prostate cancer; it can lead to a worsening of current symptoms or appearance of new symptoms such as spinal cord compression, bone pain and urethral obstruction. One approach that has been taken to avoid this problem has been to combine administration of a GnRH-R agonist with an antiandrogen, such as flutamide or bicalutamide, known as total androgen ablation therapy (AAT). The use of antiandrogens, however, is associated with serious hepatic and gastrointestinal side effects. Antagonists of the gonadotrophin releasing hormone receptor (GnRH-R) have been developed to overcome the "testosterone surge" or "flare reaction" associated with GnRH agonists. GnRH antagonists competitively bind to and block the GnRH receptors and cause a rapid decrease of LH and Follicle Stimulating Hormone (FSH) excretion, thereby reducing testosterone production with no initial stimulation/surge. However, GnRH antagonist peptides are frequently associated with the occurrence of histamine-releasing activity following administration. While the use of both GnRH agonist and antagonists in androgen deprivation therapy to treat prostate cancer has yielded promising results, there are concerns about the relative safety of the available drugs. For example, the GnRH antagonist Abarelix™ was found to carry a risk of serious allergic reactions, including anaphylaxis with hypotension and syncope, and was also found to lose efficacy over the course of treatment in some cases. Indeed, Abarelix™ (Plenaxis™ in the U.S.) was eventually approved, but only for selected patients with advanced prostate cancer, and was eventually withdrawn from the market in 2005 for commercial reasons apparently related to these problems. The present applicants have developed a third generation GnRH antagonist, degarelix, for treatment of prostate cancer. Degarelix is a synthetic decapeptide antagonist of GnRH. A long term evaluation in a multicentre randomised study demonstrated that degarelix is effective and well-tolerated without evidence of systemic allergic reactions. An application for marketing authorisation/new drug application for a formulation for monthly administration was submitted to the FDA and EMEA on 27 February 2008. Marketing Authorisation was granted by the FDA on 24 December 2008, and by EMEA on 27 February 2009. Currently, the one-month dosing regimen of degarelix, administered subcutaneously (s.c.) at a starting dose of 240 mg (40 mg/mL) and a maintenance dose of 80 mg (20 mg/mL), is approved in more than 50 countries including US, Canada and EU countries. The one month regimen requires monthly attendance of the patient at a hospital or clinic, where the degarelix is administered by a medical practitioner. There is a need for a formulation which can provide sustained release of degarelix, which would therefore reduce the requirement for the patient to attend the hospital. The applicants have found that to maintain serum testosterone (in the human) below 0.5ng/ml_ (i.e. to maintain the androgen deprivation therapy and prevent "testosterone breakthrough") over a longer period it is necessary to administer degarelix in such a way that the mean plasma concentration (between doses of degarelix) is maintained above 9 to 10 ng/mL. The prior (FDA, EMEA approved) formulations (e.g. the formulation for monthly administration) do not prevent testosterone breakthrough over a period of 3 months after administration. Simply increasing the amount of degarelix in the formulation, however, is not straightforward because of the risk of side effects, and also because the dose size may become unmanageable (requiring two or more injections to provide the dose). A Phase 3 one-year (active control - goserelin) trial with a 3-month degarelix dosing regimen has recently been completed. 565 patients were treated with a starting dose of 240 mg (40 mg/mL) degarelix administered subcutaneously followed by maintenance dose of 480 mg (two 240 mg injections at a concentration of 60 mg/mL) administered subcutaneously at month 1 and subsequently at 3-month intervals. No new safety issues were identified in this trial. There was a higher incidence of injection site reactions after the 480 mg maintenance doses compared to those observed after 80 mg maintenance doses associated with the one month dosing regimen. There remains a need for a formulation which can provide sustained release of degarelix for three months or more after a single administration (e.g. a single injection). Providing such a formulation is far from straightforward, because it can be difficult to incorporate sufficient quantities of antagonist peptides (such as degarelix) into sustained release formulations [Cook and Sheridan, The Oncologist, 5:162-168 (2000)]. Further, it can be difficult to provide a formulation which provides sustained release but can also be injected through e.g. a 23 gauge needle. According to the present invention in a first aspect there is provided a pharmaceutical formulation comprising a solid matrix of (e.g. formed from) one or more biodegradable polymers, the solid matrix including a pharmaceutically active substance or a pharmaceutically acceptable salt thereof distributed homogeneously or substantially homogeneously within the matrix; wherein the pharmaceutically active substance is gonadotropin releasing hormone (GnRH), a GnRH agonist (e.g.