HK1170950A - Composition for the treatment of benign prostate hyperplasia - Google Patents

Description

Composition for treating benign prostatic hyperplasia

The present invention relates to compositions for treating Benign Prostatic Hyperplasia (BPH), and methods of treating BPH using these compositions.

Background

Benign Prostatic Hyperplasia (BPH), sometimes referred to as benign prostatic hypertrophy or benign prostatic obstruction, is a condition in which abnormal proliferation of prostate cells leads to benign enlargement of the organ, which may ultimately lead to urinary tract obstruction and lower urinary tract symptoms. According to the national institute of health, BPH affects more than 50% of men over 60 years of age and as many as 90% of men over 70 years of age.

BPH can be treated by surgical removal of prostate tissue. This reduces the physical volume of the prostate gland, thus reducing obstruction and urinary tract symptoms. Transurethral prostatectomy (TURP) is the gold standard surgical treatment of urinary tract symptoms due to BPH. While this approach is effective and reasonably well tolerated, it is associated with post-operative morbidity such as urinary incontinence and retrograde ejaculation. Therefore, although TURP is effective, it is considered the last resort, and drug therapy has become the first choice for treating symptomatic BPH.

The primary goal of treating men with BPH is to alleviate lower urinary tract symptoms and prevent the progression of the disease, especially the risk of acute urinary retention and the need for surgery. The risk of progression is directly related to the volume of the prostate. Thus, it has been demonstrated that drugs that reduce prostate volume exhibit the greatest effect in preventing the progression of the disease. Two classes of drugs, alpha-blockers and 5-alpha-reductase inhibitors, are currently approved by the authorities for the treatment of BPH. Only 5-alpha-reductase inhibitors, alone or in combination with alpha-blockers, have been demonstrated to reduce prostate volume and prevent the risk of acute urinary retention and the need for BPH surgery.

While currently available drugs can significantly improve lower urinary tract symptoms in BPH, there are many patients who do not benefit from or tolerate such treatment. The degree of improvement achieved with current drug therapies (as measured by IPSS score, see below) has not been comparable to the results achieved with surgical treatment (see figure 2). There is therefore a need for an improved drug therapy which is well tolerated and comparable or more comparable in efficacy to surgery. In addition, currently available drugs are associated with known side effects that sometimes result in discontinuation of treatment or lack of compliance. These side effects include significant dizziness and retrograde ejaculation caused by alpha-blockers and impotence and loss of libido caused by 5-alpha-reductase inhibitors. Thus, there is also a need for drug therapies with improved safety features and/or improved patient compliance.

Summary of The Invention

According to the present invention, in a first aspect, there is provided a pharmaceutical composition for (use in) the treatment of benign prostatic hyperplasia; the pharmaceutical composition comprises 4-79 mg (such as 9-33 mg) of degarelix or a pharmaceutically acceptable salt (such as acetate); and a solvent; wherein the concentration of degarelix or salt thereof in the solvent is 5-80 mg/mL, such as 10-75 mg/mL, such as 20-60 mg/mL, such as 25-50 mL, such as 35-45 mg/mL (e.g., 40 mg/mL).

The composition may be administered by injection (e.g., by syringe, e.g., by a dual chamber syringe, or a dual chamber cartridge, e.g., for an injection "pen", as is well known in the art).

Preferably the composition is administered in a single dose. The composition may be administered in one or more doses, for example two separate doses separated by, for example, 1 to 21 days, for example 14 days.

The composition may further comprise an excipient (e.g. a sugar, such as a sugar alcohol, e.g. mannitol). Degarelix or salt thereof may be co-lyophilized powder (colyophilinate) with the excipients. The solvent may be, for example, water, or a mixture of water and mannitol. The composition may comprise, for example, 4mg, 8mg, 10mg, 15mg, 16mg, 20mg, 24mg, 25mg, 30mg, 32mg, 36mg, 40mg, 45mg, 50mg or 64mg of degarelix or a salt thereof. The composition may comprise, for example, 9 to 33mg degarelix or salt thereof, for example 10 to 30mg degarelix or salt thereof, for example 12 to 28mg degarelix or salt thereof, for example 15 to 25mg degarelix or salt thereof, for example 17 to 23mg degarelix or salt thereof. The composition may comprise, for example, 10 to 40mg of degarelix or salt thereof. The concentration of degarelix (or salt thereof) in the solvent in the composition may be 5, 10, 15, 20, 25, 30, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 50, 55, 60, 65, 70, 75 or 80mg/mL, preferably 40 mg/mL. Preferred compositions according to the invention comprise 10mg, 16mg, 20mg, 30mg or 32mg of degarelix (e.g. in the form of degarelix acetate); and a solvent (e.g., water), wherein the concentration of degarelix (e.g., acetate) in the solvent is 40 mg/mL.

The applicant has developed degarelix, a synthetic decapeptide antagonist of GnRH, which has been approved for the treatment of prostate cancer. New drug applications for once-a-month formulations/applications for marketed authorized applications were submitted to FDA and EMEA in february 2008. FDA grants marketing authorization on 24 days 12/2008, while EMEA grants marketing authorization on 17 days 2/2009. The applicant has found that an effective dose in the treatment of prostate cancer is one which reduces serum testosterone levels to below castration levels, i.e. to serum concentrations below 50ng/dL (0.5ng/L), and maintains plasma testosterone at this level. Such doses are typically at about 240mg or even higher.

The applicant has surprisingly found that a considerably lower dose of degarelix (e.g. about 10 mg-35 mg degarelix) administered in a solution at a concentration of about, for example, 40mg/mL, can be safe and effective in the treatment of benign prostatic hyperplasia. These dosage levels can provide therapeutically effective testosterone inhibition while minimizing the time plasma testosterone is below castration levels (as opposed to the requirement for treatment of prostate cancer) and minimizing associated side effects.

The applicant has found that the composition according to the invention may be effective in the treatment of BPH when administered periodically, e.g. once every 3 to 18 months, e.g. once every 6 or 12 months. Thus, in embodiments, a composition comprising 30 or 32mg degarelix and water, wherein the concentration of degarelix in water is 40mg/mL, is administered once every 6 or 12 months. It will be appreciated that the composition may be administered in such a way that, for example, two compositions/doses of 15mg (or 16mg) degarelix separated by, for example, 14 days (and the compositions are further administered in one or two doses after, for example, 12 months).

The term "treating benign prostatic hyperplasia" as used herein includes treatment to alleviate one or more lower urinary tract symptoms associated with BPH (e.g., so-called "storage symptoms" such as urinary frequency, urgency, dysuria, nocturia, urge incontinence (urge incontinence); and/or "voiding symptoms" such as voiding weakness (por stream), voiding hesitation (hesitancy), terminal dribbling, voiding (incomplete voiding), overflow incontinence (overflow incontinence)), as indicated by a reduction in the IPSS score as discussed below; treatment thereby delaying or preventing disease progression and/or reducing the risk of acute urinary retention and/or reducing or delaying the need for surgery, and/or treatment thereby reducing the volume of the prostate, and/or treatment thereby increasing the quality of life of the patient (e.g. as shown by improvement of IPSS QOL survey, see below, or by improvement of BPH impact index), and/or treatment thereby improving (increasing) Qmax (see below).

According to the present invention in a further aspect there is provided a (pharmaceutical) formulation comprising 4mg to 79mg, such as 9 to 33mg, of degarelix or a pharmaceutically acceptable salt thereof (e.g. acetate); and a solvent, wherein the concentration of degarelix or salt thereof in the solvent is 5-80 mg/mL, such as 10-75 mg/mL, such as 20-60 mg/mL, such as 25-50 mL, such as 35-45 mg/mL (e.g., 40 mg/mL). The formulation may further comprise an excipient (e.g. a sugar, such as a sugar alcohol, e.g. mannitol). The degarelix or salt thereof may be a co-lyophilized powder with the excipient. The solvent may be, for example, water, or a mixture of water and mannitol. The pharmaceutical formulation may comprise, for example, 4mg, 8mg, 10mg, 15mg, 16mg, 20mg, 24mg, 25mg, 30mg, 32mg, 36mg, 40mg, 45mg, 50mg or 64mg of degarelix or a salt thereof. The formulation may comprise, for example, 9 to 33mg degarelix or salt thereof, for example 10 to 30mg degarelix or salt thereof, for example 12 to 28mg degarelix or salt thereof, for example 15 to 25mg degarelix or salt thereof, for example 17 to 23mg degarelix or salt thereof. The concentration of degarelix (or salt thereof) in the solvent in the formulation may be 5, 10, 15, 20, 25, 30, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 50, 55, 60, 65, 70, 75 or 80mg/mL, preferably 40 mg/mL. Preferred pharmaceutical formulations according to the invention comprise 10mg, 16mg, 20mg, 30mg or 32mg of degarelix (e.g. in the form of degarelix acetate); and a solvent (e.g., water), wherein the concentration of degarelix (e.g., acetate) in the solvent is 40 mg/mL.

The pharmaceutical formulation may be administered periodically (for treatment of BPH), for example once every 3 to 18 months, for example once every six months or annually.

In accordance with the present invention, in a further aspect there is provided a method of treating benign prostatic hyperplasia in a subject, said method comprising the step of administering to said subject a pharmaceutical composition comprising 4mg to 79mg (e.g. 9 to 33mg, 10 to 40mg) of degarelix or a pharmaceutically acceptable salt thereof (e.g. acetate); and solvents (e.g., water); wherein the concentration of degarelix or salt thereof in the solvent is 5-80 mg/mL, such as 10-75 mg/mL, such as 20-60 mg/mL, such as 25-50 mL, such as 35-45 mg/mL (e.g., 40 mg/mL). Preferably, the composition is administered in a single dose. The composition may be administered in one or more doses, for example two separate doses separated by 1 to 21 days, for example 14 days. The invention may further comprise administering the pharmaceutical compound to the patient at least once repeated 3 to 18, for example 6 to 12 months after the prior administration. The pharmaceutical composition may further comprise an excipient (e.g. a sugar, such as a sugar alcohol, e.g. mannitol). The degarelix or salt thereof may be a co-lyophilized powder with the excipient.

According to the present invention in a further aspect there is provided a kit of parts for providing (e.g. reconstituting) a composition (or pharmaceutical preparation) comprising 4 to 79mg (e.g. 9 to 33mg, 10 to 40mg) of degarelix or a pharmaceutically acceptable salt thereof (e.g. acetate); and a solvent; wherein the concentration of degarelix or salt thereof in the solvent is 5-80 mg/mL, such as 10-75 mg/mL, such as 20-60 mg/mL, such as 25-50 mL, such as 35-45 mg/mL (e.g., 40 mg/mL); the kit of parts comprises one or more containers (e.g. vials, pre-filled syringes, etc.) of degarelix or a pharmaceutically acceptable salt thereof (e.g. as a co-lyophilized powder with excipients); and one or more containers of solvent (e.g., vials, pre-filled syringes, etc.), optionally, as well as equipment for reconstitution.

The composition may further comprise an excipient (e.g. a sugar, such as a sugar alcohol, e.g. mannitol). The degarelix or salt thereof may be a co-lyophilized powder with the excipient. The solvent may be, for example, water, or a mixture of water and mannitol. The composition may comprise, for example, 4mg, 8mg, 10mg, 15mg, 16mg, 20mg, 24mg, 25mg, 30mg, 32mg, 36mg, 40mg, 45mg, 50mg or 64mg of degarelix or a salt thereof. The composition may comprise, for example, 9 to 33mg degarelix or salt thereof, for example 10 to 30mg degarelix or salt thereof, for example 12 to 28mg degarelix or salt thereof, for example 15 to 25mg degarelix or salt thereof, for example 17 to 23mg degarelix or salt thereof. The concentration of degarelix (or salt thereof) in the solvent in the composition may be 5, 10, 15, 20, 25, 30, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 50, 55, 60, 65, 70, 75 or 80mg/mL, preferably 40 mg/mL. Preferred compositions according to the invention comprise 16 or 30 or 32 or 64mg degarelix (e.g. in the form of degarelix acetate); and a solvent (e.g., water), wherein the concentration of degarelix (e.g., acetate) in the solvent is 40 mg/mL.

According to the present invention, in a further aspect there is provided a method of preparing a composition for the treatment of benign prostatic hyperplasia, said method comprising: combining at least one first container containing a composition or pharmaceutical formulation comprising 4mg to 79mg (e.g., 9 to 33mg, 10 to 40mg) of degarelix or a pharmaceutically acceptable salt thereof with at least one second container containing a solvent (e.g., water); wherein the concentration of degarelix or salt thereof in the solvent is 5-80 mg/mL, such as 10-75 mg/mL, such as 20-60 mg/mL, such as 25-50 mL, such as 35-45 mg/mL (e.g., 40 mg/mL). The pharmaceutical composition may further comprise an excipient (e.g. a sugar, such as a sugar alcohol, e.g. mannitol). The degarelix or salt thereof may be a co-lyophilized powder with the excipient.

Detailed Description

Brief Description of Drawings

Figure 1a is a graphical representation of the sum of IPSS scores obtained by follow-up and medication (initial 42 day study);

FIG. 1b is a graphical representation of IPSS self-baseline changes for an initial 42-day study and including tracking at 6, 9, and 12 months;

figure 1c shows seven questions of IPSS (Q1-Q7) assessing symptoms of urinary tract obstruction (incomplete emptying), urinary frequency, urinary hesitation, urgency, inability to urinate, detrusor (straining), nocturia) in the previous week, with a graphical representation of IPSS scores obtained by follow-up and medication for each question (initial 42-day study);

fig. 2 is a graphical representation of the relative change in IPSS score between drug and surgical treatment [ source: AUAGuideline on the Management of Benign pathological Hyperplasia (AUA guidance for treating Benign Prostatic Hyperplasia) (2006; and

figure 3 is an overview of pharmacodynamic endpoints derived from testosterone concentration/time profile (profile). Definitions and terms

The terms "plasma concentration" and "plasma trough concentration" are used interchangeably herein.

The terms "administration", "administration" or "administering" as used herein refer to both (i) the provision, administration, medication and/or prescription of degarelix by or under the direction of a medical professional or authorized agent thereof, and (ii) the ingestion, administration or injection of degarelix by the patient or individual himself.

Degarelix and related pharmaceutical formulations

Degarelix is a potent GnRH antagonist, a GnRH decapeptide with p-ureido-phenylalanine inserted at the 5 and 6 positions (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH)₂) The analogs of (Jiang et al (2001),med, chem (journal of pharmaceutical chemistry).44: 453-67). Degarelix is a selective GnRH receptor antagonist (blocking drug) that competitively and reversibly binds to the pituitary GnRH receptor, thus rapidly reducing the release of gonadotropins and thereby testosterone (T). It is indicated for the treatment of patients with prostate cancer who demonstrate androgen deprivation (including patients with elevated PSA levels after having undergone prostatectomy or radiation therapy). Unlike GnRH agonists, GnRH receptor blockers do not induce a Luteinizing Hormone (LH) surge and subsequent testosterone surge/tumor stimulation and possible symptomatic outbreaks after treatment is initiated.

The active ingredient degarelix is a synthetic linear decapeptide amide comprising seven unnatural amino acids, five of which are D-amino acids. The drug substance is acetate, but the active part of the substance is degarelix as the free base. The acetate salt of degarelix was a white to off-white amorphous powder (having a low density when obtained after lyophilization). The chemical name is D-alaninamide, N-acetyl-3- (2-naphthyl) -D-alanyl-4-chloro-D-phenylalanyl-3- (3-pyridyl) -D-alanyl-L-seryl-4- [ [ [ (4S) -hexahydro-2, 6-dioxo-4-pyrimidinyll]Carbonyl radical]Amino group]-L-phenylalanyl-4- [ (aminocarbonyl) amino]-D-phenylalanyl-L-leucyl-N6- (1-methylethyl) -L-lysyl-L-prolyl. It has the empirical formula C₈₂H₁₀₃N₁₈O₁₆Cl and a molecular weight of 1,632.3 Da. The chemical structure of degarelix has been shown previously (EP 1003774, US 5,925,730, u.s.6,214,798) and can be represented by the following formula: Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph (hor) -D-4Aph (Cbm) -Leu-Lys (iPr) -Pro-D-Ala-NH₂。

Administration and dosage

As described in further detail below, degarelix may be prepared for subcutaneous administration (as opposed to intravenous administration), typically in the abdomen. Of course, it may be administered by other methods known in the art (e.g., intramuscular administration, oral administration, transdermal administration, etc.). Like other drugs administered by subcutaneous injection, the injection site may be periodically varied to adapt the treatment to the discomfort of the injection site. Typically, the injection should be performed in an area where the patient will not be under pressure, e.g. not near the belt or belt and not near the ribs.

Degarelix administered by subcutaneous or intramuscular injection works well, but daily injections are generally not preferred by patients and therefore depot (depot) formulations of degarelix can be used as further detailed in WO 03/006049 and u.s.pub.no.20050245455 and 20040038903. Briefly, subcutaneous administration of degarelix can be performed using a depot technique in which the peptide is released from a gel-like depot over a period of (typically) one to three months. Degarelix (and related GnRH antagonist peptides) has a high affinity for the GnRH receptor and is more water soluble than GnRH analogs. Degarelix and these related GnRH antagonists are able to form a gel after subcutaneous injection, and this gel is able to act as a depot from which the peptide is released over a period of weeks or even months.

Thus, degarelix may be provided as a powder to be reconstituted (using a solvent) into a solution for injection (e.g. subcutaneous injection, e.g. to form a depot as described above). The powder may be provided as a lyophilized powder comprising degarelix (e.g. in the form of acetate) and mannitol. A suitable solvent is water (e.g., water for injection, or WFI). The solvent may be provided, for example, in a vessel (e.g., vial, pre-filled syringe, etc.) containing 5mL or 6mL of solvent.

In an embodiment, degarelix may be provided in a vial containing 40mg degarelix (acetate). After reconstitution with about 1.1mL of WFI, there is an extractable volume of 1mL of a solution containing about 40mg of degarelix. Administration (e.g., by injection) of 1mL of the solution provides such a dose: (approximately) 40mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.75mL provides such a dose: (approximately) 30mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.625mL provides such a dose: (approximately) 25mg degarelix at a concentration of 40 mg/mL; administration of 0.5mL provides such a dose: (approximately) 20mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.375mL provides such a dose: (approximately) 15mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.25mL provides such a dose: (approximately) 10mg degarelix at a concentration of 40 mg/mL; administration of 0.8mL provides such a dose: (approximately) 32mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.6mL provides such a dose: (approximately) 24mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.4mL provides such a dose: (approximately) 16mg degarelix at a concentration of 40 mg/mL; administration of 0.2mL provides such a dose: (approximately) 8mg degarelix at a concentration of 40 mg/mL; while administration of 0.1mL provides such a dose: (approximately) 4mg degarelix at a concentration of 40 mg/mL.

In another embodiment, degarelix may be provided in a vial containing 120mg degarelix (acetate) for reconstruction using 3mL WFI, such that each mL of solution contains about 40mg degarelix; reconstitution produced a 3mL solution containing approximately 120mg of degarelix. Administration (e.g., by injection) of 1mL of the solution provides such a dose: (approximately) 40mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.4mL provides such a dose: (approximately) 16mg degarelix at a concentration of 40 mg/mL; administration (e.g., by injection) of 0.8mL provides such a dose: (approximately) 32mg degarelix at a concentration of 40 mg/mL; whereas administration of 1.6mL provided such a dose: (approximately) 64mg degarelix at a concentration of 40 mg/mL.

The reconstitution solution ready for injection should be a visually clear liquid.

The dosing regimen for degarelix may be a single dose administration, for example, a 32mg single dose administered as 1 injection of 0.8mL of about 40mg/mL degarelix formulation. The dosage may be repeated, for example, after a period of six or twelve months, thereby providing "intermittent suppression" treatment of BPH.

Alternatively, a dose of, for example, 32mg degarelix ("effective dose") may be administered in the following manner: a first dose of, for example, 16mg administered as 1 injection of 0.4mL of about 40mg/mL of degarelix formulation; after a period of 14 days, a second dose of 16mg, for example, administered as 1 injection of 0.4mL of approximately 40mg/mL degarelix formulation, is followed. An "effective dose" of 32mg (as a single dose, or a first dose and a second dose of 16mg) may be repeated over a period of, for example, twelve months, to provide "intermittent inhibition" treatment of BPH.

Example 1 clinical trial

Description of the design of the study

The present study was aimed at exploring the possibility of degarelix inducing only a brief transient decrease in serum testosterone concentration to or below the castration level specified to be 0.5 ng/mL. Patients diagnosed with BPH were selected as study subjects to capture any efficacy signals. The study population was men with BPH, which: prostate volume greater than 30mL, maximum urine flow of 12mL/s (with some exceptions), IPSS score at least 13, serum Prostate Specific Antigen (PSA) below 10ng/mL and no signs of prostate cancer. In total, 52 patients with BPH were randomly assigned to four parallel groups of 13 patients each.

Randomly assigning the patient to receive one of: one injection of 64mg degarelix on day 0 ("64 mg", below); one injection of 32mg degarelix on day 0 and one injection of 32mg degarelix on day 14 (under "32 +32 mg"); one injection of 32mg degarelix ("32 mg") on day 0; or one injection of 16mg degarelix on day 0 and one injection of 16mg degarelix on day 14 ("16 +16 mg").

For each patient and each administration, an ampoule of 5mL water for injection and a total removable 120mg degarelix vial are provided. For reconstitution, a volume of 3mL of water for injection was added to the degarelix vial to obtain a solution with a concentration of 40 mg/mL. The following volumes were administered: 0.4mL for said (or each) administration of 16 mg; 0.8mL for the (or each) 32mg administration; or 1.6mL for the 64mg administration. The dose is administered to the patient by subcutaneous injection at abdominal depth.

The following parameters were measured or assessed (using the following methods) for each patient at time points on day 0 ("baseline"), day 14, day 28, and day 42 of the screening (e.g., -7 days):

patient reported outcomes-effects of degarelix on urinary tract morbidity (urinary obesity), sexual function, and overall quality of life (QoL) due to urinary tract disorders, as assessed using patient report questionnaires (IPSS, IIEF, and IPSS-integrated QoL); and

efficacy endpoints-measured peak urine flow, residual urine volume after urination, and prostate volume.

The pharmacodynamic endpoint was also measured. Serum concentrations of testosterone, DHT and SHBG (to calculate free testosterone) were measured quantitatively in triplicate using liquid chromatography (LC-MS/MS) by methods well known in the art during the treatment period. The results of testosterone are discussed below.

After the first 6 weeks of treatment had completed the exploratory study, a 12-month follow-up period was initiated to examine long-term efficacy. Temporal data of the primary efficacy variables (IPSS, IPSS integrated QoL, prostate volume, urine flow and residual urine volume after voiding-measured as described below) after 6 months of follow-up are also presented in tables 1, 2, 3, figure 1b herein, along with some 9-and 12-month IPSS data (figure 1 b).

Safety/adverse effects

Adverse events recorded in this study (data not shown) were the generally well-known side effects of subcutaneously injected degarelix and did not raise any safety concerns.

Results

1. Results reported by the patient

To assess the effects of degarelix on urinary tract pathogenesis, sexual function, and overall quality of life (QoL) due to urinary tract disorders, patient report questionnaires (IPSS, IIEF, and IPSS-integrated QoL) were used. The patient answers the questionnaire at the clinic visit according to standard procedures.

International prostate specific symptom score sheet (IPSS) and comprehensive QoL problem

The American Urological Association of Urological Urology J Urol (J Urological journal) 1992.148(5) pages 1549-57; discussion 1564) IPSS was developed in 1991 to assess The severity of BPH-related urinary tract symptoms (Barry, M.J., et al, The American Urological Association symptomaticum dex for benign positive hyperplasia, The American Urological Association of The American Urological Association of benign prostatic hyperplasia). It has been widely used in clinical studies, has undergone extensive validation and its psychometric properties are well documented in both the original version (containing 1 month recalls) and the "acute" version (containing one week recalls) used in this study. WHO has recommended the use of this tool to assess BPH and it is considered an internationally acceptable standard questionnaire for assessing lower urinary tract symptoms.

Patients were asked to complete the IPSS questionnaire to assess their urinary tract symptoms. IPSS is a questionnaire administered by the patient that contains seven items (urine endless, frequency, hesitation, urgency, weakness, detrusor, nocturia) for assessing the symptoms of urinary tract obstruction in the previous week. Each urinary tract symptom question is assigned a score from 0 to 5, indicating an increased severity of the particular symptom. Therefore, the total score ranges from 0 to 35(0 to 7: mild symptoms; 8 to 19: moderate symptoms; 20 to 35: severe symptoms). A decrease in score in treatment is indicative of improvement.

One item for evaluating QoL (IPSS — integrated QoL) is contained in the IPSS. The integrated QoL problem was developed with IPSS and formally included as part of IPSS in 1993 when the WHO formally recommended IPSS for both symptom and QoL assessments. The integrated QoL problem has demonstrated test-retest reliability, internal reliability, structural validity, sensitivity, and responsiveness. This problem assesses the extent to which the patient finds its symptoms troubling. The patient is asked as to what they will feel if they will spend the rest with the prostate symptoms they are now having. The choice for answering this quality of life question ranges from "happy" (rating 0) to "bad" (rating 6).

International erectile function index (IIEF)

IIEF was originally developed and validated in 1996-1997 with the goal of providing a compact, reliable, self-administered measure of sexual function for use in detecting treatment-related changes in patients with erectile dysfunction in a cross-cultural setting. This tool was developed via literature reviews and interviews with patients with erectile dysfunction and their partners and has been verbally effective in 37 languages. It has been widely used as a primary endpoint in more than 50 clinical studies-including several BPH studies-and is considered a "gold standard" measure for assessing efficacy in clinical studies of erectile dysfunction. IIEF meets psychometric criteria for reliability and effectiveness and has a high degree of sensitivity and specificity.

The IIEF questionnaire assesses treatment-related sexual dysfunction. IIEF is a questionnaire administered by the patient, which contains 15 questions covering five areas: erectile function (six questions), orgasm function (two questions), libido (two questions), intercourse satisfaction (three questions), and overall satisfaction (two questions). The question numbers one to ten are scored on a six point scale from zero ("asexual behavior") to five ("almost always available"). The question numbers 11-15 are scored on a five-point scale from one ("almost never or never") to five ("almost always"). For the field of erectile function, a score of one to ten indicates severe erectile dysfunction; scores from 11 to 16 indicate moderate dysfunction; scores of 17-21 indicate mild to moderate dysfunction; a score of 22-25 indicates mild dysfunction; scores of 26-30 indicate no dysfunction. Likewise for other areas, a higher score indicates less dysfunction. IIEF does not generate a total score, only calculates a domain score.

Results

IPSS scoring

The mean sum of IPSS scores between all follow-ups after degarelix dosing decreased in all treatment groups without significant dose or regimen dependence (table 1, figure 1 a). The mean changes from baseline to day 42 in the 16+16, 32+32 and 64mg groups were equal to-6.1 (SD ═ 4.6), -13.2(SD ═ 6.6), -9.6(SD ═ 4.7) and-10.0 (SD ═ 5.0) units, respectively (table 1). In other words, the mean IPSS score was improved for all treatment groups at day 42, although slightly less in the 16+16mg group than the other three groups; the improvement was most pronounced in the 32mg group. The improvement was unexpectedly early onset as evidenced by a change from baseline on day 14 (table 1); the mean IPSS score of all treatment groups improved on day 14, although considerably less in the 16+16mg group compared to the other three groups; the improvement was most pronounced in the 32mg group.

The 6 month tracking data is discussed below.

FIG. 2 shows the relative change in IPSS score in known drug and surgical treatments (AUA guidelines on the Management of benign prostatic Hyperplasia (2006). MR, Ad board and Industry reports). This confirms that surgical intervention, TURP (IPSS variation of about-14 to-15) is superior to known medications such as Tamsulosin (Tamsulosin) and the like (the maximum value of IPSS variation is about-7.5, according to the figure). It can be seen that The mean change of-13.2 shown by The degarelix 32mg group is comparable to TURP, indicating that degarelix treatment may provide significant improvement over currently available treatments such as Cetrorelix (Cetrorelix) and azarelix (Debruyne et al, Cetrorelix pamoate, an LHRheanoontiast, in The treatment of BPH, randomization, placebo-controlled, multicenter study, Urology, 68 (appendix 5A), PD-02.11, month 2006 11; deneto B et al, urinary tract, complication of surgery, surgery of obesity, hypertension, benign hyperplasia of prostate (BPH) caused by benign prostatic hyperplasia (prostate hyperplasia) of prostate (prostate cancer) in The treatment of BPH, in The treatment of BPH, Duration of efficacy and safety), Urology, 70 (appendix 3A). MP-20.02, 9 months 2007). The mean change of degarelix-13.2 shown by the degarelix 32mg group was also significantly better than that shown in the preliminary study using cetrorelix glucuronate (the maximum reduction in mean IPSS was between-5.4 and-5.9). (European Urology) 54(2008) 170-. It should be noted that these are historical comparisons with many limitations; for example, the study has no placebo control. However, the results indicate efficacy.

TABLE 1 mean IPSS score and mean change from baseline

1. Percentage of responders: number of patients defined as a reduction in IPSS by at least 30% compared to baseline

Consistent with the reduction in mean IPSS scores, the number of patients in each IPSS classification varied slightly across all treatment groups, and again there was no apparent dependence on dose or dosing regimen. All patients were classified as "moderate" (n-27) or "severe" (n-23) at baseline, while only 2 were classified as "severe" on day 42, with one in each of the 32mg and 64mg groups, 31 classified as "moderate" and the remaining 17 classified as "mild".

Figure 1c includes seven questions of IPSS (Q1-Q7) assessing symptoms of urinary tract obstruction (urine endless, frequency, hesitation, urgency, weakness, detrusor, nocturia) for the previous week. As indicated above, each urinary tract symptom question is assigned a score from 0 to 5, which indicates an increased severity of the particular symptom. For each question, figure 1c also includes a graphical representation of IPSS scores (as a change from baseline) obtained by follow-up and medication in the initial 42-day study. It can be seen that the score for the 32mg dose was reduced, as was the change from baseline, for Q1 (urine endless), Q2 (urinary frequency) and Q4 (urinary urgency) [ 32mg score is shown by the bottom line in the graph for each of Q1, Q2 and Q4 at the 28 and 42 day time points ]. Thus, the 32mg dose appears to have significant effects on Q1, Q2, and Q4. In other words, the 32mg dose appears to be associated with a significant improvement in the severity of the symptoms assessed by questions Q1, Q2, and Q4. Q3, Q5, Q6 and Q7 provide further information about the urinary tract characteristics examined.

IPSS comprehensive biological quality (QoL)

In all treatment groups, the mean IPSS combined quality of life (QoL) score was reduced without any significant dependence on dose or dosing regimen (table 2). The mean (SD) changes from baseline to day 42 in the 16+16, 32+32, and 64mg groups were-1.2 (1.4), -2.1(3.0), -2.4(1.9), and-2.2 (1.6), respectively.

Table 2 mean IPSS composite QoL score and mean change from baseline at day 42 and 6 months

In the combined group, the IPSS integrated QoL assessment varied from 48% of subjects felt happy or bad (scores 5 and 6) and 8% of subjects felt happy, happy or mostly satisfied (scores 0-2) at the baseline rating to 58% of subjects felt happy, happy or mostly satisfied and only 12% of subjects felt happy or bad at the 42 day rating.

Provisional efficacy data after 6 months of follow-up showed that the improvement in the sum of mean IPSS scores (table 1, fig. 1b) and mean IPSS composite QoL scores (table 2) for the 32mg and 32+32mg groups was about the same as after 42 days, while the improvement was less pronounced for the 16+16mg and 64mg groups. The 32mg and 32+32mg groups still showed improvement in the sum of mean IPSS scores at 9 and 12 months (figure 1 b). The IPSS score sum result is also reflected in the percentage of responders; after six months, a higher proportion of patients were responders in the 32mg and 32+32mg groups than in the 16+16mg and 64mg groups (Table 1). These results should be interpreted cautiously, since the number of patients in each group is rather low (n-4-7).

IIEF rating

Typically, a slight decrease (i.e., a slight deterioration) in IIEF score is observed. These effects are well known as side effects of androgen deprivation by GnRH receptor antagonists. However, the variation in each treatment group was large, and the average variation in IIEF rating scores was small and much smaller than the standard deviation. Therefore, it is difficult to interpret these results.

2. Efficacy end point: peak urine flow, residual urine volume after urination and prostate volume

Peak urine flow, residual urine volume after urination and prostate volume were assessed in the following order:

peak urine flow was determined by flutology using the Uropower device (Wiest, World of Medicine AG, germany). The device fulfills an International Continence Society (International Continence Society) standard for maximum urine flow. Urine flow measurements were made in a sitting position.

Residual urine volume after urination (PVR) was assessed by transabdominal ultrasound. The urinary bladder is sonicated from two directions perpendicular to each other, producing three cursor positions set by the urologist. The volume is automatically calculated. The study was performed by a urologist by methods known in the art.

Prostate volume is measured by transrectal ultrasound of the patient at a lateral position. The prostate is sonicated from two directions perpendicular to each other, resulting in three cursor positions set by the urologist. The volume is automatically calculated. The study was performed by a urologist by methods known in the art.

Prostate volume compared to baseline

A reduction in mean prostate volume as measured by transrectal ultrasound was observed in all treatment groups during the study, with the percentage changes reported most significant in the 32mg and 32+32mg groups and the changes observed least in the 16+16mg group (table 3).

At follow-up at 6 months, the inter-group differences in mean prostate volume changes had almost disappeared; except that the percentage change was smaller in the 64mg group compared to the other three groups (table 3).

TABLE 3 mean prostate volume at baseline, day 42 and month 6 and mean and percent change from baseline (CS25)

Maximum urine flow

Qmax is the maximum urine flow. It is a conventional parameter for BPH testing and is a good indicator of the degree of Bladder Outlet Obstruction (BOO).

The mean maximum urine flow from baseline to balance 42 increased in 16+16mg (from 10.0 to 10.1mL/s), 32+32mg (from 9.7 to 12.2mL/s on day 42) and 64mg groups (from 9.1 to 11.9mL/s), while the mean urine flow decreased in the 32mg group (from 11.7 to 11.2 mL/s). The urine flow varies greatly within the group (as reflected in standard deviations and ranges not shown). Compared to baseline, the maximum urine flow for 24 patients had increased at day 42, while the maximum urine flow for 25 patients was decreased and the maximum urine flow for 1 patient was also unchanged. Twelve patients in the study violated one of the admission criteria due to having a urine flow > 12 mL/sec. Furthermore, the results were significantly variable and very large standard deviations were observed. The mean maximum flux was reduced in the two groups dosed with 32mg degarelix and increased in the two groups dosed with 64mg degarelix. However, the changes were small and of a large degree of variation, and furthermore, a similar number of patients experienced reduced flow at day 42 as patients experienced increased flow. If patients violating the maximum urinary flow admission criteria are excluded (see above), relatively more patients experience increased urinary flow, in a ratio of 20 to 17. Therefore, it is difficult to draw any conclusion from the change in the average maximum urine flow.

Volume of residual urine after urination

The residual urine volume after average voiding in all treatment groups was reduced in a significantly dose-dependent manner on day 14. It further decreased in the 32mg and 32+32mg groups on day 28, but returned to baseline on day 42, although still below baseline. The intra-group variation in urine flow rate was large as reflected in the standard deviation and range. The residual urine volume after urination on day 42 was decreased in 33 patients, and increased in 17 patients, distributed among all treatment groups, compared to baseline.

Thus, the therapeutic effect on residual urine volume after urination was less pronounced at day 42. The residual urine volume after average voiding in all groups showed a time-dependent transient decrease at the initial 4 weeks, but it returned to baseline after 6 weeks. However, the mean value in all treatment groups was below the baseline value on day 42, with the 32+32 and 64mg groups showing slightly less residual urine volume after urination than the 16+16 and 32mg groups. However, the proportion of patients with respect to the increase in residual urine volume after urination did not differ between the doses.

3. End point of drug effect

The serum concentration of testosterone during treatment was measured quantitatively in triplicate using liquid chromatography (LC-MS/MS) by methods well known in the art. The term "baseline" when used in pharmacodynamic endpoint analysis refers to measurements taken on a patient prior to the first administration of degarelix. The term "baseline interval" when used in pharmacodynamic endpoint analysis refers to the individual baseline value measured before the first dose ± 25%, which reflects the internal individual variation in the placebo group observed in previous degarelix studies.

The endpoints associated with the testosterone concentration-time profile based on the measured data up to day 42 are shown in figure 3. These include: a testosterone area below the baseline; a minimum value of testosterone (Cnadir) and time of Cnadir (tnadir) after each degarelix administration; testosterone area with testosterone concentration lower than 0.5 ng/mL; a duration of testosterone concentration less than 0.5 ng/mL; time to return to baseline interval. In fig. 3, the partially shaded areas above and below the baseline represent the baseline interval, with upper and lower limits marked by dotted lines.

Results

The results are summarized below.

Testosterone concentration-time profile based on data up to day 42

A transient reduction in testosterone was observed after each administration of degarelix, although of varying extent and duration between patients.

Mean concentration of testosterone, Cnadir and tnadir after each administration of degarelix

The lowest mean testosterone level occurred on day one in the 16+16mg group (1.4ng/mL, SD 0.5ng/mL), 32mg group (0.9ng/mL, SD 0.5ng/mL) and in the 64mg group (0.4ng/mL, SD 0.2ng/mL), while the lowest mean testosterone level occurred on day 17 after the second dose in the 32+32mg group (0.4ng/mL, SD 0.3 ng/mL).

The maximum change from baseline was-4.0 ng/mL for the 16+16mg group, -4.2ng/mL for the 32mg group, -4.1ng/mL for the 32+32mg group, and-4.7 ng/mL for the 64mg group, respectively.

Compared to baseline, mean testosterone levels were reduced but still above castration levels at day 42 in the 16+16mg group (4.5ng/mL vs 5.5ng/mL at baseline), in the 32+32mg group (2.7ng/mL vs 4.5ng/mL at baseline), and in the 64mg group (3.0ng/mL vs 5.2ng/mL at baseline). In the 32mg group, the mean testosterone level at 42 th balance showed a small increase compared to baseline (5.3ng/mL versus 5.2ng/mL at baseline).

Mean testosterone minimum (C) after each degarelix administration_nadir) Lower in the high dose group than in the low dose group: compared to 0.9ng/mL in the 32mg group and 1.4ng/mL (after the first dose) and 2.0ng/mL (after the second dose) in the 16+16mg group, 0.4ng/mL in the 64mg group and 0.6ng/mL (after the first dose) and 0.4ng/mL in the 32+32mg group (after the second dose).

Calculate the mean time-point (tnadir) corresponding to Cnadir, which is earlier in the low dose group than in the high dose group: compared to 3.2 days after the first dose in the 32+32mg group and 8.8 days in the 64mg group, 1.1 days after the first dose in the 16+16mg group and 1.3 days in the 32mg group (EOT table 11). Tnadir increased slightly after the second dose and was calculated: in the 16+16mg and 32+32mg groups, 4.0 days and 4.3 days, respectively.

AUC of testosterone when below said baseline

As expected, the maximum mean area of testosterone below baseline and the baseline interval was observed in the 32+32mg and 64mg dose groups. The mean time below baseline and the baseline interval was also longer in these dose groups. The areas appeared to be approximately similar in the 16+16mg and 32mg, and 32+32mg and 64mg groups, respectively, with large inter-individual differences, however.

Time period when testosterone concentration is lower than 0.5ng/mL

The individual testosterone concentration in all subjects in all treatment groups decreased after each administration of degarelix. Time-points showing one or more castration levels with testosterone concentrations below 0.5ng/mL were found in 22 out of 50 patients, and the number of patients in the 16+16mg, 32+32mg and 64mg groups was 2 (15%), 3 (25%), 9 (75%) and 9 (69%), respectively. Four of the 5 patients in the 16+16 and 32mg groups returned testosterone levels above 0.5ng/mL within 2 days, while the remaining patients returned above 0.5ng/mL within 4 days.

Four of 9 patients in the 32+32mg group who observed testosterone ≦ 0.5ng/mL had concentrations below this level after the first degarelix administration, which returned to levels above 0.5ng/mL in 2 days in 3 patients. Five patients were not suppressed below 0.5ng/mL after the first dose, but reached this level after the second injection. Testosterone levels in three subjects did not return to > 0.5ng/mL on day 42, one of which had reached testosterone castration levels after the first degarelix administration.

Five of 8 patients with testosterone levels ≦ 0.5ng/mL in the 64mg group remained below this level on day 42, while the other three recovered within 5 days.

The mean time to castration levels with testosterone levels below 0.5ng/mL varied quite between the treatment groups, with 16+16mg showing the shortest time and 64mg showing the longest time.

Proportion of patients with testosterone levels at or below 0.5ng/mL at each time-point

The 32+32mg and 64mg dose groups showed a higher proportion of subjects with testosterone levels below the castration level of 0.5ng/mL compared to the 16+16mg and 32mg groups at all time-points, with the highest proportion observed in all time-points after the second dose in the 32+32mg group and after the only one dose in the 64mg single dose group. Only two patients in the 16+16mg group were inhibited below 0.5ng/mL after the second dose.

There was a slight trend towards patients undergoing prolonged (i.e. > 4 days) castration with slightly lower testosterone concentrations at baseline, with a median of 3.8ng/mL and a range of 2.2-6.2ng/mL compared to patients with testosterone concentrations below 0.5ng/mL for less than 5 days. However, there was considerable overlap, for example one patient with a baseline value of 3.57ng/mL but not 0.5ng/mL in the 64mg group and another patient with a baseline value of 6.23ng/mL in the same group and with prolonged testosterone levels below 0.5 ng/mL.

AUC of testosterone when testosterone levels < 0.5ng/mL

The mean area for testosterone concentrations below 0.5ng/mL was 0.0ng days/mL in the 16+16mg group (range 0.0-0.0), 0.0ng days/mL in the 32mg group (range 0.0-0.1), 2.8ng days/mL in the 32+32mg group (range 0.0-15.3) and 4.4ng days/mL in the 64mg group (range 0.0-15.2).

The time required for testosterone to return to the baseline interval

The average time required for the first return to baseline interval after the first dose was 6.1(SD ═ 2.8) days in the 16+16mg group, 9.1(SD ═ 5.2) days in the 32mg group, and 9.1(SD ═ 2.6) days in the 32+32mg group. The average time required for the second return to baseline interval (after the second dose) was 19.5(SD 33.9) days in the 16+16mg group and 64.2(SD 83.5) days in the 32+32mg group. Since several testosterone values did not return to the baseline interval value until day 42, the average time required to return to baseline and baseline interval calculated in the 64mg group was not applicable. Also in the 16+16mg group and in the 32+32mg group after the second dose, the calculated time required to return to baseline and the baseline interval was only assumed (i.e. calculated rather than measured).

Proportion of patients with testosterone levels at or above the baseline interval at each time point

The overall profile from the analysis of the baseline interval below and the time required to return to the baseline interval is further enhanced by the proportion of patients whose testosterone concentrations are at or above the baseline interval level at each assessment time. Higher ratios were seen at earlier time points in the 16+16 and 32mg groups compared to the 32+32 and 64mg groups, while dividing the dose into two injections resulted in more patients returning to baseline levels earlier.

Discussion of the related Art

Administration of low doses of degarelix to patients with symptoms of BPH resulted in a generally transient decrease in plasma testosterone concentration as expected. Testosterone reduction was dose-related as shown by: more than 2 times larger area below baseline interval and longer time to return to baseline interval in groups given a total of 64mg compared to the total dose of 32 mg. However, there were large inter-individual differences within the treatment groups.

As for the number of patients who experienced suppression of testosterone concentrations to castration levels below 0.5ng/mL, there was a clear difference between the total dose of degarelix administered, 64mg giving a higher frequency and a longer suppression time than 32 mg. Furthermore there appears to be a higher frequency and a longer inhibition time if the dose is given in a single injection than if the dose is given in two injections separated by two weeks. This is consistent with the degarelix concentration profile (data not shown), which shows higher Cmax and AUC values after all single (all-in-one) injections than after splitting the dose into two injections. From a "no castration" perspective, 16+16mg dosing is the most preferred regimen, especially if the results from the first dose of 32+32mg are combined with a single dose of 32mg data, the former resulting in castration in 2 (15%) patients for less than 2 days, and the latter resulting in castration in 8 (33%) patients, typically 2-4 days.

Conclusion

The total IPSS score and IPSS integrated QoL score were greatly improved in all treatment groups, showing beneficial effects. Unexpectedly, the improvement was found early in the treatment (14 days). All treatment groups showed a clear effect on prostate volume, a slight effect on residual urine volume after urination and an uncertain effect on maximum urine flow. The 16+16mg group showed the slightest effect in all efficacy parameters compared to the other three treatment groups.

Administration of degarelix induced a decrease in testosterone levels in all patients. The 16+16 and 32mg degarelix administrations resulted in castration levels of testosterone concentrations briefly below 0.5ng/mL in some patients, while the 32+32 and 64mg administrations resulted in longer periods of sub-castration concentrations in more patients. The IIEF score showed a slight deterioration of erectile function in all treatment groups, most evident in patients with testosterone levels below castration level on day 42.

While all treatment regimens show beneficial effects, the potential for negative effects associated with 64mg and 32+32mg suggests that the preferred range is 10-40 mg degarelix (per dose), e.g., 9-33 mg degarelix per dose, 10-30 mg degarelix per dose.

There are no safety concerns regarding any dosage or dosing regimen.

Claims (18)

1. Pharmaceutical compositions for the treatment of benign prostatic hyperplasia; the pharmaceutical composition comprises 4-79 mg of degarelix or a pharmaceutically acceptable salt thereof; and a solvent; wherein the concentration of the degarelix or the salt thereof in the solvent is 5-80 mg/mL.

2. The pharmaceutical composition according to claim 1, wherein the concentration of degarelix or salt thereof in the solvent is 35-45 mg/mL.

3. A pharmaceutical composition according to claim 1 or 2, comprising 9-33 mg degarelix or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition according to claim 1, 2 or 3 comprising 10-30 mg degarelix or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to any of the preceding claims, wherein the solvent is water.

6. The pharmaceutical composition according to any one of the preceding claims, wherein the concentration of degarelix (or salt thereof) in the solvent is 40 mg/mL.

7. A pharmaceutical formulation comprising 4mg to 79mg of degarelix or a pharmaceutically acceptable salt thereof; and a solvent, wherein the concentration of the degarelix or the salt thereof in the solvent is 5-80 mg/mL.

8. The formulation according to claim 7, wherein the concentration of degarelix or salt thereof in the solvent is 35-45 mg/mL.

9. A formulation according to claim 7 or 8, which comprises 9-33 mg degarelix or a pharmaceutically acceptable salt thereof.

10. A formulation according to claim 7, 8 or 9 comprising 10-30 mg degarelix or a pharmaceutically acceptable salt thereof.

11. A composition or formulation according to any preceding claim which further comprises an excipient.

12. A composition or formulation according to claim 11, wherein the degarelix or salt thereof is a co-lyophilized powder with the excipient.

13. A composition or formulation according to claim 11 or 12, wherein the excipient is mannitol.

14. The formulation according to any one of claims 7 to 12, wherein the solvent is water.

15. The formulation according to any one of claims 7 to 13, wherein the concentration of degarelix (or salt thereof) in the solvent is 40 mg/mL.

16. A method of treating benign prostatic hyperplasia in a subject, the method comprising the steps of: administering to the subject a pharmaceutical composition comprising 4mg to 79mg of degarelix or a pharmaceutically acceptable salt thereof; and a solvent; wherein the concentration of the degarelix or the salt thereof in the solvent is 5-80 mg/mL.

17. A kit of parts for providing a composition or a pharmaceutical formulation comprising 4mg to 79mg degarelix or a pharmaceutically acceptable salt thereof; and a solvent; wherein the concentration of the degarelix or the salt thereof in the solvent is 5-80 mg/mL; the kit of parts comprises one or more containers of degarelix or a pharmaceutically acceptable salt thereof; and one or more containers of solvent, optionally, and equipment for reconstitution.

18. A method of preparing a composition for treating benign prostatic hyperplasia, the method comprising: combining at least one first container holding a composition or pharmaceutical formulation comprising 4mg to 79mg of degarelix or a pharmaceutically acceptable salt thereof with at least one second container holding a solvent; wherein the concentration of the degarelix or the salt thereof in the solvent is 5-80 mg/mL.