Composition for treatment of prostate cancer

Abstract

To provide a composition for the treatment of prostate cancer.SOLUTION: A composition for treating prostate cancer in a patient, comprises degarelix or a pharmaceutically acceptable salt thereof, wherein the composition is used to reduce the serum testosterone level to 0.5 ng / mL or below three days after a starting dose, and to maintain the serum testosterone level at 0.5 ng / mL or below for the duration of the treatment.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention relates to a composition for treating prostate cancer.

Background Art

[0002] Prostate cancer is a major cause of death and morbidity in men in the industrialized world. Most prostate cancers grow in a testosterone-dependent manner, and current medical approaches in the management of progressive prostate cancer include androgen blockade. The aim is to reduce serum testosterone (T) to castrate levels (<T≦0.5 ng / mL). This can be achieved, for example, by bilateral orchiectomy or by administration of a gonadotropin-releasing hormone (GnRH) receptor agonist.

[0003] Gonadotropin-releasing hormone (GnRH) is a natural hormone produced by the hypothalamus and acting at the pituitary to interact with receptors and stimulate the production of luteinizing hormone (LH). To reduce the production of LH, agonists of GnRH receptor (GnRH-R) such as leuprolide (Lupron) and goserelin have been developed. Such GnRH-R agonists initially act to stimulate the release of LH and, after long-term treatment, act to desensitize GnRH-R so that LH is no longer produced, ultimately resulting in the suppression of testosterone production by the testes. However, the initial stimulation of LH production by such agonists leads to an initial surge in male hormone production. This phenomenon, known as the "testosterone surge" or "flare reaction", persists for up to 2-4 weeks and may stimulate prostate cancer. This can lead to worsening of current symptoms or spinal cord compression, bone pain, and bone fractures. may lead to the emergence of new symptoms such as urinary obstruction. To avoid this problem, one approach taken has been the administration of GnRH-R agonists, known as total androgen ablation therapy (AAT), in combination with antiandrogen drugs such as flutamide or bicalutamide. However, the use of antiandrogen drugs is associated with significant side effects in the liver and gastrointestinal tract.

[0004] Antagonists of the gonadotropin-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 the GnRH receptor and block it, causing a rapid decrease in the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby reducing testosterone production without an initial stimulus / surge. However, GnRH antagonist peptides are often associated with the development of histamine-releasing activity.

[0005] In androgen blockade therapy for treating prostate cancer, the use of both GnRH agonists and antagonists has shown promising results, but there are concerns regarding the relative safety of the available drugs. For example, the GnRH antagonist abarelix (trademark) has been found to pose a risk of serious allergic reactions, including anaphylaxis with hypotension and loss of consciousness, and has also been found to lose efficacy during treatment in some cases. In fact, abarelix (trademark) (Plenaxis (trademark) in the United States) was ultimately approved, but only for selected patients with advanced prostate cancer, and for commercial reasons clearly related to these problems. ​ , ultimately withdrew from the market in 2005. In particular, it has been suggested that certain androgen blockade therapies can have harmful effects on cardiovascular health (see Yannucci et al. (2006 ) J. Urology 176: 520 - 525, and Etzioni et al. (199 9) J. Natl. Canc. Inst. 91: 1033).

[0006] The applicants have developed a third - generation GnRH antagonist for the treatment of prostate cancer, namely degarelix. Degarelix is a synthetic decapeptide antagonist of GnRH . Long - term evaluation in a multi - center randomized trial has demonstrated that degarelix is effective and has good tolerability without the findings of systemic allergic reactions . (See Koechling et al., "Effect of various GnRH antagonists on histamine release from human ski n"; Poster, 8th Int. Symp. GnRH Analogues i n Cancer & Human Rep.; European J. Pharm., March 2009 (submitted)). An application for marketing approval / new drug application as a once - monthly administration formulation was submitted to the FDA and EMEA on February 27, 2008. Marketing approval was obtained from the FDA on December 24, 2008, and from the EMEA on February 27, 2009 . . .

[0007] However, while minimizing the dosing requirements (thus, for example, reducing the need for the patient's monthly hospital visits) , there is a need for a treatment regimen that maintains serum testosterone below 0.5 ng / mL for an extended period (e.g., over one year). There is a need for a treatment regimen that maintains serum testosterone below 0.5 ng / mL for an extended period (e.g., over one year).

[0008] The applicants have found that to maintain serum testosterone below 0.5 ng / mL over a longer period (i.e., to prevent testosterone breakthrough), it is necessary to administer degarelix such that the median trough plasma concentration is maintained above 9 - 10 ng / mL, preferably above 11 or 12 or 13 ng / mL (see Figure 1). Conventional formulations (e.g., monthly dosing formulations) do not prevent testosterone breakthrough over a three - month period. However, simply increasing the dose is not straightforward, both due to the risk of side effects and the fact that the dose size can become unwieldy. There is a need for a treatment regimen that maintains serum testosterone below 0.5 ng / mL for an extended period (e.g., over one year). There is a need for a treatment regimen that maintains serum testosterone below 0.5 ng / mL for an extended period (e.g., over one year). The applicants have found that to maintain serum testosterone below 0.5 ng / mL over a longer period (i.e., to prevent testosterone breakthrough), it is necessary to administer degarelix such that the median trough plasma concentration is maintained above 9 - 10 ng / mL, preferably above 11 or 12 or 13 ng / mL (see Figure 1). Conventional formulations (e.g., monthly dosing formulations) do not prevent testosterone breakthrough over a three - month period. However, simply increasing the dose is not straightforward, both due to the risk of side effects and the fact that the dose size can become unwieldy. (See Figure 1). Conventional formulations (e.g., monthly dosing formulations) do not prevent testosterone breakthrough over a three - month period. However, simply increasing the dose is not straightforward, both due to the risk of side effects and the fact that the dose size can become unwieldy. (See Figure 1). Conventional formulations (e.g., monthly dosing formulations) do not prevent testosterone breakthrough over a three - month period. However, simply increasing the dose is not straightforward, both due to the risk of side effects and the fact that the dose size can become unwieldy. (See Figure 1). Conventional formulations (e.g., monthly dosing formulations) do not prevent testosterone breakthrough over a three - month period. However, simply increasing the dose is not straightforward, both due to the risk of side effects and the fact that the dose size can become unwieldy.

[0009] Degarelix is formulated as a powder (degarelix acetate) that is reconstituted as a solution for subcutaneous injection. The powder is reconstituted with water for injection ("WFI") or, depending on the dose and concentration of degarelix, with a mannitol solution (e.g., 2.5% or 5%) to maintain isotonicity. Degarelix is formulated as a powder (degarelix acetate) that is reconstituted as a solution for subcutaneous injection. The powder is reconstituted with water for injection ("WFI") or, depending on the dose and concentration of degarelix, with a mannitol solution (e.g., 2.5% or 5%) to maintain isotonicity. Degarelix is formulated as a powder (degarelix acetate) that is reconstituted as a solution for subcutaneous injection. The powder is reconstituted with water for injection ("WFI") or, depending on the dose and concentration of degarelix, with a mannitol solution (e.g., 2.5% or 5%) to maintain isotonicity. Degarelix is formulated as a powder (degarelix acetate) that is reconstituted as a solution for subcutaneous injection. The powder is reconstituted with water for injection ("WFI") or, depending on the dose and concentration of degarelix, with a mannitol solution (e.g., 2.5% or 5%) to maintain isotonicity.

[0010] In an aqueous medium at a concentration of 5 mg / mL or higher, degarelix acetate exhibits nucleation - dependent fibrillation, which confers on the substance the ability to form an in - vivo gel - like depot at the injection site. Thus, when it comes into contact with body tissues such as plasma, degarelix spontaneously forms a gel depot. Degarelix is then released from the depot by sustained diffusion. The fibrillation of degarelix follows a nucleation - dependent mechanism, and thus the properties of the depot are mainly related to the degarelix concentration. In an aqueous medium at a concentration of 5 mg / mL or higher, degarelix acetate exhibits nucleation - dependent fibrillation, which confers on the substance the ability to form an in - vivo gel - like depot at the injection site. Thus, when it comes into contact with body tissues such as plasma, degarelix spontaneously forms a gel depot. Degarelix is then released from the depot by sustained diffusion. The fibrillation of degarelix follows a nucleation - dependent mechanism, and thus the properties of the depot are mainly related to the degarelix concentration. In an aqueous medium at a concentration of 5 mg / mL or higher, degarelix acetate exhibits nucleation - dependent fibrillation, which confers on the substance the ability to form an in - vivo gel - like depot at the injection site. Thus, when it comes into contact with body tissues such as plasma, degarelix spontaneously forms a gel depot. Degarelix is then released from the depot by sustained diffusion. The fibrillation of degarelix follows a nucleation - dependent mechanism, and thus the properties of the depot are mainly related to the degarelix concentration. In an aqueous medium at a concentration of 5 mg / mL or higher, degarelix acetate exhibits nucleation - dependent fibrillation, which confers on the substance the ability to form an in - vivo gel - like depot at the injection site. Thus, when it comes into contact with body tissues such as plasma, degarelix spontaneously forms a gel depot. Degarelix is then released from the depot by sustained diffusion. The fibrillation of degarelix follows a nucleation - dependent mechanism, and thus the properties of the depot are mainly related to the degarelix concentration. In an aqueous medium at a concentration of 5 mg / mL or higher, degarelix acetate exhibits nucleation - dependent fibrillation, which confers on the substance the ability to form an in - vivo gel - like depot at the injection site. Thus, when it comes into contact with body tissues such as plasma, degarelix spontaneously forms a gel depot. Degarelix is then released from the depot by sustained diffusion. The fibrillation of degarelix follows a nucleation - dependent mechanism, and thus the properties of the depot are mainly related to the degarelix concentration. In an aqueous medium at a concentration of 5 mg / mL or higher, degarelix acetate exhibits nucleation - dependent fibrillation, which confers on the substance the ability to form an in - vivo gel - like depot at the injection site. Thus, when it comes into contact with body tissues such as plasma, degarelix spontaneously forms a gel depot. Degarelix is then released from the depot by sustained diffusion. The fibrillation of degarelix follows a nucleation - dependent mechanism, and thus the properties of the depot are mainly related to the degarelix concentration.

[0011] Degarelix is proposed to be released from the depot in two stages, namely an initial rapid release responsible for the high plasma concentration levels immediately after administration and a slower release stage that determines the plasma concentration levels during the maintenance period. In the pharmacokinetic (PK) modeling of degarelix, these two different stages have been described as two primary input stages that control the release from the depot, namely a rapid input that is responsible for the initial rapid release and is represented by the rapid absorption half-life, and a slow input that is responsible for the observed long-term stage and is represented by the slow absorption half-life.

[0012] The area under the concentration-time curve (AUC) is related to both the dose and concentration of the injection solution. As the dose increases, the AUC increases, but if the concentration of the injection solution is increased, the AUC decreases. Thus, the absolute bioavailability when using dose concentrations of 10, 20, 30, 40, and 60 mg / mL was estimated to be 43.4%, 40.0%, 31.1%, 27. 4%, and 21.3%, respectively. That is, increasing the concentration results in a decrease in the overall bioavailability. The practical advantage of increasing the concentration is recognized to be, for example, a decrease in the volume of the injection solution and an associated increase in the likelihood of patient compliance.

[0013] The applicants have found that administration at high doses and high concentrations of degarelix, such as those applied during the maintenance period, unexpectedly leads to slower release characteristics of degarelix from the resulting depot (along with the overall decrease in degarelix bioavailability discussed above). ​​​​presented. This surprising effect is achieved with a defined dose of degarelix, at a defined high concentration, administered to release sufficient degarelix to have the desired therapeutic effect (i.e., the required plasma concentration), but releasing it sufficiently slowly so that its plasma concentration is maintained at a therapeutically effective level for a long period (assuming the starting dose is sufficient, e.g., for more than 3 months), which means a depot is obtained. Increasing the concentration of degarelix means that at these higher doses, there is the unexpected benefit that the sustained release ability actually increases, and the size of the injection solution is also manageable. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0014] The present inventors have developed a composition for administering degarelix at high doses and high concentrations, which, when administered according to the present invention, can provide sustained release of degarelix without the need for monthly injections.

[0015] Accordingly, according to the present invention, in a first aspect, there is provided a composition for treating prostate cancer comprising degarelix or a pharmaceutically acceptable salt thereof (e.g., acetate), comprising a lyophilizate of degarelix dissolved in a solvent (e.g., an aqueous solvent, e.g., water) and an additive (e.g., a co-lyophilizate, e.g., a sugar, e.g., mannitol), administered to a patient at a starting dose of degarelix of 200 - 300 mg and a degarelix concentration in the solvent of 20 - 80 mg / mL, and then, 14 - 56 days after the starting dose, at a maintenance dose of degarelix of 320 - 550 mg and a degarelix concentration in the solvent of 50 - 80 mg / mL, and then (optionally) one or more ​​​​​​A further maintenance dose of degarelix is 320-550 mg, and the concentration of degarelix in the solvent is 50 -80 mg / mL, and a composition in which each maintenance dose is administered at intervals of 56 to 112 days is provided.

[0016] In one example, the composition is administered to a patient at a starting dose of 200-300 mg, and then one month after the starting dose, for example 28 days later, it is administered at a maintenance dose of 320-550 mg, and then subsequently one or more further maintenance doses of 320-550 mg are administered at intervals of 3 months (for example 84 days). The starting dose of degarelix can be, for example, 240 mg, for example the concentration of degarelix in the solvent can be 40 mg / mL. The maintenance dose, or each maintenance dose, can be, for example, 360 mg or 480 mg, for example, the concentration of degarelix in the solvent can be 6 0 mg / mL.

[0017] Degarelix (or a pharmaceutically acceptable salt thereof) is administered, for example, as a solution in a solvent such as an aqueous solvent, for example water ( for example WFI), or a solution of water and mannitol. The starting dose and the maintenance dose can be administered by injection. The maintenance dose is preferably administered as two injections, each containing (substantially) half of the maintenance dose. By means of the composition, for example, starting from 28 days after the starting dose, a therapeutically effective average plasma trough concentration of degarelix (plasma concentration 9 ng / mL or more, preferably 10 ng / mL or more, for example 12 ng / mL or more, measured by techniques known in the art) can be obtained, and this therapeutically effective concentration can be maintained, for example, for at least 365 days and / or throughout the treatment duration. In this specification, the term "treatment duration" refers to the duration of maintaining the treatment with degarelix. maintenance of the treatment with degarelix. ​​means for as long as the maintenance dose is administered, and thus "maintaining this therapeutically effective concentration over the treatment continuation period" means that the therapeutically effective concentration is maintained until at least the last maintenance dose is administered. The composition can lower the patient's serum testosterone level to 0.5 ng / mL or less, for example, starting from, for example, 3 days after the starting dose, for example, 7 days after, for example, 14 days after, for example, 28 days after, and can maintain the serum testosterone level at 0.5 ng / mL or less for at least 365 days and / or over the treatment

[0018] continuation period. Experimentally, it has been demonstrated that 240 mg (40 mg / mL) is an effective starting dose. In a 1-month dosing schedule study, two types of monthly maintenance doses, namely 160 mg (40 mg / mL) and 80 mg (20 mg / mL), were demonstrated to be effective with testosterone response rates of 100% and 98% respectively from day 28 to day 364. However, at doses of 240 mg, 160 mg or 80 mg, testosterone suppression will not persist for 3 months after injection. Therefore, with a starting dose of 240 mg (40 mg / mL), additional doses will be required before 3 months (e.g., on day 28). In a simulation of a "true" 3-month dosing schedule of 480 mg [i.e., with a starting dose of 480 mg and additional doses at 3, 6, and 9 months], the PK trough level (desogestrel concentration) is approximately 8 ng / mL, suggesting it is insufficient. It is considered that the steady- It is not practical to use a higher dose as the starting dose to achieve a monthly depot. This is because a sufficient release during the start / initial dosing phase to increase the degarelix concentration in plasma and, at the same time, a sufficient long-term release to achieve a sufficiently high steady-state concentration over 3 months are both required. The Applicants have surprisingly found that, with the defined composition, for example, starting from 28 days after the starting dose, an average therapeutically effective plasma concentration of degarelix ( plasma trough concentration of 9 ng / mL or higher) can be obtained, and this therapeutically effective concentration can be maintained, for example, for at least 365 days and / or over the treatment duration without the need for a monthly maintenance dose. Even more surprisingly, the defined composition (when used in this method) and treatment by the Applicants do not involve a significant increase in the side effects associated with injection (compared to the administration of a dose of 240 mg of degarelix at a concentration of 40 mg / mL). This is particularly significant considering the high dose (and concentration) of degarelix in the defined maintenance dose(s).

[0019] The maintenance dose concentration of degarelix or its pharmaceutically acceptable salt is 50 - 80 mg / mL of degarelix in the solvent, for example 50, 51, 52, 53, 54, 55, 56, 57, 58 , 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 mg / mL, for example 55 - 65 mg / mL. The Applicants have found that the maintenance dose of degarelix or its pharmaceutically acceptable salt (such as acetate) in a solvent such as water, with degarelix and additives by dissolving a lyophilisate containing an agent (e.g. a co-lyophilisate, e.g. mannitol) formed], e.g. 360 mg, 480 mg, degarelix concentration in solvent, e.g. 55- It has been found that administration of between 65 mg / mL, e.g. 60 mg / mL, can be particularly effective. Maintenance dose of degarelix or its pharma- ceutical acceptable salt is 480 mg, degarelix in vehicle. 60 mg / mL at 84-day intervals (once every 3 months) (e.g., 2 times the starting dose) Effective suppression of testosterone by starting the first maintenance dose 8 days later (1 month later) (i.e., a rapid decline in testosterone to less than 0.5 ng / mL, and this level and the associated prevention of testosterone breakthrough) for a period of up to one year. or more can be obtained without significant likelihood of adverse effects. This is especially noteworthy given the high dose and two injections. Amazingly, this compares with the much lower monthly dose, which is a single injection. , there is no increase in injection-related side effects.

[0020] In yet another aspect of the invention, the compound is dissolved in a solvent (e.g., an aqueous solvent, e.g., water). Degarelix or a pharma- ceutically acceptable salt thereof (e.g., degarelix acetate) and lyophilisates of excipients (e.g. co-lyophilisates, e.g. mannitol) and The concentration of degarelix in the solvent is 40 to 80 mg / mL, preferably 50 to 80 mg / mL. Certain pharmaceutical formulations (e.g., injectable formulations) are provided. The concentration of the salt to be used is between 50 and 80 mg / mL of degarelix in the solvent, e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 6 5, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78 , 79, 80 mg / mL, and can be, for example, 55 - 65 mg / mL. The amount of degarelix is between 320 - 550 mg (for example, between 350 - 490 mg, for example, between 440 - 5 20 mg). The amount of degarelix can be, for example, 240 mg, 360 m g or 480 mg. The pharmaceutical preparation can be administered, for example, by injection, for example, as a single

[0021] injection, preferably as two injections, etc. In yet another aspect of the present invention, a component kit for providing a composition comprising degarelix dissolved in a solvent (for example, an aqueous solvent, for example, water) at a concentration of 20 - 80 mg / mL or a pharmaceutically acceptable salt thereof (for example, degarelix acetate) and an additive (for example, a co - lyophilized product, for example, sugar, for example, mannitol) in the form of a lyophilized product, comprising one or more containers (for example, vials) of degarelix or a pharmaceutically acceptable salt thereof and an additive, and one or more containers (for example, vials, pre - filled syringes) of the solvent, optionally together with means for administration (for example, injection) (for example, a syringe and / or a safety needle, cannula, etc.). The kit optionally includes means (for example, an adapter means, for example, an adapter) for the solvent to move (to , between 20 and 80 mg / mL, for example between 50 and 80 mg / mL, for example between 55 and 65 mg / mL, for example 56, 57, 58, 59, 60, 61, 62, 63, 64 mg / mL of the solution having a degarelix concentration can be provided. The amount of degarelix is between 220 and 550 mg of degarelix, for example between 320 and 550 mg (for example between 350 and 490 mg between, for example between 440 and 520 mg). The amount of degarelix can be, for example 240 mg, 360 mg or 480 mg. In one example, the kit can provide a solution having 480 mg of degarelix at a concentration of 60 mg / mL. The kit can, for example, include two containers (e.g., vials) of 240 mg of degarelix and, for example, a single container (vial) of a liquid preparation (e.g g., 10 mL of WFI). It will be readily understood by those skilled in the art that when each vial of degarelix is mixed with, for example, 4.2 mL of WFI, 4 mL of a solution of approximately 240 mg of degarelix at a concentration of 60 mg / mL is obtained, and combining the two vials constitutes a maintenance dose of 8 mL for a single injection or, more preferably, two injections. In a further example, the kit can include two containers (e.g., vials) of 240 mg of degarelix (as a lyophilized product with additives) and, for example, two prefilled syringes each containing WFI (4 2 mL). It will be readily understood by those skilled in the art that when a prefilled syringe containing 4.2 mL of WFI is mixed with 240 mg of degarelix in one of the containers, 4 mL of a solution (injection solution) of approximately 240 mg of degarelix at a concentration of approximately 60 mg / mL is obtained and combining two such syringes and two containers constitutes an injection maintenance dose of 8 mL [for two injections] of 480 mg will be readily understood by those skilled in the art. When a prefilled syringe containing 4.2 mL of WFI is mixed with 240 mg of degarelix in one of the containers , 4 mL of a solution (injection solution) of approximately 240 mg of degarelix at a concentration of approximately 60 mg / mL is obtained and combining two such syringes and two containers each constitutes an injection maintenance dose of 8 mL [for two injections] of 480 mg will be readily understood by those skilled in the art.

[0022] In yet another aspect of the present invention, there is provided a method of treating prostate cancer, comprising administering to a subject in need thereof A composition comprising a lyophilized form of degarelix and excipients dissolved in a solvent for patients The starting dose of degarelix was 200-300 mg, and the concentration of degarelix in the solvent was 20-80. 1 mg / mL, followed by a maintenance dose of 32 mg / mL degarelix 14 to 56 days after the starting dose. 0-550 mg, degarelix concentration in vehicle 50-80 mg / mL, then (optional 2) One or more further maintenance doses of degarelix 320-550 mg in vehicle Garelix concentrations of 50-80 mg / mL were administered at intervals of 56-112 days. The method includes administering to the subject a therapeutically effective amount of the compound.

[0023] Degarelix was administered at an initial dose of 200-300 mg, followed by 28 days (1 After 3 months, a maintenance dose of 320-550 mg is administered, followed by one or more further doses. Maintenance dose 320-550 mg, maintenance dose (one or more) for 84 days (3 months) The doses may be spaced apart.

[0024] The maintenance dose (single or multiple) concentration of degarelix or its pharma- ceutical acceptable salts is , 50 to 80 mg / mL, for example, 55 to 65 mg / mL.

[0025] In yet another aspect of the present invention, degarelix or a pharma- ceutically acceptable salt thereof and and a lyophilized product of degarelix or a pharma- ceutically acceptable salt thereof, At least one starting dose container in which the dry matter is present in an amount ranging from 200 mg to 300 mg; The present invention relates to a lyophilized product of degarelix or a pharma- ceutical acceptable salt thereof and an excipient, A kit comprising at least one maintenance dose container in which a lyophilizate of degarelix or a pharmaceutically acceptable salt thereof is present in an amount in the range of 320 mg to 550 mg, and at least one container containing a solvent is provided. In one example, the kit can provide a solution having degarelix 480 mg at a concentration of 60 mg / mL. The kit may include, for example, two containers (e.g., vials) of degarelix 240 mg and, for example, a single container (vial) of a liquid preparation (e.g., 6 mL or 10 mL of WFI) . Those skilled in the art will readily understand that when each vial of degarelix is mixed with, for example, 4.2 mL of WFI, a solution of about 240 mg of degarelix at a concentration of 60 mg / mL in 4 mL is obtained, and combining the two vials constitutes a maintenance dose of 8 mL for a single injection or, more preferably, two injections . In yet another example, a kit according to the present disclosure includes a lyophilizate of degarelix or a pharmaceutically acceptable salt thereof and an additive, and at least one first container in which a lyophilizate of degarelix or a pharmaceutically acceptable salt thereof is present in an amount in the range of 320 mg to 550 mg , and at least one second container containing a solvent. In yet another aspect of the invention, a method for preparing an initial dose concentration and a maintenance dose concentration for treating prostate cancer in a patient in need thereof is provided. The method comprises combining at least one initial dose container containing a lyophilizate of degarelix or a pharmaceutically acceptable salt thereof and an additive, and at least one container containing a solvent, with degarelix .

[0026] In yet another example, a kit according to the present disclosure includes a lyophilizate of degarelix or a pharmaceutically acceptable salt thereof, and at least one first container in which a lyophilizate of degarelix or a pharmaceutically acceptable salt thereof is present in an amount in the range of 320 mg to 550 mg , and at least one second container containing a solvent.

[0027] or a pharmaceutically acceptable salt thereof in the range of 320 mg to 550 mg, and at least one container containing a solvent . A method for preparing an initial dose concentration and a maintenance dose concentration for treating prostate cancer in a patient in need thereof is provided. The method comprises combining at least one initial dose container containing a lyophilizate of degarelix or a pharmaceutically acceptable salt thereof and an additive, and at least one container containing a solvent, with degarelix or a pharmaceutically acceptable salt thereof in the range of 320 mg to 550 mg, and at least one container containing a solvent or a lyophilized product of the lyophilized product of the lyophilized product and a pharma- ceutically acceptable salt thereof and an excipient is dissolved in a solvent and Steps to achieve a degarelix concentration range of 80 mg / mL in vehicle and form the starting dose concentration After an interval ranging from 14 to 56 days from the formation of the starting dose, degarelix or At least one maintenance dose volume containing a lyophilized form of the pharma- ceutically acceptable salt and excipients. and combining the container with at least one second container containing a solvent, Lyophilized products of pharma- ceutically acceptable salts and excipients are dissolved in a solvent and are 50-80 mg / 5. A method for producing a degarelix concentration range in 10 mL of solvent to form a maintenance dose concentration; At least one maintenance dose container is combined with at least one container containing a solvent to produce a maintenance dose. The step of forming a maintenance dose concentration is repeated at least once within 56 days of the previous maintenance dose combination. and repeating after an interval ranging from 1 to 112 days.

[0028] In yet another aspect of the invention, a method for preparing a composition for treating prostate cancer is provided. The method comprises administering degarelix or a pharma- ceutical acceptable salt thereof and an excipient to the subject. At least one first container containing the lyophilisate and at least one second container containing a solvent. and combining the degarelix or a pharma- ceutically acceptable salt thereof and excipients therewith. The dried material was dissolved in the solvent to achieve a degarelix concentration range of 50-80mg / mL in the solvent. and forming a maintenance dose concentration.

[0029] The maintenance dose concentration is between 50 and 80 mg / mL, for example 5, depending on the preparation method. 5 to 65 mg / mL, e.g., 56, 57, 58, 59, 60, 61, 62, 63 or 6 A solution having a degarelix concentration in a solvent of 4 mg / mL or any numerical value therebetween can be obtained. This is possible. The dosage of degarelix may be in the range of 320 mg to 550 mg (for example, 350 mg to 5 20 mg, for example, 440 mg to 490 mg). The dosage of degarelix may be, for example, 240 mg (starting dosage), 360 mg (maintenance dosage) or 480 mg (maintenance dosage).

Brief Description of the Drawings

[0030]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0031] Definitions In this specification, the terms “initial dosage”, “starting dosage” and “first administration dosage” are used interchangeably where possible. The term “plasma concentration” means “plasma trough concentration”.

[0032] The treatment period of 1 month is usually considered to be 28 days and, when used in the clinical trial results described in this specification, is defined as 28 days. Accordingly, 2 months refers to 56 days, 3 months refers to 84 days, 4 months refers to 112 days, and so on.

[0033] The term “prostate cancer” refers to any cancer of the prostate in which the cells of the prostate mutate and begin to grow uncontrollably. The term “prostate cancer” includes early, localized prostate cancer and late, locally advanced prostate Prostate cancer (where cancer cells spread (metastasize) from the prostate to other parts of the body, particularly the bones and lymph nodes) is included.

[0034] Degarelix and related pharmaceutical formulations Degarelix is a potent GnRH antagonist that incorporates p-ureido-phenylalanine at positions 5 and 6 into the GnRH decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-L eu-Arg-Pro-Gly-NH2) (Jiang et al. (2001) J. Med. Chem. 44:453-67 ). It is applied to the treatment of prostate cancer patients in whom androgen blockade is guaranteed (including patients whose PSA levels have risen after already undergoing prostatectomy or radiotherapy ).

[0035] Degarelix binds competitively and reversibly to pituitary GnRH receptors, thereby rapidly reducing the release of gonadotropins and, as a result, testosterone (T). It is a selective GnRH receptor antagonist (blocker). Prostate cancer is sensitive to testosterone blockade, which is a major principle in the treatment of hormone-sensitive prostate cancer. Unlike GnRH agonists, GnRH receptor blockers do not induce a luteinizing hormone (L H) surge following treatment initiation, subsequent testosterone surge / tumor stimulation, and potential symptomatic flare .

[0036] The active ingredient, degarelix, is a synthetic linear decapeptide amide that contains seven non-natural amino acids , five of which are D-amino acids. This drug substance is the acetate salt, but the active moiety of the substance is degarelix as the free base. The acetate salt of degarelix is (lyophilized ​​​​It is a low-density white to off-white amorphous powder obtained later. Its chemical name is D- Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro -D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4- [[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino no]-L-phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylala nyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl. This has the empirical formula C 82 H 103 N 18 O 16 Cl and has a molecular weight of 1,632.3 Da. The chemical structure of degarelix has been shown previously (European Patent No. 1003774, US Patent No. 5,925,730, US Patent No. 6,214,798), and can be represented by the formula: Ac-D-2N al-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cb m)-Leu-Lys(iPr)-Pro-D-Ala-NH2.

[0037] Degarelix can be formulated for subcutaneous administration (rather than intravenous administration), usually in the abdomen, as described in more detail below. As with other drugs administered by subcutaneous injection, the injection site can be changed regularly to adapt the treatment to the discomfort at the injection site. In general, the injection should be performed in an area where the patient is not exposed to pressure, such as an area not near the waistband or belt and not near the ribs. As with other drugs administered by subcutaneous injection, the injection site can be changed regularly to adapt the treatment to the discomfort at the injection site. In general, the injection should be performed in an area where the patient is not exposed to pressure, such as an area not near the waistband or belt and not near the ribs.

[0038] Administration of degarelix by subcutaneous or intramuscular injection works well, but daily injections ​​Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Therefore, degarelix can be provided as a powder that is redissolved (along with a solvent) as a solution for injection (e.g., subcutaneous injection as described above for forming a depot). The powder can be provided as a lyophilized product containing degarelix (e.g., as the acetate) and mannitol. A suitable solvent is water (e.g., water for injection, or WFI). The solvent can be provided in a container (e.g., a vial) containing, for example, 6 mL of the solvent. For example, degarelix can be provided in a vial containing 120 mg of degarelix (acetate) in order to be redissolved with 3 mL of WFI such that each 1 mL of the solution contains approximately 40 mg of degarelix. That is, upon redissolution, 3 mL of an injection solution containing approximately 120 mg of degarelix is obtained. Two injections of such a solution would provide a starting dose of approximately 240 mg of degarelix at a concentration of 40 mg / mL. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months.

[0039] Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. Since this is generally not preferred by patients, as described in more detail in WO 03 / 006049 and US Patent Application Publications Nos. 20050245455 and 20040038903, the depot formulation of degarelix can be utilized. Briefly, subcutaneous administration of degarelix can be carried out using a depot technology that releases this peptide from a gel-like depot, typically over a period of 1 to 3 months. Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogs. Degarelix and these related GnRH antagonists can form a gel after subcutaneous injection, and this gel can act as a depot that releases this peptide over periods of weeks or even months. provides a dose. In another example, degarelix can be provided in a vial containing 240 mg of degarelix (acetate). After redissolving with approximately 4 mL of WFI, each 1 mL of the solution contains approximately 60 mg of degarelix. Two injections of such a solution provide a maintenance dose of approximately 48 0 mg of degarelix at a concentration of 60 mg / mL. In another example, degarelix can be provided in a vial containing 18 0 mg of degarelix (acetate). After redissolving with approximately 3 mL of WFI, each 1 mL of the solution contains approximately 60 mg of degarelix. Two injections of such a solution provide a maintenance dose of approximately 360 mg of degarelix at a concentration of 60 mg / mL. The reconstituted solution ready for injection should be perceived as a visually clear liquid. The dosing schedule of degarelix can be as follows: as a starting dose of 240 mg, administer 3 mL of the degarelix formulation at approximately 40 mg / mL as two injections, and then as a maintenance dose of 480 mg, administer 4 mL of the degarelix formulation at approximately 60 mg / mL as two injections. After administration of the starting dose, the maintenance dose is then administered at intervals in the range of 14 to 56 days, for example 14 days,

[0040] 28 days, 56 days, or any interval in between, and for example at an interval of 28 days. The maintenance dose contains degarelix or a pharmaceutically acceptable salt, additive, and solvent thereof. The maintenance dose is in the range of 320 mg to 550 m g of degarelix or a pharmaceutically acceptable salt thereof, for example from 320 mg, to 340 mg, 360 mg, 380 mg, 400 mg,

[0041] 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 m g, etc. The maintenance dose contains degarelix or a pharmaceutically acceptable salt, additive, and solvent thereof. The maintenance dose is in the range of 320 mg to 550 m g of degarelix or a pharmaceutically acceptable salt thereof, for example from 320 mg, to 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 m g, 550 mg, or any value therebetween, as well as, for example, degarelix or 360 mg or 480 mg of degarelix or its pharma- ceutical acceptable salt. The maintenance dose concentration of the pharma- ceutically acceptable salt is in the range of 50 mg / mL to 80 mg / mL, e.g. From 50mg / mL to 55mg / mL, 60mg / mL, 65mg / mL, 70mg / mL mL, 75mg / mL, 80mg / mL, or any value in between, as well as examples For example, 60 mg / mL of degarelix or a pharma- ceutically acceptable salt thereof. The dosing regimen for degarelix is as follows: after administration of the starting dose, degarelix or its pharmacologic The maintenance dose of the salt is 360 mg or 480 mg, and the 4ml of approximately 60 mg / mL in the solvent is used. L can be administered as two injections.

[0042] Further maintenance doses may be administered at intervals of 56 to 112 days, e.g., 5 days, after administration of the first maintenance dose. It may be administered on 6 days, 84 days, 112 days, or any interval therebetween, even on 84 days, for example. Administration of additional maintenance dose(s) may continue as necessary. (e.g., a maintenance dose may be administered 56 to 112 days after the previous maintenance dose). The maintenance dose comprises degarelix or a pharma- ceutical acceptable salt thereof, excipients, and solvents. Further maintenance doses include 320 mg of degarelix or a pharma- ceutical acceptable salt thereof. ~550mg range, for example, from 320mg, 340mg, 360mg, 380mg, 4 00mg, 420mg, 440mg, 460mg, 480mg, 500mg, 520mg , 540 mg, 550 mg, or any value in between, and even Degarelli, for example. Degarelix or its pharma- ceutical acceptable salts, 360 mg or 480 mg. The concentration of the further maintenance dose of degarelix or a pharmaceutically acceptable salt thereof is in the range of 50 mg / mL to 80 mg / mL, for example, from 50 mg / mL, to 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, or any number in between, and further for example 60 mg / mL of degarelix or a pharmaceutically acceptable salt thereof. g / mL, and further for example from 50 mg / mL to, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, or any number in between, and further for example 60 mg / mL of degarelix or a pharmaceutically acceptable salt thereof. g / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, or any number in between, and further for example 60 mg / mL of degarelix or a pharmaceutically acceptable salt thereof. g / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, or any number in between, and further for example 60 mg / mL of degarelix or a pharmaceutically acceptable salt thereof. is.

Example

[0043] Administration and Dosage Example 1 - Clinical Trial During the progress of the degarelix development program, better understanding was obtained regarding PK data, PD data, and the relationships of these with other parameters using population pharmacokinetics / pharmacodynamics (PK / PD) modeling and simulation. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more. PD) modeling and simulation were used to gain a better understanding of PK data, PD data, and the relationships of these with other parameters. From the results obtained in previous trials, at a median plasma trough concentration of 7.34 ng / mL of degarelix, 96% of patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28, and at a median plasma concentration of 4.54 ng / mL, 83% of this same patient group achieved T ≤ 0.5 ng / mL on day 84. Due to the variability in the population, this median plasma concentration was considered insufficient to maintain testosterone suppression for a long period in approximately 95% of patients. Therefore, in the phase 3 trial regarding the 1-month dosing program, it was proposed that the dose administered should result in a mean serum trough level of degarelix of 9 ng / mL or more.

[0044] The proportion of castrated patients [(T) ≤ 0.5 ng / mL] after day 28 and degarelix The relationship between the concentration of α-glutamate and β-glutamate is shown in Figure 1. This is a comparison of the data from 1473 prostate cancer patients in a clinical trial. Based on the data, PK levels were set at 0–1, 1–2, 2–3 ng / mL, and so on. The observed proportions were plotted against the midpoints of the PK intervals, with smoothed lines plotted with 95% confidence intervals (CIs). This plot shows the threshold value for degarelix concentrations of 9 to 10 ng / mL. The higher end of the scale indicates that 97% of patients are castrated.

[0045] Therefore, in the 1-month dosing schedule clinical program, the starting dose was 240 mg (40 mg g / mL) resulted in castrate levels of testosterone in 95% of patients within the first 28 days The results showed that the T suppression to 0.5 ng / mL or lower was achieved. 80 mg (20 mg / mL) was sufficient for a 1-month program. The mean trough level at the maintenance dose of 20 mg / mL was approximately 12 ng / mL. Ta.

[0046] Therefore, in a one-month degarelix treatment program, A starting dose of 2 mL was established as the most effective starting dose tested. The 40 mg (40 mg / mL) dose was also used in the 3-month dosing schedule study. In the study, two maintenance doses were administered: 160 mg (40 mg / mL) and 80 mg / mL. g (20 mg / mL) were used to evaluate the testosterone response rate from days 28 to 364, respectively. It has been shown to be 100% and 98% effective. All doses tested in the study maintained testosterone suppression for up to three months after injection. The applicants have been unable to continue the study with a starting dose of 240 mg (40 mg / mL). It was found that additional doses were required around day 28.

[0047] In the Phase 2 trial of the 3-month dosing schedule, three different dosing schedules were considered. The starting dose was 24 0 mg (40 mg / mL), followed by an additional dose of 240 mg administered on day 28, and then administered at 3, 6, and 9 months, or at 4, 7, and 10 months. The maintenance dose of 24 0 mg was initially at a concentration of 40 mg / mL or 60 mg / mL in this trial and was evaluated based on the results observed with different PK profiles at different concentrations . Patients were randomly assigned to one of the following three different degarelix 3-month maintenance dose dosing schedules simultaneously. 240 mg (40 mg / mL) at 1, 3, 6, 9 months 240 mg (60 mg / mL) at 1, 3, 6, 9 months 240 mg (60 mg / mL) at 1, 4, 7, 10 months

[0048] For all three treatment regimens, the lower limit of the confidence interval was not below the 80% level. Therefore, the primary objective of demonstrating efficacy in achieving and maintaining castrate levels of testosterone over one year in at least 80% of patients was not achieved. The present applicants found that the most important predictor of the time until testosterone exceeds 0.5 ng / mL was the plasma level of degarelix during the course of treatment. Thus , patients with lower plasma levels of degarelix were more likely to have testosterone levels exceed 0.5 ng / mL during the one-year treatment period. Analysis of monthly testosterone data showed that patients remained suppressed at the two post-dose visits, but at the next dose after 3 months Individual patient data indicate that there is a tendency for testosterone escape just before reported that most patients who experience testosterone breakthrough are again suppressed after retreatment. This is true for all three treatment groups. The first time a testosterone level above 0.5 ng / mL occurred in 1 patient was the pre- Consistent with the observation that degarelix plasma trough levels were at 3 months after the first dose The median trough levels of degarelix in this study were approximately 6.5-7.5 ng / mL. This is in the range of 0.5 nM in approximately 95% of patients. Degarelix levels of 9 to 10 ng / mL are considered necessary to maintain the blood glucose level at or below 1 g / mL. , indicating that a higher maintenance dose of degarelix is required.

[0049] Therefore, in this study, the starting dose of degarelix was 240 mg (40 mg / mL), followed by A higher maintenance dose of degarelix, i.e., 360 mg (60 mg / mL) or 480 mg / mL, The latter was administered at months 1, 4, 7, and 10. Ta.

[0050] Stage and duration of prostate cancer at enrollment The study was recently completed with enrollment of 133 patients (planned enrollment was 120). Baseline disease characteristic variables were compared with those of the Phase 2 study of the 3-month dosing regimen. The results of these studies are summarized in Table 1. Approximately 10% of patients with localized cancer receive treatment with curative intent. Most patients had a Gleason score of 7–10, and most The patients had normal activity as assessed by the ECOG activity scale. The average disease duration from diagnosis is also shown.

[0051]

Table 1

[0052] This trial was a general clinical trial, and patients were administered an initial dose of 240 mg (40 mg / m L) at month 0 and then received one of two treatment regimens of the following degarelix maintenance doses . 360 mg (60 mg / mL) at months 1, 4, 7, and 10 480 mg (60 mg / mL) at months 1, 4, 7, and 10

[0053] The initial dose was administered subcutaneously as two 120 mg (40 mg / mL) injections. After 28 days, the maintenance dose of 360 mg (concentration 60 mg / mL, administered as two 3 mL injections) or 480 mg (concentration 60 mg / mL, administered as two 4 mL injections) was similarly administered as two injections (240 mg each). Thereafter, the maintenance dose was administered again in the form of two injections at intervals of once every three months. The re-dissolution of degarelix to form the depot and the subsequent subcutaneous injection technique are known to those skilled in the art and have been discussed previously in this specification. At each visit, serum testosterone, prostate-specific androgen, and the plasma concentration of degarelix were measured by techniques known in the art.

[0054] The cumulative probability of maintaining testosterone response (T≤0.5 ng / mL) from day 28 to day 364 is shown in Table 2 for each treatment dose. Compared with the 360 mg (60 mg / mL) dose regimen (8 9.0%), the higher dose of 480 mg (60 mg / mL) was numerically greater Shows a treatment response (93.3% of patients maintained castration levels of testosterone). Having a true suppression rate exceeding the 90% control threshold, even if not a statistically significant difference At the confidence inclusion probability, the difference between the two treatment groups is significant. That is, the 480 mg treatment group has a 79.9% confidence level of a true suppression rate exceeding 90%, while the 360 mg treatment group is only 39.7%.

[0055] [Table 2]

[0056] Table 3 shows the proportion of patients in whom testosterone was suppressed (T ≤ 0.5 ng / mL) at the time of the test visit.

[0057] The maintenance dose of degarelix at 480 mg (60 mg / mL) showed sustained suppression of testosterone in more than 95% of patients. With the maintenance dose of 360 mg (60 mg / mL), there was sustained suppression of testosterone in at least 90% of patients. The relatively low values occurred immediately before readministration, at 7 months (day 196, 90.6%) and 10 months (day 280, 93.3 %). Overall, 125 out of 127 patients (98%) showed suppression of testosterone levels below castration levels on day 28.

[0058] Figure 2 is a graph showing the trough plasma concentration levels of degarelix and the response of testosterone after different dosing schedules over 3 months. Median and the response of testosterone.

[0059] [Table 3]

[0060] Table 4 shows the median change rate of PSA at the time of the test visit. After 1 month, there was a further decrease in PSA, and the median decrease persisted throughout the test period (96 - 97% median decrease ).

[0061]

Table 4

[0062] Adverse events By the data cut-off date of September 2, 2008, 133 prostate cancer patients were exposed to degarelix in the 3-month dosing clinical program (CS18) of the above example, i.e., .

[0063] The relatively common adverse events that occurred during treatment and were reported in more than 5% of patients in any of the treatment groups of CS18 are summarized as follows (% values are the overall values for both the 480 mg and 360 mg dose groups combined): hot flashes (34%), injection site pain (17% ), weight gain (11%), hypertension (8%), injection site erythema (7%), testicular atrophy (6%) , asthenia (5%), arthralgia (5%), fatigue (5%), gynecomastia (5%), fever (4%) , weight loss (5%), fever (4%). Immediate-type systemic hypersensitivity reactions have been reported with previous GnRH antagonists. Immediate-type anaphylactic reactions were not reported in this degarelix clinical pro gram.

[0064] In this clinical program, the potential to cause hepatotoxicity was intensively evaluated, and as of the data cut off date, the data showed no clinically significant decrease in liver function after degarelix treatment .

[0065] ​In Example 1, the incidence of any injection site reaction was 26%, and the incidence of this any injection site reaction was comparable between the two doses. The most frequently reported injection site reaction was injection site pain (17%). Surprisingly, these data were similar to the results of a 1-month dosing clinical program using a much lower dose of degarelix (e.g., 240 mg). Most injection site reactions were mild to moderate in severity (11% each), but 5% of patients reported severe injection site reactions. Six patients who reported severe injection site reactions reported injection site pain as a severe event.

[0066] Conclusion Therefore, the Applicants have found that the pharmacodynamic (PD) dose response is logically consistent with the pharmacokinetic (PK) / pharmacodynamic relationship with the increase in degarelix dose and the median trough level of higher degarelix (at the end of 1-year treatment or the last available final measurement). Median plasma trough levels of degarelix of approximately 7 ng / mL, 10 ng / mL, and 13 ng / mL were observed for maintenance doses of 240 mg, 360 mg, and 480 mg, respectively. In addition, there were no significant differences in the incidence and pattern of adverse events in patients treated with the 360 mg and 480 mg maintenance doses. Based on these testosterone suppression and PK results, the starting and maintenance doses described herein and defined below represent an effective 3-month dosing program.

Claims

1. A composition for treating prostate cancer in a patient, comprising degarelix or a pharmaceutically acceptable salt thereof, which is used to reduce the serum testosterone level to 0.5 ng / mL or less 3 days after the starting dose and maintain it at 0.5 ng / mL or less during the treatment period.

2. The composition according to claim 1, which is used to reduce the serum testosterone level to 0.5 ng / mL or less 7 days after the starting dose and maintain it at 0.5 ng / mL or less during the treatment period.

3. The composition according to claim 1 or 2, which is used to reduce the serum testosterone level to 0.5 ng / mL or less 14 days after the starting dose and maintain it at 0.5 ng / mL or less during the treatment period.

4. The composition according to any one of claims 1 - 3, which is used to reduce the serum testosterone level to 0.5 ng / mL or less 28 days after the starting dose and maintain it at 0.5 ng / mL or less during the treatment period.

5. The composition according to any one of claims 1 - 4, wherein the serum testosterone level is maintained at 0.5 ng / mL or less for at least 365 days.

6. The composition according to any one of claims 1 - 5, which is administered to the patient at the starting dose, then at a maintenance dose 14 - 56 days after the starting dose, and then (optionally) at one or more additional maintenance doses, with each maintenance dose being administered at intervals of 56 - 112 days.

7. The starting dose is administered as degarelix 200 - 300 mg at a degarelix concentration of 20 - 80 mg / mL in a solvent, then 14 - 56 days after the starting dose, the maintenance dose is administered as degarelix 320 - 550 mg at a degarelix concentration of 50 - 80 mg / mL in a solvent, then (optionally) one or more additional maintenance doses are administered as degarelix 320 - 550 mg at a degarelix concentration of 50 - 80 mg / mL in a solvent, with each maintenance dose being administered at intervals of 56 - 112 days. The composition according to claim 6.

8. The starting dose is administered as degarelix 200 - 300 mg, then 28 days after the starting dose, the maintenance dose is administered as degarelix 320 - 550 mg, and then one or more additional maintenance doses are administered as degarelix 320 - 550 mg, with the maintenance doses being administered at intervals of 84 days. The composition according to claim 6.

9. The concentration of the initial dose is 40 mg / mL of degarelix in a solvent, The composition according to any one of claims 6 - 8, wherein the concentration of the maintenance dose (one or more times) is 55 - 65 mg / mL of degarelix in a solvent or 60 mg / mL.

10. The initial dose is 240 mg of degarelix, The composition according to any one of claims 6 - 9, wherein the maintenance dose is 360 mg or 480 mg of degarelix.

11. The composition according to any one of claims 1 - 10, comprising a lyophilizate of degarelix and an additive dissolved in a solvent.

12. The composition according to claim 11, comprising a lyophilizate of degarelix and mannitol dissolved in water.

13. The composition according to any one of claims 1 - 12, for the treatment of metastatic prostate cancer.

14. The composition according to any one of claims 1 - 12, for the treatment of locally advanced prostate cancer.

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