Compositions for treating prostate cancer

Abstract

To provide a composition for treatment of prostate cancer.SOLUTION: A composition comprises a lyophilisate of degarelix and an excipient dissolved in a solvent and is administered to a patient at a starting dose of between 200 and 300 mg of degarelix at a concentration of between 20 and 80 mg of degarelix per mL solvent; followed 14- 56 days after the starting dose by a maintenance dose of between 320 and 550 mg of degarelix at a concentration of between 50 and 80 mg degarelix per mL solvent; (optionally) followed by one or more further maintenance doses of between 320 and 550 mg of degarelix at a concentration of between 50 and 80 mg degarelix per mL solvent administered with an interval of 56 days to 112 days between each maintenance dose.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to compositions for treating prostate cancer. [Background technology]

[0002] Prostate cancer is the leading cause of death and morbidity among men in the industrialized world. The molecule grows in a testosterone-dependent manner and is a key component of the current medical approach to the management of advanced prostate cancer. The approach involves androgen deprivation, the goal of which is to reduce serum testosterone (T) to castrate levels. The goal is to reduce serum T to less than 0.5 ng / mL (T ≤ 0.5 ng / mL). This can be achieved, for example, by bilateral orchiectomy. This can be achieved by surgery or by administration of gonadotropin releasing hormone (GnRH) receptor agonists. This can be achieved.

[0003] Gonadotropin-releasing hormone (GnRH) is produced by the hypothalamus and secreted into the pituitary gland. It is a natural hormone that interacts with receptors in the ovaries to stimulate the production of luteinizing hormone (LH). Drugs such as leuprolide (Lupron) and goserelin are used to reduce LH production. Agonists for the GnRH receptor (GnRH-R) have been developed. HR agonists initially act to stimulate the release of LH and then, after prolonged treatment, This acts to desensitize the GnRH-R so that no more LH is produced, ultimately However, the L-actin agonist is not effective in suppressing testosterone production by the testes. The initial stimulation of H production leads to an initial surge in male hormone production. "Testosterone surge" This phenomenon, known as a "flare reaction," can last for as long as two to four weeks. It may stimulate prostate cancer. This may lead to worsening of current symptoms or spinal cord compression, bone pain and This can lead to the emergence of new symptoms such as urethral obstruction. One approach that has been used is the use of GnRH, known as total androgen deprivation therapy (AAT). Administration of -R agonists in combination with antiandrogens such as flutamide or bicalutamide However, the use of antiandrogens has been associated with significant hepatic and gastrointestinal side effects. This is accompanied by:

[0004] Gonadotropin-releasing hormone receptor (GnRH-R) antagonists are Developed to overcome the "testosterone surge" or "flare" reaction associated with agonists GnRH antagonists competitively bind to the GnRH receptor and block it, By causing a rapid decline in secretion of LH and follicle-stimulating hormone (FSH) It reduces testosterone production without the initial stimulation / surge. However, GnRH antagonists Histopeptides are often associated with the generation of histamine releasing activity.

[0005] GnRH agonists and The use of both antagonists has shown promising results, but the available drugs There are concerns about the relative safety of the GnRH antagonist Abare. Lix™ has been associated with serious allergic reactions, including anaphylaxis accompanied by hypotension and fainting. are found to pose a risk of adverse reactions and may even lose efficacy over the course of treatment. In fact, Abarelix (registered trademark in the United States) Lenaxis™ was ultimately approved, but it is for the treatment of selected patients with advanced prostate cancer. only for patients who have been admitted to the hospital, and for commercial reasons clearly related to these issues. It was eventually taken off the market in 2005. In particular, certain androgen deprivation therapies have been shown to be associated with cardiovascular It has been suggested that it may have adverse health effects (Yannucci et al., 2006 ) J. Urology 176:520-525, and Etzioni et al. (199 9) See J. Natl. Canc. Inst. 91:1033.

[0006] The applicants have developed a third generation GnRH antagonist for treating prostate cancer, i.e. Degarelix is ​​a synthetic decapeptide antagonist of GnRH. Long-term evaluation in a multicenter randomized trial demonstrated that degarelix is ​​effective and and was demonstrated to be well tolerated with no evidence of systemic allergic reactions. (Koechling et al., "Various GnRH antagonists inhibit histamine production from human skin" Effect of various GnRH antagonisms ist on histamine release from human ski n)”;Poster,8th Int.Symp.GnRH Analogues i n Cancer & Human Rep.;European J.Pharm., (See March 2009 (submitted).) Application for marketing approval as a once-monthly formulation / New The drug application was submitted to the FDA and EMEA on February 27, 2008. Marketing approval was granted by the FDA on February 24, 2009 and by the EMEA on February 27, 2009. .

[0007] However, it is still possible to minimize dosing requirements (thus, for example, reducing the need for patients to visit the hospital once a month). , serum testosterone below 0.5 ng / mL for a long period of time (e.g., for more than one year) There is a need for a maintenance treatment regimen.

[0008] Applicants have demonstrated that serum testosterone can be maintained below 0.5 ng / mL for longer periods of time. To maintain (i.e. prevent testosterone breakthrough), ) Median plasma trough concentration is greater than 9-10 ng / mL, preferably 11 or 12 or 1 We found that it was necessary to administer degarelix to maintain the serum concentration at >3 ng / mL. (See Figure 1.) Conventional formulations (e.g., once-monthly formulations) contain testosterone It does not prevent rash over a 3-month period. However, simply increasing the dose does not prevent side effects. This is not easy, both because of the risk of side effects and because dose sizes can be unwieldy.

[0009] Degarelix is ​​available as a powder (of degarelix acetate) that is reconstituted into a solution for subcutaneous injection. The powder may be mixed with water for injection ("WFI") or with the appropriate dose and dosage of degarelix. Depending on the concentration, mannitol solution (e.g., 2.5% or 5% mannitol) may be used to maintain isotonicity. %) and redissolved.

[0010] At concentrations of 5 mg / mL or higher in aqueous media, degarelix acetate induces nucleation-dependent fibrinogen activator The compound exhibited aryl ionization, which confirmed its ability to form a gel-like depot in vivo at the injection site. Therefore, upon contact with body tissues such as plasma, degarelix spontaneously A gel depot is then formed. Degarelix is ​​then released from the depot by sustained diffusion. The fibrillation of degarelix follows a nucleation-dependent mechanism, thus allowing the depot The disposition is primarily related to the degarelix concentration.

[0011] Degarelix is ​​a drug that is administered in two phases: immediately after administration, which is responsible for the initial high plasma concentration levels; The rapid release phase followed by a slow release phase determines the plasma concentration level during the maintenance phase. It was proposed that degarelix would be released from the depot. In the context of drug release, these two distinct steps represent the two primary inputs that control release from the depot. phase, i.e., responsible for the initial rapid release and expressed by the rapid absorption half-life The rapid entry and the slow absorption half-life are responsible for the observed prolonged phase. This has been described as gradual input.

[0012] The area under the concentration-time curve (AUC) is related to both the dose and the concentration of the injection. The AUC increases with increasing concentration, but the AUC decreases with increasing concentration of the injection solution. Therefore, when dose concentrations of 10, 20, 30, 40, and 60 mg / mL were used, The absolute bioavailability was 43.4%, 40.0%, 31.1%, and 27. The estimated bioavailability was 4% and 21.3%, respectively. This means that increasing the concentration The practical advantage to increasing the concentration is that the volume of the injection is reduced. This will increase the likelihood of patient compliance. .

[0013] The applicants have demonstrated that high doses and concentrations of degarelix, such as those applied in the maintenance phase, administration of 0.1 mg / kg / day leads to a slower release profile of degarelix from the resulting depot. Unexpectedly (along with the overall decrease in bioavailability of degarelix discussed above) This surprising effect was observed at the prescribed doses and high concentrations of degarelix. The dose should be sufficient to have the desired therapeutic effect (i.e., the required plasma concentration). The drug releases degarelix sufficiently, but the plasma concentration remains at a therapeutically effective level for a long period of time (initiation period). release it slowly enough so that the amount is sufficient to be sustained (e.g., for more than 3 months) Increasing the concentration of degarelix means that a sustained release depot is obtained. At these higher doses, there was an unexpected benefit in that the output was actually increased. This also means that the injection size is manageable. Summary of the Invention [Means for solving the problem]

[0014] Applicants have demonstrated that when administered in accordance with the present invention, monthly injections are not required. Degarelix can be administered at high doses and concentrations to obtain sustained release of degarelix. A composition for administering the same has been developed.

[0015] Thus, according to a first aspect, the present invention provides degarelix or a pharma- ceutically acceptable derivative thereof. A composition for treating prostate cancer comprising a salt (e.g., an acetate salt) of A lyophilized mixture (e.g., a lyophilized mixture of degarelix and excipients dissolved in an aqueous solvent, e.g., water) lyophilisate, e.g. a sugar, e.g. mannitol) and administering degarelix to patients The initial dose is 200-300 mg, and the degarelix concentration in the vehicle is 20-80 mg / mL. Then, 14 to 56 days after the starting dose, a maintenance dose of 320 to 550 mg of degarelix or vehicle was administered. Degarelix is ​​administered at a concentration of 50-80 mg / mL, followed by one or more Further maintenance doses of degarelix of 320-550 mg, with degarelix concentration in the vehicle at 50 mg / kg, ~80mg / mL, with maintenance doses administered 56-112 days apart Things are provided.

[0016] In one example, the composition is administered to a patient at an initial dose of 200-300 mg, followed by One month after the initial dose, for example 28 days later, a maintenance dose of 320-550 mg is administered, followed by One or more further maintenance doses of 320-550 mg at 3 months (e.g. The starting dose of degarelix is, for example, 240 mg, e.g. For example, the concentration of degarelix in the vehicle may be 40 mg / mL. The maintenance dose is, for example, 360 mg or 480 mg, e.g., 60 mg of degarelix in the vehicle. It can be 0 mg / mL.

[0017] Degarelix (or a pharma- ceutically acceptable salt thereof) may be dissolved in, for example, an aqueous solvent, such as water ( It may be administered as a liquid in a solvent such as WFI or a solution of water and mannitol. The starting dose and the maintenance dose may be administered by injection. The dose is preferably administered as two injections, each containing (substantially) half the maintenance dose. The composition provides therapeutically effective administration of degarelix, for example, starting 28 days after the initial dose. Mean plasma trough concentration (plasma concentration 9 ng / mL or more, preferably 10 ng / mL or more) or above, e.g., 12 ng / mL or above, as measured by techniques known in the art. and this therapeutically effective concentration can be maintained, for example, for at least 365 days and / or for the duration of treatment. As used herein, the term "treatment duration" refers to a period of time during which This means that the therapeutically effective concentration is maintained for as long as the sustained dose is administered. "Maintained for a period of time" means that a therapeutically effective concentration is maintained for at least the period of time that the final maintenance dose is administered. The composition is administered, for example, 3 days after the initial dose, until the initial dose is administered. For example, after 7 days, for example, after 14 days, for example, after 28 days, the patient's serum testosterone levels can be reduced to below 0.5 ng / mL, for example, for at least 365 days. and / or maintain serum testosterone levels below 0.5 ng / mL for the duration of treatment can be kept below.

[0018] Experiments have demonstrated that 240 mg (40 mg / mL) is an effective starting dose. In the one-month dosing regimen study, two monthly maintenance doses were administered: 160 mg ( 0 mg / mL) and 80 mg (20 mg / mL) from day 28 to day 364 The efficacy of estosterone was demonstrated in 100% and 98%, respectively. However, at doses of 240 mg, 160 mg, or 80 mg, testosterone suppression was 0.01% after injection. would not persist for 3 months. Therefore, the starting dose was 240 mg (40 mg / m L), an additional dose would be required before 3 months (eg, on day 28). The "true" 3-month dosing schedule of 480 mg [i.e., with a starting dose of 480 mg Simulations of additional doses at months 3, 6, and 9 showed that PK trough levels ( The galelix concentration was approximately 8 ng / mL, suggesting that it was insufficient. Steady-state levels were reached more quickly with the first month of treatment and an additional dose in month 1 This (along with the formulation, dosage and concentration) is important. It is not practical to use a higher dose as the starting dose for a 2-month depot. This provides sufficient release during the initiation / initiation phase to increase plasma degarelix concentrations. At the same time, it has a long-term sufficient release to achieve a sufficiently high steady-state concentration over a period of three months. The applicants have surprisingly found that the defined composition provides For example, starting 28 days after the starting dose, the therapeutically effective mean plasma concentration of degarelix ( Plasma trough concentrations of 9 ng / mL or higher can be achieved, and this therapeutically effective concentration can be maintained for 10 months. and / or treatment for at least 365 days, e.g., without the need for a single maintenance dose. More surprisingly, the present invention has been found to be able to maintain the above-mentioned effects for a sustained period of time. The compositions and treatments defined by the applicants when used in this method are Injection-related adverse events compared with administration of Relix at a dose of 240 mg and a concentration of 40 mg / mL Degarelli at the prescribed maintenance dose (one or more) This is especially significant given the high doses (and concentrations) of acetaminophen.

[0019] The maintenance dose concentration of degarelix or a pharma- ceutical acceptable salt thereof is 50-80mg / mL, e.g. 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, e.g. 55-65 Applicants may administer degarelix or a pharma- ceutically acceptable salt thereof in an amount of 100 mg / mL. Maintenance dose of salt (e.g., acetate) [e.g., degarelix and 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 dosing 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, for example 55 to 65 mg / mL. The amount of the drug should be between 320 and 550 mg (e.g. between 350 and 490 mg, e.g. between 440 and 5 The amount of degarelix can be, for example, 240 mg, 360 mg, or between 20 mg. The pharmaceutical formulation may be administered, for example, by injection, for example, in a single dose. It may be administered as an injection, preferably as two injections or the like.

[0021] In yet another aspect of the present invention, the concentration of degarelix in the solvent is 20 to 80 mg / mL. Degarelix or a pharma- ceutically acceptable salt thereof dissolved in a solvent (e.g., an aqueous solvent, e.g., water). salts (e.g., degarelix acetate) and excipients (e.g., co-lyophilisates, e.g., sugars, A kit of parts for providing a composition comprising a lyophilisate of, for example, mannitol, One or more lyophilized products of degarelix or its pharma- ceutical acceptable salts and excipients. A number of containers (e.g., vials) and one or more containers of solvent (e.g., vials, plates, etc.) refilled syringe), optionally with a means for administration (e.g. injection) (e.g. syringe and / or A kit of parts is provided that includes, optionally, Container(s) of solvent (e.g., prefilled syringe, vial) and container of degarelix A means (e.g., a vial) for (improving) the transfer of solvent between (several) The kit may also optionally include a reconstitution means, e.g., an adaptor. The kit may also include a device for further improving or enhancing the device (e.g., a pivoting device). , between 20 and 80 mg / mL, for example between 50 and 80 mg / mL, for example between 55 and 65 mg / mL, e.g. 56, 57, 58, 59, 60, 61, 62, 63, 64 mg / mL A solution having a concentration of degarelix can be provided. The amount of degarelix can be Between 220 and 550 mg, for example between 320 and 550 mg (for example between 350 and 490 mg) The amount of degarelix can be, for example, between 440 and 520 mg. For example, the kit may contain 240 mg, 360 mg, or 480 mg. A solution having 480 mg of Relics at a concentration of 60 mg / mL can be provided. For example, two containers (e.g., vials) of degarelix 240 mg and one container (e.g., liquid For example, a single container (vial) of 10 mL of WFI may be included. Each vial of degarelix is ​​mixed with, for example, 4.2 mL of WFI to obtain approximately 240 mg of degarelix. , 4mL of solution with a concentration of 60mg / mL is obtained, and the two vials are combined to provide a single injection. Or more preferably, a maintenance dose of 8 mL for two injections will be constituted by one skilled in the art. As will be readily understood, in a further example, the kit may contain degarelix 240 mg (with excipients) As a lyophilisate) and two containers (e.g. vials) of WFI (4. 2 mL) of WFI. When a prefilled syringe containing , about 240 mg of degarelix and 4 mL of a solution (injection solution) with a concentration of about 60 mg / mL were obtained. Two such syringes and containers together provide a total of 2 injections. It will be readily understood by one of skill in the art that a maintenance dose (480 mg) constitutes 8 mL.

[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, The lyophilized product of rix or its pharma- ceutical acceptable salt is in the range of 320 mg to 550 mg. and at least one container containing a solvent. In one example, the kit contains 480 mg of degarelix in a concentration of 60 mg / mL. The kit may be provided with a solution having, for example, 240 mg of degarelix. Two containers (e.g., vials) and, e.g., a liquid drug (e.g., 6 mL or 10 mL of WFI) Each vial of degarelix may contain, for example, For example, when mixed with 4.2 mL of WFI, approximately 240 mg of degarelix is ​​obtained, with a concentration of 60 mg in the solvent. Combining the two vials will yield 4 mL of 1000 mL of solution, which can be used for a single injection or, more preferably, It will be readily apparent to one skilled in the art that the 8 mL maintenance dose constitutes a single 8 mL injection or two 8 mL maintenance doses. cormorant.

[0026] In yet another example, the kit according to the present disclosure includes degarelix or a pharma- ceutically acceptable salt thereof. and lyophilized products of degarelix or its pharma- ceutically acceptable salts and excipients. At least one first container in which the lyophilisate is present in an amount ranging from 320 mg to 550 mg. and at least one second container containing a solvent.

[0027] In yet another aspect of the present invention, a method for treating prostate cancer in a patient in need thereof is provided. A method is provided for preparing starting and maintenance dose concentrations for administering a dose of a drug to a patient, the method comprising: At least one pharmaceutical composition comprising a lyophilized product of Galelix or a pharma- ceutical acceptable salt thereof and an excipient. Combining one starting dose container with 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 Obtain a solution with a concentration of degarelix in solvent of 4 mg / mL, or any value therebetween. The dose of degarelix is ​​320 mg to 550 mg (e.g., 350 mg to 5 The dose of degarelix may be in the range of 20 mg, e.g., 440 mg to 490 mg. For example, 240 mg (initiation dose), 360 mg (maintenance dose) or 480 mg (maintenance dose) The dosage may be [Brief description of the drawings]

[0030] [Figure 1] 1 is a graph depicting treatment success rate (percentage of patients with testosterone below 0.5 ng / mL) versus plasma degarelix concentration. [Diagram 2] 1 is a graph depicting median plasma trough concentration levels of degarelix and testosterone response after different dosing regimens over a 3-month period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] definition As used herein, the terms "initial dose," "starting dose," and "initial dose" are used interchangeably. The term "plasma concentration" means "plasma trough concentration."

[0032] A month of treatment is usually considered to be 28 days, and in the clinical trial results described herein When used in this context, it is defined as 28 days. This means that two months refers to 56 days, Three months means 84 days, four months means 112 days, and so on.

[0033] The term "prostate cancer" refers to any cancer of the prostate gland in which the cells of the prostate mutate and begin to grow uncontrollably. The term "prostate cancer" refers to early stage, localized prostate cancer and late stage, locally advanced pre-prostate cancer. prostate cancer (cancer cells spread (metastasize) from the prostate to other parts of the body, especially the bones and lymph nodes) Includes.

[0034] Degarelix and related pharmaceutical formulations Degarelix incorporates p-ureido-phenylalanine at positions 5 and 6. The GnRH decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-L A potent GnRH antagonist, an analogue of eu-Arg-Pro-Gly-NH2 (Jiang et al. (2001) J. Med. Chem. 44:453-67) This is because prostate cancer patients (who have already had a prostatectomy or radiation) for whom androgen deprivation is warranted. It is used to treat patients with rising PSA levels after radiation therapy.

[0035] Degarelix competitively and reversibly binds to the pituitary GnRH receptor, thereby Rapidly reduces the release of gonadotropins and, therefore, testosterone (T) , a selective GnRH receptor antagonist (blocker). Prostate cancer is hormone-sensitive. It is sensitive to testosterone blockade, which is a fundamental principle in the treatment of prostate cancer. Unlike H agonists, GnRH receptor blockers reduce the amount of luteinizing hormone (LH) after treatment initiation. H) A sudden surge in testosterone / tumor stimulation and potential symptomatic flare. It does not emit.

[0036] The active ingredient, degarelix, is a synthetic linear decapeptide amide that contains seven unnatural amino acids. It contains 5 of these D-amino acids. The drug substance is an acetate salt, but the The active moiety is degarelix as the free base. The acetate salt of degarelix is ​​available in It is a white to off-white amorphous powder of low density 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]amine 4-[(aminocarbonyl)amino]-L-phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl N6-(1-methylethyl)-L-lysyl-L-prolyl. This is 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 previously shown (European Patent No. 1003774, US Pat. No. 5,313,636). Patent No. 5,925,730, U.S. Patent No. 6,214,798), Formula: Ac-D-2N al-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cb m)-Leu-Lys(iPr)-Pro-D-Ala-NH do.

[0037] Degarelix is ​​administered intravenously, usually in the abdomen, as described in more detail below. It can be formulated for subcutaneous administration (rather than intravenously). As with any medication, injection sites should be changed periodically to allow treatment to adapt to any discomfort at the injection site. Generally, injections are administered in areas where the patient is not exposed to pressure, such as the waistband. The device should be applied in an area that is not close to the band or belt and not close to the ribs.

[0038] Degarelix administered subcutaneously or intramuscularly works well, but daily injections are Since this is generally not preferred by patients, WO 03 / 006049 and U.S. Pat. For further details, see published patent applications 20050245455 and 20040038903. As previously described, depot formulations of degarelix are available. For example, subcutaneous administration of degarelix involves the peptide being delivered (typically for 1–2 days) from a gel-like depot. This can be done using a depot technology that releases over a 3-month period. (and related GnRH antagonist peptides) have high affinity for the GnRH receptor. It has the same properties as other GnRH analogues and is much more soluble in water. These related GnRH antagonists are capable of forming a gel after subcutaneous injection, The gel acts as a depot that releases the peptide over a period of weeks or even months. It is possible.

[0039] Thus, degarelix may be administered by injection (e.g., to form a depot as described above, e.g. It may be provided as a powder to be reconstituted (with a solvent) into a solution for, for example, subcutaneous injection. The powder is available as a lyophilisate containing degarelix (e.g., as the acetate salt) and mannitol. A suitable solvent is water (e.g., water for injection, or WFI). For example, degarelix may be provided in a container (e.g., a vial) containing 6 mL of the solvent. , reconstituted with 3 mL of WFI so that each mL of solution contains approximately 40 mg of degarelix. Degarelix (acetate) may be provided in a vial containing 120 mg of degarelix (acetate). Upon reconstitution, 3 mL of solution for injection is obtained containing approximately 120 mg of degarelix. Two injections of such a solution will provide approximately 240 mg of degarelix, a starting concentration of 40 mg / mL. In another embodiment, degarelix is ​​provided in a dosage form containing 240 mg of degarelix (acetate). After reconstitution with approximately 4 mL of WFI, each mL of solution contains approximately Two injections of such a solution contain approximately 48 mg of degarelix. In another example, degarelix is ​​administered at a dose of 18 mg / mL. The solution may be provided in a vial containing 0.0 mg of degarelix (acetate) with approximately 3 mL of WFI. After reconstitution, each mL of solution contains approximately 60 mg of degarelix. Two injections 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. do.

[0040] The degarelix dosing regimen is approximately 40 mg of degarelix formulation, with a starting dose of 240 mg. Degarelli is administered as 2 injections of 3 mL of 500 mg / mL followed by a maintenance dose of 480 mg. The drug formulation can be administered as two 4 mL injections of approximately 60 mg / mL.

[0041] The initial dose is followed by maintenance doses at intervals ranging from 14 to 56 days, e.g., 14 days, 28 days, 56 days, or any interval therebetween, even 28 days apart, for example. The maintenance dose is a combination of degarelix or its pharma- ceutical acceptable salts, excipients, and solvents. The maintenance dose is 320 mg to 550 mg of degarelix or a pharma- ceutical acceptable salt thereof. g range, for example, from 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420mg, 440mg, 460mg, 480mg, 500mg, 520mg, 540m 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. or a pharma- ceutical acceptable salt thereof, the concentration of the further maintenance dose is 50 mg / mL to 80 mg / mL. g / mL range, e.g., from 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL g / mL, 70mg / mL, 75mg / mL, 80mg / mL, or any number in between and further, for example, 60 mg / mL of degarelix or a pharma- ceutical acceptable salt thereof. It is. EXAMPLES

[0043] Administration and Dosage Example 1 - Clinical Trials Over the course of the degarelix development program, population pharmacokinetic / pharmacodynamic (PK / PD) Using modeling and simulation, PK and PD data and We now have a better understanding of the relationship between these and other parameters. The results showed that at a median plasma trough concentration of 7.34 ng / mL, 96% Patients achieved serum testosterone (T) ≤ 0.5 ng / mL on day 28 and plasma concentrations With a median of 4.54 ng / mL, 83% of this same patient group had a T ≤ 0.5 ng / mL at day 84. Due to variability in the population, the median plasma concentration was In approximately 95% of patients, this is not considered sufficient to maintain long-term testosterone suppression. Therefore, the doses administered in the Phase 3 study for the one-month dosing program were The dose should result in a mean serum trough level of degarelix of 9 ng / mL or greater. It was proposed that:

[0044] Proportion of patients who were castrated after day 28 [(T) ≤ 0.5 ng / mL] 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). Most found that an additional dose was required around day 28.

[0047] The Phase 2 study of the 3-month dosing regimen examined three different dosing regimens: starting dose 24 0 mg (40 mg / mL), followed by a further dose of 240 mg on day 28, then Maintenance doses were administered at months 3, 6, and 9, or months 4, 7, and 10. 0 mg was initially administered at concentrations of 40 mg / mL or 60 mg / mL in this study, and different concentrations The study was evaluated based on the outcomes observed with different PK profiles of Patients were randomized simultaneously to one of three different 3-month maintenance dosing regimens of degarelix. It was attached. 240 mg (40 mg / mL) at months 1, 3, 6, and 9 240 mg (60 mg / mL) at months 1, 3, 6, and 9 240 mg (60 mg / mL) at months 1, 4, 7, and 10

[0048] None of the three treatment regimens had lower confidence intervals below the 80% level. Therefore, castrate levels of testosterone should be maintained for at least one year in at least 80% of patients. The primary objective of demonstrating effectiveness in achieving and maintaining Applicants have determined that the most important predictor of time to testosterone >0.5 ng / mL The results showed that the plasma levels of degarelix during the treatment period were Patients with lower plasma levels of degarelix had lower testosterone levels during the 1-year treatment period. were more likely to have testosterone levels above 0.5ng / mL. Analysis of the data showed that patients remained suppressed for two visits after treatment but remained suppressed for the next three-month treatment visit. 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 mean disease duration from time of diagnosis is also shown.

[0051] [Table 1]

[0052] This study was an open clinical trial, and patients were randomized to receive 240 mg (40 mg / m L) and then receive one of the following two treatment regimens of degarelix maintenance doses: Ta. 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 starting dose was 120 mg (40 mg / mL) given subcutaneously as two injections.28 A maintenance dose of 360 mg (60 mg / mL, given as 2 × 3 mL injections) was administered days later. 480 mg (60 mg / mL, given as 2 × 4 mL injections) was administered in two separate doses. The drug was administered as a single injection (240 mg each time), followed by two more injections at three-month intervals. Maintenance doses are administered in the form of injections. Readministration of degarelix to form a depot The techniques for dissolution and subsequent subcutaneous injection are known to those of skill in the art and have been previously described herein. At each visit, serum testosterone, prostate-specific androgens, and and degarelix plasma concentrations were measured by techniques known in the art.

[0054] Cumulative maintenance of testosterone response (T≦0.5ng / mL) from day 28 to day 364 The product probability is shown by treatment dose in Table 2. The 360 ​​mg (60 mg / mL) dose regimen (8 9.0%), the higher dose of 480 mg (60 mg / mL) was numerically greater The study showed a treatment response (93.3% of patients maintained castrate levels of testosterone). Having a true inhibition rate above the 90% control threshold, even if the difference is not statistically significant The difference between the two treatment groups is significant in the confidence probability of inclusion: The confidence interval for true inhibition of >90% was 79.9% in the 360 ​​mg treatment group, whereas the confidence interval for true inhibition of >90% was 79.9% in the 360 ​​mg treatment group. As for the latter, only 39.7% answered yes.

[0055] [Table 2]

[0056] Table 3 shows the results for patients with suppressed testosterone (T ≦ 0.5 ng / mL) at the time of study visit. The percentage of people who are

[0057] A degarelix maintenance dose of 480 mg (60 mg / mL) was associated with TE in >95% of patients. At a maintenance dose of 360 mg (60 mg / mL), At least 90% of patients had sustained suppression of testosterone. Immediately before, 7th month (196th day, 90.6%) and 10th month (280th day, 93.3%) Overall, 125 of 127 patients (98%) had castration levels at 28 days. showed less than 10% suppression of testosterone levels.

[0058] Figure 2 shows the plasma trough concentration levels of degarelix after different dosing regimens for 3 months. Graph showing median and testosterone responses.

[0059] [Table 3]

[0060] Table 4 shows the median percent change in PSA at study visit. There was a significant decrease in the median score, and the median reduction was sustained throughout the study period (median reduction of 96-97% ).

[0061] [Table 4]

[0062] Adverse events As of the data cutoff date of September 2, 2008, 133 patients with prostate cancer had been enrolled in Phase 2 That is, in the above-mentioned 3-month administration schedule clinical program (CS18), degarelix was exposed to.

[0063] Treatment-emergent ratios reported in >5% of patients in any arm of CS18 Relatively common adverse events are summarized as follows (percentage values ​​are for the 480 mg and 360 mg groups): Overall rates for both dose groups: 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%). Previous GnRH antagonists caused immediate systemic Hypersensitivity reactions have been reported. Immediate anaphylactic reactions were not reported in this clinical trial of degarelix. No data were reported in grams.

[0064] The clinical program has been intensively evaluated for its potential to cause hepatotoxicity, and data have been collated. As of the cut-off date, the data showed no clinically significant decline in liver function following degarelix treatment. It doesn't show anything below.

[0065] In Example 1, the incidence of any injection site reaction was 26%. The incidence of site reactions was similar between the two doses. The most frequently reported injection site reactions were The most common cause of pain was injection site pain (17%). Surprisingly, these data are consistent with those of Degareliq. A one-month dosing regimen using a much lower dose of sirolimus (e.g., 240 mg) was used in the clinical program. The results were similar to those of the 1990s and 2000s. Most injection site reactions were mild to moderate in severity (11 %), but 5% of patients reported severe injection site reactions. Six patients reported injection site pain as a severe event.

[0066] conclusion Thus, Applicants believe that the pharmacodynamic (PD) dose response is consistent with increasing doses of degarelix. and higher degarelix (at the end of 1 year of treatment or at the last available measurement). Logically consistent with the pharmacokinetic (PK) / pharmacodynamic associations with median trough levels For the maintenance doses of 240 mg, 360 mg, and 480 mg, respectively, , plasma trough concentrations of degarelix of approximately 7 ng / mL, 10 ng / mL, and 13 ng / mL. In addition, median levels of 360 mg and 480 mg maintenance doses were observed. The incidence and pattern of adverse events did not differ significantly among patients receiving Based on the testosterone suppression and PK results, The starting and maintenance doses provided represent an effective 3-month dosing regimen.

Claims

1. A composition for treating prostate cancer in a patient, comprising degarelix or a pharma- ceutical acceptable salt thereof, The starting dose of degarelix is ​​200-300 mg, and the concentration of degarelix in the vehicle is 20-80 mg / mL. then 14 to 56 days after said starting dose, a maintenance dose of 320 to 550 mg of degarelix is ​​administered, with a degarelix concentration in the vehicle of 50 to 80 mg / mL; then (optionally) one or more further maintenance doses of degarelix at 320-550 mg, with a degarelix concentration in the solvent of 50-80 mg / mL, with each maintenance dose administered at intervals of 56-112 days; A composition which reduces the patient's serum testosterone levels below castration levels.

2. A composition for treating prostate cancer in a patient, comprising degarelix or a pharma- ceutical acceptable salt thereof, an initial dose of 200-300 mg of degarelix is ​​administered, followed 28 days after said initial dose by a maintenance dose of 320-550 mg of degarelix, followed by one or more further maintenance doses of 320-550 mg of degarelix, each maintenance dose being administered 84 days apart; A composition which reduces the patient's serum testosterone levels below castration levels.

3. the starting dose is 240 mg of degarelix; 3. The composition of claim 1 or 2, wherein the maintenance dose is 360 mg or 480 mg of degarelix.

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