Method of treating metastatic stage prostate cancer

Abstract

To provide compositions for the treatment of metastatic stage prostate cancer in a subject.SOLUTION: Compositions containing degarelix and methods of use thereof are provided.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Prostate cancer accounts for approximately 9% of cancer-related deaths in men, with a high incidence and mortality rate among men in industrialized countries. Prostate cancer is the second leading cause of cancer death among American men, after lung cancer. The American Cancer Society states: An estimated 27,050 US men died from prostate cancer in 2007. Prostate cancer is the third most common cause of cancer death in men in Europe, with An estimated 87,400 deaths occurred in 2017 (Ferlay et al. (2007) Ann. Oncol.; 18:581-92; Lukka et al. (2 006) Curr. Oncol.; 13:81-93).

[0002] More than 9 in 10 cases of prostate cancer are localized and locally advanced. and locally advanced stages). Compared with men of their age and race (relative survival), diagnosed with localized and locally advanced cancer The 5-year relative survival rate for men diagnosed with HER2 is nearly 100%. Men with metastatic prostate cancer, which means it has already spread to other areas, have a five-year relative survival rate of only about 32%. (Cancer Trends Progress Report (http: / / progress report.cancer.gov; SEER Program , and the National Center for Health Statistics s; see http: / / seer.cancer.gov / ). In this final metastatic stage The rapid decline in survival is accompanied by symptoms including pain (e.g., bone pain), weight loss, and fatigue. Therefore, treatments that result in a reduction or delay of bone metastatic tumor cell growth are expected to last up to approximately 3 years. These symptoms improve as well as providing an increase in life expectancy, which may be 20 years or more. It also provides an improvement in quality of life (QoL) as the patient progresses.

[0003] Because the majority of prostate cancers grow testosterone-dependently, current medical treatments for advanced prostate cancer Management is by bilateral orchiectomy or by gonadotropin-releasing hormone (GnRH) receptor agonism. androgen deprivation, which can be achieved by the administration of agonists. Removal of the testicles (castration) has been used in male genital tract infections for many years as a means of reducing the growth of prostate cancer. In recent years, the secretion of male hormones has been suppressed by the use of androgens. Chemical means by interfering with the production of luteinizing hormone (LH), which regulates the synthesis of steroid hormones. Evidence from randomized studies has shown that the presence or absence of lymph node metastasis Regardless, early endocrine therapy in non-metastatic locally advanced disease is associated with a survival benefit This strongly suggests that (Granfors et al. (1998) J. Ur ol. 159:2030-34; Messing et al. (1999) N Eng. J. Med. 341:1781-88; and (1997) B r. J. Urol. 79:235-46).

[0004] Gonadotropin-releasing hormone (GnRH) stimulates the production of luteinizing hormone (LH) A natural hormone produced by the hypothalamus that interacts with receptors in the pituitary gland to stimulate the To reduce LH production, GnRH inhibitors, such as leuprolide and goserelin, are used. GnRH-R agonists have been developed to inhibit LH release. It acts to stimulate the release of hormones, and only after long-term treatment does it stop G production so that LH is no longer produced. The initial stimulation of LH production by agonists is The initial response to the therapy is a worsening rather than an improvement in the patient's condition (e.g., tumor growth This leads to an initial surge in the production of male hormones, such as testosterone. This reduction, known as a "prolonged" or "flare reaction," can last for 2 to 4 weeks. In addition, each successive dose of agonist produces an additional small LH surge that may further exacerbate symptoms. This can lead to a surge in testosterone (known as the "exacerbation" phenomenon). Stimulating prostate cancer, worsening current symptoms, or spinal cord compression, bone pain, and urethral obstruction This can lead to the emergence of new symptoms (Thompson et al. (1990) J. Urol. 140:1479-80; Boccon-Gibod et al. 1986) Eur. Urol. 12: 400-402). For GnRH agonist therapy. The relative efficacy and safety of leuprolide (also known as Leuprolide or LUPRON DEPOT) The efficacy and safety (including side effects) of these compounds are known in the art (see, e.g., Persad, (2002) Int. J. Clin. Pract. 56:389-96; Wilson et al. (2007) Expert Opin. Invest Drugs 16:1851-63; and Berges et al. (200 6) See Curr. Med. Res. Opin. 22:649-55. One approach taken to avoid the estrogen surge (flare reaction) is to and antiandrogens such as flutamide, known as androgen deprivation therapy (AAT). , in combination with the administration of a GnRH-R agonist. Hormone therapy with GnRH-R agonists is known as adjuvant therapy for definitive prostate cancer. However, the use of antiandrogens has been associated with serious side effects. It is associated with significant hepatic and gastrointestinal side effects.

[0005] The drawback associated with antiandrogens is the "testosterone surge" associated with GnRH agonists. or gonadotropin-releasing hormone receptor (GnRH- This has led to the development of antagonists of GnRH. GnRH antagonists bind competitively to the GnRH receptor. It combines with and blocks LH and follicle-stimulating hormone (FSH) secretion, resulting in a rapid decrease. thereby reducing testosterone production without the initial stimulation / surge. However, GnRH antagonist peptides are often associated with histamine-releasing activity. This histamine-releasing activity is important because histamine release can cause side effects such as edema and itching. , which represents a serious obstacle to the clinical use of such antagonists.

[0006] The search for improved GnRH antagonists has led to the development of Antide, Cetroleum, Cetrorelix, and Antarelix (USA) The creation of the 5th and 6th positions has been achieved. GnRH antagonists with significantly modified or unnatural amino acids such as Those that demonstrate biological effects and build on Aph are generally considered to be particularly potent. A particularly useful one is Azaline B. No. 207 also contains acylated amino-substituted phenylalanine side chains at positions 5 and 6. The present inventors have also disclosed biologically effective GnRH antagonists. It is Acyline.

[0007] Despite the attractive properties of this group of GnRH antagonists, side effects have been observed. Comparative efficacy and safety (side effects) of the GnRH antagonist abarelix (PLENAXIS) (e.g., Mongiat-Artus et al. (2 004) Expert Opin. Pharmacother. 5:2171-9 ; and Debruyne et al. (2006) Future Oncol. 2:677-96). As such, even further improved GnRH antagonists, particularly those with a long duration of biological action and an improved safety profile. The search for a combination is ongoing.

[0008] Several approved drugs for the GnRH antagonist degarelix for the treatment of prostate cancer have been approved. Patents and patent applications address these desirable features (e.g., their contents). European Patent No. EP 1003774, which is incorporated herein by reference in its entirety. No., US Patent No. US 5,925,730, US Patent No. US 6,214,798, European Patent No. State Patent No. EP 02749000.2 and U.S. Patent No. USSN 12 / 1 55,897, and European Patent No. EP 08250703.9). USSN 61 / 027,742 is a patent that can be used without causing a systemic allergic reaction. Long-term, multicenter randomized clinical study demonstrating that degarelix is ​​well tolerated Degarelix treatment was also associated with a testosterone (T) surge. Rapid, significant, and sustained suppression of testosterone without side effects, and good efficacy and safety profile It brought about a view. Summary of the Invention

[0009] However, continuing research is leading to advances in the general prevention and treatment of prostate and other cancers. However, there is little evidence to support the treatment of patients with cancer in the later metastatic stages. There has been little or no focus on this. [Means for solving the problem]

[0010] The present invention relates, in part, to treating patients with metastatic prostate cancer and / or a prostate cancer risk of 50 ng / mL or higher. Administration of the GnRH antagonist degarelix to patients with PSA levels increased serum alkaline phosphatase The surprising finding is that it provides a significant and long-lasting reduction in S-ALP. This reduction indicates better control of (e.g., skeletal) metastases (Example 1, Figures 1-4, Table 2 These results further demonstrate that degarelix treatment is effective in preventing and treating patients with localized or locally advanced pre-cancerous lung cancer. Adenocarcinoma(localized and locally advulansed stag) may delay or prevent progression from prostate cancer to metastatic stage Furthermore, these results suggest that administration of degarelix to these patients may improve This suggests that S-AL is associated with a delay in progression to the tumor-resistant stage. A significant long-term decrease in P was observed after administration of the GnRH agonist leuprolide. It is not shown later.

[0011] In one aspect, the present invention provides a method for treating metastatic prostate cancer in a subject. The present invention provides a method for treating stage prastate cancer, the method comprising: The first step is to identify suitable subjects with metastatic prostate cancer, and then and administering to the subject an initial dose of 0 mg of degarelix. followed by a maintenance dose of 60–160 mg of degarelix every 20–36 days. This method thereby treats metastatic prostate cancer in a subject. The present invention involves an initial step of identifying a suitable subject with metastatic prostate cancer, followed by approximately 2 administering to the subject an initial dose of 40 mg of degarelix to the subject in a pre-metastatic stage. The present invention provides a method for treating prostate cancer. The subject is then administered a dose of 100 mg ... A maintenance dose of 60 to 160 mg of degarelix is ​​administered. The subject is treated for metastatic prostate cancer.

[0012] In one embodiment of the methods of the present invention, serum alkaline phosphatase (S-ALPHA) is measured in a candidate subject. P) value, and then the baseline S-ALP value (baseline S-ALP level) vel) is 150 IU / L or higher, for example, 160 IU / L or higher, is a candidate for treatment. In a further embodiment, the subject is identified by selecting the candidate for serum albumin. The serum alkaline phosphatase (S-ALP) level was examined, and the S-ALP reference value was 200 I If the level is ≥ 100 U / L, the person is selected as a treatment target, thereby identifying the person to be treated. In yet a further embodiment, serum alkaline phosphatase (S-ALP) levels in the candidate subject are examined. If the S-ALP reference value is 300 IU / L or higher, the patient is selected for treatment. By selecting the target of treatment, a therapeutic target is identified.

[0013] In a further embodiment of the method of the present invention, the hemoglobin (Hb) level of the potential subject is examined, If the Hb level is 130 g / L or less, the patient is selected for treatment. In yet a further embodiment, the potential subject's prostate specific antigen (PS A) Check the PSA level, and then select the patient if the PSA level is 50 ng / mL or higher. In certain embodiments, the subject's S-ALP is A decrease of at least 60 IU / L from baseline between days 112 and 364.

[0014] In a further embodiment of the method of the present invention, the serum alkaline phosphatase (S- ALP) increased by at least 50 IU / L from baseline between days 60 and 364 of treatment. In other embodiments, the subject's S-ALP is reduced between days 364 and 450 of treatment. In a further embodiment, the treatment is a reduction of at least 50 IU / L from baseline. S-ALP in elephants increased by at least 90% from baseline between days 112 and 364 of treatment. In yet a further embodiment, the S-ALP in the treated subject is reduced by 1 IU / L. Between days 112 and 364, there is a reduction of at least 160 IU / L from baseline.

[0015] In a further embodiment of the method of the present invention, the treated subject receives 0.5n maintain therapeutically low serum testosterone levels below 950 mg / ml In certain embodiments, the treated subject has the potential to: At a minimum, the goal is to maintain therapeutically low serum testosterone levels below 0.5 ng / ml. There is also a 95% chance.

[0016] In yet a further embodiment of the method of the present invention, the treated subject has, by day 14 of treatment, In one embodiment, the treatment has at least a 60% reduction in prostate-specific antigen (PSA) levels. Treated subjects have at least a 75% reduction in PSA levels by day 28 of treatment. In certain embodiments, the subject has a prostate specific antigen (PSA) of less than 5 ng / ml during treatment. It has at least an 80% chance of maintaining its value.

[0017] In a further aspect, the present invention provides a method for first identifying potential subjects. t) Prostate-specific antigen (PSA) test, and then the PSA value is 50 ng / mL or more If so, a method for treating prostate cancer is provided by selecting the cancer as a treatment target. The method further provides for determining an initial dose of degarelix of 60 to 320 mg in this manner. and then administering to the subject a compound selected from the group consisting of 2-hydroxybenzoates, ... Administer a maintenance dose of 60 to 160 mg of degarelix once every 0 to 36 days. Includes:

[0018] In one embodiment of the methods of the present invention, serum alkaline phosphatase (S-ALPHA) is measured in a candidate subject. P) value, and then the baseline S-ALP value is 150 IU / L or more, for example, 160 If the blood glucose level is ≥ 1.1 IU / L, the person is selected as a treatment target, thereby identifying the person to be treated. In some embodiments, the S-ALP in the treated subject is at baseline between days 112 and 364 of treatment. In a further embodiment, the hemoglobin level of the potential subject is reduced by at least 60 IU / L from the baseline level. Hemoglobin (Hb) levels are checked, and if the Hb level is 130 g / L or less, the patient is considered a candidate for treatment. The subject to be treated is identified by selecting the subject as:

[0019] In another aspect, the invention provides a method for the treatment of metastatic prostate cancer in a subject using degarelix. This method of using degarelix includes treating a suitable subject with metastatic prostate cancer. The subjects thus identified are then subjected to a first step of An initial dose of 320 mg of degarelix will be administered, followed by one dose every 20 to 36 days. A maintenance dose of 60 to 160 mg of degarelix is ​​administered to treat metastatic prostate cancer. Use of degarelix for the treatment of

[0020] In some embodiments of the methods of using degarelix, serum alkaline phosphatase of the candidate subject is measured. (S-ALP) value is checked, and if the baseline S-ALP value is 160 IU / L or higher, Subjects with metastatic prostate cancer are identified by selecting them for treatment. In one embodiment, the potential subject's serum alkaline phosphatase (S-ALP) levels are tested, and then If the baseline S-ALP value is 200 IU / L or higher, the patient can be selected for treatment. In yet a further embodiment, the subject is identified as having metastatic prostate cancer. The candidate's serum alkaline phosphatase (S-ALP) level is examined, and then the S-ALP group is analyzed. If the reference value is 300 IU / L or more, the patient will be selected as a candidate for metastatic prostate cancer. In one embodiment, the hemoglobin (Hb) levels of the potential subjects are examined to identify subjects with If the Hb value is 130 g / L or less, the patient is selected as a treatment target. In another embodiment, the prostate specific antibody of the candidate subject is used to identify subjects with metastatic prostate cancer. If the PSA level is 50 ng / mL or higher, treatment is recommended. Subjects with metastatic prostate cancer are identified by selecting them as subjects.

[0021] In another aspect, the present invention provides a method for preventing the progression of locally advanced prostate cancer to metastatic stage prostate cancer in a subject. The present invention provides a method of using degarelix to prevent the progression of locally advanced prostate cancer. The method of using degarelix to identify suitable subjects with locally advanced prostate cancer The first step involves administering 160 to 320 mg of steroid hormone to the subjects identified in this way. The initial dose of degarelix is ​​given, followed by one dose every 20 to 36 days for 60 to 1 A maintenance dose of 60 mg of degarelix is ​​administered. The method prevents the progression of locally advanced prostate cancer to metastatic stage prostate cancer in a subject.

[0022] In some embodiments of the method of using degarelix to prevent metastatic prostate cancer, the prophylactic The prostate-specific antigen (PSA) level of the candidate for treatment is examined, and then the PSA level is checked to see if it is between 10 and 50. If the patient has a prostate cancer risk of 20 or more, prostate cancer treatment may be recommended. In a further embodiment, the subject's prostate specific antigen (PSA) is measured. If the PSA level is between 20 and 50 ng / mL, the patient is considered a candidate for preventive treatment. By selecting for the presence of α-glucan, subjects with locally advanced prostate cancer are identified. In an embodiment, the potential subject's serum alkaline phosphatase (S-ALP) level is tested, and then The S-ALP reference value is less than about 160 IU / L, for example, between 44 and 147 IU / L. and / or between 50 and 160 IU / L, they are considered candidates for preventive treatment. Thus, subjects with locally advanced prostate cancer are identified.

[0023] In one aspect, the present invention provides a method for treating metastatic prostate cancer in a subject, comprising administering to a subject a dose of DeGarelli. In one aspect, the present invention provides a composition (e.g., a pharmaceutical composition, a drug) comprising the compound. According to the study, degassing for the treatment of prostate cancer in subjects with a PSA level of 50 ng / mL or higher Compositions (eg, pharmaceutical compositions, medicaments) containing the relics are provided.

[0024] As used herein, the term metastasis refers to the spread of cancer from its site of origin to more distant parts of the body. Into septal or distal areas, e.g., lymph nodes, bones, and / or other organs such as the brain or liver It refers to the secondary metastatic growth of a malignant tumor that forms when it spreads. Hence the term "metastatic" or The term "metastatic prostate cancer" refers to cancer that has spread from the primary tumor site, e.g., the prostate, to distant organs. This refers to cancer that has developed.

[0025] As used herein, "treating metastatic prostate cancer" and related methods of "treating metastatic prostate cancer" are used. The method includes treating metastatic disease, e.g., metastatic lesions in bone, brain, lung, and / or lymph nodes. A treatment that reduces the amount of cancerous tissue by reducing the number and / or size of tumors (tumors). As used herein, "treatment of metastatic prostate cancer" and related methods include the treatment of metastatic prostate cancer. and related methods of "treating metastatic prostate cancer" include skeletal metastases (e.g., bone scans or other methods). and related methods to reduce metastatic lesions identified in the skeleton by imaging techniques. nothing.

[0026] As used herein, "treating metastatic prostate cancer" and related methods of "treating metastatic prostate cancer" are used. The methods further include a treatment that reduces and / or ameliorates one or more symptoms associated with metastatic prostate cancer. Treatment and related methods, such as urinary disorders (e.g., obstruction, weak or intermittent urination, frequent urination, Treatment to improve and / or reduce symptoms of urinary incontinence (e.g., difficulty urinating, pain during urination, blood in the urine), Treatment to reduce and / or improve bone pain (in the hip, lower back, or thigh), and and / or weight loss, and treatment to reduce and / or ameliorate fatigue.

[0027] In another aspect of the invention, a method for reducing the number and / or size of metastatic lesions and and / or to reduce and / or ameliorate one or more symptoms associated with metastatic prostate cancer. Thus, compositions comprising degarelix for the treatment of metastatic prostate cancer are provided.

[0028] The terms "preventing metastatic prostate cancer" and related methods of "preventing metastatic prostate cancer" are used interchangeably. Furthermore, in subjects undergoing treatment for locally advanced prostate cancer, the development of metastatic activity prevent or maintain a level of metastatic activity (e.g., known at the time of initiation of medication) level, i.e., at baseline), or (e.g., S-ALP Reduce and / or delay the return of metastatic activity (as measured by The term "level of metastatic activity" in this context means , which refers to the size and / or number of metastatic tumors in a subject, but refers to the rate of metastasis in a subject isn't it.

[0029] Thus, the present invention provides a method for slowing or preventing the progression of the disease and / or for reducing the regression of the disease. bring about regression or remission or For example, "prevention of metastatic prostate cancer" and "metastatic prostate cancer" are included. The related term "preventing early stage prostate cancer" refers to methods that extend and / or improve the lifespan of a patient. This includes treatments and related methods that increase quality of life (QoL).

[0030] As used herein, the terms "treatment of metastatic (stage) prostate cancer" and "treating metastatic (stage) prostate cancer" are used interchangeably. or "treatment of prostate cancer" and "related methods of treating prostate cancer" The term hormone-refractory disease is also used. The present invention may also include treatments and related methods that delay or prevent the onset of the inflammatory bowel disease (e.g., inflammatory bowel disease) stomach.

[0031] Thus, in yet another aspect, the present invention provides a method for treating prostate cancer in a subject, comprising administering to said subject a therapeutically effective amount of a compound selected from the group consisting of acetaminophen, benzodiazepine ... and / or a composition comprising degarelix and a method for treating metastatic tumors, the method comprising administering to a subject a therapeutically effective amount of degarelix to a subject ... delay recovery and / or delay or prevent progression of the disease and / or cause or enhance the regression or remission of the disease and / or prolong the life of the patient and / or increase quality of life (QoL) and / or hormone resistance Related therapeutic methods that delay or prevent the onset of disease stages are provided.

[0032] The terms "treatment of prostate cancer" and "related methods of treating prostate cancer" also refer to Also included are cancer curative treatments and related methods.

[0033] Here, applicants are investigating whether patients with metastatic prostate cancer and / or those with P of 50 ng / mL or higher are at increased risk of developing prostate cancer. Administration of the GnRH antagonist degarelix to patients with SA levels was associated with an increase in serum alkaline phosphatase levels. It is disclosed that the compound provides a significant and long-lasting reduction in S-ALP (Figures 1 and 4, Table Not only was the reduction in S-ALP levels significant, but more importantly, it was also significant over the long term. The stable low S-ALP values ​​(see Figure 3) are a good indication of metastasis (e.g., bone). This significant long-term reduction in S-ALP was also indicative of good control. Not shown after administration of leuprolide.

[0034] For patients with metastatic prostate cancer and / or a PSA level of 50 ng / mL or higher The significant and long-term reduction in S-ALP after administration of the GnRH antagonist degarelix was consistent with these findings. Giving patients degarelix may delay the progression of cancer to the hormone-refractory stage This indicates that...

[0035] The subjects had a serum alkaline phosphatase (S-ALP) standard value of approximately 150 IU / L or more ( That is, pre-treatment, i.e., S-ALP values ​​before the administration of the first dose of testosterone), e.g. For example, a serum alkaline phosphatase (S-ALP) reference value of approximately 160 IU / L or more, e.g. , serum alkaline phosphatase (S-ALP) reference value of about 200 IU / L or more, e.g. A serum alkaline phosphatase (S-ALP) reference value of approximately 300 IU / L or higher may be required. (See Table 2).

[0036] The degarelix composition is administered for a period of about 60 to 364 days after administration of the first dose of degarelix. During this period, serum alkaline phosphatase (S-ALP) levels should be increased by at least approximately 50 IU above the baseline level. / L decrease (or, in other words, a negative change from baseline), and / or The study found that patients with ≥100% urinary tract infections (URI) had a mean urinary tract infection of 112 to 364 days after the first dose of degarelix. In one embodiment, the blood glucose level may be reduced by at least about 90 IU / L (see Table 2 and Figures 1-3). Serum alkaline phosphatase (S-ALP) levels at least 50 IU / L higher than the reference value The reduction may extend over a period of more than 364 days (depending on the continuation / maintenance dose of treatment). (see below).

[0037] The subject to be treated may have a hemoglobin (Hb) level of about 130 g / L or less. - Baseline ALP values ​​were higher in the subgroup of patients with metastatic disease and Hb<130g / mL For example, serum alkaline phosphatase (SA) levels of 300 IU / L or higher LP) reference values ​​were found in the patient population with Hb<130 g / L (see Table 2). Subjects with reduced Hb levels of about 112-36% after administration of the first dose of degarelix also had A serum alkaline phosphatase level of at least 160 IU / L below normal for a 4-day period May show a decrease (or a negative change from baseline) in S-ALP. (See Figure 2.) Bone metastases affect the bone marrow, and patients with bone metastases may become anemic. Therefore, lower than normal Hb in patients with bone metastases may be of greater importance. As explained in more detail herein, this The invention demonstrates that degarelix significantly improves the efficacy of Hb levels in this subgroup of patients with lower-than-normal Hb levels. , which may provide surprising long-term and effective inhibition of S-ALP.

[0038] According to a further aspect of the invention, a subject having a PSA level of 50 ng / mL or greater is Compositions are provided comprising degarelix for the treatment of prostate cancer (see Figure 4). The cancer may be metastatic prostate cancer.

[0039] The composition comprises administration of degarelix at an initial dose of 160 to 320 mg, followed by For administration at a maintenance dose of 60-160 mg once every 20-36 days, e.g. For example, administration of an initial dose of about 240 mg of degarelix, followed by administration of about 2 mg of degarelix per day for about two weeks of treatment. For administration at a maintenance dose of approximately 80 mg of degarelix once every 8 days. It is also possible.

[0040] The composition comprising degarelix is ​​intended to provide a subject with at least a 95% chance of receiving the steroid hormone agonist on day 28 of treatment. Maintaining therapeutically low serum testosterone levels of 0.5 ng / ml or less by Subjects had at least a 95% chance of receiving 0.5 ng / day between days 28 and 364 of treatment. Therapeutic low serum testosterone levels of less than 100 ml are maintained for the treatment of (See Figure 7-8 for example.)

[0041] The composition comprising degarelix may be for the treatment of metastatic prostate cancer, Degarelix may provide at least a 60% reduction in PSA by day 14 of treatment. The composition (or medicament) containing may provide at least a 60% reduction, for example at least a 75% reduction (see, e.g., FIG. 9). (see).

[0042] The composition maintains prostate-specific antigen (PSA) levels of less than 5 ng / ml during treatment, at least The target may be for treatment with at least an 80%, for example a 95%, probability of success.

[0043] According to another aspect of the present invention, an initial dose of 160 to 320 mg of degarelix is ​​administered to a subject. and then 60 to 160 mg of degarelix once every 20 to 36 days. administering to the subject a maintenance dose of about 240 mg of degarelix, e.g., an initial dose of about 240 mg of degarelix. and thereafter administering to the subject about 80 mg of degarelix once about every 28 days. and administering to the subject a maintenance dose of A method is provided.

[0044] According to a further aspect of the invention, a subject (e.g., a patient with localized or locally advanced prostate cancer) is provided with delaying or preventing the progression of localized or locally advanced prostate cancer to metastatic prostate cancer in subjects with prostate cancer The present invention provides a composition comprising degarelix for the treatment of rheumatoid arthritis, rheumatoid arthritis, and rheumatoid arthritis. The subject may have a PSA level of 4 to 50 ng / mL, for example, a PSA level of 20 to 50 ng / mL. May have serum alkaline phosphatase (S-ALP) levels between 4 and 147 IU / L Subjects should have serum alkaline phosphatase levels below 160 IU / L, e.g., between 50 and 160 IU / L. The composition may have a phospholipase (S-ALP) value of 160 to 320 mg degarlic acid. An initial dose of degarelix followed by 60 to 160 mg of degarelix every 20 to 36 days for administration of a maintenance dose of about 240 mg of degarelix, e.g., an initial dose of about 240 mg of degarelix, and and thereafter for a maintenance dose of approximately 80 mg of degarelix administered approximately every 28 days. It's okay to have one.

[0045] The delay or prevention of progression of locally advanced prostate cancer can be achieved, for example, by administering to the prostate of a candidate for prophylactic treatment. The prostate-specific antigen (PSA) level is then tested, and the PSA is then checked to see if it is 10 to 50 ng / mL, e.g. If the level is between 20 and 50 ng / mL, it can be selected as a target for preventive treatment to prevent local progression. The initial step may involve identifying a suitable subject with prostate cancer. The serum alkaline phosphatase (S-ALP) levels of the subjects were examined, and then the S-ALP If the reference value is less than 160 IU / L, for example, 44 to 147 IU / L, then the patient is eligible for preventive treatment. Subjects with locally advanced prostate cancer may be identified by selecting as [Brief explanation of the drawings]

[0046] [Figure 1] 1 is a graphical representation comparing the mean change over time in baseline S-ALP levels with degarelix (240 / 80 mg) and leuprolide (7.5 mg) treatment for local (regional), locally advanced, and metastatic populations. [Figure 2] 1 is a graphical representation showing the mean change in baseline S-ALP over time with degarelix (240 / 80 mg), degarelix (240 / 160 mg), and leuprolide (7.5 mg) treatment for the metastatic (+Hb<130 g / L) subpopulation. [Figure 3] 1 is a graphical representation of the mean change over time in baseline S-ALP levels, showing the difference in time for reduced baseline S-ALP levels to return to baseline when degarelix (240 / 80 mg) treatment is compared to leuprolide (7.5 mg) treatment that was "switched" to degarelix after 364 days. [Figure 4]1 is a graphical representation comparing the mean change over time in baseline S-ALP levels in subjects with PSA levels of <10 ng / mL, 10-20 ng / mL, 20-50 ng / mL, and >50 ng / mL with degarelix (240 / 80 mg) and leuprolide (7.5 mg) treatment. [Figure 5] 1 is a graphical representation showing the incidence of PSA failure in patients with baseline localized, locally advanced, and metastatic prostate cancer stages treated with degarelix (240 / 80 mg) and leuprolide (7.5 mg). [Figure 6] 1 is a graphical representation showing the incidence of PSA recurrence in subjects with baseline PSA values ​​of <10 ng / mL, 10-20 ng / mL, 20-50 ng / mL, and >50 ng / mL with degarelix (240 / 80 mg) and leuprolide (7.5 mg) treatment. [Figure 7] 1 is a graphical representation showing the median decrease in testosterone levels from day 0 to day 364 with degarelix (240 / 80 mg) and leuprolide (7.5 mg) treatment. [Figure 8] 1 is a graphical representation showing the median percent change in testosterone levels from day 0 to day 28 with degarelix (240 / 80 mg) and leuprolide (7.5 mg) treatment. [Figure 9] 1 is a graphical representation showing the median percent change in PSA values ​​from day 0 to day 56 with degarelix (240 / 80 mg) and leuprolide (7.5 mg) treatment. [Figure 10] 1 is a graphical representation showing median LH levels from day 0 to day 364 with degarelix (240 / 160 mg), degarelix (240 / 80 mg), and leuprolide (7.5 mg) treatment. [Figure 11] 1 is a graphical representation showing median FSH levels from day 0 to day 364 with degarelix (240 / 160 mg), degarelix (240 / 80 mg), and leuprolide (7.5 mg) treatment. DETAILED DESCRIPTION OF THE INVENTION

[0047] Terms and Definitions Certain aspects of the present invention are described in more detail below. The terminology used in this application is intended to reflect the applicants' intent in disclosing the present invention. The patent and scientific literature referenced herein is incorporated by reference in its entirety. be incorporated into the book.

[0048] The singular forms "a," "an," and "the" are used unless the context clearly dictates otherwise. Unless otherwise specified, this also includes plural references.

[0049] The terms "approximately" and "about" refer to As used herein, the term "and" means "approximately the same as" a number or value. The terms "that" and "about" are generally understood to encompass up to ±10% of the specified amount, frequency, or value. The term "CI" refers to a statistical confidence interval. Prostate specific antigen (PSA), hemoglobin (Hb), testosterone Regarding specific levels of steroids, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) and the subject population (e.g., subjects in Clinical Study CS21 described below) as described herein. The particular values ​​described are averages (i.e., mean) unless otherwise stated, e.g., as medians. Therefore, the specific values ​​of a subject's S-ALP, PSA, and / or Hb levels are The required aspect of the invention is that the population data (herein related The numerical data provided are based on meaningful delimitations of the target population. It is supported by a

[0050] Generally, the present invention provides a method for administering a degarelix GnRH antagonist to a subject for treating metastatic prostate cancer. Use of compositions containing the drug and related methods of treatment are provided. Specifically, the CS21 study on degarelix (European Patent Application No. 08250703.9) and U.S. Provisional Application No. 61 / 027,741). The present study, including analyses of safety, efficacy, and selective benefit for certain patient subpopulations, The basic methods for conducting and analyzing controlled clinical studies of the type described in this document are available. (Spilker (1991) Guide to Clinical Trial s Raven Press, New York; and Spilker (1996 ) Quality of Life and Pharmacoeconomics in Clinical Trials Lippincott - Raven Pu blishers New York).

[0051] The term "prostate cancer" refers to a condition in which cells of the prostate gland mutate and begin to grow uncontrollably. The extent to which prostate cancer has progressed in a patient is determined by clinical and histopathological information. The stage of cancer is evaluated taking into consideration the tumor size (T), whether there is lymph node metastasis ( N), presence of metastases (M), and tumor grading (G). Tumors classified as T1 are confined to the prostate and are too small to penetrate the rectum. T1 is further classified as T1a (less than 5% in tissue samples) and cannot be palpated by digital examination. T1c is the subdivision of the prostate gland in which the patient has elevated prostate cancer cells (less than 10% of cancer cells) and T1b (more than 5%). indicates the presence of a prostate-specific antigen (PSA, see definition below). The tumor is palpable during a digital rectal examination. If the tumor is large enough to affect only one side of the prostate, it is classified as T2. T2a is when the tumor is only on one side of the prostate (left or right). T2b means that the tumor is present on both sides. T2 is generally If the cancer is T3, it may be in the connective tissue near the prostate (T3a) or T4 means the cancer has spread to tissues next to the prostate, such as the bladder sphincter, Prostate cancer may also be a sign of spread to the rectum or pelvic wall. These T3, T4, and T5 cancers can also spread to other parts of the body, which is considered to be N1 stage prostate cancer. Stages N4 and N1 are collectively referred to as "locally advanced" or If the cancer spreads to distant sites such as the bones, it is called a regional cancer. If the cancer has spread to distant lymph nodes, it is said to have "metastasized" or be in stage M1. Prostate cancer is classified as M1a, while cancer that has spread to the bone is M1b, and cancer that has spread to the liver or If the cancer spreads to organs such as the brain, it is classified as M1c. Cancer almost exclusively metastasizes to the bones.

[0052] As used herein, terms such as "bone metastasis," "skeletal metastasis," "bone lesion," and "metastatic lesion" are used. The terms may be used interchangeably to refer to the metastatic stage. Weight loss and fatigue often accompany M1 stage. Survival rates are also significantly lower in metastatic prostate cancer. Treatments that lead to a reduction in bone metastases may also have beneficial effects such as reduced pain. Improvement in quality of life (QoL), reduction in bone loss, and more importantly, However, at some point, metastatic patients may become hormonally dependent. Sometimes the patient fails to respond to hormone-based treatment, which is known as the "hormone-refractory" stage. According to this terminology, and as employed herein, "treatment of metastatic prostate cancer" refers to The term "malignant myeloma" refers to subjects classified as M1a, M1b, or M1c, and / or N1. Including treatment.

[0053] In general, androgen deprivation is effective in 80 to 90 percent of men with advanced prostate cancer. induces remission and results in a median progression-free survival of 12 to 33 months. At that time, an androgen-independent phenotype usually emerges. Cancer (sometimes called hormone-resistant or hormone-independent prostate cancer) Castrate-level testosterone levels (20 ng / Although the patient has a T of less than 1000 dL, the patient's blood PSA level is elevated. [Murphy D. (1993) Cancer 72: 3888-3895; Hellerstedt BA and Pienta KJ (2002) CA Cancer J. Clin. 52: 154-17 9.]

[0054] Alkaline phosphatase (ALP) is a phosphate-binding enzyme that binds nucleotides, proteins, and alkalis. It is a hydrolase involved in removing phosphate groups from many types of molecules, including phosphates. In humans, ALP is present in all tissues throughout the body, but is most abundant in the liver, bile duct, and kidney. It is particularly concentrated in the liver, bone, and placenta. Its concentration values ​​can be used as a diagnostic tool. Abnormally elevated values ​​(hyperphosphatasia) may indicate several disorders. These include liver disease, bone disease, malignant tumors, osteomalacia, kidney disease (secondary hypothyroidism), This includes skeletal involvement of other primary diseases, such as thyroid disease, primary hypothyroidism, and primary hypothyroidism. Abnormally low values ​​of LP (hypophosphatasia) may be a sign of severe anemia in men, or of chondrogenesis. It may also indicate other disorders such as dysentery, cretinism, or severe enteritis in children. The level of ALP present in the serum of a subject (S-ALP level) can be measured by the treatment methods described herein. and used in connection with compositions.

[0055] S-ALP tests are well known in the art (Chernecky CC, Berge r BJ (2008), Laboratory Tests and Diagnosis stic Procedures, 5th ed., WB Saunders & Company, Philadelphia). It is generally used as a test of liver function. It is used for the treatment of bone metastatic lesions of various malignancies (breast, prostate, and colon). In metastatic prostate cancer, the S-ALP reference value (or "ALP value") ") is consistently higher than localized or locally advanced disease, reflecting bone lesions. As indicated, the subject has a serum albumin level of about 150 IU / L or greater, e.g., 160 IU / L or greater. Baseline alkaline phosphatase (S-ALP) values ​​(i.e., before treatment, i.e., testosterone) S-ALP value before the first dose of the drug), e.g., serum alkaline phosphatase of 200 IU / L or more Therefore, the treatment of patients with metastatic prostate cancer may be A decrease in baseline S-ALP levels during treatment may, under some circumstances, indicate a positive response to treatment. is.

[0056] One of the most important techniques for diagnosing prostate cancer is a blood test, specifically , the measurement of prostate-specific antigen (PSA) levels in the blood. The term "A" refers to a substance produced by cells of the prostate gland that is present in small amounts in the serum of healthy men. It refers to a protein that is often elevated in the presence of prostate cancer and other prostate diseases. A blood test measuring PSA is the most effective test currently available for early detection of prostate cancer. It is an effective test. Higher-than-normal PSA levels are a sign of both localized and metastatic prostate cancer. According to the present invention, a subject with localized or metastatic prostate cancer receives 50 ng / mL of mL or higher.

[0057] Degarelix and related pharmaceutical formulations Degarelix is ​​a G-type phenylalanine derivative incorporating p-ureido-phenylalanine at positions 5 and 6. nRH decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-P ro-Gly-NH2), a potent GnRH antagonist (Jiang et al. al. (2001) J. Med. Chem. 44:453-67). and prostate cancer patients who are advised to undergo androgen deprivation (those who have already undergone prostatectomy or radiation therapy). It is indicated for the treatment of patients with PSA rising after receiving chemotherapy.

[0058] Degarelix competitively and reversibly binds to the pituitary GnRH receptor, thereby inhibiting the Selective G, which rapidly reduces the release of nadotropin and, consequently, testosterone (T). It is an nRH receptor antagonist (blocker) for the treatment of hormone-sensitive prostate cancer. Unlike GnRH agonists, they are sensitive to testosterone blockade, which is the central principle behind their use. nRH receptor blockers may result in a subsequent testosterone surge / tumor stimulation after initiation of treatment and potential It does not induce a luteinizing hormone (LH) surge with symptomatic redness.

[0059] The active ingredient, degarelix, is a compound of seven unnatural amino acids, five of which are D-amino acids. This drug substance is an acetate salt, but The active moiety of this substance is degarelix as the free base. The acetate salt of degarelix is It is obtained after lyophilization as a low density white to off-white amorphous powder. Its chemical name is D -Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-furan Phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexyl Hydroxy-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L-phenylalanine 4-[(aminocarbonyl)amino]-D-phenylalanyl-L-leucyl-N6-(1-methyl- It is C 82 H 103 N 18 O 16 Cl It has an empirical formula of and a molecular weight of 1,632.3 Da. The chemical structure of degarelix was previously (European Patent No. EP 1003774, U.S. Patent No. US 5,925,777 30, U.S. Pat. No. 6,214,798), which may be represented by the formula: . Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cbm)- Leu-Lys(iPr)-Pro-D-Ala-NH2

[0060] Administration and Dosage Degarelix is ​​generally administered intravenously in the abdomen (intravenously), as described in more detail below. It may also be formulated for subcutaneous administration (as opposed to intravenous). As with medications, injection sites should be rotated periodically to adapt treatment to any discomfort at the injection site. Generally, the device should be placed in an area where the patient is not exposed to pressure, e.g., the waistband or or a site that is not close to the belt and not close to the ribs.

[0061] Degarelix administered by subcutaneous or intramuscular injection is effective, but daily injections are generally Therefore, a depot formulation of degarelix was developed as described in International Publication No. WO 03 / 006. 049 and U.S. Publication Nos. 20050245455 and 20040038903 Briefly, the skin of Degarelix may be used as described in more detail in For administration, the peptide is delivered to a biodegradable polymer matrix over a period of (typically) 1 to 3 months. Depot technology, where degarelix (and related GnRH antagonists) are released from the The peptide has a high affinity for the GnRH receptor, much higher than other GnRH analogs. Degarelix and these related GnRH antagonists are It is possible to form a gel immediately after application, which remains stable for a period of weeks or even months. The peptide can then be released from the vesicle and act as a depot.

[0062] The key variables for the formation of an effective degarelix depot are the amount of material administered combined with The concentration of the solution must be within the functional range. If this occurs, no depot is formed and the duration of action is lost, regardless of the amount of drug substance given. If the formulation is too thick, gel formation occurs before the drug can be administered. Effective depot-forming formulations of degarelix generally contain 5 mg / mL or more of degarelix, e.g., 5 to 10 mg / mL. It has a degarelix concentration of 40 mg / mL.

[0063] Thus, degarelix can be administered by injection (e.g., by forming a depot as described above). provided as a powder for reconstitution (with a solvent) as a solution for administration (e.g., subcutaneous injection) This powder contains degarelix (e.g., as the acetate salt) and mannitol. Suitable solvents include water (e.g., water for injection, For example, each 1 mL of liquid contains approximately 40 mg of degarelix. To reconstitute with 3 mL of WFI, use a solution containing 120 mg of degarelix (acetate). In another example, degarelix can be provided in a vial containing 80 mg of degarelix. Degarelix can be provided in a vial containing garelix (acetate salt). When reconstituted with approximately 4 mL of WFI, e.g., 4.2 mL of WFI, each 1 mL of solution It contains approximately 20 mg of degarelix.

[0064] According to the present invention, an initial dose of 160 to 320 mg of degarelix is ​​administered to a subject. followed by a maintenance dose of 60 to 160 mg of degarelix once every 20 to 36 days administering to the subject an initial dose of about 240 mg of degarelix, e.g., administering to the subject an initial dose of about 240 mg of degarelix. and then a maintenance dose of about 80 mg of degarelix once about every 28 days. and administering to the subject a will be done.

[0065] The composition contains an initial dose of 160-320 mg of degarelix, followed by 20-36 doses every 20-36 days. The dose may be for administering a maintenance dose of 60 to 160 mg of degarelix once per day. stomach.

[0066] The preferred dosing regimen for treating adult men with prostate cancer is a single starting dose of 240 mg of ribozyme. mg degarelix given as two 120 mg subcutaneous injections, followed by approximately 28 days or After 1 month, monthly degarelix maintenance dose of 80 mg will be administered as a single subcutaneous injection. is.

[0067] For example, the degarelix dosing regimen involves an initial starting dose of 240 mg divided into two doses, each of which is administered 3 m L of approximately 40 mg / mL degarelix formulation administered by injection, followed by a maintenance dose of 80 mg 4 mL of approximately 20 mg / mL degarelix formulation can be administered as a single subcutaneous injection once a month. Alternatively, for example, 4 mL of approximately 40 mg / mL degarelix can be administered monthly. A monthly maintenance dose of 160 mg may be used.

[0068] The reconstituted solution should be a clear liquid with no undissolved material. A single 240 mg dose of luteinizing hormone (luteinizing hormone) followed by monthly maintenance doses of 80 mg Decrease in levels of LH, follicle-stimulating hormone (FSH), and subsequently testosterone The plasma concentration of dihydrotestosterone (DHT) also increases rapidly. decreases in the same way.

[0069] Degarelix delivers testosterone levels well below the medical castration level of 0.5 ng / mL. As explained in more detail below, A single maintenance dose of 80 mg resulted in sustained efficacy for at least 1 year in 97% of patients. Testosterone suppression was achieved. In particular, the median testosterone level after one year of such treatment was was 0.087ng / mL.

[0070] The pharmacokinetic parameters associated with degarelix evaluated in patients with prostate cancer are shown in the table below. Summarized in 1. [Table 1]

[0071] The median degarelix trough concentration during the maintenance phase of 80 mg at a concentration of 20 mg / mL was , 10.9ng / mL.

[0072] Subcutaneous administration of 240 mg degarelix (6 mL at a concentration of 40 mg / mL) to patients with prostate cancer Degarelix is ​​then eliminated in a biphasic manner with a terminal half-life The median fe is approximately 43 days.

[0073] The long half-life after subcutaneous administration is due to the non-removal of degarelix from the depot formed at the injection site. This is always the result of slow release.

[0074] The pharmacokinetic behavior of this drug is strongly influenced by the drug concentration in the injectable suspension.

[0075] The volume of distribution in healthy elderly men is approximately 1 L / kg. Plasma protein binding is approximately 90%. It will be estimated.

[0076] Degarelix undergoes general peptidolysis during passage through the hepatobiliary system, with peptidoglycan fragments primarily found in excreta. No significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix inhibits the activity of human CYP450 (cytochrome P4 50) system. Therefore, clinical effects of other drugs are not Significant pharmacokinetic interactions are unlikely.

[0077] In healthy men, approximately 20% of the administered degarelix is ​​excreted by the kidney. This suggests that approximately 80% of the drug is excreted via the hepatobiliary system. The clearance is 35-50 mL / hr / kg.

[0078] Adverse events (side effects) Degarelix has been found to be generally well tolerated in clinical trials. The most common adverse reaction observed during treatment was the expected physiological effects of testosterone suppression. The effects of the drug were primarily due to facial flushing and weight gain, as well as side effects associated with the injection site. Adverse events (injection site-related side effects), primarily pain at the injection site and erythema at the injection site It was. [Example]

[0079] Example 1: S-AL in prostate cancer patients treated with degarelix versus leuprolide P-value Example 1 shows degarelix (240 / 80 mg) or leuprolide (7.5 mg) treatment Serum alkaline phosphatase (S-ALP) analysis in patients treated for prostate cancer gives the result.

[0080] method: Histologically confirmed prostate cancer (all stages) for which androgen deprivation therapy is indicated Patients were recruited. 610 patients (mean age 72 years, median PSA 19.0 ng / mL) ) were randomized to one of three dosing regimens: 1 month of degarelix; Sc 240 mg (starting dose), followed by 160 mg (n=202) or 80 mg g (n=207) of monthly maintenance doses of degarelix sc or leuprolide depot 7 Monthly intramuscular injection of 0.5 mg (n=201). Patients receiving leuprolide also received clinically significant Bicalutamide could be given to prevent erythema. S-ALP analysis: Blood samples were collected and analyzed for S-ALP. S-ALP values ​​at various time points were calculated for each S-ALP values ​​were measured in patients. S-ALP values ​​were measured using a standard method based on the p-nitrophenyl phosphate AMP buffer method. Standardized colorimetric assay The normal range of S-ALP is 44-147 IU / L. The S-ALP values ​​of the patients served as a control. Treatment and days were factored in. ANOVA analysis was performed on the 364th day using the baseline value as a covariate. Treatment and days were used as factors, and baseline was used as a covariate. A repeated measures analysis (incorporating all time points from day 112 onwards) was performed from day 112 to day 3. Used to determine treatment differences up to 64 days. result: Degarelix 240 / 80 and leuprolide 7.5 mg in patients with advanced prostate cancer The results of the group analysis are presented in Table 2 and Figure 1. Baseline characteristics were balanced between groups. Patients Approximately half of patients had locally advanced (29.2%) or metastatic (20.5%) disease at baseline. The overall mean age was 72 years, the median testosterone level was 39.3 ng / mL, and the PS was The median A was 19.0 ng / mL. In localized disease, S-ALP levels were related to treatment group (leuprolide or degarelix). There was no significant difference in the mean age of the patients with locally advanced disease, with a slight but gradual increase within the normal range over the study period. A small increase in the incidence of rheumatoid arthritis was observed in both treatment groups by the end of the study. Table 2 shows the Baseline S-ALP values ​​were higher in metastatic patients, and both treatments were effective in patients with Hb < 130 g / L. However, after the initial peak in both groups, As previously mentioned, S-ALP levels were significantly higher with both degarelix 80 mg and leuprolide. S-ALP was suppressed below the baseline level by α-glucan, but was more significantly suppressed by degarelix. The initial increase (peak) is associated with increased activity in bone, and metastatic patients have been shown to have skeletal metastases. At the start of any treatment that affects the immune system, a surge in S-ALP is experienced. This phenomenon is completely unrelated to a testosterone surge.

[0081] Figure 1 shows the results for degarelix (240 / 80 mg) and leuprolide (7.5 mg) treatment. The mean change in S-ALP from baseline over time was calculated based on the following criteria: localized, locally progressive, and These results demonstrate the efficacy of degarelix in the treatment of S-ALP in patients with refractory leukemia and those with metastatic leukemia. Long-term suppression is clearly demonstrated. Reference S-ALP values ​​in treated subjects with prostate cancer A decrease in indicates a positive response to treatment, for example, by reducing skeletal metastatic activity. Conversely, an increase in S-ALP indicates increased metastatic activity. significantly reduced S-ALP (at the initial stage and after the expected spike) and then for the duration of the study. Most notably, S-ALP was significantly superior to leuprolide in the later stages of the study. This recovery was observed with degarelix, indicating a recovery of metastatic activity. It was not observed until very late stages (Fig. 3). Therefore, Fig. 1 shows that degarelix Reduce the level of skeletal metastases over time (or at least maintain the same level without an increase) In contrast, leuprolide is able to maintain the levels of degarelix. It was less effective in the short term and significantly less effective in the long term compared to Similar results were obtained with the 240 / 160 mg dose of degarelix.

[0082] This effect was compared with that of patients with metastatic disease overall, with a significantly higher effect in patients with metastatic disease and Hb<130g / L. It is further enhanced in patients with hemoglobin (Hb) content (Table 2 and Figure 2). Bone metastases affect the bone marrow, and patients with bone metastases may become anemic. Lower than normal Hb in patients with bone metastases is an indicator of more extensive metastases ( In other words, it is an indicator of more severe disease.) Table 2 and Figure 2 show the S -Long-term suppression of ALP may be even more effective in this subpopulation with more severe disease Indicates that there was.

[0083] In patients with baseline PSA levels ≤ 50 ng / mL, S-ALP levels tended to increase slightly. A general trend toward increased risk of recurrence was observed in both treatment groups over time. A different trend is seen in patients with ≥ 50 ng / mL. Table 2 (category 2) shows the data Galerix (240 / 80 mg) and leuprolide (7.5 mg) treatment, baseline P SA (<10ng / mL), (10~20ng / mL), (20~50ng / mL), The S-ALP values ​​(IU / L) of the normal and normal (>50 ng / mL) groups were compared. The same pattern of S-ALP response was seen in patients with baseline PSA ≥ 50 ng / mL (Figure (See Table 2, section 2 and 4). The initial reduction was not maintained with leuprolide and continued until the end of the study. (e.g., at day 364) were above baseline, reflecting bone lesions in these patients. In contrast, the initial decrease in ALP levels was observed after treatment with degarelix (240 / 80 mg). These results were maintained throughout the study using a 2016 randomized controlled trial (NCT02221126). Particularly effective in treating subjects (patients) with prostate cancer and baseline PSA ≥ 50 ng / mL This indicates that it can be useful. [Table 2]

[0084] Category (a) in Table 2 corresponds to degarelix (240 / 80 mg) and leuprolide (7.5 mg)-treated localized, locally advanced, metastatic populations, and metastatic (Hb<30g / L ) S-ALP values ​​(IU / L) of the subpopulations are shown.

[0085] Category (b) in Table 2 is degarelix (240 / 80 mg) and leuprolide (7.5 mg), baseline PSA (<10ng / mL), (10-20ng / mL), (2 The S-ALP values ​​(IU / L) of the (0-50 ng / mL) and (>50 ng / mL) groups are shown.

[0086] Conclusion: Patients with metastatic disease and / or PSA levels ≥ 50 ng / mL at baseline experienced a greater reduction in S-ALP levels with degarelix than with leuprolide. In particular, the increase in S-ALP (or S-ALP) by leuprolide in the later stages of the study, which indicates recovery of metastatic activity, or return to baseline) until much later. This finding was not observed in the control group (g). As shown by the results, patients in the degarelix group did not show signs of treatment failure. Finally, when compared with metastatic disease overall, this effect is It was further enhanced in patients with Hb<130g / L. Therefore, these results suggest that degarelix exhibits better skeletal activity than leuprolide. It is shown that it may be possible to reduce and / or maintain the level of metastasis.

[0087] Example 2: P in prostate cancer patients treated with degarelix versus leuprolide SA recurrence This example demonstrates the efficacy and safety of degarellic compared to leuprolide over 12 months of prostate cancer treatment. The Phase 3 clinical trial CS21 (described herein) investigated the efficacy and safety of Specifically, the secondary endpoint referred to as PSA recurrence was The analysis of the data, particularly for patients with metastatic prostate cancer, compared with leuprolide treatment, , revealed a surprising beneficial effect of degarelix treatment.

[0088] Prostate-specific antigen (PSA) is a commonly used marker in the diagnosis of prostate cancer. and more recently to monitor response to treatment and disease recurrence and progression. used (Fleming et al. (2006) Nat. Clin. Pract. Oncol. 3: 658-67; Lilja, et al. (2008) Nat. Rev. Cancer 8: 268-78). In general, P Higher levels of PSA are associated with more severe forms of prostate cancer, and metastatic prostate cancer is associated with the highest PSA levels. High levels (e.g., >50 ng / mL) are associated with prostate cancer treatment. Rising PSA levels in patients are associated with incomplete or failed treatment response.

[0089] For this analysis, PSA recurrence (secondary endpoint) was observed twice compared with nadir. Time to PSA recurrence was defined as a continuous 50% increase and ≥ 5 ng / mL. , measured on two consecutive occasions at least two weeks apart from the first dose, from the nadir The number of days from the time of treatment to the time when an increase in serum PSA of ≥ 50% and ≥ 5 ng / mL was observed The second opportunity was when this criterion was met. The PSA recurrence rate was also significantly associated with stage and baseline PSA values. These analyses showed that leuprolide 7.5 mg The focus was on the comparison of degarelix 240 / 80 mg with EGFR, as this dose was associated with a pre-progression This is the dose of degarelix currently approved by the FDA for the treatment of prostate cancer. .

[0090] The incidence of PSA recurrence was significantly higher in the degarelix 240 / 80 mg group compared with the other two treatment groups. The probability of completing the study without experiencing PSA recurrence by day 364 was lower in the data group. The highest rate was observed for the garelix 240 / 80 mg group (91.1%; 95% CI: 85. The observed 364-day probability for leuprolide 7.5 mg was 85.9%. was (95% CI: 79.9-90.2).

[0091] PSA recurrence by stage criteria PSA recurrence occurred more frequently in patients with advanced disease across all treatment groups, with PSA The majority of recurrences occurred in patients with metastatic disease at baseline (Figure 5 In this subgroup of patients, a lower rate of PSA recurrence was observed with leuprolide compared with cerebrospinal fluid (CPE). were observed during degarelix 240 / 80 mg treatment (21.6% vs. 36.2%; p = .001). These results suggest that degarelix may be beneficial in reducing the incidence of PSA recurrence. This demonstrates that the present invention provides an effective treatment for metastatic prostate cancer as assessed by the present invention.

[0092] PSA recurrence by PSA reference value PSA failure occurred more frequently in patients with higher baseline PSA levels across all treatment groups. The majority of PSA recurrences occurred in patients with baseline PSA >50 ng / mL (Figure 6). In a subgroup of patients, a smaller proportion of PSA recurrences occurred with degassing compared with leuprolide. observed during Relix 240 / 80 mg treatment (29.2% vs. 40.0%; p=0.10 Similarly, in patients with baseline PSA of 20–50 ng / mL, there was no significant difference in PSA during degarelix treatment. These results therefore suggest that degarelix is ​​effective in treating advanced prostate cancer. PSA in subjects with cancer (as reflected by a baseline PSA value of >50 ng / mL) Demonstrates providing effective treatment as measured by reduced incidence of relapse It is something.

[0093] Example 3: Clinical Study of Degarelix for the Treatment of Prostate Cancer In this example, to investigate the efficacy and safety of a monthly dosing regimen of degarelix This open-label, multicenter, randomized, parallel-group study included approximately 40 patients in the two degarelix treatment groups. Patients were administered a starting dose of 240 mg of degarelix at a concentration of 160 mg / mL. g (approximately 40 mg / mL) once a month and 80 mg (approximately 20 mg / mL) once a month. Patients received one of two different dosing regimens of degarelix. The study was conducted to evaluate the efficacy and safety of 7.5 mg of leuproreductase in patients with prostate cancer requiring androgen deprivation therapy. Compared to Lido.

[0094] This study also demonstrated the effectiveness of testosterone suppression to castrate levels and its maintenance over a 12-month period. Regarding the percentage of patients with testosterone suppression of 0.5 ng / mL or less after treatment The study also investigated whether degarelix is ​​safe and effective and whether a degarelix dosing regimen is effective. Serum levels of testosterone and prostate-specific antigen (PSA) were measured during the first 28 days of treatment. This study also evaluated the efficacy and safety of leuprolide 7.5 mg in patients with rheumatoid arthritis. The safety and tolerability of the Relix regimen was evaluated with leuprolide 7.5 mg. Furthermore, the degarelix regimen increased testosterone and luteinizing hormone levels compared with treatment alone. LH, follicle-stimulating hormone (FSH), and PSA responses were assessed using leuprolide 7. The study also assessed patient-reported outcomes (quality of life factors and facial features). flushing) were treated with the degarelix regimen versus leuprolide 7.5 mg. The study also evaluated the pharmacokinetics of the degarelix dosing regimen. Overall, this study examines the effects of degarelix treatment on patients with different stages of cancer. We considered the following.

[0095] Study design A total of 620 patients were randomized 1:1:1 to one of three treatment groups. Of these, 610 patients (mean age 72 years, mean PSA 19.0 ng / mL) received Ten randomized patients withdrew from the study before dosing.

[0096] Patients in both treatment groups received 240 mg at a concentration of 40 mg / mL (240@40) on day 0. The starting dose of degarelix was administered as two equal subcutaneous (sc) injections of 120 mg each. Thereafter, patients received 80 mg (80 @ 20 mg / mL) of 20 mg / mL every 28 days. 0: Degarelix 240 / 80 mg group) or 160 mg (16 0@40: degarelix 240 / 160 mg group) In the third treatment group, patients received 12 sc doses on day 0 and every 28 days. and active treatment with leuprolide 7.5 mg administered as a single intramuscular (im) injection. Patients receiving leuprolide 7.5 mg were given a 24-hour period at the investigator's discretion. , bicalutamide could be given as clinical flare prophylaxis.

[0097] Geographic region (Central and Eastern Europe, Western Europe, and the Americas) and weight Patients were stratified according to their weight (<90 kg and ≥90 kg).

[0098] Degarelix 240 / 160 mg group This group received an initial dose of 240 mg (240@40) at a concentration of 40 mg / mL on day 0. This starting dose was administered as two equal subcutaneous (sc) injections of 120 mg each. This group then received 12 maintenance doses of degarelix every 28 days. A single sc dose of 160 mg (160@40) was administered at a concentration of 40 mg / mL. It was.

[0099] Degarelix 240 / 80 mg group This group also received an initial dose of 240 mg (240 @ 40) at a concentration of 40 mg / mL on day 0. This starting dose was administered as two equal sc injections of 120 mg each. This group then received 12 maintenance doses of degarelix, but not a single sc dose every 28 days. The dose was 80 mg (80@20) at a concentration of 20 mg / mL.

[0100] Leuprolide 7.5 mg group This group received reference therapy leuprolide 7.5 mg. This treatment began on day 0. These treatments were administered as a single intramuscular (im) injection once every 28 days. The results are summarized in Table 3 below. [Table 3]

[0101] Patients were monitored continuously and visited the clinic monthly for up to one year. Patients were clinically observed for at least 1 hour after each dose. Patients who met these criteria were offered the opportunity to receive long-term treatment and support in an extension study.

[0102] A total of 807 patients were screened, and 620 patients were treated with degarelix 240 / 1 Three treatments were administered: 60 mg, degarelix 240 / 80 mg, and leuprolide 7.5 mg. Of the 620 randomized patients, 100% received either the Garelix 240 / 160 mg, degarelix 240 / 80 mg, and leuprolide 7 610 patients were enrolled, including 202, 207, and 201 patients in the 0.5 mg treatment groups. , who actually received the study medication. A total of 504 patients completed the study.

[0103] Diagnosis and study inclusion criteria Androgen deprivation therapy is indicated (excluding neoadjuvant hormone therapy), Men aged 18 years or older with histologically confirmed prostate cancer (any stage) Men were eligible to participate. A signed information form was required before beginning any study-related activities. Informed consent was obtained. Patients had baseline testosterone levels >1.5 ng at screening. / mL and PSA levels of 2 ng / mL or higher. Patients with rising PSA after surgery or radiotherapy could be included in this study. Patients were required to have an ECOG score of ≤2 and a life expectancy of at least 12 months. Previous or current hormonal management of prostate cancer (surgical castration or other hormonal manipulation, e.g., GnRH agonist, GnRH antagonist, antiandrogen, or estrogen However, patients who underwent prostatectomy or radiotherapy with curative intent were excluded from the study. Patients who have received radiation therapy and neoadjuvant hormonal therapy are screened for Neoadjuvant hormonal therapy if discontinued at least 6 months prior to treatment Patients receiving 5-α-reductase inhibitors for up to 6 months were also accepted as study subjects. Concomitant treatment with other drugs was also excluded from the study. Patients who were candidates for chemotherapy (radiotherapy) were excluded. Severe hypersensitivity reactions or clinically significant disorders (prostate Patients with a history of cancer (other than adenocarcinoma) were ineligible to enter the study. Patients with significant baseline prolongation of the QT / QTcF interval (>450 ms) or Patients taking concomitant medications that may cause torsades de pointes ventricular arrhythmias or those with a history of torsades de pointes ventricular arrhythmias Patients with a history of risk factors for urinary incontinence were excluded. Patients with serum ALT or bilirubin levels above the threshold, or known or suspected Patients were also excluded if they had suspected hepatic or symptomatic biliary disease. Known hypersensitivity to any component was excluded. In addition, patients with prostate cancer and surgically removed prostate glands were excluded. Any form of cancer within the past 5 years, except for basal or squamous cell carcinoma of the skin Patients were excluded from the study if they suffered from: mental incapacity making full understanding or cooperation impossible; Patients who had language barriers or language barriers were also ineligible to participate in the study. No other study medications were to be administered within 28 days.

[0104] Duration of treatment Patients in the degarelix treatment arm received a starting dose of 240@40 on day 0 and 160@40 (degarelix 240 / 160 mg group) or 80@20 (degarelix Degarelix was administered 12 times at a maintenance dose of 240 mg / 80 mg. and thereafter for 28 days (± 7 days) until the end of study treatment, i.e., day 364 (± 7 days). Patients who completed the study and met the appropriate criteria were included in the extension study. They were offered access to long-term treatment and support.

[0105] Patients in the reference therapy group were treated with leuprolide 7.5 mg on day 0, followed by Patients received 12 maintenance doses every 8 days. Patients completed the study with a total of 13 doses. Patients who completed the study and met the appropriate criteria received degassing in an extension study. These patients were offered a switch to degarelix treatment. Patients were randomized to receive either 0 mg or 240 / 160 mg of steroids on study day 0. Patients were randomized to receive either 0 mg or 240 / 160 mg of steroids previously administered in study CS21. In patients treated with leuprolide 7.5 mg in A starting dose of degarelix was administered, followed by 80 mg (20 mg / mL) or 160 mg (20 mg / mL) of degarelix. A monthly maintenance dose of either 40 mg / mL was administered.

[0106] Patients in the comparison group received 7.5 mg of leuprolide intramuscularly, prefilled in a dual-chamber syringe. Patients were treated with an intravenous injection (im) on day 0 and once every 28 days thereafter. and leuprolide 7.5 mg administered as a single im injection. Calutamide could be given as clinical flare prophylaxis.

[0107] Criteria for evaluating efficacy In one aspect of the present invention, the composition (or medicament) may be for therapeutic purposes. Treated subjects have at least a 95% chance of achieving a blood glucose level of 0.5 ng / ml or less by day 28 of treatment. maintain therapeutically low serum testosterone levels, e.g., at least 95% of the time Possibly, from day 28 to day 364 of treatment, the therapeutically low level of 0.5 ng / ml or less Maintain serum testosterone levels.

[0108] The composition (or medicament) may be for treatment, and the subject may be a second Prostate-specific antigen (PSA) reduction of at least 60% (e.g., at least 75%) by day 8 The composition (or agent) has at least an 80% chance of reducing the 5 ng / mL blood glucose level during treatment. The treatment may be for maintaining a prostate specific antigen (PSA) level below 1 / ml.

[0109] The primary efficacy endpoint was the maintenance of testosterone levels ≤0 from days 28 to 364. The chances were that the level would remain at 0.5ng / mL.

[0110] Secondary efficacy endpoints were the number of patients with a testosterone surge during the first 2 weeks of treatment Percentage of patients with testosterone levels ≤ 0.5 ng / mL on day 3; Percentage of patients with testosterone levels ≤ 0.5 ng / mL on day 28 Percent change from baseline in PSA; testosterone ≤ 0.5ng from day 56 to day 364 Probability of / mL; serum testosterone, LH, FSH, and PSA over time throughout the study defined as two consecutive 50% increases compared to the nadir and at least 5 ng / mL Time to PSA failure; Risk factors and trough values ​​on days 308 and 336; Testosterone levels on days 255 and / or 259 compared with Frequency and magnitude of increase in thyroid function; Days 0, 28, 84, 168, and study visit quality of life at the end of the study; frequency and intensity of hot flushes experienced (from the start of the study to the end of the study treatment) In addition, sufficient testing was performed from day 28 to day 364. Probability of testosterone response (patients with testosterone levels >1.0 ng / mL after day 28) or two consecutive testosterone levels >0.5 ng / mL This patient was considered to have had an inadequate testosterone response), and P Two additional secondary endpoints were added: percent change from baseline in SA.

[0111] Safety evaluation criteria Frequency and severity of adverse events (AEs), laboratory parameters (clinical chemistry, hematology, and Presence of clinically significant changes in urine, electrocardiogram (ECG) and vital signs, physical Safety variables in this study were assessed for laboratory-detectable changes and body weight.

[0112] Body weight was measured at screening and at the end of the study visit. Height (barefoot) was measured by the Body mass index (BMI) is calculated as an individual's weight divided by their height squared. The formula widely used in medicine is kg / m 2 This gives rise to a unit of measurement for the body. The score index may be calculated exactly using any of the formulas known in the art. stomach.

[0113] statistical methods All statistical analyses were performed using the statistical analysis software SAS (trademark) version 9 or higher. Analyses were performed and summary statistics were calculated. The populations for analysis were as follows:

[0114] The intent-to-treat (ITT) analysis set included all patients who received at least one dose of degarelix. All randomized patients were included.

[0115] The per-protocol (PP analysis set) is all ITT analyses without major protocol violations. Set included.

[0116] The safety population was the same as the ITT analysis set, therefore all safety analyses were performed on the ITT The TT analysis was performed in the set.

[0117] The primary efficacy endpoint was analyzed for both the ITT and PP analysis sets. The intention-to-treat analysis set was considered the primary. The primary efficacy endpoint was determined using Kaplan-Meier method. Analysis was performed using the Yahr method. For each of the three treatment groups, a log-log transformation of the survivor function was performed. Testosterone response rates with 95% confidence intervals (CI) were calculated by: The difference between the steroid treatment group and leuprolide 7.5 mg was calculated using pooled standard errors. The 97.5% CI calculated by the normal approximation with standard error was used. It was evaluated using

[0118] To assess the efficacy of degarelix, two hypotheses were tested.

[0119] (1) U.S. Food & Drug Administration The FDA criteria is cumulative testosterone ≤ 0.5 ng / mL from day 28 to day 364. Determine whether the lower limit of the 95% confidence interval (CI) for the product probability was within 90%. That was the case.

[0120] (2) European Medicines Agency (EME) A) The criterion was a cumulative prognosis of testosterone ≤ 0.5 ng / mL from day 28 to day 364. To determine whether degarelix is ​​non-inferior to leuprolide 7.5 mg in terms of efficacy The non-inferiority margin for the difference between treatments (degarelix vs. leuprolide 7.5 mg) was (non-inferiority limit) was -10 percent.

[0121] Unless otherwise stated, all secondary efficacy endpoints were assessed in the ITT and PP analysis sets. Fisher's exact test was used to analyze the difference between the first 2 weeks of treatment and the second week of treatment. The proportion of patients with a testosterone surge during the study period was analyzed. Testosterone levels ≤ 0 on day 3 Fisher's exact test was also used to analyze the proportion of patients who showed a serum creatinine concentration of 0.5 ng / mL. The percent change in PSA from baseline to the 28-day endpoint was calculated using the Wilcoxon test. Both Fisher's exact test and Wilcoxon test showed that the treatment Treatment group, geographic region, weight strata (<90 kg, ≥90 kg), and leuprolide 7. Separate data were presented for the 5 mg subgroup.

[0122] Secondary endpoint: testosterone ≤ 0.5 from day 56 to day 364 Probability of PSA recurrence in ng / mL, time to PSA recurrence, and adequate PSA recurrence from days 28 to 364 Probability of testosterone response was analyzed by the Kaplan-Meier method.

[0123] Efficacy Results The primary objective of this study was to achieve testosterone suppression ≤0.5 ng / mL during 12 months of treatment. Achievement and maintenance of castrate-level testosterone suppression assessed as the proportion of patients who achieved The objective of this study was to demonstrate the efficacy of degarelix in

[0124] Results showed that degarelix, delivered in a 240 / 80 mg regimen, significantly improved testosterone levels. This resulted in rapid and effective suppression, which remained low throughout the 364 days of treatment. This shows that (Figure 7).

[0125] Coupled probability of achieving testosterone ≤ 0.5 ng / mL between days 28 and 364 The von Meyer estimates were for degarelix 240 / 160 mg and degarelix 24 mg, respectively. The rates were 98.3%, 97.2%, and 99.2% for the 0 / 80 mg and 7.5 mg leuprolide groups, respectively. and 96.4%. For all three treatment groups, the lower bounds of the 95% CIs were The identified 90% threshold was exceeded. Testosterone ≤ 0 from day 28 to day 364. Regarding the probability of achieving a blood glucose level of 5 ng / mL, treatment with degarelix was significantly higher than treatment with leuprolide 7.5 mg. Both degarelix treatment groups demonstrated non-inferiority to leuprolide 7 The overall 97.5% CI for the difference in probability compared with the 0.5 mg group is the non-inferiority margin of -1 0 percent. Therefore, this study is not supported by FDA and and EMEA standards.

[0126] The robustness of the primary efficacy endpoint results was supported by observed case analyses. This analysis revealed that ≤0.5 ng / mL of test results were obtained from days 28 to 364. Similar estimates were obtained for the overall proportion of patients showing steroid hormones, and they were lix 240 / 160 mg group, degarelix 240 / 80 mg group, and leuprolide 7 The rates were 98.2%, 97.0%, and 96.0% for the 0.5 mg group, respectively. The analysis findings were: Probability of testosterone ≤ 0.5 ng / mL from day 56 to day 364 This was further supported by a secondary efficacy analysis.

[0127] As expected, there was a rapid increase in testosterone (increase ≥ 15% from baseline) during the first 2 weeks of treatment. ) is the pooled degarelix group A significantly higher proportion of patients in the leuprolide 7.5 mg group compared with 0.2% in 1 patient 80.1%) (p<0.0001, Fisher's exact test). Patients treated with methicillin-resistant Staphylococcus aureus (MMa) had low baseline testosterone levels (0.0065 ng / mL). L), therefore, a sudden increase from such a low baseline would not be significant. These patients could be considered artifacts. Conversely, on day 3, leuprolide 7. Patients in the 5 mg group showed no testosterone suppression compared with those receiving degarelix 96% of patients who underwent steroid therapy demonstrated testosterone suppression (p<0.0001, Fisher's As shown in Figures 7 and 8, the degarelix 240 / 80 mg dosage The study showed that leuprolide 7.5 mg rapidly and effectively suppressed testosterone levels. , which worked much more gradually and only after the initial testosterone surge.

[0128] As shown in Figure 9, the degarelix 240 / 80 mg dosing regimen was associated with a significant improvement in leuprolide 7. It also produced a more rapid and effective reduction in PSA levels than treatment with 5 mg. A reduction was observed in patients treated with degarelix. In contrast, leuprolide PSA levels in the 0.5mg group plateaued during the first week of treatment and then exponentially declined to suppressed levels. The degarelix patients had a significantly reduced BP compared with the leuprolide 7.5 mg patients. There was a significantly greater reduction in median PSA levels from baseline (p<0.0001, Wilcox PSA from the combined degarelix group was observed on days 14 and 28. The probability of being less than 1 was significantly higher on the first day (0.70) than on the 28th day (0.70) from the leuprolide 7.5 mg group. The odds of completing the study without experiencing a PSA recurrence were slightly higher at 4 days (0.82). The highest rate was in the Degarelix 240 / 80 group (91.2%), and the Degarelix 240 / 160m The results were slightly lower for both the 7.5 mg and leuprolide 7.5 mg groups (approximately 85.8%). ), this difference was not statistically significant.

[0129] Antiandrogen therapy as per protocol, leuprolide 7.5 mg for flare prevention 22 patients in the group were assessed at the start of treatment. PSA data for these patients were obtained from antiandrogen-dependent Compared with patients in the leuprolide 7.5 mg group who did not receive genotherapy, on day 14 (61. The median percent change from baseline was greater on Day 1 (7% reduction) and Day 28 (89.1%). In this case, patients in the leuprolide 7.5 mg group who did not receive antiandrogen therapy The reduction rates were 15.3% and 61.7% on days 14 and 28, respectively. The median percent change in PSA levels in patients receiving leuprolide plus an antiandrogen was This is similar to patients treated with Galerix, and therefore, this may result in a reduction in the risk of death at the start of treatment. Degarelix is ​​more effective than conventional GnRH agonist therapy in suppressing PSA in men Degarelix is ​​not recommended for use with additional concomitant medications to prevent flares. The starting dose of 240 mg does not require any additional treatment, and the PSA level is significantly lower than that of GnRH agonists and anti-inflammatory drugs. It has a similar effect to androgen combinations.

[0130] The profile of serum LH levels over time was similar to that observed for testosterone. After administration of degarelix, the median LH levels in the ITT analysis set decreased rapidly. , <0.7 IU / L on day 1, which was a decrease of approximately 88% from baseline. For the degarelix treatment group, median LH levels were suppressed until the end of the study, day 364. In contrast, for patients in the leuprolide 7.5 mg group, LH levels remained A rapid increase in median blood glucose levels was observed, peaking at 31.0 IU / L on day 1 (>100 from baseline) after which the median blood glucose level increased by 10.0 IU / L. 400% increase), which exponentially decreased to 0.035 IU / L by day 56 and then to 0.035 IU / L by day 364. It remained at this value until the day (see Figure 10).

[0131] A rapid decrease in FSH levels was also observed in patients treated with degarelix. Administration of 10 mg / kg / day resulted in a reduction in mean FSH levels to ≤1.5 IU / L by day 7, This was a >80% decrease from baseline. For both degarelix treatment groups, FSH levels Median values ​​remained suppressed through the end of the study on day 364. Leuprolide 7.5 mg For patients in the group, there was an initial surge in FSH levels similar to that observed for LH levels. It peaked at 22.5 IU / L on day 1 (a 146% increase from baseline) and remained at 22.5 IU / L by day 14. There was an exponential decrease in FSH levels to 2.0 IU / L on day 56, followed by a median FSH decrease of 1.0 IU / L on day 56. The serum creatinine concentration increased to a plateau of approximately 4.40 IU / L around day 364 and remained there until day 364 (Figure 1 See 1).

[0132] The pharmacodynamic profile of degarelix is ​​characteristic of a GnRH antagonist and is associated with increased testosterone levels. Serum levels of LH, LH, and FSH were rapidly suppressed. In contrast, leuprolide 7.5 For patients in the 1 mg group, serum levels of testosterone, LH, and FSH were Within 1 week of the 2016 flu-induced leukemia, the levels of flu-induced leukemia increased rapidly and then decreased to inhibitory levels (Figs. 7, 8, 10, and 11). (See

[0133] Safety Results Safety and tolerability were assessed by observed and reported treatment-emergent AEs. These include injection site reactions, hematology, clinical chemistry, and urinalysis laboratory parameters, vital signs, Clinical observations included weight measurement and physical examination, ECG and concomitant medications.

[0134] Safety parameters were assessed for all patients included in the ITT analysis set, which consisted of , which included all 610 randomized patients who received at least one dose of study drug. .

Claims

1. The subject's metastatic stage prostate cancer A composition comprising degarelix for treating cer.

2. The subject's baseline serum alkaline phosphatase (S-ALP) level level) (before treatment) is about 150 IU / L or more, for example, about 160 IU / L or more; The composition of claim 1.

3. 10. The subject's baseline serum alkaline phosphatase level is 200 IU / L or greater. Or the composition described in 2.

4. The subject's serum alkaline phosphatase activity was measured for a period between approximately 60 and 364 days of treatment. The serum S-ALP level is reduced by at least 50 IU / L or more from the reference level (S-ALP).

4. The composition according to any one of 1 to 3.

5. the subject's serum alkaline phosphatase during the period between days 364 and 450 of treatment 5. Any of claims 1 to 4, wherein the value is reduced by about 50 IU / L or more from the reference value (S-ALP). The composition according to any one of the preceding claims.

6. the subject's serum alkaline phosphatase during the period between days 112 and 364 of treatment; 6. Any of claims 1 to 5, wherein the value is reduced by about 90 IU / L or more from the reference value (S-ALP). The composition according to any one of the preceding claims.

7. 7. The method of claim 1, wherein the subject has a hemoglobin (Hb) level of 130 g / L or less. The composition described above.

8. The subject's serum alkaline phosphatase (S-ALP) reference value is 300 IU / L or more. The composition according to any one of claims 1 to 7.

9. the subject's serum alkaline phosphatase during the period between days 112 and 364 of treatment; 8. Claims 6 and 7, wherein the value is reduced by about 160 IU / L or more from the reference value (S-ALP). The composition according to any one of the preceding claims.

10. 10. The method of claim 1, wherein the subject has a PSA level of 50 ng / mL or greater. Composition of.

11. During the period between days 112 and 364 of treatment, the subject's serum alkaline phosphatase 10. The method according to claim 1, wherein the α-ALP level is reduced by about 60 IU / L or more from the reference level (S-ALP). The composition described in

12. Degarelix is ​​administered at an initial dose of 160-320 mg, followed by a maintenance dose of 60-16 12. The method according to claim 1, wherein the compound is administered at a dose of 0 mg once every 20 to 36 days. composition.

13. Degarelix is ​​administered at an initial dose of about 240 mg and thereafter at maintenance doses of about 80 mg.

13. The composition of any one of claims 1 to 12, for administration once every 28 days.

14. There is at least a 95% chance that the subject will have a blood glucose level of 0.5 ng / ml or greater by day 28 of treatment.

14. The method of claim 1, wherein the method maintains a therapeutically low serum testosterone level of 0.5 or less. The composition described above.

15. There is at least a 95% chance that the subject will achieve a 0.5% or higher survival rate between days 28 and 365 of treatment.

15. The method of claim 1, wherein the testosterone level is maintained at a therapeutically low level of 0.5 mg / mL or less. The composition described in any one of the above.

16. The subject's PSA is reduced by at least 60% by day 14 of treatment, e.g., by day 14 of treatment.

16. The composition of any of claims 1 to 15, wherein the composition provides at least a 75% reduction by 28 days.

17. For treatment with at least an 80% chance of maintaining PSA levels below 5 ng / ml during treatment The composition according to any one of claims 1 to 16.

18. and degarelix for the treatment of prostate cancer in subjects with PSA levels of 50 ng / mL or greater. A composition comprising:

19. The subject's serum alkaline phosphatase (S-ALP) reference value is approximately 150 IU / L or higher.

19. The composition of claim 18, wherein the IL-14 concentration is about 160 IU / L or more.

20. The subject's serum alkaline phosphatase (S- 20. The method of claim 18 or 19, wherein the baseline ALP level is negatively changed by about 60 IU / L or more. Composition of.

21. 20. The method of claim 18, wherein the subject has a hemoglobin (Hb) level of 130 g / L or less. The composition according to any one of the preceding claims.

22. Subjects with localized or locally advanced prostate cancer The progression of advanced prostate cancer to metastatic prostate cancer 10. A composition comprising degarelix for delaying or preventing rheumatoid arthritis.

23. 23. The composition of claim 22, wherein the subject has a PSA level of 10 to 50 ng / mL.

24. 24. The method according to claim 22 or claim 23, wherein the subject has a PSA level of 20 to 50 ng / mL. The composition described.

25. The subject has a serum alkaline phosphatase (S-ALP) level between 44 and 147 IU / L.

25. The composition of any of claims 22 to 24, having

26. The subject has a serum alkaline phosphatase (S-ALP) level of less than 160 IU / L.

25. The composition of any one of claims 22 to 24.

27. The subject has a serum alkaline phosphatase (S-ALP) level of 50-160 IU / L. The composition of claim 26.

28. Degarelix 160-320 mg initial dose, and then once every 20-36 days 28. The method according to claim 18, wherein the maintenance dose of degarelix is ​​60 to 160 mg. The composition described in any one of the above.

29. 1. Use of degarelix in the manufacture of a medicament for the treatment of metastatic prostate cancer in a subject, comprising: The treatment consists of administering degarelix at an initial dose of 160-320 mg, followed by and administering at a maintenance dose of 60-160 mg once every 20-36 days.

30. Delaying or preventing the progression of localized or locally advanced prostate cancer to metastatic stage prostate cancer in a subject Use of degarelix in the manufacture of a medicament for treating , 160-320 mg at an initial dose, followed by 6 doses every 20-36 days. and administering at a maintenance dose of 0 to 160 mg.

31. The treatment comprises an initial dose of about 240 mg of degarelix, followed by about 28 days of and administering a maintenance dose of about 80 mg of degarelix once every 10 days.

31. The use according to any one of claims 1 to 30.

32. 1. A method of treating metastatic prostate cancer in a subject, comprising administering an initial dose of about 240 mg of degarelix. to said subject, and thereafter administering about 80 mg of administering to said subject a maintenance dose of 160 to 320 mg of garelix. administering to said subject an initial dose of rixuloxetine, and then once every 20 to 36 days. and administering to said subject a maintenance dose of 60 to 160 mg of degarelix. Law.

Images