Method of treating prostate cancer using the gnrh antagonist degarelix

Abstract

To provide a dosage regimen for safely and effectively treating androgen-dependent prostate cancer without causing testosterone surge and / or other side effects of GnRH agonist therapy such as urinary tract infection or joint pain-related or cardiovascular side effects.SOLUTION: A relatively low dose of degarelix GnRH antagonist is provided about once every 28 days (e.g. once a month).SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] Prostate cancer is the leading cause of morbidity and mortality in men in industrialized countries. In 2007, the American Cancer Society reported that It is estimated that approximately 218,890 new cases of prostate cancer will be diagnosed. Prostate cancer is the second leading cause of cancer death among men in the United States, surpassed only by lung cancer. However, approximately one in six men will be diagnosed with prostate cancer during their lifetime. In reality, only 1 in 35 men will die from prostate cancer. estimated that 27,050 men in the United States will die from prostate cancer in 2007. Prostate cancer accounts for approximately 9% of cancer-related deaths in men.

[0002] The incidence of prostate cancer increased dramatically in the late 1980s, but this increase was largely due to Widespread use of prostate-specific antigen (PSA) testing has improved detection and diagnosis In fact, the incidence of prostate cancer has been declining since the 1990s. The death rate from prostate cancer has been declining since the early 1990s. (SEER Program and National Center for Health th Statistics(http: / / seer.cancer.gov / )) More than 9 out of 10 cases of prostate cancer are local and regional. d regional stages) (localized means prostate cancer Regional means that the prostate cancer has spread from the prostate to nearby areas. (This means that the cancer has spread to other parts of the body but not to distant areas such as the bones.) These men had a 5-year survival rate compared with men of the same age and race who had not undergone chemotherapy (relative survival rate). The relative survival rate is nearly 100%, but prostate cancer may have already spread to distant parts of the body at the time of diagnosis. The five-year relative survival rate for men with breast cancer is only about 32%. It is estimated that approximately $8 billion is spent on treating prostate cancer alone. r Trends Progress Report(http: / / progress report.cancer.gov)).

[0003] Most prostate cancers grow in a testosterone-dependent manner, and the current medical treatment for advanced prostate cancer is Definitive management involves androgen deprivation, which can be achieved by bilateral orchiectomy or by gonadotropin removal. This can be achieved by administering tropin-releasing hormone (GnRH) receptor agonists. Removal of the testicles (gonadectomy) has long been used as a means of slowing the growth of prostate cancer. It was the standard method of blocking the secretion of male hormones by the gonads. By means of interfering with the production of luteinizing hormone (LH), which regulates the synthesis of androgens This leads to impaired male hormone secretion. In non-metastatic, locally advanced disease, with or without lymph node metastasis, It has been strongly suggested that early endocrine therapy is associated with survival (Granfors et al. 1998) J. Urol. 159:2030~34; Messing et al. (1999) N. Eng.J.Med.341:1781~88; and (1997) Br.J.Urol (See 79:235-46).

[0004] Gonadotropin-releasing hormone (GnRH) is produced by the hypothalamus and secreted into the pituitary gland It is a natural hormone that stimulates the production of LH by interacting with receptors in the To reduce GnRH receptor (GnRH-R) agonists such as erelin have been developed. Such GnRH agonists generally comprise a compound that binds to GnRH, i.e., the decapeptide pyroGlu -His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 For example, GnRH analogs having a D-isomer instead of Gly at position 6 are Agonists have a higher affinity / strength of binding to receptors and a higher One example is the use of hydroxybenzoates (described in U.S. Pat. No. 4,072,668). pGlu-His-Trp-Ser-Tyr-D-Ala-Leu-Ar g-Pro-Gly-NH2 [D-Ala 6 ]-GnRH. The action of RH-R agonists initially stimulates LH release, and after long-term treatment This desensitizes the GnRH-R, so that LH is no longer produced. The stimulation of LH production by the hormone causes an initial surge in the production of male hormones, and therefore Therefore, the initial response to agonist therapy is not remission but rather a worsening of the patient's condition. This phenomenon is called the "testosterone surge ( testosterone surge" or "flare reaction" This is known as a "hyperactivity disorder" and can last for as long as 2-4 weeks. Each subsequent administration of steroids may result in additional small LH surges (called "acute exacerbations"). This is known as the "chronic cute-on" phenomenon, which can make the condition worse. The surge in testosterone can stimulate prostate cancer and worsen the current symptoms. This may lead to worsening of symptoms or the appearance of new symptoms such as spinal cord compression, bone pain, and urethral obstruction ( Thompson et al. (1990) J. Urol. 140:1479~80;Boccon -Gibod et al. (1986) Eur. Urol. 12:400-402) One approach that has been taken to prevent this is the use of GnRH-R agonists and flutamide. It is administered in combination with anti-androgen drugs such as This is known as adrenergic ablation therapy (AAT). Hormone therapy using GnRH-R agonists in combination with antiandrogens is a potential cure. It is now used as a pre-treatment before radical prostatectomy and is known as adjuvant therapy. However, the use of antiandrogens can be associated with significant hepatic and gastrointestinal side effects. accompanied by.

[0005] Gonadotropin-releasing hormone receptor (GnRH-R) antagonists act as It was developed to overcome the "testosterone surge" or "flare reaction" associated with smoking. However, GnRH antagonist peptides are often accompanied by histamine-releasing activity. This histamine-releasing activity can cause adverse side effects such as edema and itching, This activity poses a significant obstacle to the clinical use of such antagonists.

[0006] The search for improved GnRH antagonists has led to the development of Antide, i.e. [Ac-D-2Nal 1 ,D-4ClPhe 2 ,D-3Pal 3 ,Lys(Nic) 5 ,D- Lys(Nic) 6 ,ILys 8 ,D-Ala 10 ]-GnRH; and Cetroreli x, i.e., [Ac-D-2Nal 1 ,D-4ClPhe 2 ,D-3Pal 3 ,D-Ci t 6 ,D-Ala 10 ]-GnRH. GnR is said to be more effective than Antide in suppressing plasma testosterone H antagonists, e.g., [Ac-D-2Nal 1 ,D-4ClPhe 2 ,D-3Pal 3 ,D-Nε-carbamoylLys 6 ,Ilys 8 ,D-Ala 10 ]-GnRH It is called Antarelix. No. 6,468 discloses the design and synthesis of several GnRH antagonists, The side chains of selected residues are reacted to generate cyanoguanidino moieties, followed by Some of these are suitable for the formation of the desired heterocycle, e.g., 3-amino-1,2,4-triazole (a Such cyanoguanidino moieties are found in amino acid side chains, e.g., Lysine, ornithine, 4-aminophenylalanine (4Aph) or 4-aminophosphatase It is constructed on the omega-amino group in its chain-extended form, such as 4Ahp. The amino acids with such significantly modified or unnatural amino acids at positions 5 and 6 are GnRH antagonists based on Aph show good biological efficacy, and those based on Aph show It is generally considered to be particularly powerful. One particularly useful one is Azal ine B, i.e., [Ac-D-2Nal 1 ,D-4ClPhe 2 ,D-3Pal 3 , 4Aph(atz) 5 ,D-4Aph(atz) 6 ,ILys 8 ,D-Ala 10 ]-GnR H. U.S. Patent No. 5,506,207 discloses a method for treating 5- and 6-position hydroxylase inhibitors that exhibit biological efficacy. We developed GnRH antagonists with acylated, amino-substituted phenylalanine side chains. One such decapeptide is Acyline, i.e., [Ac-D -2Nal 1 ,D-4ClPhe 2 ,D-3Pal 3 ,4Aph(Ac) 5 ,D-4Aph( Ac) 6 ,ILys 8 ,D-Ala 10 ]-GnRH. This group of GnRH antagonists Despite the attractive properties of GnRH antagonists, there are still many improvements to be made, especially with regard to GnRH antagonists. The search continues for compounds that have long-lasting biological effects. For both therapeutic and long-term treatment indications, peptide analogs are used to stimulate prolonged LH Secretory activity, i.e., the ability of peptides to be broken down by proteolytic enzymes in the body. It may be important to demonstrate properties that can be enhanced by resistance to these drugs. To facilitate the administration of these compounds to mammals, particularly humans, without significant gelation, Such GnRH antagonist decapeptides are active at normal physiological pH, i.e., about pH 5. Its high water solubility at about pH 7.4 is considered highly advantageous.

[0007] Androgen deprivation therapy for treating prostate cancer GnRH agonists and GnRH antagonists in tion therapy Promising results have been obtained using both drugs, but the relative effectiveness of available drugs is unclear. For example, abarelix, a GnRH drug, has been linked to hypotension. and the risk of serious allergic reactions, including anaphylaxis with fainting. and in some cases, a loss of efficacy over time. In fact, Abarelix (trademark in the US, Plenaxis The drug was ultimately approved, but only for patients with advanced prostate cancer. was only ever released in 2005 for commercial reasons clearly related to these issues. Furthermore, although prostate cancer-specific mortality rates have declined, mortality in this group remains high. There was little overall effect on the rate of prostate cancer, suggesting that the risk of prostate cancer from causes unrelated to prostate cancer was low. In particular, there is a possibility that certain androgen deprivation drugs may increase the risk of death. It has been suggested that some therapies may have adverse effects on cardiovascular health. (Yannucci et al. (2006) J. Urology 176:520-525; and and Etzioni et al. (1999) J. Natl. Canc. Inst. 91:1033. See the reference. Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, the adverse consequences of GnRH agonist-induced testosterone surges are also available. for prostate cancer without the unwanted side effects of available GnRH antagonist therapy. New treatment regimens are needed. [Means for solving the problem]

[0009] Applicants have demonstrated that relatively low doses of degarelix GnRH antagonist Providing steroids approximately once every 28 days (e.g., once a month) can increase testosterone levels in prostate cancer patients. It can safely and quickly suppress levels to therapeutic levels, resulting in a rapid rise in testosterone. and does not cause cardiac (other than side effects related to the administration site, e.g., injection site) Undesirable side effects associated with androgen deprivation therapy, such as dyspnea, joint pain, and / or urinary tract infections The study found that the risk of developing steroid use was significantly reduced. The benefit of using Garelix is ​​that it does not cause any adverse organ or tissue reactions, adverse events, or side effects. This may include a reduction in the likelihood of the occurrence of symptoms of the disease and / or a reduction in the severity of such symptoms. This can be done.

[0010] A first aspect of the present invention provides a composition comprising degarelix for treating prostate cancer in a subject. and in this treatment, the incidence of side effects other than those related to the injection site and The composition can be used to treat prostate cancer in a subject, and / or the likelihood of the subject being treated is reduced. This treatment can be used to reduce the incidence and / or severity of side effects other than those related to the administration site. In a further aspect, the present invention provides a method for treating prostate cancer in a subject. The present invention provides for the use of degarelix in the manufacture of a pharmaceutical product, in which the treatment involves injection sites. The incidence and / or likelihood of side effects other than those associated with the drug is reduced.

[0011] This treatment may result in cardiovascular and / or vascular side effects (e.g., myocardial infarction, chest pain, Development, heart murmur, development of heart murmur, myocardial ischemia, atrioventricular block, deep vein thrombosis (DVT), heart failure The incidence of one or more of arrhythmias, coronary artery disorders and / or cardiac disorders and / or or reduced likelihood), musculoskeletal disorders (e.g., joint pain and / or muscle / bone Development of one or more of the following: stiffness, connective tissue disorders, disorders of the urinary and / or renal systems causing or relating to a reduction in the incidence or likelihood of such occurrence or likelihood It can be related.

[0012] This composition (or drug product) contains degarelix at an initial dose of 160 to 320 mg. and thereafter, a maintenance dose of 60-160 mg should be administered once every 20-36 days. This composition (or pharmaceutical product) can prevent side effects related to the injection site and / or administration site. The incidence and / or likelihood of side effects other than those listed above is significantly higher with the GnRH agonist leuprolide. the incidence or likelihood of such side effects associated with the previous treatment is reduced compared with that of the previous treatment. It's fine.

[0013] The composition (or medicament) has a therapeutic value of 0.5 ng / mL or less by day 28 of treatment. Subjects have at least a 95% chance of maintaining substantially low serum testosterone levels. For example, by day 28 to day 365 of treatment, 0. Maintaining therapeutically low serum testosterone levels below 5 ng / mL for at least 95 The composition (or medicament) has a % chance of causing a reduction in the number of patients with HIV by day 14 of treatment. Elephants experience at least a 30% reduction in prostate-specific antigen (PSA) (e.g., at least a 50% The composition (or pharmaceutical product) may be for the treatment of a condition in which the patient is at risk of developing a rheumatoid arthritis (a decrease in the level of rheumatoid arthritis). By day 28 of treatment, the subject experiences at least a 60% decrease in prostate-specific antigen (PSA). (e.g., at least a 75% reduction) The product (or drug) should maintain a prostate-specific antigen (PSA) level of less than 5 ng / mL during treatment. There may be at least an 80% chance of treatment maintaining the

[0014] The composition (or medicament) is administered, for example, to a subject to treat cardiovascular and / or hemodynamic disorders. It is used in treatments that reduce the incidence and / or likelihood of one or more adverse drug reactions. For example, myocardial infarction, chest pain, development of chest pain, heart murmur, development of heart murmur, myocardial infarction blood, atrioventricular block, deep vein thrombosis (DVT), cardiac arrhythmia, coronary artery disease and / or cardiac The treatment can be used to reduce the incidence and / or likelihood of one or more of the disorders. do.

[0015] The composition (or medicament) is administered, for example, to treat musculoskeletal disorders and / or is used to treat a decrease in the incidence and / or likelihood of one or more connective tissue disorders For example, subjects with locally advanced prostate cancer and / or incidence or likelihood of joint pain and / or musculoskeletal stiffness (in subjects under 65 years of age or younger) It can be used to treat a decrease in

[0016] The composition (or medicament) can be used to, for example, reduce the incidence and severity of disorders of the urinary or renal system. and / or reduce the likelihood of urinary retention. Used to treat infections (e.g., non-infectious cystitis) that may reduce the incidence and / or increase the likelihood of infection. This composition (or pharmaceutical product) can be used to treat locally advanced prostate cancer (loc Treating subjects with rheumatoid arthritis (rheumatoid arthritis) It is possible.

[0017] This composition (or drug) provides 30 kg / m 2 Body mass index (BMI) below Subjects with a pulmonary embolism can be treated, for example, at a blood pressure of 20 kg / m 2 and 30 kg / m 2 Between, for example For example, 20 kg / m 2 and 25 kg / m 2 Treating subjects with a body mass index (BMI) between This composition (or medicine) can reduce cholesterol levels above 4 mmol / L. A subject with a role level can be treated.

[0018] In a further aspect, the present invention provides a method for manufacturing a gypsum laden sieve comprising: 2 and 30 kg / m 2 have a body mass index between Target, e.g., 20 kg / m 2 and 25 kg / m 2 prostate in subjects with a body mass index between A composition comprising degarelix for treating cancer is provided. For treating prostate cancer in a subject with a cholesterol level of 4 mmol / L or greater, Compositions comprising degarelix are provided.

[0019] In one aspect, the present invention provides a method of treating prostate cancer in a subject, the method comprising administering a GnRH agonist therapy for testosterone surge or This approach reduces the likelihood of other side effects from the initial administration of degarelix. administering to the subject a dose of approximately 240 mg of degarelix, followed by a maintenance dose of approximately 80 mg of degarelix. and administering to the subject approximately once every 28 days, thereby Reduces the likelihood of causing a steroid surge or other GnRH agonist side effects , to treat prostate cancer in a subject.

[0020] In a further aspect, the present invention provides a method of treating prostate cancer in a subject, the method comprising: Gonadotropin-releasing hormone (GnRH) agonist therapy testosterone surge or This approach reduces the likelihood of other side effects. A step of administering a dose of 160 to 320 mg to subjects, followed by a maintenance dose of degarelix and administering 60 to 160 mg to the subject once every 20 to 36 days, thereby This may cause a testosterone surge or other GnRH agonist side effects. The subject's prostate cancer is treated by reducing the level of vasopressin in the blood.

[0021] In certain embodiments of these methods of the invention, the maintenance dose is administered monthly. In embodiments, the subject is administered a gonadotropin-releasing hormone (GnRH) agonist Compared to treatment with leuprolide, there were no undesired side effects during treatment. In certain embodiments, the treated subject is less likely to develop or experience adverse side effects. Treatment with the gonadotropin-releasing hormone (GnRH) agonist leuprolide In comparison, there were no cardiovascular or vascular side effects (such as myocardial infarction, chest pain, or heart murmur) during treatment. For example, the likelihood of developing or experiencing a deep vein thrombosis (DVT) is reduced. In an embodiment, the method comprises administering to a subject a therapeutically effective amount of ... In particularly useful embodiments, the treatment results in a reduced likelihood of the treated subject experiencing side effects related to the treatment. The treatment target is 30 kg / m 2 Body mass index (BMI) less than 25 kg / m 2 Less than BM In a further useful embodiment, the subject has a blood cholesterol level of 4 mmol / L (155 mg / L). Have a cholesterol level of 1000 0.5 dL or higher.

[0022] In a further embodiment, the methods of the present invention are used to treat a subject at risk for cardiovascular disease. In a particularly useful embodiment, the methods of the present invention include treating The method further includes identifying a subject with prostate cancer who is also at risk for cardiovascular disease.

[0023] In yet a further embodiment, the subject is treated with gonadotropin-releasing hormone (Gn Compared with treatment with the rheumatoid arthritis (RH) agonist leuprolide, there was no significant difference in joint pain and / or muscular aches during treatment. This is particularly useful in reducing the likelihood of experiencing an increase in or onset of musculoskeletal stiffness. In embodiments, the subject has locally advanced prostate cancer and / or is under 65 years of age. .

[0024] In a further embodiment, the subject is Compared with treatment with the agonist leuprolide, there was a significant increase in musculoskeletal disorders and / or In certain embodiments, the likelihood of developing a musculoskeletal disorder and / or a connective tissue disorder is reduced. Or the connective tissue disorder is joint pain. In other embodiments, the connective tissue disorder is a musculoskeletal disorder and / or A connective tissue disorder is musculoskeletal stiffness.

[0025] In yet further embodiments of these methods of the present invention, the subject is Treatment compared with treatment with the gonadotropin-releasing hormone (GnRH) agonist leuprolide Reduces the chance of developing non-infectious cystitis during

[0026] In another embodiment, the subject is treated with gonadotropin-releasing hormone (GnRH) receptor antagonists. Less urinary or renal damage compared to treatment with nistruprolide In certain embodiments, the urinary or renal system disorder is a urinary tract infection. In a particularly useful embodiment thereof, the subject has locally advanced prostate cancer. In one embodiment, the urinary or renal system disorder is increased urinary retention. , a disorder of the urinary or renal system is non-infectious cystitis.

[0027] In yet other embodiments, the subject is treated with gonadotropin-releasing hormone (G development of erectile dysfunction during treatment compared with treatment with the nRH agonist leuprolide In other embodiments, the subject is less likely to experience gonadotropin release. Compared with treatment with the hormone (GnRH) agonist leuprolide, The likelihood of cravings decreasing decreases.

[0028] In certain embodiments of the above methods of the invention, by day 28 of treatment, At least approximately 95% chance of maintaining serum testosterone levels below therapeutically low levels In certain embodiments, by day 28 to day 364 of treatment, the treated subject has 0.5 Maintaining therapeutically low serum testosterone levels of at least about 95 ng / ml or less In yet a further embodiment, by day 14 of treatment, the treated subject has a % chance of: Treated subjects exhibit at least about a 30% decrease in prostate-specific antigen (PSA). In some embodiments, by day 14 of treatment, the treated subject has a prostate-specific antigen (PSA) level of at least In a further embodiment, by day 28 of treatment, the treated subject exhibits a reduction of about 50%. In yet further embodiments, the patient exhibits at least about a 60% reduction in prostate specific antigen (PSA). By day 28 of treatment, the treated subject will have a prostate-specific antigen (PSA) level of at least about 75%. The percentage reduction is shown.

[0029] In a further embodiment of the method of the present invention, during treatment, a low prostate gland level of less than about 5 ng / mL is achieved. maintain a PSA level of at least about 80% (e.g., 95%) The subject of treatment has this gender.

[0030] In a further embodiment of the method of the present invention, the subject has locally advanced prostate cancer and is By day 14, the patient shows at least about a 40% decrease in PSA.

[0031] In yet a further embodiment, the subject has metastatic prostate cancer and is on day 14 of treatment. already shows at least about a 60% reduction in PSA.

[0032] In certain embodiments of the above methods of the present invention, the subject is 2 Less than 25kg / m 2 In a further aspect, the present invention provides a method for treating cardiovascular disease. and a method for treating prostate cancer in a subject at increased risk of developing the disease or disorder. In a further aspect, the present invention provides a composition comprising a compound that inhibits the development of a cardiovascular disease or disorder. Degassing in the manufacture of a pharmaceutical product for treating prostate cancer in subjects with an increased likelihood of developing the disease This composition (or pharmaceutical product) provides a method for administering degarelix to a patient for the first time. Administer at a single dose of 160-320 mg, followed by a maintenance dose of 60-160 mg for 20-3 consecutive days. This composition (or pharmaceutical product) can be administered once every six days. oxalate at an initial dose of approximately 240 mg and treated with degarelix at a maintenance dose of approximately 80 mg. The composition or medicament can be administered approximately once every 28 days. and identifying a suitable subject having a cardiovascular disease or disorder and at risk for the disease. The cardiovascular disease or disorder may be, for example, a heart murmur, an atrioventricular block, or myocardial It may be ischemia.

[0033] This composition or medicinal product may cause an increased and / or high risk of cardiovascular disease Indicators of increased risk of cardiovascular disease can be treated. High blood pressure, high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol The causes of these disorders are one or more of: high blood glucose, high blood sugar, and habitual smoking. The medication can treat subjects with blood pressure of 130 / 85 mmHg or higher. This composition or medicament can be used to treat subjects who smoke daily. Low-density lipoprotein cholesterol of approximately 160 mg / dL or higher due to a compound or drug This composition or medicament can treat subjects with 35 mg / dL。 High density lipoprotein cholesterol level of less than 1 / dL. This composition or medicament can reduce fasting glucose levels above about 120 mg / dL. Subjects with a high risk of cardiovascular disease can be treated. reactive protein (CRP), high serum homocysteine, high serum fibrinogen and high blood The composition or medicament is one or more of serum lipoprotein(a) (Lp(a)). The product can treat subjects with C-reactive protein levels greater than 3 mg / dL. This composition or medicine can prevent serum homocysteine ​​levels above 30 μmol / L. This composition or medicament can treat subjects with 7.0 g Subjects with serum fibrinogen levels of greater than 1000 mg / L can be treated with this composition. or the drug is used to treat subjects with serum Lp(a) levels greater than 30 mg / dL. It is possible.

[0034] This composition or medicine can 2 Less than, for example, 25 kg / m 2 Less than The composition or pharmaceutical product can be used to treat subjects with a body mass index of 2. 0kg / m 2 and 30 kg / m 2 Between, for example, 20-25 kg / m 2 have a body mass index of This composition or pharmaceutical product can be used to treat subjects with blood cholesterol levels of 4 mmol / L or higher. A subject having a cholesterol level of

[0035] In another aspect, the present invention provides a method for administering a therapeutically effective dose of degarelix to a patient suffering from a cardiovascular disease or disorder. and administering the compound to subjects with prostate cancer at risk of cardiovascular disease or disorders. In certain embodiments, methods of treating prostate cancer in a subject at risk are provided. The initial dose of degarelix is ​​160-320 mg, and the monthly maintenance dose of degarelix is ​​160-320 mg. In a further embodiment, the therapeutically effective dose of degarelix is , including treatment with a maintenance dose of approximately 80 mg of degarelix approximately once every 28 days. In embodiments, the therapeutically effective dose of degarelix is ​​a single initial dose of degarelix at the start of treatment. Further comprising a dose of about 240 mg.

[0036] In certain embodiments, the subject of treatment is a cardiac disorder, such as a heart murmur, atrioventricular block, and / or myocardial ischemia. Identified as being at risk for certain cardiovascular diseases or disorders.

[0037] In a further embodiment, the subject is diagnosed with an indication of increased risk of cardiovascular disease, e.g., High blood pressure, high low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol roll, high serum glucose and / or addictive smoking habits. In a further embodiment, the subject has high blood pressure of 130 / 85 mmHg or higher. The subject smokes cigarettes daily. In yet a further embodiment, the subject smokes about 160 mg / day have elevated low-density lipoprotein cholesterol levels of ≥ 1000 ng / L. In embodiments, the subject to be treated has low high density lipoprotein cholesterol of less than 35 mg / dL. In other embodiments, the subject has a blood glucose level of greater than about 120 mg / dL. , have elevated fasting glucose levels.

[0038] In yet other particularly useful embodiments, the subject has elevated serum C-reactive protein ( CRP), high serum homocysteine, high serum fibrinogen and / or high serum lipoproteins These individuals have markers of increased risk of cardiovascular disease, such as high levels of protein(a) (Lp(a)). In this embodiment, the subject has elevated C-reactive protein levels greater than 3 mg / dL. In other embodiments, the subject has an elevated serum IL-1 level of greater than 30 μmol / L. In a further embodiment, the subject has a homocysteine ​​level greater than 7.0 g / L. In yet a further embodiment, the treatment The treated subject has an elevated serum Lp(a) level of greater than 30 mg / dL.

[0039] In certain embodiments, the subject is receiving treatment at a rate of 30 kg / m 2 Less than (especially 25 kg / m 2 (less than) Have a body mass index.

[0040] In a further embodiment, the subject is receiving gonadotropin-releasing hormone (GnRH) therapy. ) compared with treatment with the agonist leuprolide, cardiac arrhythmias, coronary artery disease, and / or or a reduced likelihood of developing cardiovascular side effects such as cardiac damage. , the treatment target is 30 kg / m 2 Less than (especially 25 kg / m 2 Body mass index (BM) In other embodiments, the subject has a blood cholesterol level of 4 mmol / L (155 mg / dL ) or higher cholesterol levels.

[0041] In yet another aspect, the present invention provides a method for treating a patient with prostate cancer who is also at risk for a cardiovascular disease or disorder. by first identifying suitable subjects for the study who are at risk for cardiovascular disease or disorder. The present invention provides a method for treating prostate cancer in a subject. The method then comprises administering to said subject a therapeutically effective amount of prostate cancer treatment to said subject at risk for cardiovascular disease. Subjects with this condition will receive an initial dose of approximately 240 mg of degarelix, followed by 240 mg of degarelix. A maintenance dose of approximately 80 mg of methadone is administered approximately once every 28 days, which reduces the risk of cardiovascular disease. or to treat prostate cancer in a subject at risk of the disorder. A monthly maintenance dose of cefotaxime is administered.

[0042] In a further aspect, the present invention provides a method for treating a patient with prostate cancer who is at risk for a cardiovascular disease or disorder. By first identifying suitable subjects, it is possible to identify subjects at risk for cardiovascular disease or disorders. The present invention provides a method for treating prostate cancer in elephants. Subjects were administered an initial dose of 160-320 mg of degarelix, followed by 10 mg of degarelix. A maintenance dose of 60-160 mg of rixolone is delivered approximately once every 28 days, thereby Reduced likelihood of causing estrogen spikes or other GnRH agonist side effects and treating prostate cancer in a subject at risk for cardiovascular disease or disorder. In certain embodiments of this aspect, the maintenance dose of degarelix is ​​administered monthly. The treatment target is 30 kg / m 2 Body mass index less than 25 kg / m 2 (BMI below 100%) In further embodiments, the subject to be treated includes a heart murmur, atrioventricular block, and / or myocardial At risk for cardiovascular disease or disorders, such as ischemia. The subject has indicators of increased risk of cardiovascular disease. The treatment targets those with markers of increased risk of cardiovascular disease, such as high blood pressure, high low-density lipoproteins (LDLPs), and Protein cholesterol, low high-density lipoprotein cholesterol, high serum glucose and / or habitual smoking. In certain embodiments, the subject is In a further embodiment, the subject has high blood pressure of 85 mmHg or higher. In yet a further embodiment, the subject is diagnosed with elevated hypodensity of about 160 mg / dL or greater. In a further embodiment, the subject has a moderate level of lipoprotein cholesterol. , have low high-density lipoprotein cholesterol levels, less than 35 mg / dL. In other embodiments, the subject has elevated fasting glucose levels of greater than about 120 mg / dL. It has a level of

[0043] In still other embodiments, the subject is a patient with elevated serum C-reactive protein (CRP), High serum homocysteine, high serum fibrinogen and / or high serum lipoproteins ( a) (Lp(a)). In the case of a rheumatoid arthritis, the subject has an elevated C-reactive protein level of greater than 3 mg / dL. In other embodiments, the subject is treated with elevated serum homocysteine ​​of greater than 30 μmol / L. In a further embodiment, the subject has an elevated erythrocyte proliferation rate of greater than 7.0 g / L. In yet a further embodiment, the subject has a serum fibrinogen level of: have elevated serum Lp(a) levels greater than 30 mg / dL. In a treated subject, the gonadotropin-releasing hormone (GnRH) agonist leuproreductase Cardiovascular risk factors such as cardiac arrhythmias, coronary artery disease and / or heart damage compared to treatment with In certain embodiments thereof, the subject is at least 30 years of age or older and is less likely to develop vascular side effects. g / m 2 Less than (especially 25 kg / m 2 have a body mass index of less than 18.5;

[0044] In yet another embodiment, the present invention provides a method for manufacturing a gyro having ... viscosity of about 25 kg / m 2 Prostate cancer in people with a body mass index below and identifying subjects with prostate cancer, thereby providing a method for treating prostate cancer in a preferred subject. The preferred subjects thus identified will receive a single initial dose of degarelix of 160-320 mg. followed by monthly doses of 60-160 mg of degarelix on days 20-36. In certain embodiments, the subject is administered a single dose of gonadotropin-releasing hormone (GRH). Compared with treatment with the GnRH agonist leuprolide, The likelihood of developing cardiovascular side effects such as stroke and / or heart damage is reduced. In this formulation, the initial dose of degarelix is ​​approximately 240 mg, and the maintenance dose of degarelix is ​​approximately 8 mg. In a further specific embodiment, preferred subjects receive 4 mmol / Have a cholesterol level of 155 mg / dL or higher. [Brief explanation of the drawings]

[0045] [Figure 1] FIG. 1 shows the chemical structure of degarelix. [Figure 2] 1 is a graph showing the effect of degarelix 240 mg / 80 mg administration on plasma testosterone from day 0 to day 364 of treatment. [Figure 3]1 is a graph showing the effect of degarelix 240 mg / 80 mg administration compared to Lupron 7.5 mg administration on percent change in plasma testosterone from day 0 to day 28 of treatment. [Figure 4] 1 is a graph showing the effect of degarelix 240 mg / 160 mg and degarelix 240 mg / 80 mg compared to the effect of Lupron 7.5 mg on median luteinizing hormone (LH) levels over the period from day 0 to day 364 of treatment. [Figure 5] 1 is a graph showing the effect of degarelix 240 mg / 160 mg and degarelix 240 mg / 80 mg compared to the effect of Lupron 7.5 mg on median follicle-stimulating hormone (FSH) levels from day 0 to day 364 of treatment. [Figure 6] 1 is a graph showing the effect of degarelix 240 mg / 80 mg compared to Lupron 7.5 mg on prostate-specific antigen (PSA) levels from day 0 to day 56 of treatment. DETAILED DESCRIPTION OF THE INVENTION

[0046] Certain aspects of the invention are described in more detail below. The academic literature is incorporated herein by reference.

[0047] overview In general, the present invention provides a method for treating prostate cancer, particularly in specific patient subgroups. and other androgen deprivation therapies, especially GnRH agonist therapies such as leuprolide. Optimal efficacy and fewer serious side effects (e.g., those related to the administration site) compared with Other side effects, such as cardiovascular disease and joint pain, are reduced using a dosing regimen. Uses (and methods of treatment) of Relics GnRH antagonists are provided.

[0048] GnRH agonist therapy leuprolide (also leuprorelin or LUPRO) The relative efficacy and safety (including adverse side effects) of N DEPOT® are well known in the art. It is known (e.g., Persad (2002) Int. J. Clin. Prac t.56:389~96;Wilson et al.(2007)Expert Opin.Inv est. Drugs 16:1851-63; and Berges et al. (2006) Cur (See, for example, J. Med. Res. Opin. 22:649-55). Comparative efficacy and safety of nRH antagonist therapy abarelix (PLENAXIS) The efficacy and safety of thrombin have also been reported (e.g., Mongiat-Artus et al. (2004) Ex pert Opin.Pharmacother.5:2171~9; and Debru See Yne et al. (2006) Future Oncol. 2:677-96). Controlled clinical trials of the type described herein may be conducted to assess safety, efficacy, and efficacy in specific patient subpopulations. A summary of the basic methods for analyzing this study, including analysis of selective benefit for the group, is provided. Theories are available (Spilker (1991) Guide to Clinical Trials Raven Press, New York; and Spilker ( 1996)Quality of Life and Pharmacoeconomi cs in Clinical Trials Lippincott-Raven P (See Publishers New York).

[0049] definition The singular forms "a," "an," and "the" are used unless the context clearly dictates otherwise. Unless otherwise specified, this also includes references to the plural.

[0050] As used herein, the term "ADR" refers to an adverse drug reaction and the term "AE" refers to an adverse drug reaction. Refers to "adverse events."

[0051] 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. I want to be done that.

[0052] As used herein, the term "agonist" refers to an agent that mimics or inhibits the biological activity of a protein. An agonist is intended to refer to an agent that upregulates (e.g., enhances or supplements). , a wild-type protein or a derivative thereof that exhibits at least one biological activity of the wild-type protein. It may be a body.

[0053] As used herein, an "antagonist" refers to an agent that inhibits at least one biological activity of a protein. It is intended to refer to an agent that downregulates (eg, suppresses or inhibits) activity.

[0054] As used herein, the term "arthralgia" refers to pain in one or more joints, It can be a symptom of injury, infection, disease, especially arthritis, or an allergic reaction to medicines. When distinguishing between the terms "arthralgia" and "arthritis," specifically refers to a non-inflammatory condition, and if the condition is an inflammatory condition, the term "arthritis" is used. It should be noted that " should be used.

[0055] The term "Body Mass Index" (BMI) refers to a statistical measure of a person's weight compared according to their height. , which is an approximate measure of the relative percentage of fat and muscle mass in a human body. BMI is defined as a person's weight divided by the square of their height and is used in medicine. From this equation, kg / m 2 The unit of measurement is obtained.

[0056] The term "CI" refers to a statistical confidence interval.

[0057] As used herein, the term "cardiovascular" refers to conditions involving the heart and / or blood vessels. Refers to...

[0058] As used herein, the term "cardiac arrhythmia" refers to irregular or irregular electrical activity of the heart. It is any of a group of conditions in which the blood flow is either faster or slower than normal.

[0059] As used herein, the term "coronary artery disorder" or "coronary artery disease" refers to a condition that affects the coronary arteries. This refers to a condition (such as hardening or a blood clot) that reduces blood flow through the arteries to the heart muscle.

[0060] As used herein, the term "cardiac disorders" includes coronary heart disease, heart attack, cardiovascular disease, Several abnormal organ conditions affecting the heart, including heart disease, pulmonary heart disease, and high blood pressure It refers to one of the following.

[0061] The term "deep-vein thrombosis" (deep-venous thrombosis) or DVT ) is the formation of a blood clot (a "thrombus") in a deep vein. Deep vein thrombosis usually occurs in the veins of the lower legs, such as the femoral or popliteal veins, or in the deep veins of the pelvis. Sometimes the veins in the arms are also affected (known as Paget-Schroetter disease) Thrombophlebitis is a more common class of this condition. There is a significant risk of embolization, traveling to the lungs and causing pulmonary embolism.

[0062] The term "ECG" refers to an electrocardiogram.

[0063] The term "MedDRA" stands for Medical Dictionary for Drug Regulation. tionary for regulatory activities).

[0064] The term "myocardial infarction" refers to a sudden onset of chest pain, shortness of breath, nausea and loss of consciousness, and sometimes death. "Infarction" refers to an infarction of the myocardium, which may be characterized by the death of a muscle, typically resulting from occlusion of a coronary artery. refers to the process by which an infarct forms, which is a localized blockage of the circulation caused by a thrombus or embolus. It is a necrotic area of ​​tissue or organ resulting from disruption of the ring.

[0065] "Male sexual dysfunction" includes impotence, loss of libido and erectile dysfunction. is a disorder in which male mammals are unable to achieve erection, ejaculation, or both.

[0066] The term "prostate cancer" refers to a cancer of the prostate gland in which prostate cells mutate and begin to grow uncontrollably. The term "prostate cancer" refers to early stage, localized prostate cancer. Late locally advanced prostate cancer(locally advanced cancer of the prostat) and late-stage metastatic prostate cancer r of the prostate gland) (in this case, cancer cells has spread (metastasized) to other parts of the body, especially the bones and lymph nodes include.

[0067] The term "prostate-specific antigen" or "PSA" refers to a serum antibody produced by prostate cells in normal men. It refers to a protein that is present in small amounts in the prostate gland, but is also present in the presence of prostate cancer and other prostate disorders. Blood tests to measure PSA can help detect prostate cancer early. Higher than normal PSA levels are a sign of localized It is associated with both primary and metastatic prostate cancer (CaP).

[0068] The term "PD" refers to pharmacodynamics and the term "PK" refers to pharmacokinetics.

[0069] The term "PT" refers to preferred term.

[0070] The term "SAE" refers to serious adverse events.

[0071] The term "SD" refers to standard deviation.

[0072] The term "SOC" refers to system organ class.

[0073] The term "SUSAR" refers to a suspected, unexpected, serious adverse reaction.

[0074] A "subject" or "patient" is a male mammal, more preferably a male human. Male mammals include, but are not limited to, livestock, sport animals, and pets. Examples include:

[0075] A "urinary tract infection" (UTI) is a bacterial infection that affects any part of the urinary tract and The tracts are the tubes through which urine passes, including the renal tubules and renal pelvis of the kidney, the ureters, the bladder, and the urethra. The most common type of UTI is an infection of the bladder, often called cystitis. Another type of UTI is a kidney infection known as pyelonephritis, which is a more serious condition. This is the state.

[0076] Degarelix and related pharmaceutical preparations Degarelix is ​​a potent GnRH antagonist, inhibiting p- The GnRH decapeptide (pGlu-Hi) incorporates ureido-phenylalanine. s-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) It is a homologue (Jiang et al. (2001) J. Med. Chem. 44:453-67). This is because PSA levels are elevated after a prostatectomy or radiation therapy. It is indicated for the treatment of patients with prostate cancer in whom androgen deprivation is warranted (including patients with prostate cancer).

[0077] Degarelix is ​​a selective GnRH receptor antagonist (blocker) that blocks the pituitary G It competitively and reversibly binds to the nRH receptor, thereby inhibiting gonadotropins and thus the Prostate cancer is a type of hormone-sensitive prostate cancer. It is sensitive to testosterone removal, which is the main principle of treatment. Unlike steroids, GnRH receptor blockers inhibit luteinizing hormone (LH) secretion after treatment is initiated. It does not cause a rapid increase in testosterone levels, followed by a rapid increase in testosterone / tumor stimulation, but does cause symptomatic redness. There is also a low possibility of rubbing.

[0078] The active ingredient, degarelix, is a synthetic linear decapeptide amide containing seven unnatural amino acids. It contains 20 amino acids, 5 of which are D-amino acids. The drug substance is an acetate salt. However, the active moiety of this substance is degarelix as a free base. The salt is obtained after lyophilization as a white to off-white, low-density amorphous powder. D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chlor 4-(3-pyridinyl)-D-alanyl-L-seryl-4-ol -[[[(4S)-Hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl] Amino]-L-phenylalanyl-4-[(aminocarbonyl)amino]-D-phenyl Alanyl-L-leucyl-N6-(1-methylethyl)-L-lysyl-L-propyl This is the empirical formula C 82 H 103 N 18 O 16 Cl and has a molecular weight of 1,632.3 Da. The chemical structure of degarelix has been previously shown (EP1003774, US5,925, 730, US 6,214,798), which is shown in Figure 1. This also has the formula: Ac-D- Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cbm)- It can also be represented by Leu-Lys(iPr)-Pro-D-Ala-NH2.

[0079] Administration and Dosage Degarelix is ​​generally administered intraperitoneally, as opposed to intravenously, as described in more detail below. It can be formulated for subcutaneous administration in the subcutaneous area. As with any other medication, change injection sites periodically to adapt treatment to any discomfort at the injection site. Generally, injections are administered in areas where the patient is not exposed to pressure, such as the waistband. It should be applied in an area away from the neck or belt and away from the ribs. Degarelix administered by subcutaneous or intramuscular injection works well, but generally requires repeated doses. Because daily administration is poorly tolerated, WO03 / 006049 and U.S. Patent Publication No. 200 As described in more detail in Nos. 50245455 and 20040038903 Depot formulations of degarelix are also available. The peptide is delivered to the patient via a biodegradable polymer matrix over a period of time (typically ) This can be done using a depot technology that releases over a period of 1 to 3 months. and related GnRH antagonist peptides are described in WO03 / 006049 and As described in U.S. Publication Nos. 2005 / 0245455 and 2004 / 0038903 As shown in the figure, it exhibits high affinity for the GnRH receptor and is superior to other GnRH analogues. Degarelix and these related GnRH antagonists are After subcutaneous injection, the peptide can form a gel, which can be used for several weeks or even several months. It can act as a depot that releases over a period of as long as months.

[0080] The primary variables for forming an effective degarelix depot are the amount and composition of the administered material. The concentration of the combined solution must be within the functional range. If it is too low, no depot will be formed regardless of the amount of drug substance given, resulting in poor prolongation of action. If the formulation is too concentrated, gel formation occurs before the drug can be administered. Effective depot-forming formulations of degarelix generally contain 5 mg / mL or more of degarelix, For example, with a concentration of degarelix of 5 to 40 mg / mL.

[0081] Thus, injection (using a solvent) (e.g., to form a depot, as described above) Degarelix is ​​available as a powder for reconstitution into a liquid for administration (e.g., subcutaneous injection) The powder can be provided as a mixture of degarelix (e.g., as the acetate salt) and mannitol. Suitable solvents include water (e.g., ethanol) and lyophilisates containing ethanol. Water for Injection (WFI). For example, each 1 mL of the solution contains approximately 40 mg of degarelix. To reconstitute 120 mg of degarelix ( In another example, degarelix can be provided in a vial containing: Degarelix is ​​provided in vials containing 80 mg of degarelix (acetate). When reconstituted with approximately 4 mL of WFI, e.g., 4.2 mL of WFI, the liquid Each mL contains approximately 20 mg of degarelix.

[0082] The composition contains degarelix at an initial dose of 160-320 mg followed by a maintenance dose of 160-320 mg. It may be administered once every 20 to 36 days at a dose of 60 to 160 mg. The composition contains degarelix at an initial dose of about 240 mg followed by a maintenance dose of about 80 mg. mg for administration approximately once every 28 days.

[0083] The preferred dosing regimen for treating adult men with prostate cancer is a single dose of degarelix. The starting dose is 240 mg, divided into two subcutaneous injections of 120 mg each, followed by the initial Approximately one month after the initial dose, a maintenance dose of 80 mg of degarelix will be administered as a single subcutaneous injection once a month. Administer.

[0084] 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. In another example, for example, 4 mL of about 40 mg / ml degarelix may be administered monthly. This allows for a monthly maintenance dose of 160 mg.

[0085] The reconstituted solution should be a clear liquid and contain 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, similar to that of testosterone. It decreases in the same way.

[0086] Degarelix suppresses testosterone at a level equivalent to medical castration, 0.5ng / m Effective in achieving and maintaining L well below. As shown in Figure 1, a monthly maintenance dose of 80 mg was shown to provide sustained relief in 97% of patients for at least 1 year. The testosterone suppression was sustained. In particular, the testosterone level after one year of treatment The median value was 0.087 ng / mL.

[0087] Table 1 below lists the relevant pharmacokinetic parameters of degarelix evaluated in patients with prostate cancer. Degarelix in the maintenance phase using 80 mg at a concentration of 20 mg / mL The median trough concentration was 10.9 ng / mL.

[0088] [Table 1]

[0089] Degarelix 240 mg (6 ml at a concentration of 40 mg / mL) was administered subcutaneously to patients with prostate cancer. After administration, degarelix is ​​eliminated in a biphasic manner with a terminal half-life. The median half-life is approximately 43 days. As a result of the very slow release of degarelix from the depot formed at the injection site (above), The pharmacokinetic behavior of this drug is strongly influenced by its concentration in the injectable suspension. do.

[0090] The resulting volume of distribution in healthy elderly men is approximately 1 L / kg. Protein binding is estimated to be approximately 90%.

[0091] Degarelix undergoes normal peptidolysis during passage through the hepatobiliary system, primarily to form peptide fragments. After subcutaneous administration, no significant metabolites were detected in plasma samples. In vitro studies have shown that degarelix is ​​a substrate of the human CYP450 system. Therefore, there are no clinically significant pharmacokinetic differences with other drugs. Interactions are unlikely to occur.

[0092] In healthy men, approximately 20% of a given dose of degarelix is ​​excreted by the kidney. This indicates that in humans, approximately 80% is excreted via the hepatic bile system. It has been suggested that clearance in healthy elderly men is 35-50 mL / h / kg. be.

[0093] Adverse events (side effects) Degarelix has been found to be generally well tolerated in clinical trials. The most commonly observed adverse reaction during FIRMAGON therapy is testosterone suppression. This is due to the expected physiological effects of Injection site-related adverse events (side effects related to the injection site), primarily injection site pain and There was erythema at the injection site.

[0094] Degarelix subcutaneous (sc) vs. A confirmatory controlled trial comparing intramuscular (im) leuprolide In the current active-controlled clinical trial, The most frequently reported side effects were pain (28%), erythema (17%), swelling (6%), and induration ( Injection site adverse events (injection site-related adverse events) included nodules (4%) and small nodules (3%). Most of these adverse events were transient and mild to moderate in severity. The intensity was high and was mainly due to the starting dose, with very few discontinuations (<1% Most injection site adverse events did not require any treatment. Of these, 20% were due to patients using over-the-counter (OTC) medications such as painkillers or cold compresses. In addition, several other adverse events were also frequently observed. These include weight gain, fatigue, chills, hot flashes, and high blood pressure, as summarized in Table 2 below. , back pain, joint pain and urinary tract infection.

[0095] [Table 2]

[0096] No clinically significant changes in liver function were demonstrated. These changes were generally mild and transient. Safety data from all clinical trials using degarelix in the treatment of prostate cancer, including patients Sexual data were pooled. The following adverse reactions not previously described were reported: erectile dysfunction , gynecomastia, excessive sweating, testicular atrophy, and diarrhea are drug-related in ≥1% of patients. This was reported by the investigator.

[0097] The literature includes no data on patients who have undergone orchiectomy or been treated with GnRH agonists. Decreased bone mineral density has been reported in some men. Surgery can be expected to have an effect on bone density.

[0098] The benefits of degarelix regimens for treating prostate cancer include increased risk of other organ or Reduced likelihood of and / or occurrence of adverse tissue reactions, adverse events or side effects This includes a reduction in the severity of symptoms such as: I have come to write it down.

[0099] The adverse reaction glossary allows investigators to identify the same adverse reaction using the same term and Adverse reactions can be identified using different terminology. However, there is a specialized pharmaceutical guide to define adverse reaction terms and their synonyms. A glossary has been developed (Gillum (1989) "The Merck Regula tory dictionary:A pragmatically develop d drug effects vocabulary”Drug Info.J.23 :217-220). Also, the World Health Organization WHO (World Health Organization) Glossary of Adverse Reactions The Drug Terminology (DTA) also defines the scope of what constitutes a drug-induced adverse reaction. (See, for example, Saltzman (1985) "Adverse reaction terminology standardization”Dru (See Info.J.19:35-41.) Also, Coding Symb ols for a Thesaurus of Adverse Reaction The Temrs (COSTART) system is also known in the art (e.g., NcNe il et al. (1982) N. Engl. J. Med. 306:1259-62; and Te al and Dimmig (1985) "Adverse drug experiences" See Drug Info.J.19:17-25. These lists are often categorized by body system, and certain terms may have alternative classifications. It is annotated using

[0100] COSTART is the basis for a unified vocabulary for adverse reaction reports from diverse sources. COSTART is primarily organized by anatomical morphology. From the broadest hierarchy (body tissue categories) to the narrowest hierarchy (specific base terms or special terms) The COSTART vocabulary is organized hierarchically, with terms ranging from basic to advanced (even subcategory). Food and Drug Administration (FDA) Center for Drugs and Biologics It is used and maintained for quality control and is supported by many senior managers in various audit departments. COSTART has four indexes. Index A is a body tissue search index. Three lists, including categories, and special search categories (e.g., neoplasms) nothing.

[0101] The WHO adverse reaction terminology system is relatively short. Code numbers are used to identify these terms. This ensures that the same code is used when a term is translated into different languages. The WHO system uses a hierarchy of "preferred terms" to record adverse reactions. Other commonly used terms are listed below. " and these are listed with their base words.

[0102] The FDA and many pharmaceutical companies have changed how adverse reactions are obtained, collected, processed, and defined. The FDA is currently evaluating the medical terminology used by the FDA ("The Center for Drugs and Biologics Ingredie The "Nutrient Dictionary" is known in the art and provides categories of adverse events. Its use in drug development has been addressed (e.g., Forbes et al. (1986) Drug Info. J. 20:135-45; and Turner et al. (1986) Drug I (See Info.J.20:147-50).

[0103] Specific advantages and disadvantages of COSTART, SNOMED, ​​and the WHO Adverse Reaction Terminology , reviewed by Stephens ("The Detection of N ew Adverse Drug Reactions”pp.18~124, Stoc kton Press, New York).

[0104] MedDRA, the medical terminology for drug regulatory review, identifies adverse events related to drug trials. MedDRA is a pragmatic, medically relevant terminology. It utilizes the ease of data entry, search, analysis and display, as well as regulatory compliance. The emphasis is on the appropriate balance between sensitivity and specificity within a range of environments. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Developed by the International Committee on Harmonisation (ICH) and entrusted to the ICH Steering Committee The International Federation of Pharmaceutical Manufacturers and Associations (IFPA), which is active in on of Pharmaceutical Manufacturers and A is owned by the International Federation of Scientific and Technical Associations (IFPMA) and is readily available commercially. (e.g., the MedDRA homepage at www.meddramsso.com (See page 10.) MedDRA International Maintenance Organization The Medical Support Services Organization (MSSO) We have entered into a contract with the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to maintain and support the work of this glossary. The MedDRA terminology applies to all phases of drug development except animal toxicology. and is utilized in the following examples.

[0105] As described in more detail below, unexpectedly, cardiovascular abnormalities (e.g., cardiac arrhythmias) several other conditions, including heart problems, coronary artery disease, and heart problems, joint pain, and urinary tract infections. Adverse reactions may be due to prior art androgen deprivation drugs such as the GnRH antagonist leuprolide. occurs less frequently than therapy.

[0106] cardiovascular disease The present invention provides a method for treating individuals with prostate cancer who are at risk for developing cardiovascular disease. and the use of prostate cancer in otherwise normal patients who may develop cardiovascular side effects. This aspect of the invention includes a method for treating patients with low androgen deprivation potential. In patients treated with chemotherapy, there are no side effects other than prostate cancer, particularly with regard to cardiovascular health. Recent studies suggest that there may be an increased risk of death from causes related to adverse effects of This is particularly significant in light of findings (Yannucci et al. (2006) J. Urol. 17 6:520-5).

[0107] Signs of risk for developing cardiovascular disease have been extensively investigated and are known in the art. It is known (e.g., Wilson et al. (1998) Circulation 97:1 837-47; see Hackam (2003) JAMA 290:932-940 These cardiovascular risk factors include high blood pressure (specifically, blood pressure above 130 / 85 mmHg). high levels of low-density lipoprotein cholesterol (specifically, 160 mg / d L or higher); low levels of high-density lipoprotein cholesterol (specifically, 35 mg / L) high levels of serum glucose (specifically, greater than about 120 mg / dL fasting) glucose levels); high serum levels of C-reactive protein (CRP) (specifically, levels above 3 mg / dL); high serum levels of homocysteine ​​(specifically, 30 μmol high serum levels of serum fibrinogen (specifically, levels above 7.0 g / L); levels above 100mg; and high serum levels of lipoprotein(a) (Lp(a)) (specifically (This includes levels above 30 mg / dL). Additionally, habitual smoking also increases the risk of cardiovascular disease. It has been shown to be associated with an increase in

[0108] Additionally, measures of overall weight, body mass index (BMI) and "metabolic syndrome" The presence of α-glucan has also been reported to be associated with cardiovascular disease risk (e.g., Behn and Ur 2006) Curr. Opin. Cardiol. 21:353-60; and Rom See Ero-Corral et al. (2006) The Lancet 368:666-78 I want to be illuminated).

[0109] The present invention is further illustrated by the following examples, which should not be construed as limiting the invention. This provision should not be construed as meaning that [Example]

[0110] Clinical trials of degarelix for the treatment of prostate cancer In this example, an open-label, multicenter, randomized, parallel-group study was conducted to evaluate the efficacy of degarelix The efficacy and safety of a monthly dosing regimen of degarelix were investigated in patients in the two degarelix treatment groups. Degarelix was administered at a starting dose of 240 mg, with a concentration of approximately 40 mg / mL, followed by 2 Two monthly dosing regimens, namely, 160 mg (approximately 40 mg / mL) and 80 mg These degarelix dosing regimens were: LUPRON DE in patients with prostate cancer requiring androgen deprivation therapy Compared to POT™ 7.5 mg.

[0111] This study also evaluated the achievement and maintenance of testosterone suppression to castrate levels (12 months). 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 dosing regimen was evaluated with leuprolide 7.5 mg. Furthermore, the degarelix regimen significantly reduced testosterone, yellowing hormone levels, and steroid hormone levels compared with the previous treatment. Somatogenic hormone (LH), follicle-stimulating hormone (FSH) and PSA responses were assessed by leuproreductase Additionally, this study compared patient-reported outcomes (life expectancy) during treatment. The quality of life factors and hot flashes were also significantly different between the degarelix dosing regimen and leuprolide 7.5 mg. Finally, the study evaluated the pharmacokinetics of the degarelix dosing regimens investigated. .

[0112] Study design A total of 620 patients were randomized 1:1:1 to one of three treatment groups. Of these, 610 patients had IMP (Investigational Medicine) Ten randomized patients withdrew before administration.

[0113] Patients in both treatment groups received a starting dose of 240 mg degarelix at a concentration of 40 mg on day 0. g / mL (240 @ 40) divided into two equal doses of 120 mg each, given subcutaneously (sc) Thereafter, patients received 80 mg of 20 mg / mL (80 mg / mL) once every 28 days. @20: Degarelix 240 / 80 mg group) or 160 mg, concentration 40 mg / mL (1 60@40: degarelix 240 / 160 mg group) In the third treatment group, patients received 12 additional sc doses of leuprolide 7 mg / kg. Active treatment with 0.5 mg was administered as a single intramuscular (im) injection on days 0 and 28. For patients receiving treatment with leuprolide 7.5 mg, At the investigator's discretion, bicalutamide could be administered for protection against clinical flares. .

[0114] Patients were classified by geographic region (Central and Eastern Europe, Western Europe, and North and South America); Further stratification was performed according to body weight (<90 kg and ≥90 kg).

[0115] Degarelix 240 / 160 mg group This group received an initial dose of 240 mg at a concentration of 40 mg / mL (240@40) on day 0. This starting dose was given in two equal subcutaneous (sc) injections of 120 mg each. This group then received degarelix at a maintenance dose of 160 mg at a concentration of 40 mg / mL. mL (160@40) as a single sc dose, administered once every 28 days for 12 doses .

[0116] Degarelix 240 / 80 mg group This group also received an initial dose of 240 mg at a concentration of 40 mg / mL (240@4 This starting dose was given as two equal 120 mg sc injections. This group then received degarelix at a maintenance dose of 80 mg at a concentration of 20 mg / mL. (80@20) was administered as a single sc dose once every 28 days for 12 doses.

[0117] Leuprolide 7.5 mg group This group received the reference therapy, leuprolide 7.5 mg, administered as a single intramuscular It was administered as an intravenous (im) injection starting on day 0 and once every 28 days thereafter.

[0118] [Table 3]

[0119] Patients were monitored continuously and visited monthly for up to one year. Each drug administration was followed by clinical observation for at least 1 hour. Patients who meet the appropriate criteria will have the opportunity to receive long-term treatment and support in an extension study. was provided.

[0120] A total of 807 patients were screened, and 620 patients were randomly assigned to one of three treatments in a 1:1:1 ratio. groups, i.e., degarelix 240 / 160 mg, degarelix 240 / 80 mg, and Of the 620 patients randomized, 61 received leuprolide 7.5 mg. 0 patients actually received the study drug, and these were degarelix 240 / 160m g treatment group, degarelix 240 / 80 mg treatment group, and leuprolide 7.5 mg treatment group The groups included 202, 207, and 201 patients, respectively, for a total of 504 patients. completed the test.

[0121] Diagnostic and testing criteria Androgen deprivation therapy is indicated (excluding neoadjuvant hormone therapy), Patients aged 18 years or older with histologically confirmed prostate adenocarcinoma (all stages) (according to Peterson's grade) The above men were eligible to participate. All study-related activities were conducted in an informed manner. At screening, patients were required to have a blood glucose level >1.5n baseline testosterone levels of ≥ 2 mg / mL and PSA levels of ≥ 2 ng / mL PSA after curative prostatectomy or radiation therapy Patients with elevated ECOG scores of ≤2 were eligible for inclusion in the study. Patients had to have a history of prostate cancer and a life expectancy of at least 12 months. Hormonal management (surgical castration or other hormonal manipulation, e.g., GnRH agonists) , GnRH antagonists, antiandrogens or estrogens) However, patients who underwent prostatectomy or radiotherapy with curative intent were excluded from the study. Patients who have received neoadjuvant hormonal therapy at least once before the screening visit If discontinued before 6 months, neoadjuvant hormonal therapy should be continued for up to 6 months. In addition, subjects receiving 5-α-reductase inhibitors were also accepted as research subjects. Patients receiving concomitant treatment with steroids were also excluded from this study. Patients who were candidates for chemotherapy (or radiotherapy) were excluded. Severe hypersensitivity reactions or clinically significant disorders (other than prostate cancer) determined by the investigator to be Patients with a history of adverse events were not eligible to participate in this study. If you were taking any of the following drugs that can cause torsade de pointes ventricular arrhythmias: history of additional risk factors for cerebrospinal fluid purpura (CPE) and significant baseline prolongation of the QT / QTcF interval (> Patients with a ≥450 ms BP (≥100 bp) or a BP above the upper limit of normal range at the screening visit were excluded. have had or have had an elevation of serum ALT or total bilirubin levels above the normal range Patients with known or suspected liver or symptomatic biliary disease were also excluded. Patients were also excluded if they had known hypersensitivity to any of the components of P. Additionally, prostate cancer and surgically removed basal or squamous cell carcinoma of the skin were Patients who had suffered from any form of cancer within the past five years were also excluded from the study. It also applies to patients who have mental incapacity or language barriers that prevent adequate understanding or cooperation. Other IMPs were ineligible to participate in the study. The patient was not administered the drug within the period.

[0122] Duration of treatment Patients in the degarelix treatment group received a starting dose of 240@40 on day 0 and 12 maintenance doses. Dose 160@40 (degarelix 240 / 160 mg group) or 80@20 (degarelix The subjects received IMP on days 0, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, On day 28 (± 2 days), and then once every 28 days (± 7 days), at the end-of-study visit Patients who completed the study and met the appropriate criteria were included in the study. Participants were offered the opportunity to receive long-term treatment and support in an extension study.

[0123] Patients in the reference therapy group received treatment with leuprolide 7.5 mg on day 0 and This was followed by 12 maintenance doses, administered once every 28 days. Patients who completed the study: A total of 13 doses were administered. Patients who completed the study and met the appropriate criteria were In the extension study, patients were offered a switch to degarelix treatment. Patients were randomized to receive 240 / 80 mg or 240 / 160 mg of coadministration. Previously treated with leuprolide 7.5 mg in study CS21. Patients receiving degarelix should receive a starting dose of 240 mg (40 mg / mL) followed by 8 doses of Maintenance doses of either 0 mg (20 mg / mL) or 160 mg (40 mg / mL) were administered. The drug was administered once a month.

[0124] Patients in the comparison group were administered leuprolide 7.5 mg intramuscularly in a two-chamber syringe. Patients were treated with leuprolide 7.5 mg on day 0 or The study was administered as a single im injection followed by one every 28 days. At discretion, bicalutamide could be administered for protection from clinical flares.

[0125] Criteria for evaluating efficacy The primary efficacy endpoint was a test result of ≤0.5 ng / mL from days 28 to 364. It was possible to maintain steroid levels.

[0126] A secondary efficacy endpoint was the number of patients who showed a testosterone surge during the first 2 weeks of treatment. Percentage of patients with testosterone levels ≤ 0.5 ng / mL on day 3; Percent change from baseline in PSA by day 28; days 56 to 364 the possibility of ≤0.5ng / mL testosterone; Testosterone, LH, FSH and PSA levels; 2 consecutive 5-point comparisons compared to the nadir PSA failure (PSA failure) was defined as a PSA rise of 0.0% and at least 5 ng / mL. time to re); degarelix concentrations over the first month and on days 308 and 3 Day 36 trough levels; Day 255 and Day 252 testosterone levels compared Frequency and magnitude of testosterone increases on days 0, 28, and / or 259; Quality of life at 84-day, 168-day, and end-of-study visits; frequency and intensity of hot flashes experienced The degree of difficulty was scored daily from the start of the study to the visit at the end of the study. Secondary endpoint, i.e., adequate testosterone response from days 28 to 364 Possibility of (patient has one or more testosterone levels >1.0 ng / mL after day 28) If two consecutive testosterone levels >0.5 ng / mL are observed, the patient is considered to be inadequate. and baseline PSA by day 14. Added percent change from in.

[0127] Criteria for safety assessment Safety variables in this study were assessed for: frequency and severity of adverse events (AEs); severity; presence of clinically significant changes in laboratory parameters (clinical chemistry, hematology, and urinalysis) changes in electrocardiogram (ECG) and vital signs; changes detected by physical examination; Rabi weight.

[0128] Adverse events (AEs) were reported either in patients receiving IMP or in clinical trial subjects. Defined as an adverse medical event, this does not necessarily have to be causally related to the study treatment. Therefore, AEs, whether related to this IMP or not, may occur with the use of this drug. Any untoward or unintended symptom (abnormal laboratory findings) temporally related to ), symptoms or diseases.

[0129] This definition also includes accidental injuries and variations in medication (drug and / or dosage). Reason for change, consultation with any doctor, nurse or pharmacist, or hospitalization or surgery This was based on commonly observed AEs and the pharmacological effects of IMP. AEs were also included, including those expected in the setting of a clinically significant event of sufficient severity to require active management. Injection site reactions (i.e., dose modification, discontinuation of study drug, more frequent follow-up, or injection site relapse) Any adverse events (treatment of other drugs) were considered to be AEs and reported in the AE log. This was the minimum requirement for reporting AEs related to injection site reactions. However, circumstances could arise where a reaction was still considered an AE.

[0130] Adverse drug reactions (ADRs) that investigators believe are likely to be associated with treatment with IMP AEs were defined as AEs assessed as possible or suspected to be AEs.

[0131] Unexpected AEs should be reported to the sponsor's current investigator profile or to the leuprolide 7.5m Any properties not identified in the "Unwanted Effects" section of the g package insert, serious AEs were defined as any severity or frequency of AEs.

[0132] AEs may be provided spontaneously by the patient or may be related to the patient's living conditions by the investigator. It may be a response to a general medical history about the These may be changes in tolerance, laboratory parameters or results of physical examination. All AEs will be recorded. The nature of each event, the date and time of onset, duration, intensity, criteria for determining severity, and the causes of Describe the cause and relationship to this study drug, the need for specific therapy, and the treatment outcome. Actions taken due to AEs were classified according to drug (no change, discontinued, [specific (Other changes may be necessary). All medications used to treat AEs should be recorded in the concomitant medication log. I recorded it.

[0133] experienced an AE, whether or not considered related to the use of this study drug All patients were followed until the AE resolved and stabilized, or the patient's participation in this study was terminated. (i.e., until the patient completes the end-of-study visit) It was decided.

[0134] Any incidents that the investigator believes to be serious, severe, and / or potentially related to this IMP Any AEs determined to be probable or likely to be probable should be treated until they resolve or the patient is notified. The patient's medical condition has stabilized and all relevant follow-up information has been provided to Ferring Pharm. The AEs will be tracked until they are reported to Aceteuticals A / S. All liver function tests (LFTs) were to be followed by the investigator. Outcomes were classified as recovered, recovered with sequelae, not yet recovered, or death. Ta.

[0135] All AEs, no matter how minor, should be considered by the investigator to be IMP-related events. If the intensity of the AE worsened and the patient recovered during the observation period, the AE was documented. If the AE did not resolve, the most severe individual AE was recorded. The reporting period for an AE was determined by the time the patient was admitted. The time period was from the time the informed consent was signed to the end-of-study visit. Any AEs that occur should be treated using accepted standards of medical care to preserve the health and well-being of the patient. In an emergency, appropriate resuscitation equipment and medications were provided to ensure the best possible treatment. I was able to use the product.

[0136] AE was administered by the National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CI) The stage was determined according to the Committee on Cardiovascular Diseases for Adverse Events (CTCAE). According to the TCAE criteria, AEs were classified as mild, moderate, severe, serious or disabling, and AEs were rated on a 5-point scale corresponding to incidence and death. For the AEs, a different 5-point rating scale was used to rate the intensity of the AE, as shown below.

[0137] Grade 1 AE: Mild to minor; no specific medical intervention; asymptomatic laboratory findings only; radiological findings Examination findings only; minimal clinical relevance.

[0138] Stage 2 AE: Moderate - minimal to local or non-invasive intervention.

[0139] Stage 3: Severe - significant symptoms, requiring hospitalization or invasive intervention; blood transfusion; elective radiation Radiation interventional procedures; therapeutic endoscopy or surgery.

[0140] Stage 4: Severe or disabling - acute life-threatening events such as circulatory failure, bleeding, sepsis, etc. complications of cerebrovascular disease; life-threatening physiological consequences; intensive care or emergency care requiring urgent interventional radiological procedures, therapeutic endoscopy or Or surgery.

[0141] Stage 5: Death

[0142] Additionally, a 4-point scale was used to grade the causal relationship between the AE and the IMP as follows: I did it.

[0143] Likely - There is a clear temporal relationship to improvement with discontinuation or dose reduction of the study drug. reappears upon re-exposure; follows known pattern of response to test drug.

[0144] possible - following a reasonable temporal sequence after administration; the patient's clinical situation; or environmental factors Or it may have been caused by other therapies administered.

[0145] Not feasible - Does not follow a reasonable time sequence after administration, clinical situation, or environment This may be due to factors or other therapies administered.

[0146] Unrelated - clearly and indisputably attributable to an exogenous cause, unlikely, likely Does not meet the criteria in the possible or probable list.

[0147] Serious adverse events (SAEs) were defined as fatal, life-threatening, or Leading to persistent or significant disability / incapacity requiring hospitalization or extension of current hospitalization is a serious medical event or leads to birth defects / abnormalities, either for It was defined as an adverse medical event.

[0148] Deaths of patients enrolled in this study are not considered events in themselves, but rather treatment outcomes. Fatal outcomes, including death, occurring within 4 weeks after the end of treatment were considered. All incidents were fully documented and reported, regardless of their causal relationship to IMP.

[0149] The term "serious" in the definition of an SAE refers to an event in which the patient is at immediate risk of death at the time of the event. This did not refer to events that, if more severe, could cause death. Ta.

[0150] Laboratory parameters (Table 4) were recorded at screening and during the study. Details of the methods and apparatus, as well as normal ranges for various parameters, are known in the art. There are.

[0151] [Table 4]

[0152] Additionally, blood samples taken pre-dose on Day 0, Day 168, and at the end-of-study visit were also collected. The presence of anti-degarelix antibodies was determined.

[0153] clinically significant laboratory abnormalities, i.e., those suggestive of disease or organ toxicity, and Active management (i.e., dose modification, drug discontinuation, more frequent follow-up, or diagnostic Any adverse events of a severity requiring further investigation were to be reported as AEs.

[0154] Blood pressure and pulse were measured at screening, before dosing at each dosing visit, and at the end of the study. Diastolic and systolic blood pressure and pulse were measured at the time of the patient's visit. Patients were clinically observed for at least 1 hour after each administration of IMP. During this observation period, patients were observed for any immediate onset hypersensitivity reaction. Systolic blood pressure and pulse rate were measured 5, 10, 30 and 60 minutes after administration.

[0155] 12-lead electrocardiograms (ECGs) were obtained by screening site personnel on days 0, 3, and 4. After day 0, the test was conducted once every 12 weeks (84 days) and at the end of the study. If a consultation was scheduled, an ECG was performed before administration. The ECG was digitized and available. The measurements were performed as known in the art. The ECG measurements were performed to measure the heart rate, P These included R, QRS interval, QT and QTc, T wave and U wave.

[0156] Each patient also underwent a physical examination at screening, day 0, and every 12 weeks thereafter. Clinically significant abnormalities observed at screening Any clinically significant abnormal findings observed thereafter were recorded as AEs. and recorded it.

[0157] Weight was measured at screening and at the end-of-study visit. Height (without shoes) was measured. was measured at screening. Body mass index (BMI) was calculated by dividing the individual's height by the square of their height. This formula, which is widely used in medicine, gives the mass of an individual in kg / m 2 The body mass index is calculated accurately using one of the following formulas: It is possible.

[0158] statistical methods All statistical analyses were performed and statistical summaries were compiled using statistical analysis software SAS (trademark ) 9th edition or later. The populations analyzed were as follows:

[0159] The intention-to-treat (ITT) analysis set was small. All randomized patients who received at least one dose of IMP were included.

[0160] Per protocol (PP analysis set) refers to any major All intention-to-treat (ITT) analysis sets without any significant protocol violations were included.

[0161] The safety population was the same as the ITT analysis set, therefore all safety analyses were performed on the ITT The analysis was performed on the TT analysis set.

[0162] The primary efficacy endpoint was assessed for both the ITT and PP analysis sets. The primary efficacy endpoint was the Kaplan-Meier method. Analysis was performed using the Meyer method. For each of the three treatment groups, a 95% confidence interval was used. The inter-inferiority (CI) testosterone response rate was calculated by log-log transformation of the logarithm of the survival function. For normal approximation using pooled standard error Therefore, using the calculated 97.5% CI, the degarelix treatment group and leuprolide 7.5 The difference between mg was determined.

[0163] To determine the efficacy of degarelix, two hypotheses were tested.

[0164] The FDA's criteria for determining whether testosterone levels are elevated between 28 and 364 days are met. The lower limit of the 95% confidence interval (CI) for the cumulative probability of a serotonin level of ≤0.5 ng / ml is 90. The objective was to determine whether the α-glucan concentration was greater than or equal to 100%.

[0165] (2) The European Medicines Agency (EMEA) criteria are based on the 28th to 364th day of testing. The cumulative probability of having steroids ≤ 0.5 ng / mL was significantly higher for degarelix than for leuprolide. The objective of this study was to determine whether degarelix was non-inferior to 7.5 mg. Non-inferiority margin for the difference between Prolide 7.5 mg and imit) was -10%.

[0166] All secondary efficacy endpoints were assessed in the intention-to-treat analysis set and in the placebo group unless otherwise stated. Both PP analysis sets were analyzed. The proportion of patients who received steroids was analyzed using Fisher's exact test. Using the exact probability test, patients with testosterone levels of ≤0.5 ng / mL on day 3 were The percentage of patients who achieved PSA change from baseline to day 28 was also analyzed. The endpoints were analyzed by Wilcoxon test. For both the constant and Wilcoxon tests, separate data were stratified by treatment group, geographic Stratification by region, stratification by weight (<90 kg, ≥90 kg), and leuprolide A 7.5 mg subgroup was presented.

[0167] The secondary endpoint was a test result of ≤0.5 ng / mL from days 56 to 364. Probability of steroid use, time to PSA recurrence, and adequate PSA response from days 28 to 364 Probability of testosterone response was analyzed by the Kaplan-Meier method.

[0168] Efficacy Results The primary objective of this study was to determine whether patients with a testosterone level of ≤0.5 ng / mL were at risk for 12 months of treatment. Testosterone suppression to castrate levels assessed as the percentage of patients who showed suppression The objective of this study was to demonstrate the effectiveness of degarelix in achieving and maintaining Ta.

[0169] Results showed that degarelix, delivered in a 240 / 80 mg dose regimen, significantly reduced testosterone levels. Rapid and effective suppression of steroid levels was achieved throughout the 364-day period of treatment. It has been shown that the levels were kept low (Figure 2).

[0170] Capsules for the probability of testosterone being ≤0.5 ng / mL between days 28 and 364 The Rann-Meier estimates were 0.01 for the degarelix 240 / 160 mg group and 0.01 for the degarelix 240 / 160 mg group, respectively. 98.3% and 97.2% for the 40 / 80 mg and leuprolide 7.5 mg groups and 96.4%. For all three treatment groups, the lower limits of the 95% CIs were The 90% threshold identified for this study was exceeded. Testosterone levels were ≤0.05 between days 28 and 364. Regarding the probability of achieving 0.5ng / mL, treatment with degarelix was significantly higher than that with leuprolide 7. The degarelix treatment regimen demonstrated non-inferiority to the 5 mg regimen. The overall 97.5% CI for the difference in probability compared with the loride 7.5m group is the margin of non-inferiority. This was greater than the 10% observed in the FDA's assessment of efficacy. Meets the standards and EMEA criteria.

[0171] The robustness of the results for the primary efficacy endpoint was confirmed by observational case analysis. This analysis supports the conclusion that Overall, patients with testosterone levels ≤0.5 ng / mL from day 28 to day 364 Similar estimates of the rates were obtained and were consistent across the degarelix 240 / 160 mg and degarelix 240 / 160 mg groups. 9 for each of the garelix 240 / 80 mg and leuprolide 7.5 mg groups. The primary analysis findings were 8.2%, 97.0%, and 96.0%. A secondary efficacy analysis was conducted to assess the probability of achieving testosterone levels ≤0.5 ng / mL by day 364. This is further supported.

[0172] As expected, during the first 2 weeks of treatment, the pooled degarelix group d degarelix groups) (0.2%: 1 patient) compared with A significantly higher proportion of patients (80.1%) in the Prolide 7.5 mg group experienced a testosterone surge ( ≥15% increase from baseline (p<0.0001, Fisher's exact test) A patient treated with degarelix had a low baseline test score. This indicates that the steroid hormone (0.0065 ng / mL) is essential for the treatment of steroid-resistant steroids. Since a sudden increase from the normal value would not be significant, this patient's results are likely an artifact. On the other hand, on the third day, all patients in the leuprolide 7.5 mg group 9 patients treated with degarelix showed no testosterone suppression compared with 9 patients treated with degarelix. 6% showed testosterone suppression (p<0.0001, Fisher's exact test) As shown in Figure 3, the degarelix 240 / 80 mg dosing regimen significantly improved testosterone levels. Lupron 7.5 mg suppressed testosterone quickly and efficiently, but Only after a surge did it take effect, much more gradually.

[0173] The time profile of serum LH levels was observed for testosterone. Following administration of degarelix, LH levels for the ITT analysis set were similar. The median level rapidly decreased to <0.7 IU / L on day 1, which was For both degarelix treatment groups, LH levels were reduced by approximately 88% from baseline. The median suppression of leukemia was maintained until the end of the study, day 364. A sharp increase in median LH levels was observed for patients in the leuprolide 7.5 mg group. This peaked at 31.0 IU / L on day 1 (>400% increase from baseline). increased) and then exponentially decreased to 0.035 IU / L by day 56, and this level This was maintained until day 364 (see Figure 4).

[0174] A rapid decrease in FSH levels was also observed in patients treated with degarelix. Degarelix treatment resulted in median FSH levels of ≤1.5 IU by day 7. / L, a >80% reduction from baseline. For the steroid-treated group, the median suppression of FSH levels was 1.0 at the end of the study, i.e., day 36. For patients in the leuprolide 7.5 mg group, FSH levels were maintained up to day 4. showed an initial surge similar to that observed for LH levels, reaching 22.5 I on day 1. A peak of 2 U / L was reached (a 146% increase from baseline) by day 14. Subsequently, the median FSH level decreased exponentially to 0.0 IU / L around day 56. The serum creatinine concentration increased to a plateau of approximately 4.40 IU / L at day 1 and maintained this level until day 364 (Figure 5 (See

[0175] As shown in Figure 6, the degarelix 240 / 80 mg regimen was also significantly superior to Lupron 7. resulted in a more rapid and efficient reduction in PSA levels than treatment with 0.5 mg A rapid decline in PSA levels was observed in patients treated with degarelix. In contrast, in the leuprolide 7.5 mg group, PSA levels were The effect plateaued during treatment and then decreased exponentially to suppressed levels. Compared with patients receiving leuprolide 7.5 mg, baseline median PSA levels were significantly lower. A significantly greater decrease from baseline was observed on days 14 and 28 ( p<0.0001, Wilcoxon test). A probability was found to be higher on day 14 (0.70) than on day 28 (0.70) from the leuprolide 7.5 mg group. The probability of completing the study without experiencing a PSA recurrence was slightly higher (0.82). The rate was highest in the degarelix 240 / 80 mg group (91.2%), and Slightly lower in both the 40 / 160 mg and leuprolide 7.5 mg groups The proportion of patients with HIV infection was approximately 85.8%, but this difference was not statistically significant.

[0176] Antiandrogen therapy was administered according to protocol to prevent leuprorelin erythema for protection from flares. 22 patients in the 7.5 mg cohort were given the drug at the start of treatment. PSA data were available for these patients. compared with patients in the leuprolide 7.5 mg group who did not receive antiandrogen therapy. There were also larger decreases on days 14 (61.7% decrease) and 28 (89.1%). The median percent change from baseline is shown. For patients in the leuprolide 7.5 mg group who received leuprolide, the percent reduction was greater on days 14 and 15. On day 28, the rates were 15.3% and 61.7%, respectively. The median percent change in PSA levels in patients receiving degarelix was This is similar to patients treated with CI, and therefore, it is possible to predict the PS at the start of treatment. Degarelix is ​​more effective than conventional GnRH agonist therapy in suppressing A. It should be noted that degarelix was not an additional concomitant medication for flare prevention. However, a starting dose of 240 mg does not require any prescription drugs, and the PSA level It has been shown to have a similar effect to the combination of a GnRH agonist and an antiandrogen.

[0177] The pharmacodynamic profile of degarelix is ​​characteristic of a GnRH antagonist. and serum levels of testosterone, LH, and FSH were rapidly suppressed. For patients in the leuprolide 7.5 mg group, blood levels of testosterone, LH, and FSH were Serum levels increased rapidly within the first week of treatment and then dropped to suppressive levels.

[0178] 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, and These included signs / clinical observations, as well as weight measurement and physical examination, ECG, and concomitant medications.

[0179] Safety parameters were assessed for all patients included in the ITT analysis set and were included in this set. The study included all 610 randomized patients who received at least one dose of study drug. All safety tables were divided into four columns: three treatment groups, which were listed separately; Includes combined degarelix group.

[0180] A brief summary of adverse events Adverse events occurring between the first dose and the end of the study were classified as "treatment-emergent" (tr Screening and initial IMP intervention were considered “emergent.” Adverse events occurring during the treatment period were considered "pre-treatment." As mentioned above, all AEs were classified into MedDRA (version 10.0) System Organ Classes (SOCs). Classify according to the frequency of occurrence in alphabetical order and by preferred term (PT). Treatment-emergent AEs were classified by severity (using NCI's CTCAE) and trial The overall summary of treatment-emergent AEs is presented in Table 5. vinegar.

[0181] [Table 5]

[0182] The overall percentage of patients who experienced treatment-emergent AEs was 100% across all three treatment groups. The degarelix 240 / 80 mg group had 163 (79%) patients and 156 (78%) patients in the leuprolide 7.5 mg group. 167 (83%) patients in the 240 / 160 mg group reported treatment-emergent AEs. In total, ADRs were reported in 238 (58%) degarelix patients. In the degarelix 240 / 160 mg group, 120 (59%) patients In the leuprolide 7.5 mg group, 118 patients (57%) In the 2010 study, 42% of patients reported ADRs. This difference is expected and is due to the fact that all were injection-related ADRs. These AEs can be explained by injection site-related adverse events (AEs), and these AEs are The incidence of ADRs was higher in the Lixpool treatment group. Excluding injection site ADRs, the remaining ADRs The incidence of DR was similar in the three treatment groups.

[0183] In the degarelix 240 / 160 mg group, excluding injection site reactions, 88 patients (44%) The patient reported an ADR.

[0184] In the degarelix 240 / 80 mg group, 90 (43%) patients had steroid-resistant ... A person reported an ADR.

[0185] In the leuprolide 7.5 mg group, 84 patients (42%) had an IVF reaction, excluding injection site reactions. ADR was reported.

[0186] These results were obtained with degarelix maintenance doses (80 @ 20 mg / mL or 160 @ 40 These results suggest that both cephalosporins (mg / ml) showed similar ADR incidence rates.

[0187] A total of 45 (11%) degarelix patients had complications, resulting in 67 cases, including 10 deaths. Overall, 21 patients (10%) in the degarelix 240 / 80 mg group reported serious AEs. 28 (14%) patients in the leuprolide 7.5 mg group, including 9 deaths in the leuprolide 7.5 mg group. 24 (12%) patients in the degarelix 240 / 160 mg group had severe cerebrospinal fluid (CSF) compared with 10 (14%) patients in the degarelix 240 / 160 mg group. All deaths were either unrelated or possibly related to study treatment. In interpreting such results, it is important to consider whether this group had a history of prostate cancer. In an elderly patient population (mean age 72 years) with both adenocarcinoma and other underlying health problems It should also be understood that there is.

[0188] Thirty-four (8%) degarelix patients had complications, i.e., degarelix 240 / 160 19 (9%) patients in the 240 / 80 mg group and 15 (7%) in the degarelix 240 / 80 mg group of patients withdrew due to AEs (including both fatal and non-fatal AEs) In the leuprolide 7.5 mg group, 12 patients (6%) withdrew. Among the combined degarelix patients, 17 reported SAEs leading to withdrawal .

[0189] Detailed analysis of adverse events The overall incidence of adverse events was significantly higher in the two degarelix treatment groups and the leuprolide control group. In the degarelix treatment group, the majority of such events were The only injection site reaction was related to the subcutaneous / depot delivery system utilized for However, intramuscular leuprolide was associated with a similar overall incidence of adverse events. and was not accompanied by such a high rate of injection site reactions. To describe the incidence of adverse events, the exact number of adverse events occurring in each study group was used. A detailed analysis of the various types of leuprolide-treated patients was performed to determine whether injection Types of adverse events other than site reactions (side effects related to the injection site) were characterized.

[0190] Table 6 provides an overview of the number of patients reporting treatment-emergent AEs by SOC. All treatment-emergent AEs were classified by system organ class and Med-DRA preferred term. This is shown.

[0191] [Table 6] TIFF2026027448000008.tif39163 Treatment-emergent AEs reported were of comparable severity across all three treatment groups. The degarelix 240 / 160 mg group, the degarelix 240 / 80 mg group, 83%, 79%, and 78% for the leuprolide 7.5 mg and leuprolide 7.5 mg groups, respectively. As shown in Table 6 above, the two degarelix treatment groups were affected There were no significant differences between the SOCs. The most common system organ class was "common disorders and administration site conditions," with a combined data rate of 47%. This was reported in 18% of patients taking garelix and 18% of patients taking leuprolide 7.5 mg. The majority of these AEs were injection site pain, which occurred in 29% of patients with concomitant degarelix. Additionally, "vascular events," primarily hot flashes, occurred in 33% of degarelix patients. and 30% of patients receiving leuprolide 7.5 mg. Effects were reported in ≥15% of patients. Other SOCs affected were 27% of degarelix patients and 31% of leuprorelin patients. In the 7.5 mg and 8 mg patients, the "investigation" was in 20% and 24% of patients, respectively. and infestations,” and “musculoskeletal and connective tissue disorders” in 17% and 26% of patients, respectively. The most common side effects were "drug-related disorders" in 17% and 19% of patients, and "gastrointestinal disorders" in 17% and 19% of patients, respectively. The most frequent musculoskeletal and connective tissue disorders occurred in 6% of degarelix patients and 8% of leuproreductase patients. Back pain was reported in 4% of patients taking Lorid 7.5 mg and in 9% of patients taking Degarelix. Leuprolide 7.5 mg patient reported joint pain.

[0192] When examining the SOC of AEs associated with degarelix treatment compared with leuprolide, Several areas of increased risk for leuprolide compared with steroids emerged. For example, "musculoskeletal and connective tissue disorders" occurred in only 17% of degarelix patients compared with the overall This occurred in 26% of leuprolide patients (in the degarelix 240 / 80 mg treatment group). (The risk of kidney and urinary disorders was even lower at 15%). occurred in 13% of patients receiving euprolide but only in 13% of patients receiving degarelix, "Reproductive and breast disorders" occurred in 10% of leuprolide patients, but In addition, the overall incidence of "heart disorders" was The increase was observed with leuprolide treatment (13%) and with degarelix (overall difference between the two treatment groups). As mentioned above, the art has reported that certain There is some concern that androgen deprivation therapy may have adverse effects on cardiovascular health. This may be of particular interest because logy 176:520-525; and Etzioni et al. (1999) J. Natl. (See Canc. Inst. 91:1033). Therefore, cardiovascular side effects Androgen deprivation therapy, which minimizes the risk of

[0193] The majority of adverse events seen with degarelix were related to adverse overall effects on other organ systems. The fact that this is not a physical effect but merely an injection site reaction related to the mode of subcutaneous delivery Nevertheless, compared with degarelix, leuprolide was associated with fewer cardiac, musculoskeletal, and joint disorders. Increased risk of tissue damage, kidney and urinary damage, and reproductive damage explains the overall similarity of adverse events between leuprolide and degarelix That would be a possibility.

[0194] As shown in Table 7, the most frequently reported outcomes in patients treated with degarelix were Treatment-emergent AEs were injection site reactions (particularly pain and erythema at the injection site). The most frequent adverse events during this study were observed in both degarelix and leuprolide patients. The AE reported in the degarelix 240 / 80 mg group was flushing. 53 (26%) patients in the leuprolide 7.5 mg group and 43 (21%) patients in the leuprolide 7.5 mg group Compared with the degarelix 240 / 160 mg group, 52 (26%) patients reported hot flashes. He declared.

[0195] [Table 7] TIFF2026027448000010.tif102168

[0196] Long-term treatment with degarelix and leuprolide 7.5 mg resulted in hot flashes, sexual Harms associated with testosterone suppression, such as loss of desire, impotence and infertility, and increased sweating Therefore, the phenomenon of flushing is relatively common and generally and expected to be considered possibly or likely to be related to treatment. However, only a few AEs related to sexual dysfunction or sweating were reported. , 22 (5%) patients with concomitant degarelix and 21 (10%) patients with leuprolide Patients presented with reproductive / breast disorders, occurring in approximately 1% of patients treated with degarelix. Six (1%) patients were reported to have sweating disorders (SOC of the skin and subcutaneous tissue). Erectile dysfunction was reported, 6 (1%) patients reported night sweats, and 4 (<1%) patients reported testicular pain. experienced pelvic pain, 3 (<1%) patients reported pelvic pain, and 3 (<1%) patients experienced excessive sweating. reported that two (2%) patients each experienced gynecomastia, prostatitis, or testicular atrophy. All other reproductive / breast disorders were reported by one patient (<1%), and No other sweating disorders were reported.

[0197] Analysis of these SOC / preferred term data showed that degarelix compared with leuprolide treatment The reduction in musculoskeletal disorders, and renal and urinary disorders for steroid therapy has been discussed above. During the course of treatment, for example, 9% of leuprolide patients experienced a urinary tract infection, compared with 10% of all degarelix-treated patients. Only 3% experienced a urinary tract infection. Similarly, 9% experienced a lupus during the course of treatment. -Prolide patients experienced arthralgia (pain in the joints), but all degarelix-treated patients Only 4% of people experienced joint pain.

[0198] In summary, the incidence of treatment-emergent AEs was significantly higher in degarelix-treated patients than in leuproreceptor-treated patients. Treatment-emergent AEs were similar in patients treated with degarelix 7.5 mg and those treated with degarelix 7.5 mg. 330 (81%) patients in the steroid treatment group and 156 (7%) in the leuprolide 7.5 mg group AEs were reported by 8% of patients. Most AEs were mild or moderate in intensity.

[0199] 58% of patients treated with degarelix had a risk of developing a condition that investigators considered potentially related to an IMP. Any AEs (ADRs) that were considered likely or likely to occur were reported, and leuprolide 7.5 mg Patients treated with acetaminophen showed 42% ADRs. However, the majority of treatment-emergent ADRs were The combined degarelix group had injection site reactions in 173 (42%) patients. The most common disorders and administration site conditions were: The overall incidence of treatment-emergent injection site reactions was 4.4 per 100 injections. Most injection site reactions occurred after the first of two injections of degarelix. The incidence of injection site reactions decreased over time. The incidence of injection site pain (2.5 per 100 injections) was 0.01 for the combined degarelix group. 9 per 100 injections) and injection site erythema (1.9 per 100 injections). Preferred terms showed an incidence of 0.5 or less per 100 injections. There was no immediate onset of hypersensitivity reactions, none of which were considered serious. Five (1.2%) patients reported degarelix-associated injection site reactions, which led to its withdrawal. The reported ADR was hot flashes, which is an expected adverse reaction associated with testosterone suppression. In total, 104 (25%) degarelix-treated patients and 42 (21%) A patient treated with leuprolide 7.5 mg reported hot flashes. One patient reported an ADR of hot flashes, which led to withdrawal. Although it was expected that sexual dysfunction-related AEs would result from testosterone suppression, Only a few cases were actually reported.

[0200] There were 121 serious adverse events (SAEs) reported by 73 (12%) patients. This showed relatively equal incidence across treatment groups. The most common SAE was complicated degassing. Ten patients (2%) in the Relix group and 10 patients (5%) in the leuprolide 7.5 mg group Cardiac disorders occurred in 1 patient in the degarelix group and 10 (2%) patients in the combined degarelix group. Renal and urinary complications occurred in 6 (3%) patients in the leuprolide 7.5 mg group. It was an obstacle.

[0201] Weight gain is a known effect of androgen deprivation and is not considered significant, with a weight gain of ≥7% from baseline. Abnormal weight gain occurred in 10% of degarelix-treated patients and 13% of leuprolide-treated patients. Other occurrences of markedly abnormal changes in vital signs occurred in patients treated with 1 mg of ribavirin. This is consistent with the fact that the majority of patients were elderly and had a history of heart disease or hypertension.

[0202] Therefore, a significant number of subjects experienced minor injection site reactions as a result of degarelix treatment. However, these adverse effects were among the adverse effects associated with the GnRH agonist leuprolide. It is surprising that most of these were not as serious as others. Severe injection site reactions have been reported with another GnRH antagonist, Abarelix (P These were far less severe than the potentially serious side effects associated with lenaxis (www. See fda.gov / cder / drug / infopage / plenaxis In fact, Abarelix / Plenaxis has been associated with serious allergic reactions (e.g. Symptoms include swelling of the tongue / throat, asthma, wheezing and severe breathing problems, and therefore This means that this drug must be administered by a physician with the correct techniques to administer and monitor this drug. It is only available through a special "User Safety Program" that ensures that the product is used safely. It is available.

[0203] Further statistical analysis of subgroup populations Degastric, which has superior efficacy and / or reduced side effects compared to leuprolide treatment Any of the benefits of treatment with Relics may be particularly pronounced in certain patient subgroups. Further statistical analysis of the CS21 clinical trial will be conducted to determine whether Degarelix treatment compared with leuprolide treatment for heart and joint pain and / or urinary tract infections in specific patient subgroups Particular attention was paid to whether

[0204] Summary of Clinical Efficacy (SCE) and Summary of Clinical Safety (SCS) Findings The results were used to analyze different patient subgroups. Subgroup discriminators included race (white) and (black, black, and others), age (<65 years, ≥65 to <70 years, and ≥75 years), body mass index (BMI) Weight (<70 kg, ≥70 kg to <90 kg, and ≥90 kg), body mass index (BMI) (≦20kg / m 2 , >20 kg / m 2 ~30kg / m 2 , and >30 kg / m 2 ),region (North America, Western Europe, Central and Eastern Europe, and others), as well as prostate The stage of the cancer (eg, localized, locally advanced, and metastatic) was included.

[0205] SCS was conducted in all study arms, including the CS21 study arm (a controlled phase 3 study arm), and and for all subgroups, including exact 95% CIs based on the Poisson model, Adverse events listed according to MedDRA preferred terms (and grouped by SOC) Crude incidence rate (n / N) and incidence rate (at least one study adverse event per 1,000 person-years) In short, the Poisson model summarizes both the exact 1 -provides the lower confidence limit (LL) and upper confidence limit (UL) of α, which are respectively

[0206]

number

[0207]

number

[0208] Two-tailed Fisher's exact test and warning measures for the phase 3 controlled trial (CS21) The corresponding P values ​​were used as a flagging device to evaluate the efficacy of degarelix. The crude incidence rates in the leuprolide 7.5 mg treatment group were compared with the crude incidence rates in the leuprolide 7.5 mg treatment group. The value is * (0.01 <P≦0.05)、 ** (0.001 <P≦0.01)、および*** (P Similarly, the incidence rate was calculated using the UMPU test based on the Poisson model. Comparisons were made using the P values ​​associated with the experiments. i ≒ Poisson (λ i T i ) [in the formula, xi = number of subjects showing the event, T i = total number of 1,000 person-years in treatment group i, and λ i = treatment incidence in group i (i = 1, 2)], P value = 2min(P(S ≥ 1), P (S≦x1), 0.5) [where S≈binomial (x1+x2, T1 / (T1+T2))] For example, Lehmann (1986) Testing Statistical Hypothesis otheses, 2nd edition, Springer-Verlag, New York. sea ​​bream).

[0209] Based on these results, degarelix treatment was associated with a significant improvement in overall survival compared with leuprolide 7.5 mg. In the treatment group, the results were statistically significant (P ≤ 0.05) or marginally significant (P ≤ 0.05). <P<0 .2) All adverse events (at the SOC or PT level) that have a low incidence or incidence rate was identified.

[0210] Cardiovascular events during SCS were investigated more specifically at a more integrated MedDRA level. Namely, the following High Level Group Terms: The incidence and incidence of subjects with AEs in the AE group were tabulated by study arm and treatment.

[0211] HLGT = Central nervous system vascular disorders

[0212] HLGT = cardiac arrhythmias

[0213] HLGT = coronary artery disease

[0214] HLGT = Heart Failure

[0215] Degarelix has a lower incidence of certain cardiac disorders than leuprolide. Further fleshing out apparent but potentially isolated evidence at the level of detailed base words To this end, the HLGTs listed above and the SOC to which these HLGTs belong (Cardiac Disorders) Survival rates were compared with possible risk factors (cholesterol, BMI, weight, diastolic / systolic blood pressure). Subgroups based on blood pressure, history of cardiac disorders, age, and pulse rate were examined. The group analysis was not pre-planned as part of the SCS. At the time of analysis, statistical significance of risk factors was confirmed by treatment (degarelix / leuprolide 7.5mg). g) by testing for interactions with the Cox proportional hazards model. covariates were screened for potential subgroup effects. The number of patients with glaucoma, and to a lesser extent, cholesterol, were identified. <25 kg / m 2 , 25 kg / m 2 ~<30kg / m 2 , and ≥ 30 kg / m 2 ), and The subgroups of very low / normal cholesterol (≤4 mmol / L and >4 mmol / L, respectively) The difference in incidence between degarelix and leuprolide was calculated using the CI values ​​(mmol / L) for The Poisson model mentioned in

[10] was also used to test and quantify BMI < 25 kg / m 2 In patients with cerebrospinal fluid deficiency, a statistically significant lower incidence was observed compared with leuprolide. , SOC = cardiac disorders (P = 0.0045), HLGT = coronary artery disorders (P = 0.005), and HLGT = cardiac arrhythmia (borderline, P = 0.056), and the relative risk was The results were 0.242 (95% CI: 0.08-0.67) and 0.0 (95% CI: 0.0-0.00), respectively. 0.47) and 0.312 (95% CI: 0.09-1.03) for 4 mmol. In patients with cholesterol levels above 1 / L, A significantly lower incidence was observed for HLGT = cardiac arrhythmias (P = 0.035), with a relative The risk was 0.41 (95% CI: 0.18-0.94).

[0216] Subgroup efficacy findings from SCE are shown in Tables 8-10, and from SCS Subgroup findings are listed in Tables 11-19, and exploratory specific findings regarding cardiovascular risk are listed in Tables 11-19. See Tables 20-23 for findings in differentiated subgroups. Important findings include the following:

[0217] In the subgroup <65 years, test scores on day 28, between day 56 and day 364 Time to telonectin escape was significantly longer with both degarelix dosing regimens compared with LUPRON DEPO T® 7.5 mg was significantly superior (see Table 8 below).

[0218] [Table 8]

[0219] In the >75 year old group, the time to PSA recurrence was , significantly superior to LUPRON DEPOT® 7.5 mg (P=0.0 3), and the results were also significantly better in the <65 years old group (P=0.06) (see Table 9 below). See the reference.

[0220] [Table 9]

[0221] Percent change from baseline in PSA in patients with metastatic stage prostate cancer All subgroups were more prominent in the LUPRON group (see Table 10 below). Statistically significantly better than DEPOT® 7.5 mg.

[0222] [Table 10] TIFF2026027448000016.tif97168

[0223] Notable statistically significant findings in the overall study population were the following (see Table 11): See the reference.

[0224] Myocardial infarction (PT): 0.5% (2 / 409, degarelix, total) vs. 2.5% (5 / 2 01, LUPRON DEPOT (registered trademark) 7.5 mg),

[0225] Peripheral edema (PT) 2% (8 / 409, degarelix, total) vs. 5% (10 / 201, LUPRON DEPOT® 7.5 mg),

[0226] Chest pain: 0.5% (2 / 409, degarelix, total) vs. 3% (6 / 201, LUPRO N DEPOT® 7.5 mg),

[0227] Urinary tract infection (PT) 3% (13 / 409, degarelix, total) vs 9% (18 / 201, LUPRON DEPOT® 7.5 mg),

[0228] Heart murmur (PT): 0% (0 / 409, degarelix, total) vs. 1.5% (3 / 201, LUPRON DEPOT® 7.5 mg),

[0229] Musculoskeletal and connective tissue disorders (SOC): 17% (68 / 409, degarelix, total ) vs. 26% (53 / 201, LUPRON DEPOT® 7.5 mg),

[0230] Arthralgia (PT belonging to SOC Musculoskeletal and CTD): 4.2% (17 / 409, Dega Relics, total) vs. 9% (18 / 201, LUPRON DEPOT® 7.5 mg),

[0231] Musculoskeletal stiffness (PT belonging to SOC Musculoskeletal and CTD): 0% (0 / 409, Degare LUPRON DEPOT® 7.5 mg ),

[0232] Decreased libido: 0% (0 / 409, degarelix, total) vs. 1.5% (3 / 201, LU) PRON DEPOT® 7.5 mg),

[0233] Urinary retention: 1.2% (5 / 409, degarelix, total) vs. 4.5% (9 / 201, LUP) RON DEPOT® 7.5 mg),

[0234] Non-infectious cystitis: 0% (0 / 409, degarelix, total) vs. 2% (4 / 201, LU) PRON DEPOT® 7.5 mg),

[0235] Erectile dysfunction: 1.5% (6 / 409, degarelix, total) vs. 4.5% (9 / 201, L UPRON DEPOT® 7.5 mg),

[0236] DVT: 0% (0 / 409, degarelix, total) vs. 1.5% (3 / 201, LUPR) ON DEPOT® 7.5 mg).

[0237] Statistically significant findings of particular interest within and across subgroups This shows the view.

[0238] [Table 11] TIFF2026027448000018.tif18154

[0239] The predominance of musculoskeletal and connective tissue disorders (SOC) and arthralgia was metastatic It is not limited to only the subgroups of stage 1, but extends to all stage subgroups (see Table 12). In patients with locally advanced disease, joint pain is statistically significant.

[0240] [Table 12] TIFF2026027448000020.tif228165TIFF2026027448000021.tif154166

[0241] Renal and urinary disorders, and skeletal and connective tissue disorders in the <65 year old group (See Table 13)

[0242] [Table 13]

[0243] See Tables 14 and 15 for additional subgroup findings.

[0244] [Table 14] TIFF2026027448000024.tif108155

[0245] [Table 15] These results, shown in Tables 16 and 17 below, demonstrate that androgen deprivation, along with degarelix, When administered with acetaminophen, the treated subjects were less likely to develop coronary artery disease, heart disease, or other heart conditions compared to Lupron. significantly reduced risk of developing coronary artery disease, myocardial infarction, cardiac arrhythmia, coronary artery disease, or heart failure This shows that it has been shown.

[0246] [Table 16]

[0247] [Table 17]

[0248] Mortality rates by subgroup (preliminarily determined as part of the ISS) showing statistically significant findings was planned)

[0249] [Table 18]

[0250] [Table 19]

[0251] [Table 20]

[0252] These results are based on the 30 kg / m 2 Less than (e.g., 25 kg / m 2 Less than, for example, 20 to 2 5kg / m 2 ) patients with a BMI of 1.0 or lower should receive androgen deprivation therapy in combination with degarelix. Compared to Lupron, patients receiving fluoxetine experienced a significant reduction in the risk of developing cardiac arrhythmias. This shows that it has been shown.

[0253] [Table 21]

[0254] These results are based on the 25 kg / m 2 Less than, for example, 20-25 kg / m 2 have a BMI of Subjects receiving androgen deprivation therapy with degarelix should be treated with Lupro. showed a significant reduction in the risk of developing coronary artery disease compared with control.

[0255] [Table 22]

[0256] These results are based on the 30 kg / m 2 Less than (e.g., 25 kg / m 2 Less than, for example, 20 to 2 5kg / m 2 ) patients with a BMI of 1.0 or lower should receive androgen deprivation therapy in combination with degarelix. showed a significant reduction in the risk of developing heart damage when compared with Lupron. This shows that

[0257] [Table 23]

[0258] These results suggest that subjects with cholesterol levels above 4 mmol / L are at increased risk of developing If androgen deprivation therapy is administered with Garelix, GnR with Lupron A significant reduction in the risk of developing cardiac arrhythmias compared with H antagonist therapy This indicates that the number of cases was small.

Claims

[Claim 1] The invention described herein.

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