Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
  • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• Prostate cancer is a leading cause of morbidity and mortality for men in the industrialized world, accounting for about 9% of cancer-related deaths in men.
• Prostate cancer is the second leading cause of cancer death in American men, behind only lung cancer.
• the American Cancer Society has estimated that 27,050 men in the United States died of prostate cancer in 2007.
• prostate cancer is the third most common cause of death from cancer in men in Europe, with 87,400 deaths estimated in 2006 (see Ferlay et al. (2007) Ann. Oncol.; 18:581-92; Lukka et al. (2006) Curr. Oncol.; 13:81-93.).
• GnRH Gonadotrophin releasing hormone
• LH luteinizing hormone
• the initial stimulation of LH production by the agonist leads to an initial surge in the production of male sex hormones such that the initial response to agonist therapy is aggravation, rather than amelioration, of the patient's condition (e.g., tumor growth may increase).
• This phenomenon known as the "testosterone surge” or “flare reaction,” can last for as long as two to four weeks.
• each successive administration of the agonist can cause an additional small LH surge (known as the "acute-on chronic” phenomenon) that can further worsen the condition.
• the testosterone surge stimulates prostate cancer and can lead to a worsening of current symptoms or appearance of new symptoms such as spinal cord compression, bone pain and urethral obstruction (Thompson et al. (1990) J. Urol.
• GnRH-R gonadotrophin releasing hormone receptor
• FSH Follicle Stimulating Hormone
• GnRH antagonists having such significantly modified or unnatural amino acids in the 5- and 6-positions exhibit good biological potency, and those built upon Aph are generally considered to be particularly potent.
• One that is especially useful is Azaline B.
• U.S. Pat. No. 5,506,207 also discloses biopotent GnRH antagonists with acylated, amino-substituted phenylalanine side chains of residues in the 5- and 6-positions; one such decapeptide is Acyline.
• the invention is based, in part, upon the surprising finding that administration of the GnRH antagonist degarelix to patients with metastatic stage prostate cancer, and/or to patients having PSA levels of 50 ng/mL or greater, provides a remarkable, and long term, reduction of serum alkaline phosphatase (S-ALP). This reduction is indicative of better control of (e.g. skeletal) metastases (see Example 1 , Figures 1-4, Table 2).
• S-ALP serum alkaline phosphatase
• the results further indicate that administration of degarelix may delay or prevent progression from localized or locally advanced stage prostate cancer to metastatic stage. Further, the results indicate that administration of degarelix to these patients is associated with a delay in progression to hormone refractory stage.
• the invention provides a method of treating metastatic stage prostate cancer in a subject.
• the method includes the initial step of identifying a suitable subject with metastatic stage prostate cancer, and then administering an initial dose of degarelix of 160 to 320 mg to the subject.
• the subject is then administered a maintenance dose of degarelix of 60 to 160 mg once every 20 to 36 days thereafter.
• the method thereby treats the metastatic stage prostate cancer in the subject.
• the invention provides a method of treating metastatic stage prostate cancer in a subject, which includes the initial step of identifying a suitable subject with metastatic stage prostate cancer, and then administering an initial dose of degarelix of about 240 mg to the subject. The subject is then administered a maintenance dose of degarelix of 60 to 160 mg once every 20 to 36 days thereafter. The method thereby treats the metastatic stage prostate cancer in the subject.
• the subject to be treated is identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for treatment if the subject's baseline S-ALP level is 150 IU/L or greater, e.g. 160 IU/L or greater.
• the subject to be treated is identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for treatment if the subject's baseline S-ALP level is 200 IU/L or greater.
• the subject to be treated is identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for treatment if the subject's baseline S-ALP level is 300 IU/L or greater.
• S-ALP serum alkaline phosphatase
• the subject to be treated is identified by testing the hemoglobin (Hb) level of a potential subject and then selecting the subject for treatment if the subject's Hb level is 130 g/L or less.
• the subject to be treated is identified by testing the prostate-specific antigen (PSA) level of a potential subject and then selecting the subject for treatment if the subject's PSA level is greater than or equal to 50 ng/mL.
• the treated subject's S-ALP is reduced by at least 60 IU/L from the baseline level between day 112 and day 364 of treatment.
• the treated subject's serum alkaline phosphatase is reduced by at least 50 IU/L from the baseline level between day 60 and day 364 of treatment. In other embodiments, the treated subject's S-ALP is reduced by at least 50 IU/L from the baseline level between day 364 and day 450 of treatment. In further embodiments, the treated subject's S-ALP is reduced by at least 90 IU/L from the baseline level between day 112 and day 364 of treatment. In still further embodiments, the treated subject's S-ALP is reduced by at least 160 IU/L from the baseline level between day 112 and day 364 of treatment.
• the treated subject has at least a 95% likelihood of having a therapeutically low serum testosterone level of less than or equal to 0.5 ng/mL by day 28 of treatment. In particular embodiments, the treated subject has at least a 95% likelihood of maintaining a therapeutically low serum testosterone level of less than or equal to 0.5 ng/mL from day 28 to day 365 of treatment.
• the treated subject has at least a 60% decrease in the level of prostate-specific antigen (PSA) by day 14 of treatment. In certain embodiments, the treated subject has at least a 75% decrease in the level of PSA by day 28 of treatment. In further embodiments, the treated subject has at least an 80% likelihood of maintaining a prostate-specific antigen (PSA) level of less than 5 ng/mL during treatment.
• PSA prostate-specific antigen
• the invention provides a method of treating prostate cancer by first testing the prostate-specific antigen (PSA) of a potential subject, and then selecting the potential subject for treatment if the subject's PSA level is greater than or equal to 50 ng/mL.
• the method further includes the steps of administering an initial dose of degarelix of 160 to 320 mg to the subject thus identified, and then administering a maintenance dose of degarelix of 60 to 160 mg to the subject once every 20 to 36 days thereafter, so as to treat the prostate cancer in the subject.
• PSA prostate-specific antigen
• the subject to be treated is further identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for treatment if the subject's baseline S-ALP level is 150 IU/L or greater, e.g. 160 IU/L or greater.
• the treated subject's S-ALP is reduced by at least 60 IU/L from the baseline level between day 112 and day 364 of treatment.
• the subject to be treated is further identified by testing the hemoglobin (Hb) level of the potential subject and then selecting the subject for treatment if the subject's Hb level is 130 g/L or less.
• Hb hemoglobin
• the invention provides methods of using degarelix for the treatment of metastatic stage prostate cancer in a subject.
• the methods of use of degarelix include an initial step of identifying a suitable subject with metastatic stage prostate cancer.
• the suitable subject thus identified is then administered an initial dose of degarelix of 160 to 320 mg, followed by maintenance doses of 60 to 160 mg of degarelix once every 20 to 36 days thereafter, thereby using degarelix for the treatment of metastatic stage prostate cancer.
• the subject with metastatic stage prostate cancer is identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for treatment if the subject's baseline S-ALP level is 160 IU/L or greater.
• the subject with metastatic stage prostate cancer is identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for treatment if the subject's baseline S-ALP level is 200 IU/L or greater.
• the subject with metastatic stage prostate cancer is identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for treatment if the subject's baseline S-ALP level is 300 IU/L or greater.
• the subject with metastatic stage prostate cancer is identified by testing the hemoglobin (Hb) level of a potential subject and then selecting the subject for treatment if the subject's Hb level is 130 g/L or less.
• the subject with metastatic stage prostate cancer is identified by testing the prostate-specific antigen (PSA) level of a potential subject and then selecting the subject for treatment if the subject's PSA level is greater than or equal to 50 ng/mL.
• S-ALP serum alkaline phosphatase
• PSA prostate-specific antigen
• the invention provides methods of using degarelix to prevent the progression of locally advanced prostate cancer to metastatic stage prostate cancer in a subject.
• the methods of use of degarelix to prevent the progression of locally advanced prostate cancer include the initial step of identifying a suitable subject with locally advanced prostate cancer. The suitable subject thus identified is then administered an initial dose of degarelix of 160 to 320 mg, followed by maintenance doses of 60 to 160 mg of degarelix once every 20 to 36 days thereafter. This method of use of degarelix thereby prevents the progression of locally advanced prostate cancer to metastatic stage prostate cancer in the subject.
• the subject with locally advanced prostate cancer is identified by testing the prostate-specific antigen (PSA) level of a potential subject and then selecting the subject for preventive treatment if the subject's PSA is 10-50 ng/mL.
• the subject with locally advanced prostate cancer is identified by testing the prostate-specific antigen (PSA) level of a potential subject and then selecting the subject for preventive treatment if the subject's PSA is 20-50 ng/mL.
• the subject with locally advanced prostate cancer is identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for preventive treatment if the subject's baseline S-ALP level is less than about 160 IU/L, for example between 44 and 147 IU/L and/or between 50 and 160 IU/L.
• S-ALP serum alkaline phosphatase
• a composition e.g. a pharmaceutical composition, a medicament
• a composition e.g. a pharmaceutical composition, a medicament
• a composition comprising degarelix for the treatment of prostate cancer in a subject having prostate specific androgen (PSA) level of greater than or equal to 50 ng/mL.
• PSA prostate specific androgen
• metastasis refers to a secondary metastatic growth of a malignant tumor that forms when cancer has spread from an original site to more remote or distant parts of the body, for example the lymph nodes, bone, and/or other organs such as the brain or liver.
• metastasis refers to a secondary metastatic growth of a malignant tumor that forms when cancer has spread from an original site to more remote or distant parts of the body, for example the lymph nodes, bone, and/or other organs such as the brain or liver.
• metalastatic or “metastatic stage prostate cancer” refers to a cancer that has spread to distant organs from the original tumour site, e.g., the prostate gland.
• treatment of metastatic stage prostate cancer and associated methods of “treating metastatic stage prostate cancer” include treatments and associated methods to reduce the amount of cancerous tissue, e.g. by reducing the number and/or size of metastatic lesions (tumors), such as metastatic lesions in the bone, brain, liver and/or lymph nodes.
• treatment of metastatic stage prostate cancer and associated methods of “treating metastatic stage prostate cancer” includes treatments, and associated methods, to reduce skeletal metastases (metastatic lesions identified in the skeleton, e.g., by bone scan or other imaging technique).
• treatment of metastatic stage prostate cancer and associated methods of “treating metastatic stage prostate cancer” further include treatments and associated methods to reduce and/or ameliorate one or more symptoms associated with metastatic stage prostate cancer, e.g. treatment to ameliorate and/or reduce the symptoms of urinary disorders (e.g. obstruction, weak or interrupted urination, frequent urination, inability to urinate, pain while urinating, blood in the urine), treatment to reduce and/or ameliorate bone pain (e.g. in the lower back, hips or thighs), and/or treatment to reduce and/or ameliorate weight loss, fatigue.
• urinary disorders e.g. obstruction, weak or interrupted urination, frequent urination, inability to urinate, pain while urinating, blood in the urine
• treatment to reduce and/or ameliorate bone pain e.g. in the lower back, hips or thighs
• treatment to reduce and/or ameliorate weight loss, fatigue e.g. in the lower back, hips or thighs
• composition comprising degarelix for the treatment of metastatic stage prostate cancer in a subject to reduce the number and/or size of metastatic lesions and/or to reduce and/or ameliorate one or more symptoms associated with metastatic stage prostate cancer.
• prevention of metastatic stage prostate cancer and associated methods of "preventing metastatic stage prostate cancer” further include treatments, and associated methods that prevent the onset of metastatic activity or that maintains the level of metastatic activity (e.g. at the level known at start of medication, i.e. baseline), or that reduce and/or delay the return of metastatic activity (e.g. as measured by S-ALP), in a subject being treated for prostate cancer who is at the locally advanced stage.
• the level of metastatic activity in this context refers to the size and/or number of metastatic tumors in the subject, and not the rate of metastasis in the subject per se.
• the invention includes treatments and associated methods to delay or prevent progression of the disease and/or to bring on or enhance regression or remission of the disease.
• prevention of metastatic stage prostate cancer and associated “methods of preventing metastatic stage prostate cancer” include treatments and associated methods to prolong the life and/or increase the quality of life (QoL) of the patient.
• treatment of metastatic [stage] prostate cancer and associated “methods of treating metastatic [stage] prostate cancer”
• treatment of prostate cancer and associated “methods of treating prostate cancer” may also include treatments and associated methods that delay or prevent onset of the hormone-refractory disease stage.
• composition comprising degarelix for the treatment of prostate cancer in a subject and associated methods of treatment that reduce the likelihood of, and/or delay, the return of metastatic tumor activity, and/or that delay or prevent progression of the disease, and/or bring on or increase regression or remission of the disease, and/or prolong the life and/or increase the quality of life (QoL) of the patient, and/or delay or prevent onset of the hormone-refractory disease stage.
• QoL quality of life
• treatment of prostate cancer and associated “methods of treating prostate cancer” also include treatment and associated methods to cure the prostate cancer.
• S-ALP serum alkaline phosphatase
• the subject may have a baseline serum alkaline phosphatase (S-ALP) level (that is, a S-ALP level prior to treatment i.e. prior to administration of the initial dose of testosterone) of about 150 IU/L or greater, e.g., a baseline serum alkaline phosphatase (S-ALP) level of about 160 IU/L or greater, e.g., a baseline serum alkaline phosphatase (S-ALP) level of about 200 IU/L or greater, e.g. a baseline serum alkaline phosphatase (S-ALP) level of about 300 IU/L or greater (See Table 2).
• S-ALP serum alkaline phosphatase
• the degarelix composition may provide a reduction below the baseline (or alternatively articulated, a negative change from baseline) of serum alkaline phosphatase (S-ALP) level of at least about 50 IU/L below the baseline (S-ALP) for a period between about 60 and 364 days after administration of the initial dose of degarelix, and/or, at least about 90 IU/L below the baseline level for a period between 112 and 364 days after administration of the initial dose of degarelix. (See Table 2, Figures 1-3).
• reduction in serum alkaline phosphatase (S-ALP) level of at least about 50 IU/L below the baseline level may extend for a period beyond 364 days (depending on continuation of therapy/ maintenance doses, see below).
• the subject to whom the treatment is administered may have a hemoglobin (Hb) level of about 130 g/L or less.
• Hb hemoglobin
• Baseline S-ALP levels were particularly elevated in the subgroup of patients with metastatic disease and Hb ⁇ 130 g/L; for example a baseline serum alkaline phosphatase (S-ALP) level of 300 IU/L or greater was found in a population of patients having a Hb ⁇ 130 g/L (See Table 2).
• the subject with the aforementioned depressed Hb level may also show a reduction (alternatively, a negative change from baseline) of serum alkaline phosphatase (S-ALP) level of at least 160 IU/L below the baseline level for a period between 112 and 364 days after administration of the initial dose of degarelix (See Figure 2).
• S-ALP serum alkaline phosphatase
• Bone metastases affect bone marrow and a patient with bone metastasis may become anemic; thus lower than normal Hb in patients with bone metastasis is indicative of greater degree of metastasis (more serious disease).
• the invention may provide a surprisingly long term and effective suppression of S-ALP by degarelix in this sub-population of patients with lower than normal Hb levels.
• a composition comprising degarelix for the treatment of prostate cancer in a subject having a prostate specific androgen (PSA) level of greater than or equal to 50 ng/mL (See Figure 4).
• PSA prostate specific androgen
• the prostate cancer may be metastatic prostate cancer.
• the composition may be for administration of degarelix at an initial dose of 160 to 320 mg; and at a maintenance dose of 60 to 160 mg, once every 20 to 36 days thereafter, for example for administration at an initial dose of degarelix of about 240 mg; and at a maintenance dose of about 80 mg degarelix once every approximately 28 days of treatment.
• composition comprising degarelix may be for treatment wherein the subject has at least a 95% likelihood of maintaining a therapeutically low serum testosterone level of less than or equal to 0.5 ng/mL by day 28 of treatment, for example wherein the subject has at least a 95% likelihood of maintaining a therapeutically low serum testosterone level of less than or equal to 0.5 ng/mL from day 28 to day 364 of treatment. (See, e.g., Figures 7-8).
• the composition comprising degarelix may be for treatment of metastatic prostate cancer and may provides a 60% decrease in PSA by day 14 of treatment.
• the composition (or medicament) comprising degarelix may provide at least a 60% decrease, e.g., at least a 75% decrease, in prostate specific antigen (PSA) by day 28 of treatment. (See, e.g., Figure 9).
• the composition may be for treatment with at least an 80%; for e.g., a 95% likelihood, of maintaining a prostate specific antigen (PSA) level of less than 5 ng/mL during treatment.
• PSA prostate specific antigen
• a method of treating metastatic prostate cancer in a subject comprising administering an initial dose of 160-320 mg of degarelix to the subject; and administering a maintenance dose of 60-160 mg of degarelix to the subject once every 20-36 days thereafter; for example, administering an initial dose of about 240 mg of degarelix to the subject; and administering a maintenance dose of about 80 mg of degarelix to the subject once every approximately 28 days thereafter.
• a composition comprising degarelix for delaying or preventing the progression of localized or locally advanced prostate cancer to metastatic stage prostate cancer in a subject (e.g. a subject having localized or locally advanced prostate cancer).
• the subject may have a prostate specific androgen (PSA) level of 10 - 50 ng/mL, for example a prostate specific androgen (PSA) level of 20 - 50 ng/mL.
• PSA prostate specific androgen
• the subject may have a serum alkaline phosphatase (S-ALP) level of between 44 and 147 IU/L.
• the subject may have a serum alkaline phosphatase (S-ALP) level of less than 160 IU/L, for example between 50 and 160 IU/L.
• S-ALP serum alkaline phosphatase
• the composition may be for administration at an initial dose of degarelix of 160 to 320 mg; and at a maintenance dose of 60 to 160 mg, once every 20 to 36 days thereafter, for example for administration at an initial dose of degarelix of about 240 mg; and at a maintenance dose of about 80 mg degarelix once every approximately 28 days thereafter.
• the delaying or prevention of progression of locally advanced prostate cancer may include an initial step of identifying a suitable subject with locally advanced prostate cancer, for example by testing the prostate-specific antigen (PSA) level of a potential subject and then selecting the subject for preventive treatment if the subject's PSA is 10-50 ng/mL, for example 20-50 ng/mL.
• PSA prostate-specific antigen
• the subject with locally advanced prostate cancer may be identified by testing the serum alkaline phosphatase (S-ALP) level of a potential subject and then selecting the subject for preventive treatment if the subject's baseline S-ALP level is less than 160 IU/L, for example 44 to 147 IU/L.
• S-ALP serum alkaline phosphatase
• Figure 1 is a graphical representation comparing the mean change in baseline S-ALP levels versus time, for the local (localized), locally advanced and metastatic populations, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 2 is a graphical representation showing the mean change in baseline S-ALP levels, versus time, for the Metastatic (+Hb ⁇ 130 g/L) subpopulation using degarelix (240/80 mg), degarelix (240/160 mg) and leuprolide (7.5 mg) treatments.
• Figure 3 is a graphical representation showing the mean change in baseline S-ALP values, versus time, using degarelix (240/80 mg) treatment as compared to leuprolide (7.5 mg) treatment that was "switched” to degarelix after day 364, which demonstrates the difference in time for the reduced baseline S-ALP values to return to baseline level.
• Figure 4 is a graphical representation comparing the mean change in baseline S-ALP values, versus time, in subjects having PSA levels of ⁇ 10 ng/mL, 10-20 ng/mL, 20-50 ng/mL, and > 50 ng/mL, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 5 is a graphical representation showing the incidence of PSA failure in subjects with baseline localized, locally advanced, and metastatic prostate cancer stages, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 6 is a graphical representation showing the incidence of PSA failure in subjects with baseline PSA levels of ⁇ 10 ng/mL, 10-20 ng/mL, 20-50 ng/mL, and > 50 ng/mL, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 7 is a graphical representation showing the decrease in median testosterone levels from day 0 to day 364, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 8 is a graphical representation showing the median percentage change in testosterone level from day 0 to day 28, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 9 is a graphical representation showing the median percentage change in PSA level from day 0 to day 56, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 10 is a graphical representation showing the median LH level from day 0 to day 364, using degarelix (240/160 mg), degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Figure 11 is a graphical representation showing the median FSH level from day 0 to day 364, using degarelix (240/160 mg), degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• S-ALP serum alkaline phosphatase
• PSA prostate specific antigen
• Hb hemoglobin
• testosterone luteinizing hormone
• FSH follicle stimulating hormone
• the invention provides use of a composition comprising degarelix GnRH antagonist for treating metastatic prostate cancer in a subject, and related methods of treatment.
• the disclosure of the invention has been exemplified by data obtained from clinical studies, in particular, the CS21 study on Degarelix (EP application No. 08250703.9, and U.S. provisional application No. 61/027,741).
• prostate cancer refers to any cancer of the prostate gland in which cells of the prostate mutate and begin to multiply out of control.
• the extent to which prostate cancer has progressed in a patient is assessed taking into account clinical and histopathological information.
• the stage of cancer is classified based on tumour size (T), whether there is lymph node involvement (N), the presence of metastasis (M), and the tumour grading (G).
• T1 is confined to the prostate gland and too small to be felt by digital rectal examination.
• T1 further includes T1a (fewer than 5% cancerous cells in tissue sample) and T1b (more than 5%) subdivisions.
• T1c indicates the patient has an elevated Prostrate Specific Antigen (PSA; see definition later).
• T2a means only one side of the prostate gland (left or right) is involved; T2b means both sides have a tumour(s).
• T2 is commonly termed "localized cancer". If the cancer is T3, it has spread to the connected tissue near the prostate (T3a) or the seminal vesicles (T3b). T4 indicates cancer spread to tissue next to the prostate, for example the bladder sphincter, rectum or pelvis wall. The prostate cancer may also spread into the regional lymph nodes of the pelvis and this is assessed as N1 stage of prostate cancer. These stages of T3, T4 and N1 are collectively termed "locally advanced" or regional cancer.
• cancer has spread to distant sites, such as the bone, it is said to be "metastasized” or at the M1 stage.
• Prostate cancer that has spread to distant lymph nodes is categorized as M 1a while that which has spread to bone is M1b and that which has spread to organs such as liver or brain is assessed as M1c. Left untreated, prostate cancer almost universally metastasizes to bone.
• Hormone refractory prostate cancer (which may also be referred to as hormone-resistant prostate cancer or hormone independent prostate cancer) is broadly defined herein as prostate cancer wherein the patient's blood PSA is rising despite having a castrate level of testosterone (T less than 20 ng/dL) caused by hormone blockade therapy.
• Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. In humans, ALP is present in all tissues throughout the entire body, but is particularly concentrated in liver, bile duct, kidney, bone and the placenta. Its concentration level may be used as a diagnostic tool; abnormally elevated levels (hyperphosphatasemia) may indicate several disorders. These include liver disease, bone disease, skeletal involvement of other primary diseases such as malignant tumours, osteomalacia, renal disease (secondary hypothyroidism), and primary hypothyroidism.
• abnormally lowered levels of ALP may indicate other disorders, such as severe anemia in men, or achondroplasia, cretinism, or severe enteritis in children.
• levels of ALP present in a subject's serum S-ALP levels are used in conjunction with the treatment methods and compositions described herein.
• S-ALP testing is well known in the art (Chernecky CC, Berger BJ (2008), Laboratory Tests and Diagnostic Procedures. 5th ed., WB Saunders & Company, Philadelphia). It is generally used as a test of liver function, but is also known as an indicator for metastatic lesions in the bone for different malignancies (breast, prostate and colon). In metastatic prostate cancer, baseline S-ALP levels (or alternatively, "ALP levels”) are consistently higher than in localized or locally advanced disease reflecting bone lesions. As disclosed in the present invention, the subject may have a baseline serum alkaline phosphatase (S-ALP) level (that is, a S-ALP level prior to treatment i.e.
• S-ALP serum alkaline phosphatase
• S-ALP serum alkaline phosphatase
• PSA prostate-specific antigen
• PSA prostate-specific antigen
• a blood test to measure PSA is the most effective test currently available for the early detection of prostate cancer.
• Levels of PSA, which are higher than normal, are associated with both localized and metastatic prostate cancer.
• the subjects with localized or metastatic stage prostate cancer may have a prostate specific androgen (PSA) level of greater than or equal to 50 ng/mL.
• Degarelix is a potent GnRH antagonist that is an analog of the GnRH decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly -NH 2 ) incorporating p-ureido-phenylalanines at positions 5 and 6 (Jiang et al. (2001) J. Med. Chem. 44:453-67). It is indicated for treatment of patients with prostate cancer in whom androgen deprivation is warranted (including patients with rising PSA levels after having already undergone prostatectomy or radiotherapy).
• Degarelix is a selective GnRH receptor antagonist (blocker) that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of gonadotrophins and consequently testosterone (T).
• Prostate cancer is sensitive to testosterone deprivation, a mainstay principle in the treatment of hormone-sensitive prostate cancer.
• GnRH receptor blockers do not induce a luteinizing hormone (LH) surge with subsequent testosterone surge/tumor stimulation and potential symptomatic flare after the initiation of treatment.
• the active ingredient degarelix is a synthetic linear decapeptide amide containing seven unnatural amino acids, five of which are D-amino acids.
• the drug substance is an acetate salt, but the active moiety of the substance is degarelix as the free base.
• the acetate salt of degarelix is a white to off-white amorphous powder of low density as obtained after lyophilisation.
• the chemical name is D-Alaninamide, N-acetyl-3-(2- naphthaleny ⁇ -D-alanyl ⁇ -chloro-D-phenylalanyl-S- ⁇ -pyridiny ⁇ -D-alanyl-L- seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-L Ieucyl-N6-(1- methylethyl)-L-lysyl-L-prolyl.
• Degarelix may be formulated for administration subcutaneously (as opposed to intravenously), generally in the abdominal region, as described in further detail below.
• the injection site may vary periodically to adapt the treatment to injection site discomfort.
• injections should be given in areas where the patient will not be exposed to pressure, e.g. not close to waistband or belt and not close to the ribs.
• degarelix by subcutaneous or intramuscular injection works well, but daily injections are generally not acceptable and so a depot formulation of degarelix may be utilized as describe in further detail in WO 03/006049 and U.S. Pub. Nos. 20050245455 and 20040038903.
• subcutaneous administration of degarelix may be conducted using a depot technology in which the peptide is released from a biodegradable polymer matrix over a period of (typically) one to three months.
• Degarelix (and related GnRH antagonist peptides) have a high affinity for the GnRH receptor and are much more soluble in water than other GnRH analogues.
• Degarelix and these related GnRH antagonists are capable of forming a gel after subcutaneous injection, and this gel can act as a depot from which the peptide is released over a period of weeks or even months.
• a key variable for formation of an effective degarelix depot is the concentration of the solution in combination with the amount of substance administered per se. The concentration must be within a functional range. If the formulation is too dilute then no depot is formed and the long duration of action is lost, regardless of the amount of drug substance given. If the formulation is too concentrated then gel formation will occur before the drug can be administered.
• Effective depot-forming formulations of degarelix generally have a concentration of not less than 5 mg/mL degarelix, e.g. 5 to 40 mg/mL of degarelix.
• degarelix may be provided as a powder for reconstitution (with a solvent) as solution for injection (e.g., subcutaneous injection, e.g., to form a depot as described above).
• the powder may be provided as a lyophilisate containing degarelix (e.g. as acetate) and mannitol.
• a suitable solvent is water (e.g., water for injection, or WFI).
• degarelix may be provided in a vial containing 120 mg degarelix (acetate) for reconstitution with 3 ml_ WFI such that each ml_ of solution contains about 40 mg degarelix.
• degarelix may be provided in a vial containing 80 mg degarelix (acetate). After reconstitution with about 4 mL (e.g., 4.2 mL) WFI, each mL solution contains about 20 mg degarelix.
• a method of treating metastatic prostate cancer in a subject comprising administering an initial dose of 160-320 mg of degarelix to the subject; and administering a maintenance dose of 60-160 mg of degarelix to the subject once every 20-36 days thereafter; for example, administering an initial dose of about 240 mg of degarelix to the subject; and administering a maintenance dose of about 80 mg of degarelix to the subject once every approximately 28 days thereafter.
• the composition may be for administration of degarelix at an initial dose of 160 to 320 mg; and at a maintenance dose of 60 to 160 mg, once every 20 to 36 days thereafter.
• a preferred dosing regimen for treating adult males with prostate cancer is a single 240 mg starting dose of degarelix administered as two subcutaneous injections of 120 mg; and followed by monthly maintenance doses of 80 mg of degarelix administered as a single subcutaneous injection beginning approximately 28 days or one month after the initial starting dose.
• the dosing regimen for degarelix may be administered as an initial, starting dose of 240 mg administered as 2 injections of 3 ml_ of about 40 mg/mL degarelix formulation, followed by monthly maintenance doses of 80 mg administered as a single injection of 4 mL of about 20 mg/mL degarelix formulation.
• monthly maintenance doses of 160 mg may be utilized, e.g., by administering 4 mL of about 40 mg/mL degarelix every month.
• the reconstituted solution should be a clear liquid, free of undissolved matter.
• the plasma concentration of dihydrotestosterone (DHT) decreases in a manner similar to that of testosterone.
• Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration level of 0.5 ng/mL. As described below in further detail, maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in 97% of patients for at least one year. In particular, the median testosterone level after one year of such treatment was 0.087 ng/mL.
• the resulting distribution volume in healthy elderly men is approximately 1 L/kg.
• Plasma protein binding is estimated to be approximately 90%.
• Degarelix is subject to common peptidic degradation during the passage of the hepato-biliary system and is mainly excreted as peptide fragments in the feces. No significant metabolites were detected in plasma samples after subcutaneous administration. In vitro studies have shown that degarelix is not a substrate for the human CYP450 (cytochrome P450) system. Therefore, clinically significant pharmacokinetic interactions with other drugs are unlikely to occur.
• CYP450 cytochrome P450
• Degarelix has been found to be generally well tolerated in clinical trials. The most commonly observed adverse reactions during therapy were due to the expected physiological effects of testosterone suppression, mainly hot flushes and increased weight, and injection site related adverse events (injection site related side effects), mainly injection site pain and injection site erythema.
• Example 1 S-ALP Levels in Prostate Cancer Patients Treated with Deqarelix versus Leuprolide
• Example 1 gives the results of the analyses of serum alkaline phosphatase (S-ALP) performed on patients undergoing treatment for prostrate cancer, using alternatively, degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• S-ALP serum alkaline phosphatase
• the S-ALP levels were measured in each patient at various time points, by taking a blood sample and analyzing for S-ALP. S-ALP levels were measured using a standardised colorimetric assay based on the p-nitrophenyl phosphate AMP buffer method. The normal range for S-ALP is 44-147 IU/L. The S-ALP values in non-metastatic patients serve as controls. An ANOVA analysis with treatment and day as factors and baseline value as covariate, was used to determine between treatment differences at Day 364. A repeated measures analysis (incorporating all time points from Day 112) with treatment and day as factors and baseline value as covariate, was used to assess between treatment differences from Day 112 to Day 364.
• Results The results of S-ALP analyses for the degarelix 240/80 mg and leuprolide 7.5 mg groups in patients with advanced prostate cancer are are presented in Table 2 and Figure 1. Baseline chracteristics were well balanced between groups. Approximately half of patients had locally advanced (29.2%) or metastatic (20.5%) disease at baseline and overall, mean age was 72 years, median testosterone was 39.3 ng/mL and PSA was 19.0 ng/mL.
• S-ALP levels showed a small but gradual increase within normal range over the study period, irrespective of treatment group (leuprolide or degarelix). Similarly, in locally advanced disease, a small increase was observed by the end of the study in both treatment groups. Table 2 shows that baseline S-ALP levels are high in metastatic patients, and even more so in the patients with Hb ⁇ 130 g/L, whichever the treatment. However, after initial peaks in both groups, as described earlier for hormonal treatments, S-ALP levels were suppressed below baseline with both degarelix 80 mg and leuprolide, though more significantly with degarelix.
• An initial increase (peak) in S-ALP is associated with increased activity in bone, and metastatic patients experience a surge in S-ALP at the initiation of all therapies having an effect on skeletal metastasis. This is a well described phenomenon and totally independent of testosterone surge.
• Figure 1 compares the mean change from baseline of S-ALP levels versus time for the localized, locally advanced, and metastatic populations, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments. These results clearly illustrate the long-term suppression of S-ALP using degarelix.
• a decrease in baseline S-ALP levels in a treated subject suffering from prostate cancer indicates a positive response to the treatment-, for example by reducing skeletal metastatic activity.
• an increase in S-ALP indicates increased metastatic activity.
• Figure 1 shows that degarelix treatment significantly reduces S-ALP (after an initial and expected surge) and then maintains the reduction for the duration of the study.
• Hb haemoglobin
• Section (a) of Table 2 shows the S-ALP values (IU/L) for the localized, locally advanced, metastatic populations and metastatic (Hb ⁇ 130 g/L) subpopulation, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Section (b) of Table 2 shows the S-ALP values (IU/L) for the baseline PSA ( ⁇ 10 ng/mL), (10-20 ng/mL), (20-50 ng/mL), (> 50 ng/mL) populations, using degarelix (240/80 mg) and leuprolide (7.5 mg) treatments.
• Example 2 PSA Failure in Prostate Cancer Patients Treated with Degarelix versus Leuprolide
• This example provides additional PSA level analyses from the phase III clinical trial CS21 (described herein), which examined the efficacy and safety of degarelix compared with leuprolide over 12 months of prostate cancer treatment.
• analysis of a secondary endpoint termed PSA failure revealed a surprisingly advantageous effect of degarelix treatment as compared to leuprolide treatment, particularly for patients with metastatic stage prostate cancer.
• Prostate-specific antigen is a commonly used marker in the diagnosis of prostate cancer and has more recently also been used to monitor response to treatment as well as disease recurrence and progression (Fleming et al. (2006) Nat. Clin. Pract. Oncol. 3: 658-67; Lilja, et al. (2008) Nat. Rev. Cancer 8: 268-78).
• PSA Prostate-specific antigen
• higher levels of PSA are associated with more severe forms of prostate cancer, with metastatic stage prostate cancer being associated with the highest levels of PSA (e.g., > 50 ng/mL). Accordingly, rising PSA levels in patients undergoing prostate cancer treatment are associated with incomplete or failed efficacy of the treatment.
• PSA failure (a secondary endpoint) was defined as two consecutive increases in PSA of 50% and ⁇ 5 ng/mL compared with nadir.
• the time to PSA failure was defined as the number of days from first dosing to where an increase in serum PSA of ⁇ 50% from nadir and ⁇ 5 ng/mL, measured on two consecutive occasions at least two weeks apart, was noted. The second occasion was the time point of meeting the criterion.
• PSA failure rates were also analyzed by disease stage and baseline PSA level. In these analyses, the focus was on a comparison of degarelix 240/80 mg versus leuprolide 7.5 mg as this is the degarelix dose now approved by the FDA for the treatment of advanced prostate cancer.
• Example 3 Clinical Study of Degarelix for the Treatment of Prostate Cancer
• the study also investigated whether degarelix is safe and effective with respect to achieving and maintaining testosterone suppression to castrate levels, evaluated as the proportion of patients with testosterone suppression ⁇ 0.5 ng/mL during 12 months of treatment.
• the study assessed serum levels of testosterone and prostate-specific antigen (PSA) during the first 28 days of treatment using a degarelix dosing regimen as compared to leuprolide 7.5 mg.
• PSA prostate-specific antigen
• the study further compared the safety and tolerability using a degarelix dosing regimen compared to treatment with leuprolide 7.5 mg, and, further, compared testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and PSA response with a degarelix dosing regimen compared to leuprolide 7.5 mg.
• the study further compared patient reported outcomes (quality of life factors and hot flushes) using a degarelix dosing regimen as compared to leuprolide 7.5 mg during treatment.
• the study also evaluated the pharmacokinetics of the degarelix dosing regimens investigated.
• the study examined the effects of using the degarelix treatment on patients suffering from different stages of cancer.
• degarelix doses of either 80 mg at a concentration of 20 mg/mL (80@20: degarelix 240/80 mg group) or 160 mg at a concentration of 40 mg/mL (160@40: degarelix 240/160 mg group) administered s.c. every 28 days.
• bicalutamide could be given as clinical flare protection at the investigator's discretion.
• 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 administered as two equivalent subcutaneous (s.c.) injections of 120 mg each. The group then received 12 maintenance doses of 160 mg at a concentration of 40 mg/mL (160@40) as single s.c doses of degarelix every 28 days.
• This group also received an initial dose of 240 mg at a concentration of 40 mg/mL (240@40) on day 0. This starting dose was administered as two equivalent s.c. injections of 120 mg each. The group then received 12 maintenance doses of 80 mg at a concentration of 20 mg/mL (80@20) as single s.c doses of degarelix every 28 days.
• This group received the reference therapy leuprolide 7.5 mg. This treatment was administered as a single intramuscular (i.m.) injection, once every 28 days starting at day O. These treatment regimens are summarized in Table 3 below.
• patients in the reference therapy group received treatment with leuprolide 7.5 mg on day 0 and every 28 days thereafter for 12 maintenance doses. Patients who completed the study received thirteen doses in total. Patients who completed the study and met appropriate criteria were offered a switch to degarelix treatment in a continuing study. These patients were randomized to degarelix treatment 240/80 mg or 240/160 mg. On day 0 of the study, patients previously treated with leuprolide 7.5 mg in study CS21 received a 240 mg (40 mg/mL) degarelix starting dose followed by monthly maintenance doses of either 80 mg (20 mg/mL) or 160 mg (40 mg/mL).
• the composition (or medicament) may be for treatment wherein the subject has at least a 95% likelihood of maintaining a therapeutically low serum testosterone level of less than or equal to 0.5 ng/mL by day 28 of treatment, for example wherein the subject has at least a 95% likelihood of maintaining a therapeutically low serum testosterone level of less than or equal to 0.5 ng/mL from day 28 to day 364 of treatment.
• the composition (or medicament) may be for treatment wherein the subject has at least a 60% decrease (for example at least a 75% decrease) in prostate specific antigen (PSA) by day 28 of treatment.
• the composition (or medicament) may be for treatment with at least an 80% likelihood of maintaining a prostate specific antigen (PSA) level of less than 5 mg/mL during treatment.
• the primary efficacy endpoint was the probability of testosterone levels remaining ⁇ 0.5 ng/mL from day 28 through day 364.
• the secondary efficacy endpoints were: the proportion of patients with testosterone surge during the first 2 weeks of treatment; the proportion of patients with testosterone level ⁇ 0.5 ng/mL at day 3; the percentage change in PSA from baseline to day 28; the probability of testosterone ⁇ 0.5 ng/mL from day 56 through day 364; the levels of serum testosterone, LH, FSH and PSA over time through the study; the time to PSA failure, defined as two consecutive increases of 50%, and at least 5 ng/mL as compared to nadir; degarelix concentration over the first month and trough levels at day 308 and 336; the frequency and size of testosterone increases at day 255 and/or 259 compared to the testosterone level at day 252; the quality of life on days 0, 28, 84, 168 and end of study visit; the frequency and intensity of hot flushes experienced (scored daily from study start until end of study visit).
• AEs adverse events
• ECGs electrocardiograms
• Body weight was measured at screening and the end of study visit. Height (without shoes) was measured at screening.
• Body mass index (BMI) is defined as the individual's body weight divided by the square of their height. The formulas universally used in medicine produce a unit of measure of kg/m 2 . Body mass index may be accurately calculated using any of the formulas known in the art.
• the intention-to-treat (ITT) analysis set included all randomized patients who received at least one dose of degarelix.
• the per protocol comprised all the ITT analysis set without any major protocol violations.
• the safety population was identical to the ITT analysis set, and therefore all safety analyses were performed on the ITT analysis set.
• the primary efficacy endpoint was analyzed for both the ITT and PP analysis sets, with the ITT analysis set considered primary.
• the primary efficacy endpoint was analyzed using the Kaplan Meier method.
• testosterone response rates with 95% confidence interval (Cl) were calculated by log-log transformation of survivor function.
• Differences between the degarelix treatment groups and leuprolide 7.5 mg were assessed using a 97.5% Cl calculated by normal approximation using pooled standard error.
• the Food & Drug Administration (FDA) criterion was to determine whether the lower bound of the 95% confidence interval (Cl) for the cumulative probability of testosterone ⁇ 0.5 ng/mL from day 28 to day 364 was no lower than 90%.
• FDA Food & Drug Administration
• EMEA European Medicines Agency
• the primary objective of this study was to demonstrate the effectiveness of degarelix in achieving and maintaining testosterone suppression to castrate levels, evaluated as the proportion of patients with testosterone suppression ⁇ 0.5 ng/mL during 12 months of treatment.
• ⁇ 0.5 ng/mL from day 28 to day 364 were 98.3%, 97.2% and 96.4% for the degarelix 240/160 mg, degarelix 240/80 mg and leuprolide 7.5 mg groups, respectively.
• the lower bound of the 95% Cl was above the pre-specified 90% threshold.
• Treatment with degarelix was demonstrated to be non-inferior to leuprolide 7.5 mg therapy with respect to the probability of testosterone ⁇ 0.5 ng/mL from day 28 to day 364.
• the entire 97.5% Cl for the difference in probability compared with the leuprolide 7.5 mg group was greater than the non-inferiority limit of -10 percentage points.
• the degarelix 240/80 mg dosing regimen also produced a more rapid and efficient reduction in PSA levels than did treatment with leuprolide 7.5 mg.
• a rapid reduction in PSA levels was observed for patients treated with degarelix.
• PSA levels in the leuprolide 7.5 mg group reached a plateau during the first week of treatment before decreasing exponentially to suppressed levels.
• the probability of a PSA observation from the pooled degarelix groups being less than one from the leuprolide 7.5 mg group was slightly higher on day 14 (0.82) than on day 28 (0.70).
• the probability of completing the study without experiencing PSA failure was highest in the degarelix 240/80 group (91.2%) and slightly lower ( ⁇ 85.8%) for both the degarelix 240/160 mg and leuprolide 7.5 mg groups, although this difference was not statistically significant.
• the pharmacodynamic profile for degarelix was characteristic of a GnRH antagonist with serum levels of testosterone, LH and FSH suppressed rapidly.
• serum levels of testosterone, LH and FSH increased rapidly within the first week of treatment before falling to suppress levels.
• Safety and tolerability were evaluated by observed and reported treatment-emergent AEs, including injection site reactions, haematological, clinical chemistry and urinalysis laboratory parameters, vital signs/clinical observations, and body weight measurements and physical examination, ECGs and concomitant medication.
• Safety parameters were evaluated for all patients included in the ITT analysis set, comprising all 610 randomized patients who received at least one dose of study medication.

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