U.S. patent application number 17/710889 was filed with the patent office on 2022-07-14 for methods of treating prostate cancer with gnrh antagonist.
This patent application is currently assigned to Ferring B.V.. The applicant listed for this patent is Ferring B.V.. Invention is credited to Per Cantor, Jens-Kristian Slott Jensen, Tine Kold Olesen, Bo-Eric Persson, Egbert A. van der Meulen.
Application Number | 20220218782 17/710889 |
Document ID | / |
Family ID | 1000006239005 |
Filed Date | 2022-07-14 |
United States Patent
Application |
20220218782 |
Kind Code |
A1 |
Olesen; Tine Kold ; et
al. |
July 14, 2022 |
METHODS OF TREATING PROSTATE CANCER WITH GnRH ANTAGONIST
Abstract
The invention provides methods and dosing regimens for safely
and effectively treating androgen-dependent prostate cancer with a
gonadotrophin releasing hormone (GnRH) antagonist without causing a
testosterone spike and/or other side effect of GnRH agonist therapy
such as a urinary tract infection, or an arthralgia-related or
cardiovascular side effect.
Inventors: |
Olesen; Tine Kold; (New
York, NY) ; Persson; Bo-Eric; (St-Prex, CH) ;
Cantor; Per; (Charlottenlund, DK) ; van der Meulen;
Egbert A.; (Dalby, SE) ; Jensen; Jens-Kristian
Slott; (Bagsvaerd, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ferring B.V. |
Hoofddorp |
|
NL |
|
|
Assignee: |
Ferring B.V.
Hoofddorp
NL
|
Family ID: |
1000006239005 |
Appl. No.: |
17/710889 |
Filed: |
March 31, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17199733 |
Mar 12, 2021 |
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17710889 |
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16851179 |
Apr 17, 2020 |
10973870 |
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17199733 |
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15405552 |
Jan 13, 2017 |
10729739 |
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16851179 |
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14139922 |
Dec 24, 2013 |
9579359 |
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15405552 |
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12368935 |
Feb 10, 2009 |
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14139922 |
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61027741 |
Feb 11, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 38/08 20130101;
A61K 9/0019 20130101; A61K 38/09 20130101 |
International
Class: |
A61K 38/09 20060101
A61K038/09; A61K 38/08 20060101 A61K038/08; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 29, 2008 |
EP |
08250703.9 |
Claims
1-89. (canceled)
90. A method of treating advanced stage prostate cancer in a
subject, comprising: administering an initial dose of 240 mg of
degarelix to the subject as two injections of 120 mg each, and
administering a maintenance dose of 80 mg of degarelix to the
subject as one injection, wherein the maintenance dose is
administered approximately every 28 days after the previous dose of
degarelix for a duration of treatment, wherein the treated subject
has a decreased likelihood of urinary tract infection during
treatment compared to treatment with a gonadotrophin releasing
hormone (GnRH) agonist.
91. The method of claim 90, wherein the subject has locally
advanced stage prostate cancer.
92. The method of claim 90, wherein the subject is less than 65
years old.
93. The method of claim 90, wherein the initial dose of degarelix
is given as two subcutaneous injections of 120 mg each at a
concentration of 40 mg/mL.
94. The method of claim 90, wherein the maintenance dose of
degarelix of 80 mg is given as one subcutaneous injection at a
concentration of 20 mg/mL.
95. The method of claim 90, wherein the GnRH agonist is
leuprolide.
96. The method of claim 90, wherein the treatment with a GnRH
agonist is treatment with monthly intramuscular injections of 7.5
mg leuprolide.
Description
[0001] This application claims the benefit of priority of U.S.
Provisional Patent Application No. 61/027,741, filed Feb. 11, 2008,
and European Patent Application No. 08250703.9, filed Feb. 29,
2008, the entire contents of both of which are incorporated by
reference.
[0002] Prostate cancer is a leading cause of morbidity and
mortality for men in the industrialized world. The American Cancer
Society estimates that during 2007 about 218,890 new cases of
prostate cancer will have been diagnosed in the United States
alone. Prostate cancer is the second leading cause of cancer death
in American men, behind only lung cancer. However, while about 1
man in 6 will be diagnosed with prostate cancer during his
lifetime, only 1 man in 35 will actually die of it. The American
Cancer Society estimates that 27,050 men in the United States will
die of prostate cancer in 2007. Prostate cancer accounts for about
9% of cancer-related deaths in men.
[0003] While prostate cancer incidence rates rose dramatically in
the late 1980s, much of this increase is thought to reflect
improvements in detection and diagnosis through widespread use of
prostate-specific antigen (PSA) testing. Indeed, the incidence of
prostate cancer has been declining since the early 1990s, and
mortality rates for prostate cancer have also declined since the
early 1990s (see SEER Program and the National Center for Health
Statistics (http://seer.cancer.gov/). More than 9 out of 10
prostate cancers are found in the local and regional stages (local
means it is still confined to the prostate; regional means it has
spread from the prostate to nearby areas, but not to distant sites,
such as bone). When compared to men of the same age and race who do
not have cancer (relative survival), the 5-year relative survival
rate for these men is nearly 100%, however the 5-year relative
survival rate for men whose prostate cancers have already spread to
distant parts of the body at the time of diagnosis is only about
32%. It is estimated that approximately $8 billion is spent on
prostate cancer treatment each year in the United States alone
(Cancer Trends Progress Report
(http://progressreport.cancer.gov)).
[0004] The majority of prostate cancers are dependent on
testosterone for growth, and the current medical management of
advanced prostate cancer involves androgen deprivation, which may
be achieved by bilateral orchiectomy or by administration of
gonadotrophin releasing hormone (GnRH) receptor agonists. Removal
of the testes (castration) was for many years the standard method
of preventing the secretion of male hormones by the gonads as a
means for reducing growth of prostate cancers. More recently,
secretion of male hormones has been perturbed by chemical means by
interfering with production of luteinizing hormone (LH), which
regulates the synthesis of the androgens. Evidence from randomized
studies strongly suggests that early endocrine therapy in
non-metastatic, locally advanced disease with or without lymph node
metastases is associated with a survival benefit (see 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. 79:235-46).
[0005] Gonadotrophin releasing hormone (GnRH) is a natural hormone
produced by the hypothalamus that interacts with a receptor in the
pituitary to stimulate production of LH. To decrease LH production,
agonists of the GnRH receptor (GnRH-R), such as leuprolide and
goserelin, have been developed. Such GnRH agonists are generally
analogs of GnRH, the decapeptide
pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2. For example,
GnRH agonists having a D-isomer instead of Gly in the 6-position
have greater binding affinity/strength to the receptor and greater
biological potency than the native hormone; one example is the
[D-Ala.sup.6]-GnRH (described in U.S. Pat. No. 4,072,668) having
the following formula:
pGlu-His-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-Gly-NH.sub.2. Such GnRH-R
agonists initially act to stimulate LH release and only after
prolonged treatment act to desensitize GnRH-R such that LH is no
longer produced. 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. Additionally, 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. 140:1479-80;
Boccon-Gibod et al. (1986) Eur. Urol. 12: 400-402). One approach
that has been taken to avoid this problem has been to combine
administration of a GnRH-R agonist with an antiandrogen, such as
flutamide, known as total androgen ablation therapy (AAT). Hormonal
therapy with an GnRH-R agonist in combination with an antiandrogen
has been used as a pre-treatment prior to radical prostatectomy
known as adjuvant therapy. The use of antiandrogens, however, is
associated with serious hepatic and gastrointestinal side
effects.
[0006] Antagonists of the gonadotrophin releasing hormone receptor
(GnRH-R) have been developed to overcome the "testosterone surge"
or "flare reaction" associated with GnRH agonists. However, GnRH
antagonist peptides are frequently associated with the occurrence
of histamine-releasing activity. This histamine-releasing activity
represents a serious obstacle to the clinical use of such
antagonists because histamine release results in adverse side
effects such as edema and itching.
[0007] The search for improved GnRH antagonists has resulted in the
making of Antide, i.e. [Ac-D-2Nal.sup.1, D-4ClPhe.sup.2,
D-3Pal.sup.3, Lys(Nic).sup.5, D-Lys(Nic).sup.6, ILys.sup.8,
D-Ala.sup.10]-GnRH; and Cetrorelix, i.e. [Ac-D-2Nal.sup.1,
D-4ClPhe.sup.2, D-3Pal.sup.3, D-Cit.sup.6, D-Ala.sup.10]-GnRH. U.S.
Pat. No. 5,516,887 describes GnRH antagonists which are said to be
more effective than Antide in suppressing plasma testosterone, e.g.
[Ac-D-2Nal.sup.1, D-4ClPhe.sup.2, D-3Pal.sup.3,
D-N.sup..epsilon.-carbamoyl Lys.sup.6, Ilys.sup.8,
D-Ala.sup.10]-GnRH, which is referred to as Antarelix. Furthermore,
U.S. Pat. No. 5,296,468 discloses the design and synthesis of a
number of GnRH antagonists wherein the side chains of selected
residues are reacted to create cyanoguanidino moieties, some of
which subsequently spontaneously convert to a desired heterocycle,
e.g. a 3-amino-1,2,4-triazole(atz). Such cyanoguanidino moieties
are built upon the omega-amino group in an amino acid side chain,
such as lysine, ornithine, 4-amino phenylalanine (4Aph) or an
extended chain version thereof, such as 4-amino homophenylalanine
(4Ahp). 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, i.e. [Ac-D-2Nal.sup.1, D-4ClPhe.sup.2, D-3Pal.sup.3,
4Aph(atz).sup.5, D-4Aph(atz).sup.6, ILys.sup.8, D-Ala.sup.10]-GnRH.
U.S. Pat. No. 5,506,207 discloses biopotent GnRH antagonists with
acylated, amino-substituted phenylalanine side chains of residues
in the 5- and 6-positions; one such decapeptide is Acyline, i.e.
[Ac-D-2Nal.sup.1, D-4ClPhe.sup.2, D-3Pal.sup.3, 4Aph(Ac).sup.5,
D-4Aph(Ac).sup.6, lLys.sup.3, D-Ala.sup.10]-GnRH. Despite the
attractive properties of this group of GnRH antagonists, the search
has continued for still further improved GnRH antagonists,
particularly those which exhibit long duration of biological
action. It can frequently be important that a peptide analog should
exhibit a long duration of activity with respect to LH secretion, a
property which may be enhanced by the peptide's resistance to
proteolytic enzyme degradation in the body for both short-term and
long-term treatment indications. In addition, to facilitate
administration of these compounds to mammals, particularly humans,
without significant gelling, it is considered extremely
advantageous for such GnRH antagonistic decapeptides to have high
solubility in water at normal physiologic pH, i.e. about pH 5 to
about pH 7.4.
[0008] While the use of both GnRH agonist and antagonists in
androgen deprivation therapy to treat prostate cancer has yielded
promising results, there are concerns about the relative safety of
the available drugs. For example, the GnRH abarelix was found to
carry a risk of serious allergic reactions, including anaphylaxis
with hypotension and syncope, and was also found to lose efficacy
over the course of treatment in some cases. Indeed, Abarelix.TM.
(Plenaxis.TM. in the U.S.) was eventually approved, but only for
patients with advanced prostate cancer, and was eventually
withdrawn from the market in 2005 for commercial reasons apparently
related to these problems. Furthermore, while prostate
cancer-specific mortality has been decreasing, there has been
little overall effect on mortality in this group, suggesting the
possibility of an increased risk of death from nonprostate cancer
related causes. In particular, it has been suggested that certain
androgen deprivation therapies could adversely affect
cardiovascular health (see Yannucci et al. (2006) J. Urology
176:520-525: and Etzioni et al. (1999) J. Natl. Canc. Inst.
91:1033).
[0009] Accordingly, new therapeutic regiments for prostate cancer
are needed that are free of both the adverse consequences of the
GnRH agonist testosterone spike, as well as the undesirable side
effects of available GnRH antagonist therapies.
SUMMARY OF THE INVENTION
[0010] Applicants have found that a relatively low dose of
degarelix GnRH antagonist, delivered about once every 28 days
(e.g., monthly), can safely and rapidly suppress testosterone
levels to therapeutic levels in prostate cancer patients, without
causing a testosterone spike and with an appreciably diminished
risk of causing an undesirable side effect associated with androgen
deprivation therapy such as a cardiac disorder, arthralgia, and/or
a urinary tract infection.
[0011] In one aspect, the invention provides a method of treating
prostate cancer in a subject with a reduced likelihood of causing a
testosterone spike or other side effect of a gonadotrophin
releasing hormone (GnRH) agonist therapy. The method includes
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, and thereby treating prostate cancer in the subject
with a reduced likelihood of causing a testosterone spike or other
GnRH agonist side effect.
[0012] In a further aspect, the invention provides a method of
treating prostate cancer in a subject with a reduced likelihood of
causing a testosterone spike or other side effect of a
gonadotrophin releasing hormone (GnRH) agonist therapy. The method
includes 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, and
thereby treating prostate cancer in the subject with a reduced
likelihood of causing a testosterone spike or other GnRH agonist
side effect.
[0013] In certain embodiments of these methods of the invention,
the maintenance dose is administered monthly. In further
embodiments, the treated subject has a decreased likelihood of
developing or experiencing an undesirable side effect during
treatment compared to treatment with the gonadotrophin releasing
hormone (GnRH) agonist leuprolide. In particular embodiments, the
treated subject has a decreased likelihood of developing or
experiencing a cardiovascular side effect such as a myocardial
infarction, chest pain, a cardiac murmur or a vascular side effect
(e.g., deep vein thrombosis (DVT)) during treatment compared to
treatment with the gonadotrophin releasing hormone (GnRH) agonist
leuprolide. In further embodiments, the methods provide the treated
subject with a decreased likelihood of developing a side effect
selected from the group consisting of a cardiac arrhythmia, a
coronary artery disorder, and a cardiac disorder. In particularly
useful embodiments, the treated subject has a body mass index (BMI)
of less than 30 kg/m.sup.2, particularly a BMI of less than 25
kg/m.sup.2. In further useful embodiments the treated subject has a
cholesterol level of greater than or equal to 4 mmol/L (155
mg/dL).
[0014] In further embodiments, the methods of the invention are
used to treat a subject who is at risk for cardiovascular disease.
In particularly useful embodiments, the methods of the invention
further include the step of identifying a prostate cancer subject
who is also at risk for cardiovascular disease for treatment by the
method.
[0015] In still further embodiments, the treated subject has a
decreased likelihood of developing or experiencing an increase in
arthralgia and/or musculoskeletal stiffness during treatment
compared to treatment with the gonadotrophin releasing hormone
(GnRH) agonist leuprolide. In particularly useful embodiments
thereof, the treated subject has locally advanced prostate cancer
and/or is less than 65 years old.
[0016] In further embodiments, the treated subject has a decreased
likelihood of developing a musculoskeletal disorder and/or a
connective tissue disorder during treatment compared to treatment
with the gonadotrophin releasing hormone (GnRH) agonist leuprolide.
In particular embodiments, the musculoskeletal disorder and/or a
connective tissue disorder is arthralgia. In other embodiments, the
musculoskeletal disorder and/or a connective tissue disorder is
musculoskeletal stiffness.
[0017] In still further embodiments of these methods of the
invention, the treated subject has a decreased likelihood of
developing noninfective cystitis during treatment compared to
treatment with the gonadotrophin releasing hormone (GnRH) agonist
leuprolide.
[0018] In another embodiment, the treated subject has a decreased
likelihood of developing a urinary or renal system disorder
compared to treatment with the gonadotrophin releasing hormone
(GnRH) agonist leuprolide. In certain embodiments, the urinary or
renal system disorder is a urinary tract infection. In particularly
useful embodiments thereof, the treated subject has locally
advanced prostate cancer. In another embodiment, the urinary or
renal system disorder is an increase in urinary retention. In still
another embodiment, the urinary or renal system disorder is a
noninfective cystitis.
[0019] In still other embodiments, the treated subject has a
decreased likelihood of developing erectile dysfunction during
treatment compared to treatment with the gonadotrophin releasing
hormone (GnRH) agonist leuprolide. In other embodiments, the
treated subject has a decreased likelihood of decreased libido
during treatment compared to treatment with the gonadotrophin
releasing hormone (GnRH) agonist leuprolide.
[0020] In particular embodiments of the above methods of the
invention, the treated subject has at least about 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. In certain
embodiments, the treated subject has at least about a 95%
likelihood of maintaining a therapeutically low serum testosterone
level of less than or equal to 0.5 ng/mL from day 28 through day
364 of treatment. In still further embodiments, the treated subject
has at least about a 30% decrease in prostate specific antigen
(PSA) by day 14 of treatment. In particular embodiments, the
treated subject has at least about a 50% decrease in prostate
specific antigen (PSA) by day 14 of treatment. In further
embodiments, the treated subject has at least about a 60% decrease
in prostate specific antigen (PSA) by day 28 of treatment. In still
further embodiments, the treated subject has at least about a 75%
decrease in prostate specific antigen (PSA) by day 28 of
treatment.
[0021] In further embodiments of the method of the invention, the
treated subject has at least about an 80% (e.g., a 95%) likelihood
of maintaining a low prostate specific antigen (PSA) level of less
than about 5 ng/mL during treatment.
[0022] In further embodiments of the method of the invention, the
treated subject has locally advanced prostate cancer and has at
least about a 40% decrease in PSA by day 14 of treatment.
[0023] In still further embodiments, the treated subject has
metastatic prostate cancer and has at least about a 60% decrease in
PSA by day 14 of treatment.
[0024] In particular embodiments of the above methods of the
invention, the treated subject has a body mass index of less than
30 kg/m.sup.2 (especially less than 25 kg/m.sup.2).
[0025] In another aspect, the invention provides methods of
treating prostate cancer in a subject at risk for a cardiovascular
disease or disorder by administering a therapeutically effective
dose of degarelix to the subject with prostate cancer who is at
risk for a cardiovascular disease or disorder. In particular
embodiments, the therapeutically effective dose includes an initial
starting dose of 160 to 320 mg of degarelix, and a monthly
maintenance dose of 60 to 160 mg of degarelix. In further
embodiments, the therapeutically effective dose of degarelix
includes a maintenance dose of about 80 mg of degarelix once every
approximately 28 days of treatment. In certain embodiments thereof,
the therapeutically effective dose of degarelix further includes a
single initial dose of about 240 mg of degarelix at the start of
treatment.
[0026] In particular embodiments, the subject treated has been
identified to be at risk of a specific cardiovascular disease or
disorder such as cardiac murmur, atrioventricular blockage, and/or
myocardial ischemic.
[0027] In further embodiments, the treated subject possesses an
indicator of increased risk for cardiovascular disease, e.g. high
blood pressure, high low-density lipoprotein cholesterol, low
high-density lipoprotein cholesterol, high serum glucose and/or a
habitual smoking habit. In particular embodiments, the treated
subject has high blood pressure of greater than or equal to 130
over 85 mm Hg. In further embodiments, the treated subject smokes
cigarettes daily. In still further embodiments, the treated subject
has an elevated level of low-density lipoprotein cholesterol of
greater than or equal to about 160 mg/dl. In further embodiments,
the treated subject has a low level of high-density lipoprotein
cholesterol of less than 35 mg/dl. In other embodiments, the
treated subject has an elevated fasting glucose level of greater
than about 120 mg/dL.
[0028] In still other particularly useful embodiments, the treated
subject possesses an indicator of increased risk for cardiovascular
disease such as high serum C-reactive protein (CRP), high serum
homocysteine, high serum fibrinogen, and/or high serum
lipoprotein(a) (Lp(a)). In particular embodiments, the treated
subject has an elevated level of C-reactive protein of greater than
3 mg/dL. In other embodiments, the treated subject has an elevated
level of serum homocysteine of greater than 30 .mu.mol/L. In
further embodiments, the treated subject has an elevated level of
serum fibrinogen of greater than 7.0 g/L. In still further
embodiments, the treated subject has an elevated level of serum
Lp(a) of greater than 30 mg/dL.
[0029] In certain embodiments, the treated subject has a body mass
index of less than 30 kg/m.sup.2 (particularly less than 25
kg/m.sup.2).
[0030] In further embodiments, the treated subject has a decreased
likelihood, compared to treatment with the gonadotrophin releasing
hormone (GnRH) agonist leuprolide, of developing a cardiovascular
side effect such as cardiac arrhythmia, coronary artery disorder,
and/or a cardiac disorder. In particular embodiments thereof, the
treated subject has a body mass index (BMI) of less than 30
kg/m.sup.2 (especially less than 25 kg/m.sup.2). In other
embodiments, the treated subject has a cholesterol level of greater
than or equal to 4 mmol/L (155 mg/dL).
[0031] In still another aspect, the invention provides a method of
treating prostate cancer in a subject at risk for a cardiovascular
disease or disorder by first identifying a suitable subject with
prostate cancer that is also at risk for a cardiovascular disease
or disorder. The suitable subject with cardiovascular disease risk
is then administered an initial dose of about 240 mg of degarelix,
followed by a maintenance dose of about 80 mg of degarelix once
every approximately 28 days thereafter, thereby treating prostate
cancer in the subject at risk for a cardiovascular disease or
disorder. In certain embodiments, the maintenance dose of degarelix
is administered monthly.
[0032] In a further aspect, the invention provides a method of
treating prostate cancer in a subject at risk for a cardiovascular
disease or disorder by first identifying a suitable subject with
prostate cancer and at risk for a cardiovascular disease or
disorder. The suitable subject with cardiovascular disease risk is
then administered an initial dose of 160-320 mg of degarelix,
followed by a maintenance dose of 60-160 mg of degarelix delivered
once every approximately 28 days thereafter, thereby treating
prostate cancer in the subject at risk for a cardiovascular disease
or disorder with a reduced likelihood of causing a testosterone
spike or other GnRH agonist side-effect. In certain embodiments,
the maintenance dose of degarelix is administered monthly. In
particular embodiments of this aspect, the treated subject has a
body mass index of less than 30 kg/m.sup.2 (particularly a BMI of
less than 25 kg/m.sup.2). In further embodiments, the treated
subject is at risk of a cardiovascular disease or disorder, such as
a cardiac murmur, an atrioventricular blockage, and/or myocardial
ischemia. In still other embodiments, the treated subject possesses
an indicator of increased risk for cardiovascular disease. In
further particular embodiments, the treated subject possesses an
indicator of increased risk for cardiovascular disease, e.g. high
blood pressure, high low-density lipoprotein cholesterol, low
high-density lipoprotein cholesterol, high serum glucose and/or a
habitual smoking habit. In particular embodiments, the treated
subject has high blood pressure of greater than or equal to 130
over 85 mm Hg. In further embodiments, the treated subject smokes
cigarettes daily. In still further embodiments, the treated subject
has an elevated level of low-density lipoprotein cholesterol of
greater than or equal to about 160 mg/dL. In further embodiments,
the treated subject has a low level of high-density lipoprotein
cholesterol of less than 35 mg/dl. In other embodiments, the
treated subject has an elevated fasting glucose level of greater
than about 120 mg/dL.
[0033] In still other embodiments, the treated subject possesses an
indicator of increased risk for cardiovascular disease such as high
serum C-reactive protein (CRP), high serum homocysteine, high serum
fibrinogen, and/or high serum lipoprotein(a) (Lp(a)). In particular
embodiments, the treated subject has an elevated level of
C-reactive protein of greater than 3 mg/dL. In other embodiments,
the treated subject has an elevated level of serum homocysteine of
greater than 30 .mu.mol/L. In further embodiments, the treated
subject has an elevated level of serum fibrinogen of greater than
7.0 g/L. In still further embodiments, the treated subject has an
elevated level of serum Lp(a) of greater than 30 mg/dL. In other
embodiments, the treated subject has a decreased likelihood, when
compared to treatment with the gonadotrophin releasing hormone
(GnRH) agonist leuprolide, of developing a cardiovascular side
effect such as a cardiac arrhythmia, a coronary artery disorder,
and/or a cardiac disorder. In certain embodiments thereof, the
treated subject has a body mass index of less than 30 kg/m.sup.2
(particularly less than 25 kg/m.sup.2).
[0034] In yet another aspect, the invention provides a method of
treating prostate cancer in a preferred subject by identifying a
subject with prostate cancer having a body mass index of less than
about 25 kg/m.sup.2. The preferred subject thus identified is
administered a single initial dose of 160-320 mg of degarelix,
followed by monthly doses of 60-160 mg of degarelix administered
once every 20-36 days thereafter. In certain embodiments, the
treated subject has a decreased likelihood, when compared to
treatment with the gonadotrophin releasing hormone (GnRH) agonist
leuprolide, of developing a cardiovascular side effect such as a
cardiac arrhythmia, a coronary artery disorder, and/or a cardiac
disorder. In particular embodiments, the initial dose of degarelix
is about 240 mg, and the maintenance dose of degarelix is about 80
mg administered monthly. In further particular embodiments, the
preferred subject has a cholesterol level of greater than or equal
to 4 mmol/L (155 mg/dL).
[0035] In further embodiments, the methods of treatment of the
invention may be with, or associated with, a reduced incidence or
likelihood of one or more of cardiovascular and/or vascular side
effects (for example with reduced incidence and/or likelihood of
one or more of myocardial infarction, chest pain, chest pain
development, cardiac murmur, cardiac murmur development, myocardial
ischemia, atrioventricular blockage, deep vein thrombosis (DVT),
cardiac arrhythmia, coronary artery disorder, and/or cardiac
disorder), musculoskeletal disorder (for example arthralgia and/or
musculoskeletal stiffness), connective tissue disorder, urinary
and/or renal system disorder.
BRIEF DESCRIPTION OF THE FIGURES
[0036] FIG. 1 is a depiction of the chemical structure of
degarelix.
[0037] FIG. 2 is a graphical representation of the effect of
degarelix 240 mg/80 mg dosing on plasma testosterone from day 0 to
day 364 of treatment.
[0038] FIG. 3 is a graphical representation comparing the effect of
degarelix 240 mg/80 mg dosing with the effect of Lupron 7.5 mg
dosing on the percentage change in plasma testosterone from day 0
to day 28 of treatment.
[0039] FIG. 4 is a graphical representation comparing the effect of
degarelix 240 mg/160 mg and degarelix 240 mg/80 mg dosing with the
effect of Lupron 7.5 mg dosing on the median levels of luteinizing
hormone (LH) over time from day 0 to day 364 of treatment.
[0040] FIG. 5 is a graphical representation comparing the effect of
degarelix 240 mg/160 mg and degarelix 240 mg/80 mg dosing with the
effect of Lupron 7.5 mg dosing on the median levels of follicle
stimulating hormone (FSH) over time from day 0 to day 364 of
treatment.
[0041] FIG. 6 is a graphical representation comparing the effect of
degarelix 240 mg/80 mg dosing with the effect of Lupron 7.5 mg
dosing on prostate specific antigen (PSA) levels from day 0 to day
56 of treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0042] Particular aspects of the invention are described in greater
detail below. The patent and scientific literature referred to
herein are hereby incorporated by reference.
General
[0043] In general, the invention provides methods of treating
prostate cancer with degarelix GnRH antagonist using a dosing
regimen that results in optimal efficacy, and reduced serious
side-effects, particularly in certain patient subgroups, compared
to other androgen deprivation therapies, particularly GnRH agonist
therapies such as leuprolide.
[0044] The relative efficacy and safety (including adverse side
effects) of the GnRH agonist therapy leuprolide (also leuprorelin
or LUPRON) is known in the art (see e.g., Persad (2002) Int. J.
Clin. Pract. 56:389-96; Wilson et al. (2007) Expert Opin. Invest.
Drugs 16:1851-63; and Berges et al. (2006) Curr. Med. Res. Qpin.
22:649-55). In addition, the relative efficacy and safety of the
GnRH antagonist therapy abarelix (PLENAXIS) has also been reported
(see, e.g., Mongiat-Artus et al. (2004) Expert Opin. Pharmacother.
5:2171-9; and Debruyne et al. (2006) Future Oncol. 2:677-96). A
review of the basic methods for conducting and analyzing the type
of controlled clinical studies described herein, including analyses
of safety, efficacy and selective advantages to certain patient
subpopulations, is available (see Spilker (1991) Guide to Clinical
Trials Raven Press, New York; and Spilker (1996) Quality of Life
and Pharmacoeconomics in Clinical Trials Lippincott-Raven
Publishers New York).
Definitions
[0045] The singular forms "a," "an," and "the" include plural
reference unless the context clearly dictates otherwise.
[0046] As used herein, the term "ADR" refers to an adverse drug
reaction, and the term "AE" refers to an "adverse event."
[0047] The terms "approximately" and "about" mean to be nearly the
same as a referenced number or value. As used herein, the terms
"approximately" and "about" should be generally understood to
encompass .+-.10% a specified amount, frequency or value.
[0048] The term "agonist" as used herein, is meant to refer to an
agent that mimics or up-regulates (e.g., potentiates or
supplements) the bioactivity of a protein. An agonist can be a
wild-type protein or derivative thereof having at least one
bioactivity of the wild-type protein.
[0049] "Antagonist" as used herein is meant to refer to an agent
that down-regulates (e.g., suppresses or inhibits) at least one
bioactivity of a protein.
[0050] As used herein, the term "arthralgia" refers to pain in one
or more joints, which may occur as a symptom of injury, infection,
illnesses--in particular arthritis--or an allergic reaction to
medication. In distinguishing the term "arthralgia" from the term
"arthritis" it should be noted that "arthralgia" specifically
refers to non-inflammatory conditions, and the term "arthritis"
should be used when the condition is an inflammatory condition.
[0051] The term "body mass index" (BMI) refers to a statistical
measure of the weight of a person scaled according to height, which
is an approximating measure of the relative percentages of fat and
muscle mass in the human body. BMI is defined as the individual's
body weight divided by the square of their height, and the formulas
used in medicine produce a unit of measure of kg/m.sup.2.
[0052] The term "CI" refers to a statistical confidence
interval.
[0053] The term "cardiovascular" as used herein refers to
conditions involving the heart and/or blood vessels.
[0054] The term "cardiac arrhythmia" as used herein is any of a
group of conditions in which the electrical activity of the heart
is irregular or is faster or slower than normal.
[0055] As used herein, the terms "coronary artery disorder" or
"coronary artery disease" refers to a condition (such as sclerosis
or thrombosis) that reduces the blood flow through the coronary
arteries to the heart muscle.
[0056] The term "cardiac disorder" as used herein refers to any of
a number of abnormal organic conditions affecting the heart
including coronary heart disease, heart attack, cardiovascular
disease, pulmonary heart disease and high blood pressure.
[0057] The term "deep-vein thrombosis" (also known as deep-venous
thrombosis or DVT) is the formation of a blood clot ("thrombus") in
a deep vein. Deep-vein thrombosis commonly affects the leg veins,
such as the femoral vein or the popliteal vein or the deep veins of
the pelvis. Occasionally the veins of the arm are affected (known
as Paget-Schrotter disease). Thrombophlebitis is the more general
class of pathologies of this kind. There is a significant risk of
the thrombus embolizing and traveling to the lungs causing a
pulmonary embolism.
[0058] The term "ECG" refers to an electrocardiogram.
[0059] The term "MedDRA" refers to the Medical dictionary for
regulatory activities.
[0060] The term "myocardial infarction" refers to an infarction of
the myocardium that results typically from coronary occlusion,
which may be marked by sudden chest pain, shortness of breath,
nausea, and loss of consciousness, and sometimes death. An
"infarction" refers to the process of forming an infarct, which is
an area of necrosis in a tissue or organ resulting from obstruction
of the local circulation by a thrombus or embolus.
[0061] "Male sexual dysfunction" includes impotence, loss of
libido, and erectile dysfunction. "Erectile dysfunction" is a
disorder involving the failure of a male mammal to achieve
erection, ejaculation, or both.
[0062] The term "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 term "prostate cancer" includes early
stage, localized, cancer of the prostate gland; later stage,
locally advanced cancer of the prostate gland; and later stage
metastatic cancer of the prostate gland (in which the cancer cells
spread (metastasize) from the prostate to other parts of the body,
especially the bones and lymph nodes).
[0063] The term "prostate-specific antigen" or "PSA" refers to a
protein produced by the cells of the prostate gland that is present
in small quantities in the serum of normal men, but is often
elevated in the presence of prostate cancer and in other prostate
disorders. A blood test to measure PSA is the most effective test
currently available for the early detection of prostate cancer.
Higher than normal levels of PSA are associated with both localized
and metastatic prostate cancer (CaP).
[0064] The term "PD" refers to pharmacodynamic, and the term "PK"
refers to pharmacokinetic.
[0065] The term "PT" refers to a preferred term.
[0066] The term "SAE" refers to a serious adverse event".
[0067] The term "SD" refers to standard deviation.
[0068] The term "SOC" refers to a system organ class.
[0069] The term "SUSAR" refers to a suspected, unexpected serious
adverse reaction.
[0070] A "subject" or "patient" is a male mammal, more preferably a
human male. Non-human male mammals include, but are not limited to,
farm animals, sport animals, and pets.
[0071] A "urinary tract infection" (UTI) is a bacterial infection
that affects any part of the urinary tract, which is the tract
through which urine passes and includes the renal tubules and renal
pelvis of the kidney, the ureters, the bladder, and the urethra.
The most common type of UTI is a bladder infection which is also
often called cystitis. Another kind of UTI is a kidney infection,
known as pyelonephritis, which is a more serious condition.
Degarelix and Related Pharmaceutical Formulations
[0072] 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.sub.2) incorporating
pureido-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).
[0073] 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. Unlike GnRH agonists, 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.
[0074] Degarelix is available as a powder for injectable
formulation and a solvent for reconstitution of the powder. The
powder for injectable formulation is a lyophilisate containing
degarelix and mannitol, and the solvent consists of water for
injection provided in 6 mL vials.
[0075] 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-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridin-
yl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]-
amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-L
leucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical
formula of C.sub.82H.sub.103N.sub.18O.sub.16Cl and a molecular
weight of 1,632.3 Da.
[0076] The chemical structure is of degarelix is shown in FIG. 1
and may also be represented by the formula:
Ac-D-Nal-D-Cpa-D-Pal-Ser-Aph(Hor)-D-Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH.s-
ub.2
[0077] Degarelix is one member of a family of GnRH antagonists,
described in further detail in U.S. Pat. No. 5,925,730 and EP
1003774 that carry modifications in positions 5 and 6 and have
potent GnRH receptor binding activity as well as the particularly
advantageous property of long duration of bioactivity. Related GnRH
antagonists are known in the art and described, e.g., in U.S. Pat.
Nos. 5,821,230 and 6,214,798.
Administration and Dosing
[0078] 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 one month
after the initial starting dose.
[0079] Degarelix may be formulated for administration
subcutaneously, as opposed to intravenously, generally in the
abdominal region, as described in further detail below. As with
other drugs administered by subcutaneous injection, the injection
site may vary periodically to adapt the treatment to injection site
discomfort. In general, 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.
[0080] Administration of 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.
[0081] Briefly, 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
as described in WO 03/006049 and U.S. Pub. Nos. 2005/0245455 and
2004/0038903, 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.
[0082] 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 of the 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. Accordingly, the dosing regimen
for degarelix may be administered as an initial, starting dose of
240 mg administered as 6 mL of about 40 mg/mL (e.g., 2 injections
of about 3 mL (e.g., 3.2 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.
Alternatively, monthly maintenance doses of 160 mg may be utilized,
e.g. by administering 4 mL of about 40 mg/mL degarelix every
month.
[0083] Thus, degarelix may be provided as a powder for
reconstitution (with a solvent) as a 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). For example, degarelix may be
provided in a vial containing 120 mg degarelix (acetate) for
reconstitution with about 3 mL WFI (e.g., 3.2 mL) such that each mL
of solution contains about 40 mg degarelix. In another example,
degarelix may be provided in a vial containing 80 mg degarelix
(acetate). After reconstitution with about 4 mL WFI each mL
solution contains about 20 mg degarelix.
[0084] The reconstituted formulation should be a clear liquid, free
of undissolved matter. A single dose of 240 mg degarelix, followed
by a monthly maintenance dose of 80 mg, rapidly causes a decrease
in the concentrations of the luteinizing hormone (LH), follicle
stimulating hormone (FSH) and subsequently testosterone. The plasma
concentration of dihydrotestosterone (DHT) decreases in a similar
manner to testosterone.
[0085] 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 and median testosterone
levels after one year of treatment were 0.087 ng/mL.
[0086] The relevant pharmacokinetic parameters for degarelix
evaluated in prostate cancer patients are summarized in Table 1,
below. Median degarelix trough concentrations in the maintenance
phase with 80 mg at a concentration of 20 mg/mL was 10.9 ng/mL.
TABLE-US-00001 TABLE 1 Degarelix pharmacokinetic parameters after
subcutaneous administration of 240 mg at a concentration of 40
mg/mL Pharmacokinetic degarelix parameter 240 mg Cmax (ng/mL) 53.4
Tmax (days) 1.4 T1/2 (days) 43 AUC (day ng/mL) 1240
[0087] Following subcutaneous administration of 240 mg degarelix (6
mL at a concentration of about 40 mg/mL) to prostate cancer
patients, degarelix is eliminated in a biphasic fashion, with a
median terminal half-life of approximately 43 days. The long
half-life after subcutaneous administration is a consequence of a
very slow release of degarelix from the depot formed at the
injection site(s). The pharmacokinetic behavior of the drug is
strongly influenced by its concentration in the injection
formulation.
[0088] The resulting distribution volume in healthy elderly men is
approximately 1 L/kg. Plasma protein binding is estimated to be
approximately 90%.
[0089] 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 system. Therefore, clinically significant
pharmacokinetic interactions with other drugs are unlikely to
occur.
[0090] In healthy men, approximately 20% of a given dose of
degarelix was renally excreted, suggesting that approximately 80%
is excreted via the hepato-biliary system in humans. The clearance
in healthy elderly men is 35-50 mL/hr/kg.
Adverse Events (Side Effects)
[0091] Degarelix has been found to be generally well tolerated in
clinical trials. The most commonly observed adverse reactions
during degarelix therapy were due to the expected physiological
effects of testosterone suppression, mainly hot flushes and
increased weight, and injection site related adverse events, mainly
injection site pain and injection site erythema.
[0092] In the confirmatory active-controlled clinical trial
comparing degarelix subcutaneous (s.c.) with leuprolide
intramuscular (i.m.) for 12 months of treatment of patients with
prostate cancer, the most frequently reported side effects were
adverse events occurring at the injection site including pain
(28%), erythema (17%), swelling (6%), induration (4%) and nodule
(3%). These adverse events were mostly transient, of mild to
moderate intensity and occurred primarily with the starting dose
and led to very few discontinuations (<1%). The majority of
injection site adverse events did not require any treatment. Of the
reported events 20% were ameliorated by the patients receiving
treatment with over the counter (OTC) remedies such as analgesics
or cold packs. In addition, there were a number of other frequent
adverse events including weight increase, fatigue, chills, hot
flush, hypertension, back pain, arthralgia, and urinary tract
infection, as summarized in Table 2 below.
TABLE-US-00002 TABLE 2 Comparison of Most Frequent Adverse Events
for degarelix versus leuprolide Treatment degarelix leuprolide
240/80 mg (s.c.) 7.5 mg (i.m.) N = 207 N = 201 % % Percentage of
subjects with adverse 79 78 events Body as a whole Injection site
adverse events** 35 <1 Weight increase* 9 12 Fatigue 3 6 Chills
5 0 Cardiovascular system Hot flush* 26 21 Hypertension 6 4
Musculoskeletal system Back pain 6 8 Arthralgia 5 9 Urogenital
system Urinary tract infection 5 9 Digestive system Constipation 5
5
[0093] There was no evidence of any clinically significant changes
in liver function. Few elevations of the liver enzymes were seen,
and these changes were generally mild and transient. Safety data
from all clinical trials with degarelix in the treatment of
prostate cancer, including patients receiving other dosing
regimens, were pooled. The following adverse reactions, not already
listed, were reported to be drug-related by the investigator in
.gtoreq.1% of patients: erectile dysfunction, gynaecomastia,
hyperhidrosis, testicular atrophy, and diarrhea.
[0094] Decreased bone density has been reported in the medical
literature in men who have had orchiectomy or who have been treated
with a GnRH agonist. It can be anticipated that long periods of
medical castration in men will have effects on bone density.
[0095] Advantages of the degarelix therapeutic dosing regimen for
the treatment of prostate cancer include a diminished likelihood of
occurrence and/or diminished severity of symptoms of adverse
reactions, adverse events or side effects to other organs or
tissues. An extensive panel of potential adverse events related to
drug therapies has been described.
[0096] An adverse reaction dictionary allows investigators to
identify the same adverse reaction with the same term and to
identify different adverse reactions with different terms. A
standard dictionary may be used, however specialized pharmaceutical
dictionaries have been develop to define adverse reaction terms and
their synonyms (see Gillum (1989) "The Merck regulatory dictionary:
A pragmatically developed drug effects vocabulary" Drug Info. J.
23:217-220). The World Health Organization (WHO) Adverse Reaction
Terminology is also available for delimiting the meanings of
drug-induced side effects (see, e.g., Saltzman (1985) "Adverse
reaction terminology standardization" Drug Info. J. 19:35-41). The
Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART)
system is also known in the art (see, e.g., NcNeil et al. (1982) N.
Engl. J. Med. 306:1259-62; and Teal and Dimmig (1985) "Adverse drug
experience management" Drug Info. J. 19:17-25). These lists are
often divided by body system and certain terms are annotated with
alternative classifications.
[0097] COSTART provides a basis for vocabulary control of adverse
reaction reports that emanate from a variety of sources. COSTART is
organized primarily by anatomy. It has a hierarchical arrangement
of terms, from the broadest (body-system categories) to the
narrowest (specific preferred terms or even special search
categories). The COSTART dictionary is used and maintained by the
Center for Drugs and Biologics at the Food and Drug Administration
(FDA) for marketed medicine surveillance and has been endorsed by
many senior managers in the various reviewing sections. There are
four indexes in COSTART: index A, comprising three lists including
a body-system search categories, and a special search categories
(e.g., neoplasia).
[0098] The WHO terminology system of adverse reactions is
relatively short. A code number is assigned to each of these terms.
This provides the advantage that the same code is retained when the
term is translated into different languages. The WHO system uses a
hierarchy of "preferred terms" to describe adverse reactions. Other
commonly used terms are called "included terms," which are listed
with their preferred terms.
[0099] The FDA and many pharmaceutical companies have gone through
an evolution of systems in how they obtain, collect, process, and
define adverse reactions. The medicine dictionary that has been
used by the FDA ("The Center for Drugs and Biologics Ingredient
Dictionary") is known in the art and its use in adverse event
categorization has been addressed (see, e.g., Forbes et al. (1986)
Drug Info. J. 20:135-45; and Turner et al. (1986) Druq Info. J.
20:147-50).
[0100] Certain advantages and disadvantages of COSTART, SNOMED and
WHO Adverse Reaction Terminology are reviewed by Stephens ("The
Detection of New Adverse Drug Reactions" pp. 18-124, Stockton
Press, New York).
[0101] The MedDRA Medical dictionary for regulatory activities is a
particularly useful source for definitions of adverse events
relating to drug trials. MedDRA utilizes pragmatic, medically valid
terminology with an emphasis on ease of use for data entry,
retrieval, analysis, and display, as well as a suitable balance
between sensitivity and specificity within the regulatory
environment. It was developed by the International Conference on
Harmonisation (ICH) and is owned by the International Federation of
Pharmaceutical Manufacturers and Associations (IFPMA) acting as
trustee for the ICH steering committee, and is readily available
commercially (see, e.g., the MedDRA website at www.meddramsso.com).
The MedDRA Maintenance and Support Services Organization (MSSO)
holds a contract with the international Federation of
Pharmaceutical Manufacturers Associations (IFPMA) to maintain and
support the implementation of the terminology. MedDRA terminology
applies to all phases of drug development, excluding animal
toxicology, and has been utilized in the examples that follow.
[0102] As described in further detail below, a number of other
adverse reactions including cardiovascular anomalies (e.g., cardiac
arrhythmias, coronary artery disorders and cardiac disorders),
arthralgia, and urinary tract infection unexpectedly occur at a
lower frequency than prior art androgen depletion therapies such as
the GnRH antagonist leuprolide.
Cardiovascular Disease
[0103] The invention includes methods for treating individuals with
prostate cancer who are at risk for developing a cardiovascular
disease, as well as methods of treating otherwise normal prostate
cancer patients with a decreased likelihood of developing a
cardiovascular side effect. This aspect of the invention is
particularly significant, in light of recent findings suggesting
the possibility of an increased risk of death from nonprostate
cancer causes, particularly relating to adverse effects on
cardiovascular health, in patients being treated with prior art
androgen deprivation therapies (see Yannucci et al. (2006) J. Urol.
176:520-5).
[0104] The indicia of risk for developing cardiovascular disease
have been investigated extensively and are known in the art (see,
e.g., Wilson et al. (1998) Circulation 97:1837-47; Hackam (2003)
JAMA 290:932-940). These cardiovascular risk factors include: high
blood pressure (particularly greater than or equal to 130 over 85
mm Hg); high levels of low-density lipoprotein cholesterol
(particularly greater than or equal to 160 mg/dL); low levels of
high-density lipoprotein cholesterol (particularly less than 35
mg/dL); high levels of serum glucose (particularly levels of
fasting glucose levels greater than about 120 mg/dL); high serum
levels of C-reactive protein (CRP) (particularly levels greater
than 3 mg/dL); high serum levels of homocysteine (particularly
levels greater than 30 .mu.mol/L); high serum levels of serum
fibrinogen (particularly levels greater than 7.0 g/L); and high
serum levels of lipoprotein(a) (Lp(a)) (particularly levels of
greater than 30 mg/dL). In addition, habitual smoking has been
shown to be associated with an increased risk for cardiovascular
disease.
[0105] Furthermore, the association of overall body weight, body
mass index (BMI) and the presence of indicators of "metabolic
syndrome" with risk for cardiovascular disease have been reported
(see e.g., Behn and Ur (2006) Curr. Opin. Cardiol. 21:353-60; and
Romero-Corral et al. (2006) The Lancet 368:666-78).
[0106] This invention is further ustrated by the following
examples, which should not be construed as limiting.
EXAMPLES
Clinical Study of Degarelix for the Treatment of Prostate
Cancer
[0107] In this example, an open-label, multi-center, randomized,
parallel-group study was conducted to investigate the efficacy and
safety of degarelix one month dosing regimens. Patients in two
degarelix treatment groups received a degarelix starting dose of
240 mg at a concentration of 40 mg/mL followed by either of two
different once-a-month dosing regimens, 160 mg (40 mg/mL) and 80 mg
(20 mg/mL). These degarelix dosing regimens were compared to LUPRON
DEPOT.TM. at 7.5 mg in patients with prostate cancer requiring
androgen ablation therapy.
[0108] 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 .ltoreq.0.5 ng/mL during 12
months of treatment, and compared serum levels of testosterone and
prostate-specific antigen (PSA) using a degarelix dosing regimen
versus leuprolide 7.5 mg during the first 28 days of treatment. 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. Finally, the study evaluated
the pharmacokinetics of the degarelix dosing regimens
investigated.
Study Design
[0109] A total of 620 patients were randomized 1:1:1 to one of
three treatment groups. Of these, 610 patients were administered
Investigational Medicinal Product (IMP). Ten randomized patients
withdrew from the study before dosing.
[0110] Patients in two treatment groups received a degarelix
starting dose of 240 mg at a concentration of 40 mg/mL (240@40) on
Day 0 administered as two equivalent subcutaneous (s.c.) injections
of 120 mg each. Thereafter, patients received 12 additional single
s.c. 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. In the third treatment group, patients received
active treatment with leuprolide 7.5 mg on Day 0 and every 28 days
administered as a single intramuscular (i.m.) injection. For
patients receiving treatment with leuprolide 7.5 mg, bicalutamide
could be given as clinical flare protection at the Investigator's
discretion.
[0111] Patients were stratified according to geographic region
(Central and Eastern Europe, Western Europe and The Americas) and
body weight (<90 kg and .gtoreq.90 kg).
Degarelix 240/160 mg Group
[0112] 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.
Degarelix 240/80 mg Group
[0113] 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.
Leuprolide 7.5 mg Group
[0114] 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 0.
TABLE-US-00003 TABLE 3 Treatment Methodology Treatment Group
Starting Dose Maintenance Doses Degarelix 240@40 (as 2 doses 160@40
(as 12 single 240/160 mg on Day 0) doses, one every 28 days)
Degarelix 240@40 (as 2 doses 80@20 (as 12 single 240/80 mg on Day
0) doses, one every 28 days) Leuprolide 7.5 mg administered at Day
0 and every 28 days via 7.5 mg single intramuscular injection.
Bicalutamide was given at the Investigator's discretion.
[0115] Patients were monitored on an ongoing basis and visited the
clinic at monthly intervals up to one year. Patients were observed
clinically for at least 1 hour after each administration of study
drug. Patients who completed the study and met appropriate criteria
were offered the opportunity to receive long-term treatment and
support in an extension study.
[0116] A total of 807 patients were screened and 620 patients were
randomized 1:1:1 into three treatment groups, degarelix 240/160 mg,
degarelix 240/80 mg and leuprolide 7.5 mg. Of the 620 patients
randomized, 610 patients actually received study medication
including 202, 207 and 201 patients in the degarelix 240/160 mg,
degarelix 240/80 mg and leuprolide 7.6 mg treatment groups,
respectively. A total of 504 patients completed the study.
Diagnosis and Criteria for Study Inclusion
[0117] Males aged 18 years and over with histologically confirmed
(Gleason graded) adenocarcinoma of the prostate (all stages), in
whom androgen ablation treatment was indicated (except for
neoadjuvant hormonal therapy) were eligible to participate. Signed
informed consent was obtained before any study-related activity
occurred. Patients were to have a baseline testosterone level
>1.5 ng/mL and a PSA level of .gtoreq.2 ng/mL at the time of
screening. Patients with rising PSA after having undergone
prostatectomy or radiotherapy with curative intent could be
included in the study. Patients were required to have an ECOG score
of .ltoreq.2 and a life expectancy of at least 12 months. Previous
or present hormonal management of prostate cancer (surgical
castration or other hormonal manipulation, e.g. GnRH agonists, GnRH
antagonists, antiandrogens, or estrogens) resulted in exclusion
from the study. However, in patients having undergone prostatectomy
or radiotherapy with curative intention, neoadjuvant hormonal
treatment was accepted for a maximum duration of 6 months provided
that this treatment had been terminated for at least 6 months prior
to the screening visit. Concurrent treatment with a
5-.alpha.-reductase inhibitor also resulted in exclusion from the
study. Patients who were candidates for a curative therapy (i.e.
radical prostatectomy or radiotherapy) were excluded. Patients with
histories of severe hypersensitivity reactions or clinically
significant disorders (other than prostate cancer) that might
affect the conclusion of the study as judged by the Investigator
were not eligible to enter into the study. Patients with a marked
baseline prolongation of QT/QTcF interval (>450 msec), had used
concomitant medications that may prolong QT/QTcF interval or who
had a history of additional risk factors for Torsade de Pointes
ventricular arrhythmias were excluded. Patients who had elevated
serum ALT or total bilirubin levels above upper level of normal
range at the screening visit or who had known or suspected hepatic,
symptomatic biliary disease were also excluded. Patients were also
excluded if they had a known hypersensitivity to any component of
the investigational products. In addition, patients with any form
of cancer within the last five years, with the exception of
prostate cancer and surgically removed basal or squamous cell
carcinoma of the skin, were excluded from the study. Patients who
had a mental incapacity or language barriers precluding adequate
understanding or co-operation were also ineligible to participate
in the study. No other investigational drug was to be administered
within 28 days preceding the screening visit.
Duration of Treatment
[0118] Patients in the degarelix treatment groups received a
starting dose of 240@40 on Day 0 and 12 maintenance doses of 160@40
(degarelix 240/160 mg group) or 80@20 (degarelix 240/80 mg group)
every 28 days. Administration of investigational medicinal products
took place on Day 0, Day 28 (.+-.2 days) and every 28 day (.+-.7
days) thereafter until the end of study visit; day 364 (.+-.7
days). Patients who completed the study and met appropriate
criteria were offered the opportunity to receive long-term
treatment and support in an extension study.
[0119] 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 starling dose followed by monthly
maintenance doses of either 80 mg (20 mg/mL) or 160 mg (40
mg/mL).
[0120] Patients in the comparator group were treated with
leuprolide 7.5 mg pre-filled, dual-chamber syringe for
intramuscular (i.m.) injection. Patients received leuprolide 7.5 mg
on Day 0 and every 28 days subsequently, administered as a single
i.m. injection. At the investigator's discretion, bicalutamide
could be given as clinical flare protection.
Criteria for Evaluation of Efficacy
[0121] The primary efficacy endpoint was the probability of
testosterone levels remaining .ltoreq.0.5 ng/mL from day 28 through
day 364.
[0122] 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
.ltoreq.0.5 ng/mL at day 3; the percentage change in PSA from
baseline to day 28; the probability of testosterone .ltoreq.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. In addition, two further secondary endpoints were
added: the probability of sufficient testosterone response from day
28 through day 364 (a patient was considered to have insufficient
testosterone response if he had one testosterone value >1.0
ng/mL or two consecutive testosterone values >0.5 ng/mL at day
28 onwards); and the percentage change in PSA from baseline to Day
14.
Criteria for Evaluation of Safety
[0123] The safety variables for this study were assessed on the
following: the frequency and severity of adverse events (AEs); the
presence of clinically significant changes in laboratory parameters
(clinical chemistry, hematology and urinalysis); changes in
electrocardiograms (ECGs) and vital signs; changes detected by
physical examination; and body weight.
[0124] An adverse event (AE) was defined as any untoward medical
occurrence in a patient or clinical investigation subject
administered an investigational medical product (IMP) and which did
not necessarily have a causal relationship with the study
treatment. An AE was therefore any unfavorable or unintended sign
(including an abnormal laboratory finding), symptom or disease
temporally associated with the use of the product, whether or not
related to the IMP.
[0125] This definition also included accidental injuries and
reasons for changes in medication (drug and/or dose), any medical,
nursing or pharmacy consultation, or admission to hospital or
surgical operations. It also included AEs commonly observed and AEs
anticipated based on the pharmacological effect of the IMP. Any
clinically significant injection site reaction of a severity
requiring active management (i.e. change in dose, discontinuation
of study drug, more frequent follow-up or treatment of the
injection site) was also considered to be an AE and was to be
reported on the AE log. This definition was the minimum requirement
for reporting of an AE related to injection site reactions. There
may have been situations where there was no active follow-up but
the reaction was still considered to be an AE.
[0126] An adverse drug reaction (ADR) was defined as an AE
evaluated by the investigator as being probably or possibly related
to treatment with the IMP.
[0127] An unexpected AE was defined as an AE not identified in
nature, severity, or frequency in the section "undesirable effects"
in the sponsor's current investigator's summary or in the
leuprolide 7.5 mg package insert.
[0128] AEs could be volunteered spontaneously by the patient, or in
response to general questioning about their well-being by the
investigator, or as a result of changes in systemic and local
tolerability, laboratory parameters or physical examinations. All
AEs were recorded. The nature of each event, time and date of
onset, duration, intensity, seriousness criteria, an assessment of
its cause and relationship to the study medication, the need for
specific therapy and its outcome were described. The action taken
because of an AE was classified according to medicinal product (no
change, discontinued, other change [specified]). All medications
used to treat the AE were recorded in the concomitant medication
log.
[0129] All patients experiencing AEs, whether considered associated
with the use of the study medication or not, were to be followed
until the AE resolved, stabilized or the patient's participation in
the study ended (i.e. until end of study visit was completed for
that patient).
[0130] Any AE assessed by the investigator as serious, severe
and/or possibly or probably related to the investigational product
was to be followed until it had resolved or until the medical
condition of the patient was stable and all relevant follow-up
information had been reported to Ferring Pharmaceuticals A/S. In
addition, any AE related to liver function test (LFT) was to be
followed by the investigator. The outcome of an AE was classified
as recovered, recovered with sequelae, not yet recovered or
death.
[0131] All AEs, however minor, were documented whether or not the
investigator considered the event to be related to IMP. If an AE
worsened in intensity and the patient did not recover between
observations, a single AE with the highest intensity was recorded.
The AE reporting period was from the time the patient signed the
informed consent until the end of study visit. AEs requiring
therapy were treated with recognized standards of medical care to
protect the health and well being of the patient. Appropriate
resuscitation equipment and medicines were available to ensure the
best possible treatment of an emergency situation.
[0132] AEs were graded according to the National Cancer Institute
(NCI) Common Terminology Criteria for Adverse Events (CTCAE). In
accordance with the CTCAE criteria, AEs were rated on a five-point
scale corresponding to mild, moderate, severe, life-threatening or
disabling and death. For those AEs not described in the CTCAE, a
separate five-point rating scale was used for rating of the
intensity of AEs as follows below:
[0133] Grade 1 AEs: Mild--Minor; no specific medical intervention;
asymptomatic laboratory findings only, radiographic findings only;
marginal clinical relevance.
[0134] Grade 2 AEs: Moderate--minimal intervention to local
intervention, or non-invasive intervention.
[0135] Grade 3: Severe--significant symptoms, requiring
hospitalization or invasive intervention; transfusion; elective
interventional radiological procedure; therapeutic endoscopy or
operation.
[0136] Grade 4: Life-threatening or disabling--complicated by
acute, life-threatening metabolic or cardiovascular complications
such as circulatory failure, haemorrhage, sepsis; life-threatening
physiologic consequences; need for intensive care or emergent
invasive procedure; emergent interventional radiological procedure,
therapeutic endoscopy or operation.
[0137] Grade 5: Death.
[0138] Furthermore, a four-point scale was used for rating the
causal relationship of the AE to the investigational product as
follows.
[0139] Probable--clear-cut temporal association with improvement on
cessation of test drug or reduction in dose; reappears upon
re-challenge; follows a known pattern of response to test drug.
[0140] Possible--follows a reasonable temporal sequence from
administration; may have been produced by the patient's clinical
state or by environmental factors or other therapies
administered.
[0141] Unlikely--does not follow a reasonable temporal sequence
from administration. May have been produced by the subject's
clinical state or by environmental factors or other therapies
administered.
[0142] Unrelated--clearly and incontrovertibly due to extraneous
causes, and does not meet criteria listed under unlikely, possible
or probable.
[0143] Serious adverse events (SAES) were defined as any untoward
medical occurrence that at any dose resulted in death, was
life-threatening, required in-patient hospitalization or
prolongation of existing hospitalization, resulted in persistent or
significant disability/incapacity, was an important medical event
or resulted in a congenital anomaly/birth defect.
[0144] The death of a patient enrolled in this study was not
considered an event per se, but rather an outcome. Any event
resulting in a fatal outcome was fully documented and reported,
including death, which occurred within the four weeks after
treatment end, and regardless of the causality relationship to the
IMP.
[0145] The term `life-threatening` in the definition of SAEs
referred to an event in which the patient was at immediate risk of
death at the time of the event. It did not refer to an event, which
might have caused death, if it had been more severe.
[0146] Laboratory parameters (Table 4) were recorded at screening
and during the study. Details of methodology and equipment used,
and the normal ranges for the various parameters are known in the
art.
TABLE-US-00004 TABLE 4 Laboratory Parameters Haematology Clinical
chemistry Urinalysis Haematocrit Albumin Haemoglobin Haemoglobin
Alkaline phosphatase Glucose Mean cell haemoglobin concentration
Alanine aminotransferase (ALT) Ketones (MCHC) Aspartate
aminotransferase (AST) White blood cells Mean cell volume (MCV)
Bicarbonate Leucocytes Platelet count Calcium pH Reticulocytes
Cholesterol Protein Red blood cell count (RBC) Creatinine Casts,
granular White blood cell count (WBC) with
Gamma-glutamyltransferase Casts, hyaline differential count
(basophils, eosinophils, (Gamma-GT) Casts, red blood cells
lymphocytes, monocytes, neutrophils Potassium Casts, waxy Sodium
White blood cell casts Total bilirubin Bacteria Urea/Blood urea
nitrogen (BUN) Cholesterol Uric Acid Cystine crystals Leucine
crystals Tyrosine crystals
[0147] In addition, blood samples taken pre-dose at day 0, day 168
and at the end of study visit were assessed for the presence of
anti-degarelix antibodies.
[0148] Clinically significant laboratory abnormalities suggesting a
disease or organ toxicity and of a severity requiring active
management (i.e. change of dose, discontinuation of drug, more
frequent follow-up or a diagnostic investigation) were to be
reported as AEs.
[0149] Blood pressures and pulse were measured at Screening, before
dosing at each dosing visit, and at the end of study visit.
Diastolic and systolic blood pressure and pulse were measured after
resting for five minutes in a sitting position. Patients were
observed clinically for at least 1 hour after each administration
of investigational medical product (IMP) to observe for any
immediate onset hypersensitivity reaction. During the observation
period, diastolic and systolic blood pressure and pulse were
measured at 5, 10, 30 and 60 minutes after dosing.
[0150] A 12-lead electrocardiogram (ECG) was performed by site
personnel at screening, day 0, day 3, every 12 weeks (84 days)
after day 0 and at the end of study visit. ECGs were performed
before dosing, if a dosing visit was scheduled. The ECGs were
acquired digitally and the measurements were performed as known in
the art. The ECG measurements included heart beat, PR, QRS
intervals, QT and QTc, T and U wave.
[0151] Each patient also underwent a physical examination at
screening, day 0, every 12 weeks thereafter and at the end of study
visit. Any clinically significant abnormal findings observed at
screening were recorded. Any clinically significant abnormal
findings observed thereafter were recorded as AEs.
[0152] 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/m2. Body mass index may be
accurately calculated using any of the formulas below.
Statistical Methods
[0153] All statistical analyses were performed, and summary
statistics calculated, using statistical analysis software SAS.TM.
version 9 or higher. The populations for analysis were:
[0154] The intention-to-treat (ITT) analysis set included all
randomized patients who received at least one dose of
investigational medicinal product (IMP).
[0155] The per protocol (PP analysis set) comprised all the ITT
analysis set without any major protocol violations
[0156] The safety population was identical to the ITT analysis set,
and therefore all safety analyses were performed on the ITT
analysis set.
[0157] 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. For each of the three treatment groups, testosterone
response rates with 95% confidence interval (CI) 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% CI calculated by normal approximation using pooled
standard error.
[0158] To assess the efficacy of degarelix, two hypotheses were
tested:
[0159] (1) The FDA criterion was to determine whether the lower
bound of the 95% confidence interval (CI) for the cumulative
probability of testosterone .ltoreq.0.5 ng/mL from Day 28 to Day
364 was no lower than 90%.
[0160] (2) The EMEA criterion was to determine whether degarelix
was non-inferior to leuprolide 7.5 mg with respect to the
cumulative probability of testosterone .ltoreq.0.5 ng/mL from Day
28 to Day 364. The non-inferiority limit for the difference between
treatments (degarelix versus leuprolide 7.5 mg) was -10 percentage
points.
[0161] All secondary efficacy endpoints were analyzed for both the
ITT and PP analysis sets, unless otherwise stated. The proportion
of patients with testosterone surge during the first 2 weeks of
treatment was analyzed using Fisher's exact test. Fisher's exact
test was also used to analyze the proportion of patients with
testosterone level .ltoreq.0.5 ng/mL at day 3. The percentage
change in PSA from baseline to day 28 endpoint was analyzed by a
Wilcoxon test. For both Fisher's exact test and the Wilcoxon test,
separate data presentations were made by treatment group,
geographic region, weight strata (<90 kg, .gtoreq.90 kg) and for
the leuprolide 7.5 mg subgroup.
[0162] The secondary endpoints; probability of testosterone
.ltoreq.0.5 ng/mL from Day 56 through Day 364, time to PSA failure
and probability of sufficient testosterone response from Day 28
through Day 364 were analyzed by the Kaplan-Meier method.
Efficacy Results
[0163] 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 testosterone suppression .ltoreq.0.5 ng/mL
during 12 months of treatment.
[0164] The results show that degarelix delivered at the 240/80 mg
dosing regimen produced a rapid and effective suppression in
testosterone levels, which remained low throughout the 364 day
period of treatment (FIG. 2).
[0165] Kaplan-Meier estimates of the probabilities of testosterone
.ltoreq.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. For all three treatment
groups the lower bound of the 95% CI 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 .ltoreq.0.5 ng/mL from day 28 to day
364. For both degarelix treatment groups, the entire 97.5% CI for
the difference in probability compared with the leuprolide 7.5 mg
group was greater than the non-inferiority limit of -10 percentage
points. Thus the study fulfilled the FDA and EMEA criteria for
efficacy.
[0166] The robustness of the results for the primary efficacy
endpoint was supported by an observed cases analysis, which
produced similar estimates of the overall proportion of patients
with testosterone .ltoreq.0.5 ng/mL from day 28 to day 364 for the
degarelix 240/160 mg, degarelix 240/80 mg and leuprolide 7.5 mg
groups of 98.2%, 97.0% and 96.0%, respectively. The findings of the
primary analysis were further supported by a secondary efficacy
analysis of the probability of testosterone .ltoreq.0.5 ng/mL from
day 56 to day 364.
[0167] As expected, a significantly higher proportion of patients
in the leuprolide 7.5 mg group (80.1%) had a testosterone surge
(increase .gtoreq.15% from baseline) during the first two weeks of
treatment compared with the pooled degarelix groups (0.2%: one
patient) (p<0.0001, Fisher's exact test). The patient treated
with degarelix can be considered to be an artifact as this patient
had low testosterone at baseline (0.0065 ng/mL) thus a surge from
such a low baseline value was not remarkable. Conversely, 96% of
patients receiving degarelix exhibited testosterone suppression on
day 3 compared with no patients in the leuprolide 7.5 mg group
(p<0.0001, Fisher's exact test). As shown in FIG. 3, the
degarelix 240/80 mg dosing regimen rapidly and efficiently
suppressed testosterone levels, while Lupron 7.5 mg acted much more
gradually and only after an initial testosterone surge.
[0168] The profiles for serum levels of LH over time were similar
to those observed for testosterone. Following administration of
degarelix, median LH levels for the ITT analysis set decreased
rapidly and were <0.7 IU/L on day 1, a decrease of approximately
88% from baseline. For both degarelix treatment groups median LH
levels remained suppressed until the end of the study on day 364.
In contrast, a surge in median LH levels was observed for patients
in the leuprolide 7.5 mg group, which peaked at 31.0 IU/L on day 1
(>400% increase from baseline) before decreasing exponentially
to 0.035 IU/L by day 56 and remaining at this level until day 364
(see FIG. 4).
[0169] A rapid decrease in FSH levels was also observed in patients
treated with degarelix. Administration of degarelix resulted in a
reduction in median FSH levels to .ltoreq.1.5 IU/L by day 7, a
>80% decrease from baseline. For both degarelix treatment groups
median FSH levels remained suppressed until the end of the study on
day 364. For patients in the leuprolide 7.5 mg group there was an
initial surge in FSH levels similar to that observed for LH levels
which peaked at 22.5 IU/L on day 1 (146% increase from baseline)
before decreasing exponentially to 2.0 IU/L by day 14. Median FSH
subsequently increased around day 56 to a plateau of approximately
4.40 IU/L and stayed there until day 364 (see FIG. 5).
[0170] As shown in FIG. 6, the degarelix 240/80 mg dosing regimen
also produced a more rapid and efficient reduction in PSA levels
than did treatment with Lupron 7.5 mg. A rapid reduction in PSA
levels was observed for patients treated with degarelix. In
contrast, PSA levels in the leuprolide 7.5 mg group reached a
plateau during the first week of treatment before decreasing
exponentially to suppressed levels. There was a significantly
greater reduction in median PSA levels from baseline that was
observed on day 14 and day 28 for degarelix patients compared with
leuprolide 7.5 mg patients (p<0.0001, Wilcoxon test). 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
(.about.85.8%) for both the degarelix 240/160 mg and leuprolide 7.5
mg groups, although this difference was not statistically
significant.
[0171] Anti-androgen therapy, as per protocol, was given to 22
patients in the leuprolide 7.5 mg group at the start of treatment
for flare protection. PSA data for these patients showed a greater
median percentage change from baseline at day 14 (61.7% reduction)
and day 28 (89.1%) compared to those patients in the leuprolide 7.5
mg group who did not receive anti-androgen therapy where the
percentage reduction was 15.3% and 61.7% at days 14 and 28,
respectively. It should be noted that the median percentage change
in PSA levels in the leuprolide plus antiandrogen patients was
similar to those patients treated with degarelix, thereby
confirming that degarelix is more effective than conventional GnRH
agonist therapy at suppressing PSA at the start of treatment.
Degarelix does not require additional concomitant medication as
prophylaxis for flare, yet a starting dose of 240 mg has a similar
effect on PSA levels as the combination of GnRH agonist plus
anti-androgen.
[0172] The pharmacodynamic profile for degarelix was characteristic
of a GnRH antagonist with serum levels of testosterone, LH and FSH
suppressed rapidly. In contrast, for patients in the leuprolide 7.5
mg group, serum levels of testosterone, LH and FSH increased
rapidly within the first week of treatment before falling to
suppress levels.
Safety Results
[0173] 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.
[0174] 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. All safety tables
include four columns: the three treatment groups described
separately, and the pooled degarelix group.
Brief Summary of Adverse Events
[0175] Adverse events were regarded as `treatment-emergent` if they
occurred in the time interval from initial dosing to end-of-study.
Adverse events were considered `pre-treatment` if they occurred
between screening and the initial injections of IMP. As described
above, all AEs were classified according to MedDRA (version 10.0)
system organ class (SOC), sorted alphabetically, and by preferred
term (PT), in decreasing frequency of occurrence.
Treatment-emergent AEs were expressed in terms of intensity (using
NCI CTCAE) and relationship to study drug. An overall summary of
treatment-emergent AEs is presented in Table 5.
TABLE-US-00005 TABLE 5 Overall Summary of Treatment-Emergent
Adverse Events Treatment Group Degarelix Leuprolide Adverse events
240/160 mg 240/80 mg Total 7.5 mg category N (%) E N (%) E N (%) E
N (%) E ITT analysis set 202 (100%) 207 (100%) 409 (100%) 201
(100%) All AEs 167 (83%) 941 163 (79%) 937 330 (81%) 1878 156 (78%)
777 Deaths (Grade 5) 5 (2%) 6 5 (2%) 5 10 (2%) 11 9 (4%) 10 Serious
AEs 24 (12%) 41 21 (10%) 26 45 (11%) 67 28 (14%) 54 AEs leading to
19 (9%) 19 15 (7%) 15 34 (8%) 34 12 (6%) 12 discontinuation ADRs
120 (59%) 463 118 (57%) 459 238 (58%) 922 84 (42%) 146 N = number
of patients with adverse events % = percentage of patients with
adverse events E = number of adverse events ADR = AE assessed by
investigator as possibly/probably related to investigational
product Common Toxicity Criteria for Adverse Events used for
intensity grading
[0176] The overall percentages of patients experiencing
treatment-emergent AEs were comparable across all three treatment
groups. 167 (83%) patients in the degarelix 240/160 mg group
reported treatment-emergent AEs, compared with 163 (79%) patients
in the degarelix 240/80 mg group, and 156 (78%) patients in the
leuprolide 7.5 mg group. In total, there were reports of ADRs in
238 (58%) pooled degarelix patients, with 120 (59%) patients in the
degarelix 240/160 mg group, 118 (57%) patients in the degarelix
240/80 mg group. For the leuprolide 7.5 mg group, 42% patients
reported ADRs. This difference was expected and could be accounted
for entirely by injection-related AEs, which exhibited higher rates
in the degarelix pooled arms. Excluding injection-site ADRs, the
incidences of the remaining ADRs were similar in the three
treatment groups:
[0177] 88 (44%) patients reported ADRs, excluding injections site
reactions, in the degarelix 240/160 mg group
[0178] 90 (43%) patients reported ADRs, excluding injections site
reactions, in the degarelix 240/80 mg group
[0179] 84 (42%) patients reported ADRs, excluding injections site
reactions, in the leuprolide 7.5 mg group.
[0180] Such results suggest that both the degarelix maintenance
doses (80@20 mg/mL or 160@40 mg/mL) resulted in a similar incidence
of ADRs.
[0181] A total of 45 (11%) pooled degarelix patients reported 67
serious AEs, including ten deaths. Overall, 24 (12%) patients in
the degarelix 240/160 mg group reported serious AEs, compared with
21 (10%) patients in the degarelix 240/80 mg group, and 28 (14%)
patients, including 9 deaths, in the leuprolide 7.5 mg group. All
deaths were assessed to be unrelated or unlikely to be related to
study treatment, Such results should also be interpreted in the
knowledge that this is an elderly patient population (mean age 72
years) with both prostate cancer and other underlying health
issues.
[0182] Thirty-four (8%) pooled degarelix patients were reported as
being withdrawn due to AEs (including both fatal and non-fatal
AEs); 19 (9%) patients in the degarelix 240/160 mg group and 15
(7%) patients in the degarelix 240/80 mg group, and there were 12
(6%) patients withdrawn in the leuprolide 7.5 mg group. Of the
pooled degarelix patients, there were reports for 17 patients of
SAEs that led to withdrawal.
[0183] Detailed Analysis of Adverse Events
[0184] While the overall occurrence of adverse events was similar
in the two degarelix treatment groups and the leuprolide control
group, a large majority of such events for the degarelix treatment
groups were mere injection site reactions related to the
subcutaneous/depot delivery system employed for degarelix. In
comparison, leuprolide intramuscular injection was not associated
with such a high rate of injection site reactions even though the
overall rate of adverse occurrence was similar. Accordingly, a
detailed analysis of the precise type of adverse events occurring
in each study group was undertaken to characterize the types of
adverse events, other than injection site reactions, that must be
occurring in the leuprolide treatment group to account for the
overall similar adverse event occurrence rates.
[0185] Table 6 shows a summary of the number of patients reporting
treatment-emergent AEs, presented by SOC. All treatment-emergent
AEs are presented by system organ class and Med-DRA preferred
term.
TABLE-US-00006 TABLE 6 Treatment-Emergent Adverse Events by System
Organ Class Treatment Group Degarelix Leuprolide 240/160 mg 240/80
mg Total 7.5 mg MedDRA System Organ Class N (%) N (%) N (%) N (%)
ITT analysis set 202 (100%) 207 (100%) 409 (100%) 201 (100%)
Treatment-emergent adverse events 167 (83%) 163 (79%) 330 (81%) 156
(78%) BLOOD & LYMPHATIC SYSTEM 11 (5%) 5 (2%) 16 (4%) 12 (6%)
DISORDERS CARDIAC DISORDERS 19 (9%) 17 (8%) 36 (9%) 27 (13%)
CONGENITAL, FAMILIAL & GENETIC 1 (<1%) DISORDERS EAR &
LABYRINTH DISORDERS 3 (1%) 6 (3%) 9 (2%) 3 (1%) ENDOCRINE DISORDERS
2 (<1%) 2 (<1%) 3 (1%) EYE DISORDERS 4 (2%) 6 (3%) 10 (2%) 5
(2%) GASTROINTESTINAL DISORDERS 33 (16%) 38 (18%) 71 (17%) 39 (19%)
GENERAL DISORDERS & 102 (50%) 92 (44%) 194 (47%) 36 (18%)
ADMINISTRATION SITE CONDITIONS HEPATOBILIARY DISORDERS 2 (<1%) 2
(<1%) 4 (<1%) 3 (1%) IMMUNE SYSTEM DISORDERS 1 (<1%) 1
(<1%) 2 (<1%) INFECTIONS & INFESTATIONS 38 (19%) 45 (22%)
83 (20%) 49 (24%) INJURY, POISONING & PROCEDURAL 11 (5%) 10
(5%) 21 (5%) 17 (8%) COMPLICATIONS INVESTIGATIONS 58 (29%) 54 (26%)
112 (27%) 62 (31%) METABOLISM & NUTRITION 26 (13%) 14 (7%) 40
(10%) 15 (7%) DISORDERS MUSCULOSKELETAL & CONNECTIVE 37 (18%)
31 (15%) 68 (17%) 53 (26%) TISSUE DISORDERS NEOPLASMS BENIGN,
MALIGNANT 12 (6%) 10 (5%) 22 (5%) 16 (8%) & UNSPECIFIED (INCL
CYSTS AND POLYPS) NERVOUS SYSTEM DISORDERS 27 (13%) 24 (12%) 51
(12%) 23 (11%) PSYCHIATRIC DISORDERS 16 (8%) 16 (8%) 32 (8%) 21
(10%) RENAL & URINARY DISORDERS 26 (13%) 28 (14%) 54 (13%) 39
(19%) REPRODUCTIVE SYSTEM & BREAST 13 (6%) 9 (4%) 22 (5%) 21
(10%) DISORDERS RESPIRATORY, THORACIC & 17 (8%) 25 (12%) 42
(10%) 18 (9%) MEDIASTINAL DISORDERS SKIN & SUBCUTANEOUS TISSUE
21 (10%) 18 (9%) 39 (10%) 10 (5%) DISORDERS SURGICAL & MEDICAL
PROCEDURES 2 (<1%) 2 (<1%) VASCULAR DISORDERS 65 (32%) 71
(34%) 136 (33%) 60 (30%) N = number of patients with adverse events
% = percentage of patients with adverse events
[0186] Treatment-emergent AEs were reported for a comparable
percentage of patients across all three treatment groups: 83%, 79%
and 78% of patients in the degarelix 240/160 mg, degarelix 240/80
mg and leuprolide 7.5 mg groups, respectively. As shown in Table B
above, there were no marked differences between the SOCs affected
for the two degarelix treatment groups. The predominant
system-organ class affected for degarelix patients in both
treatment groups was `General Disorders and Administration Site
Conditions`, reported for 47% pooled degarelix patients, and 18%
leuprolide 7.5 mg patients. The majority of these AEs were
injection site pain, which occurred in 29% of pooled degarelix
patients. In addition, `vascular disorders` were reported for 33%
degarelix patients, and 30% leuprolide 7.5 mg patients, primarily
hot flushes. Other SOCs affected in .gtoreq.15% patients were:
`investigations` in 27% degarelix patients and 31% leuprolide 7.5
mg patients, `infections and infestations` in 20% and 24% patients,
respectively, `musculoskeletal and connective tissue disorders` in
17% and 26% patients, respectively, and `gastrointestinal
disorders` in 17% and 19% patients, respectively, The most frequent
musculoskeletal and connective tissue disorders were back pain,
reported by 6% of degarelix patients and 8% of leuprolide 7.5 mg
patients, and arthralgia reported for 4% of degarelix patients and
9% of leuprolide 7.5 mg patients.
[0187] In examining the SOCs of AEs associated with degarelix
treatment as compared to leuprolide, several areas of increased
risk for leuprolide as compared to degarelix emerged. For example,
`musculoskeletal and connective tissue disorders` occurred in 26%
of leuprolide patients, as compared to only 17% of degarelix
patients overall (and even lower, 15% in the degarelix 240/80 mg
treatment group). Furthermore, `renal and urinary disorders`
occurred in 19% of leuprolide patients, but only 13% of degarelix
patients, while `reproductive system and breast disorders` occurred
in 10% of leuprolide patients, but only 5% of degarelix patients.
Furthermore, `cardiac disorders` occurred at a slightly increased
overall frequency for leuprolide treatment (13%) than for degarelix
(9% overall between the two treatment groups). This may be of
particular interest, since, as addressed above, there is some
concern in the art that certain androgen deprivation therapies
adversely affect cardiovascular health (see Yannucci et al. (2006)
J. Urology 176:520-525; and Etzioni et al. (1999) J. Natl. Canc.
Inst. 91:1033). Accordingly, androgen deprivation therapies that
minimize the risk of cardiovascular side effects are particularly
desirable.
[0188] The increased risk for cardiac disorders, musculoskeletal
and connective tissue disorders, renal and urinary disorders, and
reproductive system disorders for leuprolide as compared to
degarelix likely account for the overall similarity in adverse
events between leuprolide and degarelix, despite the fact that most
of the adverse events seen with degarelix were mere injection site
reactions related to the mode of subcutaneous delivery and not to
adverse systemic effects on other organ systems.
[0189] As shown in Table 7, the most frequently reported
treatment-emergent AEs for patients treated with degarelix were
injections site reactions (particularly injection site pain and
erythema). The most frequently reported AE for both degarelix and
leuprolide patients during the study were flushing events: overall,
52 (26%) patients in the degarelix 240/160 mg group reported hot
flushes, compared to 53 (26%) patients in the degarelix 240/80 mg
group, and 43 (21%) patients in the leuprolide 7.5 mg group.
TABLE-US-00007 TABLE 7 Adverse Events by System Organ Class and
Preferred Term Occurring in .gtoreq.5% of any Treatment Group
Treatment Group Degarelix Leuprolide MedDRA System Organ Class/
240/160 mg 240/80 mg Total 7.5 mg Preferred Term N (%) N (%) N (%)
N (%) ITT analysis set 202 (100%) 207 (100%) 409 (100%) 201 (100%)
Treatment-emergent adverse events 167 (83%) 163 (79%) 330 (81%) 156
(78%) GASTROINTESTINAL DISORDERS 33 (16%) 38 (18%) 71 (17%) 39
(19%) Nausea 11 (5%) 9 (4%) 20 (5%) 8 (4%) Constipation 6 (3%) 11
(5%) 17 (4%) 10 (5%) GENERAL DISORDERS AND 102 (50%) 92 (44%) 194
(47%) 36 (18%) ADMINISTRATION SITE CONDITIONS Injection site pain
61 (30%) 58 (28%) 119 (29%) 1 (<1%) Injection site erythema 48
(24%) 36 (17%) 84 (21%) Injection site swelling 14 (7%) 13 (6%) 27
(7%) Fatigue 13 (6%) 7 (3%) 20 (5%) 13 (6%) Injection site
induration 11 (5%) 8 (4%) 19 (5%) Injection site nodule 13 (6%) 6
(3%) 19 (5%) Chills 7 (3%) 11 (5%) 18 (4%) INFECTIONS AND
INFESTATIONS 38 (19%) 45 (22%) 83 (20%) 49 (24%) Urinary tract
infection 3 (1%) 10 (5%) 13 (3%) 18 (9%) INVESTIGATIONS 58 (29%) 54
(26%) 112 (27%) 62 (31%) Weight increased 22 (11%) 18 (9%) 40 (10%)
24 (12%) Alanine aminotransferase increased 17 (8%) 20 (10%) 37
(9%) 11 (5%) Aspartate aminotransferase increased 10 (5%) 11 (5%)
21 (5%) 6 (3%) METABOLISM AND NUTRITION 26 (13%) 14 (7%) 40 (10%)
15 (7%) DISORDERS Hypercholesterolaemia 12 (6%) 7 (3%) 19 (5%) 5
(2%) MUSCULOSKELETAL AND CONNECTIVE 37 (18%) 31 (15%) 68 (17%) 53
(26%) TISSUE DISORDERS Back pain 12 (6%) 12 (6%) 24 (6%) 17 (8%)
Arthralgia 6 (3%) 11 (5%) 17 (4%) 18 (9%) VASCULAR DISORDERS 65
(32%) 71 (34%) 136 (33%) 60 (30%) Hot flush 52 (26%) 53 (26%) 105
(26%) 43 (21%) Hypertension 14 (7%) 12 (6%) 26 (6%) 8 (4%) N =
number of patients with adverse events % = percentage of patients
with adverse events
[0190] Long-term treatment with degarelix and leuprolide 7.5 mg was
anticipated to result in adverse reactions associated with
testosterone suppression such as hot flushes, loss of libido,
impotence and infertility, and increased sweating. It was therefore
to be expected that flushing events would be relatively common and
largely considered possibly or probably related to treatment.
However, very few AEs related to sexual dysfunction or sweating
were reported. In total, there were reports for 22 (5%) pooled
degarelix patients and 21 (10%) leuprolide patients with
reproductive system/breast disorders and approximately 1% patients
treated with degarelix with sweating disorders (skin and
subcutaneous tissues SOC): six (1%) of patients reported erectile
dysfunction, six (1%) of patients reported night sweats, four
(<1%) of patients experienced testicular pain, three (<1%) of
patients reported pelvic pain, three (<1%) of patients reported
hyperhidrosis, two (2%) of patients each experienced gynaecomastia,
prostatitis or testicular atrophy, and all other reproductive
system/breast disorders were reported by one (<1%) of patients,
and no other sweating disorders were reported.
[0191] An analysis of these SOC/preferred term data further support
the finding discussed above for diminished musculoskeletal
disorders, and renal and urinary disorders for degarelix as
compared to leuprolide treatments. For example, 9% of leuprolide
patients experienced urinary tract infections during the course of
treatment as compared to only 3% of all degarelix-treated patients.
Similarly, 9% of leuprolide patients experienced arthralgia (joint
pain) during the course of treatment while only 4% of all
degarelix-treated patients experienced arthralgia.
[0192] To summarize, the incidence of treatment-emergent AEs was
similar for patients treated with degarelix and leuprolide 7.5 mg.
Treatment-emergent AEs were reported by 330 (81%) patients in the
pooled degarelix treatment groups and by 156 (78%) patients in the
leuprolide 7.5 mg group. The majority of AEs were of mild or
moderate intensity.
[0193] There were 58% of patients treated with degarelix with
reported AEs considered to be possibly/probably related to IMP by
the Investigator (ADR) and those treated with leuprolide 7.5 mg had
42% ADRs., however the majority of treatment-emergent ADRs were
general disorders and administration site conditions including
injection-site reactions which occurred in 173 (42%) patients in
the pooled degarelix group. For patients treated with degarelix,
the overall incidence of treatment-emergent injection site
reactions was 4.4 per 100 injections. Most injection site reactions
occurred after the first dose of degarelix where two injections
were administered and injection site reactions were decreased over
time. Among MedDRA preferred terms, the highest incidences were
injection site pain (2.9 per 100 injections) and injection site
erythema (1.9 per 100 injections) for the pooled degarelix group.
All other preferred terms had an incidence rate of 0.5 per 100
injections or less. None of the injection-related ADRs were
considered to be serious, and there were no immediate onset
hypersensitivity reactions. Five (1.2%) patients reported
degarelix-related injection site reactions, which led to
withdrawal. Other commonly reported ADRs were hot flushes which
were an expected adverse reaction associated with testosterone
suppression. In total, hot flushes were reported by 104 (25%)
patients treated with degarelix and 42 (21%) treated with
leuprolide 7.5 mg. One patient treated with degarelix reported a
hot flush ADR, which led to withdrawal. Notably, although AEs
related to sexual dysfunction would be anticipated to result from
testosterone suppression, very few were actually reported.
[0194] There were 121 serious adverse events SAEs reported by 73
(12%) patients, with relatively equal incidence across the
treatment groups. The most common SAEs were cardiac disorders,
which occurred in ten (2%) patients in the pooled degarelix group
and ten (5%) patients in the leuprolide 7.5 mg group; and renal and
urinary disorders, which occurred in 10 (2%) patients in the pooled
degarelix group and six (3%) patients in the leuprolide 7.5 mg
group.
[0195] Weight increase is a known effect of androgen deprivation
and markedly abnormal increases in weight of .gtoreq.7% from
baseline were observed in 10% patients treated with degarelix and
13% patients treated with leuprolide 7.5 mg. The incidence of other
markedly abnormal changes in vital signs was consistent with a
group of elderly patients many of whom had a medical history of
cardiac disease or hypertension.
[0196] Therefore, while degarelix treatment resulted in a
significant number of subjects experiencing minor injection site
reactions, these adverse effects were remarkably less serious than
many of those associated with the GnRH agonist leuprolide. Notably,
these minor injection site reactions were also much less serious
than the potentially life-threatening effects associated with
another GnRH antagonist, Abarelix (Plenaxis in the U.S.) (see
www.fda.gov/cder/drug/infopage/plenaxis). Indeed Abarelix/Plenaxis
has been associated with serious allergic reactions (e.g., swelling
of the tongue/throat, asthma, wheezing and serious breathing
problems), and therefore is only available through a special "user
safety program" to ensure that it is safely used by doctors with
the right skills to administer and monitor the drug.
Further Statistical Analyses of Subgroup Populations
[0197] Further statistical analysis of the CS21 clinical study
results was undertaken in order to determine whether any of the
advantages in superior efficacy and/or diminished side effects of
degarelix over leuprolide treatment were particularly pronounced in
certain patient subgroups. Particular attention was paid to whether
particular patient subgroups were responsible for any of the
diminished cardiac, arthralgic and/or urinary tract infection side
effects seen with degarelix treatment as compared to leuprolide
treatment.
[0198] Using the results from the summary of clinical efficacy
(SCE) and summary of clinical safety (SCS) findings, different
patient subgroups were analyzed. Subgroup distinguishers included
race (white, black, and other), age (<65 years, .gtoreq.65 years
to <70 years, and .gtoreq.75 years), weight (<70 kg,
.gtoreq.70-<90 kg, and .gtoreq.90 kg), body mass index (BMI)
(.ltoreq.20, >20 to 30, and >30 kg/m.sup.2)), region
(North-America, Western Europe, Central and Eastern Europe and
Other), and stage of prostate cancer (e.g., localized, locally
advanced, and metastatic).
[0199] The SCS summarizes both crude incidences (n/N) as well as
incidence rates of adverse events (number of patients with at least
one adverse event investigated per 1,000 person years) including
exact 95% CI based on the Poisson model and presented per MedDRA
Preferred term (and grouped by SOC) for all study-groups, including
the CS21 trial (the trial comprising the controlled phase 3 study
group) and for all sub-groups. Briefly, the Poisson model provides
exact 1-.alpha. lower (LL) and upper (UL) confidence limits are
LL=.chi..sub.2x;.alpha./2.sup.2/(2T) and
UL=.chi..sub.2(x+1);1-.alpha./2.sup.2/(2T), respectively, where T
is the number of 1,000 person years and x=number of subjects at
least once having reported the adverse event under investigation
(see Gerlinger et al. (2003) Eur. J. Contracept. Reprod. Health
Care 8:87-92).
[0200] For the phase 3 controlled study (CS21), crude incidences in
the degarelix arms were compared to those in the leuprolide 7.5 mg
arm using two-sided Fisher exact test and corresponding P-value as
a flagging device. These P values were presented as
*(0.01<P.ltoreq.0.05), **(0.001<P.ltoreq.0.01), and
***(P.ltoreq.0.001). Similarly, incidence rates were compared using
P values associated with the Poison model-based UMPU test. Briefly,
assuming x.sub.i.about.Poisson(.lamda..sub.iT.sub.i), where xi=the
number of subjects with the event, T.sub.i=total number of 1,000
person years in arm i and .lamda..sub.i=incidence rate in arm i
(i=1,2), then the P value=2 min (P(S.gtoreq.1), P(S.gtoreq.1),
0.5), where S.about.Binomial (x.sub.1+x.sub.2,
T.sub.1/(T.sub.1+T.sub.2)) (see, e.g. Lehmann (1986) Testing
Statistical Hypotheses, 2.sup.nd edition, Springer-Verlag, New
York).
[0201] Based on these results all adverse events (on SOC or PT
level) that demonstrated a statistically significantly (P<=0.05)
or borderline significantly (0.05<P<0.2) lower incidence or
incidence rate in the degarelix arm as compared to leuprolide 7.5
mg were identified.
[0202] In the SCS, cardiovascular events were more specifically
investigated on more aggregated MedDRA levels, i.e. the incidence,
and incidence rates of subject with AEs in the following High Level
Group Terms were tabulated by study group and treatment:
[0203] HLGT=Central nervous system vascular disorders
[0204] HLGT=Cardiac arrhythmias
[0205] HLGT=Coronary artery disorders
[0206] HLGT=Heart failures
[0207] To further substantiate apparent, but potentially isolated
evidence on a detailed Preferred Term level that degarelix shows
lower incidence rates than leuprolide with regard to specific
cardiac disorders, the incidence rates with regard to the
above-mentioned HLGTs, as well as the SOC=Cardiac Disorders these
HLGTs belong to, were tested with regard to subgroups based on
possible risk-factor (cholesterol, BMI, body weight,
systolic/diastolic blood pressure, medical history of cardiac
disorder, age, pulse). These subgroup analyses were not pre-planned
as part of the SCS. By testing statistical significance of
risk-factor by treatment (degarelix/leuprolide 7.5 mg) interaction
in a time to event analyses (Cox Proportional hazard model) these
covariates were screened for potential subgroup effects. Body mass
index and to a lesser extent cholesterol were identified
accordingly. Next, BMI subgroups (<25, 25 to <30, and
.gtoreq.30 kg/m2) and low/normal cholesterol subgroups (.ltoreq.4
mmol/L and >4 mmol/L, respectively) were used to test and
quantify differences in incidence rates between degarelix and
leuprolide, along using the Poisson model mentioned above.
Statistically significant lower incidence rate as compared to
leuprolide were noted in patients with BMI <25 kg/m2 with regard
to SOC=Cardiac Disorders (P=0.0045), HLGT=Coronary artery disorders
(P=0.005), and HLGT=Cardiac Arrhythmias (borderline, P=0.056), with
Relative risks of respectively 0.242 (95% CI: 0.08-0.67), 0.0 (95%
CI: 0.0-0.47), and 0.312 (95% CI: 0.09-1.03]). Statistically
significantly lower incidence rate as compared to leuprolide were
noted in patients with Cholesterol greater than or equal to 4
mmol/L with regard to HLGT=Cardiac Arrhythmias (P=0.035), with
relative risks of respectively 0.41 (95% CI: 0.18-0.94).
[0208] See Tables 8-10 for efficacy findings in subgroups from the
SCE, Tables 11-19 for subgroup findings from the SCS, and Tables
20-23 for the explorative substantiating subgroup findings on
cardiovascular risk. In summary, notable findings include:
[0209] Time to testosterone escape during Days 28, 56, . . . , 364
in the age 65 subgroup is significantly superior to LUPRON
DEPOT.RTM. 7.5 mg for both degarelix dosing regimens (see Table 8
below).
TABLE-US-00008 TABLE 8 One year efficacy results for the
testosterone endpoints for Controlled Study CS21 - in the age
<65 subgroup Probablity of testosterone .ltoreq.0.5 Probability
of testosterone .ltoreq.0.5 ng/mL from Day 28 ng/mL from Day 56
Probabilty of sufficient through Day 364 through Day 364
testosterone response* Dosing regimen (%) 95% CI N (%) 95% CI N (%)
95% CI N Degarelix 240@40/80@20 97.4% 82.8; 99.6% 43 97.4% 82.8;
99.6% 43 97.4% 82.8; 99.6% 43 Degarelix 240/160@40 96.7% 78.6;
99.5% 37 96.7% 78.6; 99.5% 37 96.7% 78.6; 99.5% 37 LUPRON DEPOT
.RTM. 7.5 mg 89.5% 74.3; 95.9% 38 89.5% 74.3; 95.9% 38 92.1% 77.5;
97.4% 38 Log-rank test: Degarelix 240@40/80@20 vs. p = 0.1318 p =
0.1318 p = 0.2588 LUPRON DEPOT .RTM. 7.5 mg Degarelix 240/160@40
vs. p = 0.1851 p = 0.1851 p = 0.3373 LUPRON DEPOT .RTM. 7.5 mg
Note: P values as flagging device used only in the Phase 3 study
(head to head comparison to LUPRON DEPOT 7.5 mg), *= 0.01 < P
.ltoreq. 0.05, ** = 0.001 < P .ltoreq. 0.01, *** = P .ltoreq.
0.001 (Fisher exact, two-sided).
[0210] Time to PSA failure is significantly (P=0.03) superior in
the degarelix 240/80 mg group as compared to LUPRON DEPOT.RTM. 7.5
mg in the age >75 year group, and also (P=0.06) significantly
better in the <65 age group (see Table 9 below).
TABLE-US-00009 TABLE 9 One year efficacy results for the PSA
endpoints for Controlled Study CS21 - by age subgroups Probability
of no PSA failure* Dosing regimen (%) 95% CI N Age (years) = <65
Degarelix 240@40/80@20 85.2% 70.0; 93.1% 43 Degarelix 240/160@40
71.6% 53.6; 83.6% 37 LUPRON DEPOT .RTM. 7.5 mg 68.2% 50.9; 80.6% 38
Log-rank test: Degarelix 240@40/80@20 vs. p = 0.0679 LUPRON DEPOT
.RTM. 7.5 mg Degarelix 240/160@40 vs. p = 0.7273 LUPRON DEPOT .RTM.
7.5 mg Age (years) = >=75 Degarelix 240@40/80@20 96.6% 87.0;
99.1% 78 Degarelix 240/160@40 94.5% 85.9; 97.9% 82 LUPRON DEPOT
.RTM. 7.5 mg 86.8% 77.4; 92.5% 92 Log-rank test: Degarelix
240@40/80@20 vs. p = 0.0376 LUPRON DEPOT .RTM. 7.5 mg Degarelix
240/160@40 vs. p = 0.1125 LUPRON DEPOT .RTM. 7.5 mg Note: P values
as flagging device used only in the Phase 3 study (head to head
comparison to LUPRON DEPOT 7.5 mg), *= 0.01 < P .ltoreq. 0.05,
** = 0.001 < P .ltoreq. 0.01, *** = P .ltoreq. 0.001 (Fisher
exact, two-sided).
[0211] PSA percent change from baseline is more pronounced in the
patients with metastatic stage prostate cancer (See Table 10
below). All subgroups are statistically significantly better than
LUPRON DEPOT.RTM. 7.5 mg.
TABLE-US-00010 TABLE 10 Effect of starting dose on PSA during first
month of treatment for Controlled Study CS21 - by stage of prostate
cancer subgroups Day 14 percentage change Day 28 percentage change
in PSA in PSA InterQuartile InterQuartile Day 0 dose Median % Range
N Median % Range N PCA = Localized Degarelix 240@40 -50.6% -65.0;
-30.4% 128 -75.0% -85.2; -60.5% 128 LUPRON DEPOT .RTM. 7.5 mg
-13.2% -29.3; -0.518% 63 -55.7% -66.7; -33.8% 63 Wilcoxon rank sum
test: Degarelix 240@40 vs. p = <.0001 p = <.0001 LUPRON DEPOT
.RTM. 7.5 mg PCA - Locally advanced Degarelix 240@40 -66.6% -75.9;
-49.6% 126 -84.1% -91.8; -75.0% 126 LUPRON DEPOT .RTM. 7.5 mg
-21.3% -36.2; -9.20% 52 -73.2% -84.0; -50.0% 52 Wilcoxon rank sum
test: Degarelix 240@40 vs. p = <.0001 p = <.0001 LUPRON DEPOT
.RTM. 7.5 mg PCA = Metastatic Degarelix 240@40 -77.9% -85.3; -62.3%
78 -89.9% -95.6; -83.1% 78 LUPRON DEPOT .RTM. 7.5 mg -25.3% -53.2;
-0.943% 47 -79.7% -90.6; -70.7% 47 Wilcoxon rank sum test:
Degarelix 240@40 vs. p = <.0001 p = 0.0003 LUPRON DEPOT .RTM.
7.5 mg Note: P values as flagging device used only in the Phase 3
study (head to head comparison to LUPRON DEPOT 7.5 mg), * = 0.01
< P .ltoreq. 0.05, ** = 0.001 < P .ltoreq. 0.01, *** = P
.ltoreq. 0.001 (Fisher exact, two-sided).
[0212] Notable statistically significant findings in the total
trial population are (See Table 11):
[0213] Myocardial Infarction (PT): 0.5% (2/409, degarelix combined)
versus 2.5% (5/201, LUPRON DEPOT.RTM. 7.5 mg),
[0214] Oedema peripheral (PT) 2% (8/409, degarelix combined) versus
5% (10/201, LUPRON DEPOT.RTM. 7.5 mg),
[0215] Chest pain: 0.5% (2/409, degarelix combined) versus 3%
(6/201, LUPRON DEPOT.RTM. 7.5 mg),
[0216] Urinary Tract infection (PT) 3% (13/409, degarelix combined)
versus 9% (18/201, LUPRON DEPOT.RTM. 7.5 mg),
[0217] Cardiac murmur (PT): 0% (0/409, degarelix combined) versus
1.5% (3/201, LUPRON DEPOT.RTM. 7.5 mg),
[0218] Musculoskeletal and connective tissue disorders (SOC): 17%
(68/409, degarelix combined) versus 26% (53/201, LUPRON DEPOT.RTM.
7.5 mg),
[0219] Arthralgia (PT within Musculoskeletal and CTD SOC): 4.2%
(17/409, degarelix combined) versus 9% (18/201, LUPRON DEPOT.RTM.
7.5 mg),
[0220] Musculoskeletal stiffness (PT within Musculoskeletal and CTD
SOC): 0% (0/409, degarelix combined) versus 1% (3/201, LUPRON
DEPOT.RTM. 7.5 mg),
[0221] Libido decreased: 0% (0/409, degarelix combined) versus 1.5%
(3/201, LUPRON DEPOT.RTM. 7.5 mg),
[0222] Urinary retention: 1.2% (5/409, degarelix combined) versus
4.5% (9/201, LUPRON DEPOT.RTM. 7.5 mg),
[0223] Cystitis noninfective: 0% (0/409, degarelix combined) versus
2% (4/201, LUPRON DEPOT.RTM. 7.5 mg),
[0224] Erectile dysfunction: 1.5% (6/409, degarelix combined)
versus 4.5% (9/201, LUPRON DEPOT.RTM. 7.5 mg),
[0225] DVT: 0% (0/409, degarelix combined) versus 1.5% (3/201,
LUPRON DEPOT.RTM. 7.5 mg).
[0226] Particularly notable statistically significant findings in
and across subgroups are indicated.
TABLE-US-00011 TABLE 11 Crude Incidence of Treatment-Emergent
Adverse Events by MedDRA System Organ Class and Preferred Term
One-Month Controlled LUPRON DEPOT .RTM. MedDRA System Organ Class/
Degarelix 7.5 mg Preferred Term N (%) N (%) Exposed Subjects 409
(100%) 201 (100%) Total No. of Subjects with Adverse Events 330
(81%) 156 (78%) BLOOD AND LYMPHATIC SYSTEM 16 (4%) 12 (6%)
DISORDERS Myocardial ischaemia 2 (<1%)* 5 (2%)* GENERAL
DISORDERS AND ADMINISTRATION SITE CONDITIONS Oedema peripheral 8
(2%)* 10 (5%)* Chest pain 2 (<1%)* 6 (3%)* INFECTIONS AND
INFESTATIONS Urinary tract infection 13 (3%)** 18 (9%)*
INVESTIGATIONS 113 (28%) 62 (31%) Cardiac murmur 3 (1%)*
MUSCULOSKELETAL AND CONNECTIVE 68 (17%)** 53 (26%)** TISSUE
DISORDERS Arthralgia 17 (4%)* 18 (9%)* Musculoskeletal stiffness 3
(1%)* PSYCHIATRIC DISORDERS Libido decreased 0 3 (1%)* RENAL AND
URINARY DISORDERS Urinary retention 5 (1%)* 9 (4%)* Cystitis
noninfective 4 (2%)* REPRODUCTIVE SYSTEM AND BREAST 22 (5%)* 21
(10%)* DISORDERS Erectile dysfunction 6 (1%)* 9 (4%)* VASCULAR
DISORDERS Deep vein thrombosis 0 3 (1%)* Note: P values as flagging
device used only in the Phase 3 study (head to head comparison to
LUPRON DEPOT 7.5 mg), *= 0.01 < P .ltoreq. 0.05, **= 0.001 <
P .ltoreq. 0.01, *** = P .ltoreq. 0.001 (Fisher exact,
two-sided).
[0227] Musculoskeletal and connective tissue disorders (SOC) and
Arthralgia superiority is not just confined to the metastatic, but
in all disease stage subgroup (see Table H=Table 2.2). Arthralgia
is statistically significant in locally advanced patients.
TABLE-US-00012 TABLE 12 Crude Incidence of Treatment-Emergent
Adverse Events by MedDRA System Organ Class and Preferred Term - by
Stage of Prostate Cancer One-Month Controlled LUPRON DEPOT .RTM.
MedDRA System Organ Class/ Degarelix 7.5 mg Preferred Term N (%) N
(%) PCA = Localised Exposed Subjects 128 (100%) 63 (100%) Total No.
of Subjects with Adverse Events 104 (81%) 48 (76%) GENERAL
DISORDERS AND ADMINISTRATION SITE CONDITIONS Oedema peripheral 2
(2%)* 6 (10%)* INFECTIONS AND INFESTATIONS 22 (17%) 14 (22%)
Urinary tract infection 2 (2%)* 5 (8%)* Upper respiratory tract
infection 4 (3%) 6 (10%) MUSCULOSKELETAL AND CONNECTIVE 20 (16%) 16
(25%) TISSUE DISORDERS NEOPLASMS BENIGN, MALIGNANT 4 (3%) 6 (10%)
AND UNSPECIFIED (INCL CYSTS AND POLYPS) PSYCHIATRIC DISORDERS 11
(9%) 9 (14%) Depression 1 (<1%)* 4 (6%)* Libido decreased 2 (3%)
REPRODUCTIVE SYSTEM AND BREAST 5 (4%) 7 (11%) DISORDERS
Gynaecomastia 1 (<1%) 2 (3%) Erectile dysfunction 1 (<1%)* 4
(6%)* PCA = Locally advanced Exposed Subjects 126 (100%) 52 (100%)
Total No. of Subjects with Adverse Events 93 (74%) 37 (71%) CARDIAC
DISORDERS 4 (3%) 5 (10%) Atrioventricular block first degree 3
(6%)* GASTROINTESTINAL DISORDERS 16 (13%) 11 (21%) Diarrhoea 1
(<1%)* 4 (8%)* INFECTIONS AND INFESTATIONS 16 (13%) 11 (21%)
Urinary tract infection 1 (<1%)** 5 (10%)** INJURY, POISONING
AND PROCEDURAL 2 (2%)** 6 (12%)** COMPLICATIONS Fall 1 (<1%) 1
(2%) Excoriation 2 (4%) Muscle strain 1 (<1%) MUSCULOSKELETAL
AND CONNECTIVE 13 (10%) 10 (19%) TISSUE DISORDERS Back pain 6 (5%)
4 (8%) Arthralgia 2 (2%)** 7 (13%)** RESPIRATORY, THORACIC AND 9
(7%) 5 (10%) MEDIASTINAL DISORDERS Dyspnoea 0 3 (6%)* PCA =
Metastatic Exposed Subjects 78 (100%) 47 (100%) Total No. of
Subjects with Adverse Events 63 (81%) 39 (83%) GASTROINTESTINAL
DISORDERS 12 (15%) 12 (26%) MUSCULOSKELETAL AND CONNECTIVE 16 (21%)
17 (36%) TISSUE DISORDERS Back pain 4 (5%) 6 (13%) Arthralgia 4
(5%) 6 (13%) Pain in extremity 1 (1%) 4 (9%) Note: P values as
flagging device used only in the Phase 3 study (head to head
comparison to LUPRON DEPOT 7.5 mg), *= 0.01 < P .ltoreq. 0.05,
**= 0.001 < P .ltoreq. 0.01, *** = P .ltoreq. 0.001 (Fisher
exact, two-sided).
[0228] Renal And Urinary Disorders and Musculoskeletal and
Connective Tissue disorders in Age <65 group (see Table 13)
TABLE-US-00013 TABLE 13 Crude Incidence of Treatment-Emergent
Adverse Events by MedDRA System Organ Class and Preferred Term - in
the age <65 subgroup Age (years) = <65 One-Month Controlled
LUPRON DEPOT .RTM. MedDRA System Organ Class/ Degarelix 7.5 mg
Preferred Term N (%) N (%) Exposed Subjects 80 (100%) 38 (100%)
Total No. of Subjects with Adverse Events 60 (75%) 31 (82%)
GASTROINTESTINAL DISORDERS 7 (9%)* 9 (24%)* INFECTIONS AND
INFESTATIONS 13 (16%) 10 (26%) MUSCULOSKELETAL AND CONNECTIVE 7
(9%)** 13 (34%)** TISSUE DISORDERS Arthralgia 5 (13%)** RENAL AND
URINARY DISORDERS 8 (10%)* 11 (29%)* Urinary retention 1 (1%)* 5
(13%)* Note: No findings in the other age-categories Note: P values
as flagging device used only in the Phase 3 study (head to head
comparison to LUPRON DEPOT 7.5 mg), *= 0.01 < P .ltoreq. 0.05,
**= 0.001 < P .ltoreq. 0.01, *** = P .ltoreq. 0.001 (Fisher
exact, two-sided).
[0229] See Table 14 and Table 15 for further subgroup findings.
TABLE-US-00014 TABLE 14 Crude Incidence of Treatment-Emergent
Adverse Events by MedDRA System Organ Class and Preferred Term - by
Body Weight categories One-Month Controlled LUPRON DEPOT .RTM.
MedDRA System Organ Class/ Degarelix 7.5 mg Preferred Term N (%) N
(%) Weight (kg) = <70 Exposed Subjects 102 (100%) 39 (100%)
Total No. of Subjects with Adverse Events 80 (78%) 30 (77%)
MUSCULOSKELETAL AND CONNECTIVE 17 (17%)* 14 (36%)* TISSUE DISORDERS
Arthralgia 3 (3%)** 7 (18%)** REPRODUCTIVE SYSTEM AND BREAST 4
(4%)* 7 (18%)* DISORDERS Pelvic pain 0 3 (8%)* Weight (kg) =
70-<90 Exposed Subjects 227 (100%) 125 (100%) Total No. of
Subjects with Adverse Events 183 (81%) 95 (76%) CARDIAC DISORDERS
12 (5%)* 16 (13%)* NERVOUS SYSTEM DISORDERS 27 (12%) 13 (10%)
Syncope 3 (2%)* REPRODUCTIVE SYSTEM AND BREAST 11 (5%) 10 (8%)
DISORDERS Erectile dysfunction 2 (<1%)* 7 (6%)* Weight (kg) =
>=90 Exposed Subjects 80 (100%) 37 (100%) Total No. of Subjects
with Adverse Events 67 (84%) 31 (84%) INFECTIONS AND INFESTATIONS
21 (26%) 12 (32%) Urinary tract infection 2 (3%)* 5 (14%)*
Bronchitis 3 (8%)* MUSCULOSKELETAL AND CONNECTIVE 12 (15%)* 12
(32%)* TISSUE DISORDERS Arthralgia 4 (5%) 4 (11%) Back pain 4 (5%)*
7 (19%)* NEOPLASMS BENIGN, MALIGNANT AND 1 (1%)* 4 (11%)*
UNSPECIFIED (INCL CYSTS AND POLYPS) Note: P values as flagging
device used only in the Phase 3 study (head to head comparison to
LUPRON DEPOT 7.5 mg), *= 0.01 < P .ltoreq. 0.05, **= 0.001 <
P .ltoreq. 0.01, *** = P .ltoreq. 0.001 (Fisher exact,
two-sided).
TABLE-US-00015 TABLE 15 Crude Incidence of Treatment-Emergent
Adverse Events by MedDRA System Organ Class and Preferred Term- by
Race One-Month Controlled LUPRON DEPOT .RTM. MedDRA System Organ
Class/ Degarelix 7.5 mg Preferred Term N (%) N (%) Race = White
Exposed Subjects 339 (100%) 172 (100%) Total No. of Subjects with
Adverse Events 267 (79%) 131 (76%) CARDIAC DISORDERS 33 (10%) 25
(15%) Myocardial ischaemia 2 (<1%)* 5 (3%)* GENERAL DISORDERS
AND ADMINISTRATION SITE CONDITIONS Oedema peripheral 5 (1%)* 10
(6%)* Chest pain 2 (<1%)* 5 (3%)* INFECTIONS AND INFESTATIONS 64
(19%) 39 (23%) Upper respiratory tract infection 3 (<1%)* 7
(4%)* INVESTIGATIONS 88 (26%) 52 (30%) Cardiac murmur 3 (2%)*
MUSCULOSKELETAL AND CONNECTIVE 52 (15%)** 44 (26%)** TISSUE
DISORDERS Musculoskeletal stiffness 0 3 (2%)* RENAL AND URINARY
DISORDERS 46 (14%) 34 (20%) Urinary retention 4 (1%)* 7 (4%)* RENAL
AND URINARY DISORDERS (cont.) Cystitis noninfective 0 4 (2%)*
VASCULAR DISORDERS 106 (31%) 52 (30%) Orthostatic hypotension 0 3
(2%)* Deep vein thrombosis 0 3 (2%)* Race = Other Exposed Subjects
42 (100%) 19 (100%) Total No. of Subjects with Adverse Events 40
(95%) 16 (84%) INFECTIONS AND INFESTATIONS 14 (33%) 7 (37%) Urinary
tract infection 2 (5%)* 5 (26%)* REPRODUCTIVE SYSTEM AND BREAST 4
(10%) 5 (26%) DISORDERS Erectile dysfunction 1 (2%)* 4 (21%)* Note:
no findings in Blacks Note: P values as flagging device used only
in the Phase 3 study (head to head comparison to LUPRON DEPOT 7.5
mg), *= 0.01 < P .ltoreq. 0.05, **= 0.001 < P .ltoreq. 0.01,
*** = P .ltoreq. 0.001 (Fisher exact, two-sided).
[0230] These results shown in Tables 16 and 17 below demonstrate
that treated subjects had a significantly reduced risk of
developing coronary artery disease, heart failure, myocardial
infarction, cardiac arrhythmia, coronary artery disease or heart
failure when receiving androgen depletion therapy with degarelix as
compared to Lupron.
TABLE-US-00016 TABLE 16 Incidence Rate (in 1,000 py) of
Cardiovascular Events compared to Background Incidence Rates
Degarelix LUPRON DEPOT .RTM. 7.5 mg Incidence Incidence CV Event
type N (%) PY Rate 95% CI N (%) PY Rate 95% CI Stroke 3 (<1%)
0.354 8.49 [1.75; 24.8] 1 (<1%) 0.178 5.63 [0.142; 31.4] P = 1.0
Coronary artery 12 (3%) 0.351 34.2 [17.7; 59.7] 11 (5%) 0.174 63.4
[31.6; 113] P = 0.2 disease Heart failure 5 (1%) 0.354 14.1 [4.59;
33.0] 5 (2%) 0.176 28.4 [9.21; 66.2] P = 0.42 MI 2 (<1%) 0.354
5.64 [0.683; 20.4] 4 (2%) 0.177 22.6 [6.15; 57.8] P = 0.2 Note: P
values as flagging device used only in the Phase 3 study (head to
head comparison to LUPRON DEPOT 7.5 mg), * = 0.01 < P .ltoreq.
0.05, ** = 0.001 < P .ltoreq. 0.01, *** = P .ltoreq. 0.001
(Fisher exact, two-sided).
TABLE-US-00017 TABLE 17 Incidence Rate of Cardiovascular Events
defined by High Level Group Terms Degarelix LUPRON DEPOT .RTM. 7.5
mg Incidence Incidence MedDRA HLGT N (%) PY Rate 95% CI N (%) PY
Rate 95% CI Central nervous 5 (1%) 0.353 14.2 [4.60; 33.1] 1
(<1%) 0.178 5.63 [0.142; 31.4] P = 0.69 system vascular
disorders Cardiac arrhythmias 20 (5%) 0.347 57.7 [35.3; 89.1] 17
(8%) 0.170 100 [58.2; 160] P = 0.13 Coronary artery 12 (3%) 0.351
34.2 [17.7; 59.7] 11 (5%) 0.174 63.4 [31.6; 113] P = 0.21 disorders
Heart failures 5 (1%) 0.354 14.1 [4.59; 33.0] 5 (2%) 0.176 28.4
[9.21; 66.2] P = 0.42 Note: P values as flagging device used only
in the Phase 3 study (head to head comparison to LUPRON DEPOT 7.5
mg), * = 0.01 < P .ltoreq. 0.05, ** = 0.001 < P .ltoreq.
0.01, *** = P .ltoreq. 0.001 (Fisher exact, two-sided).
[0231] Mortality Subgroups with statistically (pre-planned as part
of the ISS) significant findings
TABLE-US-00018 TABLE 18 Mortality by Treatment group Age (years) =
>=65-<75 No. of Crude PY of Mortality per 1,000 PY Treatment
Group N Deaths Mortality Exposure Estimate 95% CI Degarelix 169 3
(2%) 0.148 20.2 [4.17; 59.1] LUPRON DEPOT .RTM. 7.5 mg 71 6 (8%)
0.061 99.0 [36.3; 216] Test for homogeneity of P = 0.0426 mortality
rates:
TABLE-US-00019 TABLE 19 Mortality by Treatment group PCA =
Localized No. of Crude PY of Mortality per 1,000 PY Treatment Group
N Deaths Mortality Exposure Estimate 95% CI Degarelix 128 0 (0%)
0.113 0 [0, 32.6] LUPRON DEPOT .RTM. 7.5 mg 63 4 (6%) 0.057 70.3
[19.2; 180] Test for homogeneity of P = .0251 mortality rates:
TABLE-US-00020 TABLE 20 Incidence rates ratios by BMI of Cardiac
Arrhythmias in CS21 - Degarelix vs Luprolide Degarelix Lupron
Relative Risk Body Mass Index Incidence Incidence P value Category
Rate 95% CI Rate 95% CI RR 95% CI (a) 1: <25 kg/m2 46.58
(17.1-101) 149.3 (64.4-294) 0.312 (0.09-1.03) .0556 2: 25-<30
kg/m2 52.66 (24.1-100) 93.09 (40.2-183) 0.566 (0.19-1.68) .3495 3:
>=30 kg/m2 84.50 (27.4-197) 26.73 (0.68-149) 3.161 (0.35-150)
.5069 (a) P value for for homogeneity of incidence rates PY in
1,000 person years
[0232] These results show that treated subjects with BMIs of less
than 30 kg/m.sup.2 (e.g., less than 25 kg/m.sup.2, e.g., 20-25
kg/m.sup.2) had a significantly reduced risk of developing a
cardiac arrhythmia when receiving androgen depletion therapy with
degarelix as compared to Lupron.
TABLE-US-00021 TABLE 21 Incidence rates ratios by BMI of Coronary
Artery Disorders in CS21 - Degarelix vs Luprolide Degarelix Lupron
Relative Risk Body Mass Index Incidence Incidence P value Category
Rate 95% CI Rate 95% CI RR 95% CI (a) 1: <25 kg/m2 0.00
(0.00-28.0) 87.96 (28.6-205) 0.000 (0.00-0.47) 0.0050 2: 25-<30
kg/m2 46.88 (20.2-92.4) 46.27 (12.6-118) 1.013 (0.27-4.60) 1.000 3:
>=30 kg/m2 65.16 (17.8-167) 53.53 (6.48-193) 1.217 (0.17-13.5)
1.000 (a) P value for homogeneity of incidence rates PY in 1,000
person years
[0233] These results show that treated subjects with BMIs of less
than 25 kg/m.sup.2 (e.g., 20-25 kg/m.sup.2) had a significantly
reduced risk of developing a coronary artery disorder when
receiving androgen depletion therapy with degarelix as compared to
Lupron.
TABLE-US-00022 TABLE 22 Incidence rates ratios by BMI of Cardiac
Disorders (SOC) in CS21 - Degarelix vs Luprolide Degarelix Lupron
Relative Risk Body Mass Index Incidence Incidence P value Category
Rate 95% CI Rate 95% CI RR 95% CI (a) 1: <25 kg/m2 54.32
(21.8-112) 224.9 (116-393) 0.242 (0.08-0.67) .0045 2: 25-<30
kg/m2 101.5 (59.1-162) 132.6 (66.2-237) 0.765 (0.34-1.81) .6106 3:
>=30 kg/m2 209.6 (108-366) 107.7 (29.4-276) 1.946 (0.59-8.28)
.3606 (a) P value for for homogeneity of incidence rates PY in
1,000 person years
[0234] These results show that treated subjects with BMIs of less
than 30 kg/m.sup.2 (e.g., less than 25 kg/m.sup.2, e.g. 20-25
kg/m.sup.2) had a significantly reduced risk of developing a
cardiac disorder when receiving androgen depletion therapy with
degarelix as compared to Lupron.
TABLE-US-00023 TABLE 23 Incidence rates ratios by Cholesterol of
Cardiac Arrhythmias in CS21 - Degarelix vs Luprolide Degarelix
Lupron Relative Risk Cholesterol Incidence Incidence P value
Category Rate 95% CI Rate 95% CI RR 95% CI (a) 1: <4 mmol/L
156.1 (62.8-322) 79.12 (16.3-231) 1.973 (0.45-11.8) .4981 2: >=4
mmol/L 41.39 (22.0-70.8) 100.7 (55.1-169) 0.411 (0.18-0.94) .0350
(a) P value for homogeneity of incidence rates PY in 1,000 person
years
[0235] These results show that treated subjects with cholesterol
levels of greater than or equal to 4 mmol/L had a significantly
reduced risk of developing a cardiac arrhythmia when receiving
androgen depletion therapy with degarelix as compared to GnRH
antagonist therapy with Lupron.
Equivalents
[0236] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described herein. Such
equivalents are intended to be encompassed in the scope of the
following claims.
* * * * *
References