Degarelix
Encyclopedia
Degarelix or degarelix acetate (USAN
) (tradename Firmagon) is a hormonal therapy used in the treatment of prostate cancer
. During development it was known as FE200486.
Testosterone
is a male hormone
that promotes growth of many prostate tumours and therefore reducing circulating testosterone to very low (castration
) levels is often the treatment goal in the management of men with advanced prostate cancer. Degarelix has an immediate onset of action, binding to gonadotropin-releasing hormone
(GnRH) receptors in the pituitary gland
and blocking their interaction with GnRH. This induces a fast and profound reduction in luteinising hormone (LH), follicle-stimulating hormone
(FSH) and in turn, testosterone suppression.
(FDA) approved degarelix for the treatment of patients with advanced prostate cancer in the USA. It was subsequently approved by the European Commission at the recommendation of the European Medicines Agency
(EMEA) on February 17, 2009 for use in adult male patients with advanced, hormone-dependent prostate cancer. Ferring Pharmaceuticals
markets the drug under the name Firmagon.
blockers) such as degarelix are a new type of hormonal therapy for prostate cancer. These agents are synthetic peptide
derivatives of the natural GnRH decapeptide – a hormone that is made by neurons in the hypothalamus
. GnRH antagonists compete with natural GnRH for binding to GnRH receptors in the pituitary gland. This reversible blinding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the testes and subsequently reduces the size and growth of the prostate cancer. This in turn results in a reduction in prostate-specific antigen (PSA) levels in the patient's blood. Measuring PSA levels is a way to monitor how patients with prostate cancer are responding to treatment.
Unlike the GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis
(HPGA), leading to a surge in testosterone levels, and under certain circumstances, a flare-up of the tumour, GnRH antagonists do not cause a surge in testosterone or clinical flare. Clinical flare is a phenomenon that occurs in patients with advanced disease, which can precipitate a range of clinical symptoms such as bone pain
, ureteral obstruction, and spinal cord compression
. Drug agencies have issued boxed warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an antiandrogen
as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists such as degarelix.
GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer where fast control of disease is needed.
(CS21) in prostate cancer compared androgen deprivation with one of two doses of degarelix or the GnRH agonist, leuprolide
. Both degarelix doses were at least as effective as leuprolide at suppressing testosterone to castration
levels (≤0.5 ng/mL) from Day 28 to study end (Day 364). Testosterone levels were suppressed significantly faster with degarelix than with leuprolide, with degarelix uniformly achieving castration levels by Day 3 of treatment which was not seen in the leuprolide group. There were no testosterone surges with degarelix compared with surges in 81% of those who received leuprolide. Degarelix resulted in a faster reduction in PSA levels compared with leuprolide indicating faster control of the prostate cancer. Recent results also suggest that degarelix therapy may result in longer control of prostate cancer compared with leuprolide.
. Due to its mode of administration (subcutaneous injection
), degarelix is also associated with injection-site reactions such as injection-site pain, erythema
or swelling. Injection-site reactions are usually mild or moderate in intensity and occur predominantly after the first dose, decreasing in frequency thereafter.
s are selectively expressed on the luminal
surface of the blood vessels of a wide range of tumors. There may be a potential role for suppression of FSH or FSH receptors. This work is in early stages. It is thought that FSH receptors are important in tumor angiogenesis
by signalling via two pathways, one involving VEGF, and a Gq/11
mechanism that activates VEGFR-2 independently of VEGF.
United States Adopted Name
United States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
) (tradename Firmagon) is a hormonal therapy used in the treatment of prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
. During development it was known as FE200486.
Testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
is a male hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
that promotes growth of many prostate tumours and therefore reducing circulating testosterone to very low (castration
Castration
Castration is any action, surgical, chemical, or otherwise, by which a male loses the functions of the testicles or a female loses the functions of the ovaries.-Humans:...
) levels is often the treatment goal in the management of men with advanced prostate cancer. Degarelix has an immediate onset of action, binding to gonadotropin-releasing hormone
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
(GnRH) receptors in the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
and blocking their interaction with GnRH. This induces a fast and profound reduction in luteinising hormone (LH), follicle-stimulating hormone
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) and in turn, testosterone suppression.
Status
On 24 December 2008, the Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approved degarelix for the treatment of patients with advanced prostate cancer in the USA. It was subsequently approved by the European Commission at the recommendation of the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMEA) on February 17, 2009 for use in adult male patients with advanced, hormone-dependent prostate cancer. Ferring Pharmaceuticals
Ferring Pharmaceuticals
Ferring Pharmaceuticals is a pharmaceutical company that specializes in the development and marketing of drugs for use in human medicine.It was founded by Frederik Paulsen Sr in Malmö, Sweden, in 1950, initially as the Nordiska Hormon Laboratoriet, renamed Ferring in 1954. A ferring in Frisian is a...
markets the drug under the name Firmagon.
Mode of action
GnRH antagonists (receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
blockers) such as degarelix are a new type of hormonal therapy for prostate cancer. These agents are synthetic peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
derivatives of the natural GnRH decapeptide – a hormone that is made by neurons in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. GnRH antagonists compete with natural GnRH for binding to GnRH receptors in the pituitary gland. This reversible blinding blocks the release of LH and FSH from the pituitary. The reduction in LH subsequently leads to a rapid and sustained suppression of testosterone release from the testes and subsequently reduces the size and growth of the prostate cancer. This in turn results in a reduction in prostate-specific antigen (PSA) levels in the patient's blood. Measuring PSA levels is a way to monitor how patients with prostate cancer are responding to treatment.
Unlike the GnRH agonists, which cause an initial stimulation of the hypothalamic-pituitary-gonadal axis
Hypothalamic-pituitary-gonadal axis
The hypothalamic–pituitary–gonadal axis refers to the effects of the hypothalamus, pituitary gland, and gonads as if these individual endocrine glands were a single entity as a whole...
(HPGA), leading to a surge in testosterone levels, and under certain circumstances, a flare-up of the tumour, GnRH antagonists do not cause a surge in testosterone or clinical flare. Clinical flare is a phenomenon that occurs in patients with advanced disease, which can precipitate a range of clinical symptoms such as bone pain
Bone pain
Bone pain is a debilitating form of pain emanating from the bone tissue. It occurs as a result of a wide range of diseases and/or physical conditions and may severely impair the quality of life for patients who suffer from it...
, ureteral obstruction, and spinal cord compression
Spinal cord compression
Spinal cord compression develops when the spinal cord is compressed by bone fragments from a vertebral fracture, a tumor, abscess, ruptured intervertebral disc or other lesion...
. Drug agencies have issued boxed warnings regarding this phenomenon in the prescribing information for GnRH agonists. As testosterone surge does not occur with GnRH antagonists, there is no need for patients to receive an antiandrogen
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...
as flare protection during prostate cancer treatment. GnRH agonists also induce an increase in testosterone levels after each reinjection of the drug – a phenomenon that does not occur with GnRH antagonists such as degarelix.
GnRH antagonists have an immediate onset of action leading to a fast and profound suppression of testosterone and are therefore especially valuable in the treatment of patients with prostate cancer where fast control of disease is needed.
Clinical effectiveness
A Phase III, randomised, 12 month clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
(CS21) in prostate cancer compared androgen deprivation with one of two doses of degarelix or the GnRH agonist, leuprolide
Leuprolide
Leuprorelin or leuprolide acetate is a GnRH analog. Proper Sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt - Mode of action:Leuprolide acts as an agonist at pituitary GnRH receptors...
. Both degarelix doses were at least as effective as leuprolide at suppressing testosterone to castration
Castration
Castration is any action, surgical, chemical, or otherwise, by which a male loses the functions of the testicles or a female loses the functions of the ovaries.-Humans:...
levels (≤0.5 ng/mL) from Day 28 to study end (Day 364). Testosterone levels were suppressed significantly faster with degarelix than with leuprolide, with degarelix uniformly achieving castration levels by Day 3 of treatment which was not seen in the leuprolide group. There were no testosterone surges with degarelix compared with surges in 81% of those who received leuprolide. Degarelix resulted in a faster reduction in PSA levels compared with leuprolide indicating faster control of the prostate cancer. Recent results also suggest that degarelix therapy may result in longer control of prostate cancer compared with leuprolide.
Side effects
As with all hormonal therapies, degarelix is commonly associated with hormonal side effects such as hot flushes and weight gainWeight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
. Due to its mode of administration (subcutaneous injection
Subcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...
), degarelix is also associated with injection-site reactions such as injection-site pain, erythema
Erythema
Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...
or swelling. Injection-site reactions are usually mild or moderate in intensity and occur predominantly after the first dose, decreasing in frequency thereafter.
FSH receptors in other solid tumors
FSH receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s are selectively expressed on the luminal
Luminal
Luminal may refer to:* A trade name for the anti-epileptic drug phenobarbital* Luminal , a 2004 film by Italian director Andrea Vecchiato starring Denis Lavant* In biology, pertaining to the lumen, the interior of a hollow structure...
surface of the blood vessels of a wide range of tumors. There may be a potential role for suppression of FSH or FSH receptors. This work is in early stages. It is thought that FSH receptors are important in tumor angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
by signalling via two pathways, one involving VEGF, and a Gq/11
Gq alpha subunit
Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
mechanism that activates VEGFR-2 independently of VEGF.