Firmagon Mechanism of Action





Zuellig Pharma
Full Prescribing Info
Pharmacology: Pharmacodynamics: Degarelix is a selective gonadotrophin-releasing hormone (GnRH) blocker that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of the gonadotrophins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and thereby reducing the secretion of testosterone by the testes. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that removes the source of androgen. Unlike GnRH agonists, GnRH blockers do not induce a LH surge with subsequent testosterone surge/tumour stimulation and potential symptomatic are after the initiation of treatment.
A single dose of degarelix 240 mg, followed by a monthly maintenance dose of 80 mg, rapidly causes a decrease in the concentrations of LH, FSH and subsequently testosterone. The plasma concentration of dihydrotestosterone (DHT) decreases in a similar manner to testosterone.
Degarelix is effective in achieving and maintaining testosterone suppression well below medical castration level of 0.5 ng/mL. Maintenance monthly dosing of 80 mg resulted in sustained testosterone suppression in 97% of patients for at least 1 year. Median testosterone levels after 1 year of treatment were 0.087 ng/mL (interquartile range 0.06-0.15) N=167.
Results of the Confirmatory Phase III Study: The efficacy and safety of degarelix was evaluated in an open-label, multicentre, randomised, active comparator controlled, parallel-group study. The study investigated the efcacy and safety of 2 different degarelix monthly dosing regimens with a starting dose of 240 mg (40 mg/mL) followed by monthly doses SC administration of 160 mg (40 mg/mL) or 80 mg (20 mg/mL), in comparison to monthly IM administration of 7.5 mg leuprorelin in patients with prostate cancer requiring androgen deprivation therapy. In total, 620 patients were randomised to 1 of the 3 treatment groups, of which 504 (81%) patients completed the study. In the degarelix 240/80 mg treatment group, 41 (20%) patients discontinued the study, as compared to 32 (16%) patients in the leuprorelin group.
Of the 610 patients treated, 31% had localised prostate cancer; 29% had locally advanced prostate cancer; 20% had metastatic prostate cancer; 7% had an unknown metastatic status; 13% had previous curative intent surgery or radiation and a rising prostate specific antigen (PSA).
Baseline demographics were similar between the arms. The median age was 74 years (range 47-98 years). The primary objective was to demonstrate that degarelix is effective with respect to achieving and maintaining testosterone suppression to <0.5 ng/mL, during 12 months of treatment.
The lowest effective maintenance dose of degarelix 80 mg was chosen.
Attainment of Serum Testosterone ≤0.5 ng/mL: Firmagon is effective in achieving fast testosterone suppression (see Table 1).

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Avoidance of Testosterone Surge: Surge was defined as testosterone exceeding baseline by ≥15% within the 1st 2 weeks.
None of the degarelix-treated patients experienced a testosterone surge; there was an average decrease of 94% in testosterone at day 3. Most of the leuprorelin-treated patients experienced testosterone surge; there was an average increase of 65% in testosterone at day 3. This difference was statistically significant (p<0.001) (see Figure 1).

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The primary end-point in the study was testosterone suppression rates after 1 year of treatment with degarelix or leuprorelin. The clinical benefit for degarelix compared to leuprorelin plus antiandrogen in the initial phase of treatment has not been demonstrated.
Long-Term Effect: Successful response in the study was defined as attainment of medical castration at day 28 and maintenance through day 364 where no single testosterone concentration was >0.5 ng/mL (see Table 2).

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Attainment of Prostatic Specific Antigen (PSA) Reduction: Tumour size was not measured directly during the clinical trial programme, but there was an indirect beneficial tumour response as shown by a 95% reduction after 12 months in median PSA for degarelix.
The median PSA in the study at baseline for the degarelix 240/80 mg treatment group was 19.8 ng/mL (interquartile range: P25 9.4 ng/mL, P75 46.4 ng/mL) and for the leuprorelin 7.5-mg treatment group was 17.4 ng/mL (interquartile range: P25 8.4 ng/mL, P75 56.5 ng/mL) (see Figure 2).

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This difference was statistically significant (p<0.001) for the pre-specified analysis at day 14 and day 28.
Prostate specific antigen levels are lowered by 64% 2 weeks after administration of degarelix, 85% after 1 month, 95% after 3 months and remained suppressed (approximately 97%) throughout the 1 year of treatment.
From day 56-364, there were no significant differences between degarelix and the comparator in the percentage change from baseline.
In the confirmatory study comparing Firmagon to leuprorelin, periodic electrocardiograms were performed. Both therapies showed QT/QTc intervals exceeding 450 msec in approximately 20% of the patients. From baseline to end of study, the median change for Firmagon was 12 msec and for leuprorelin it was 16.7 msec.
Anti-degarelix antibody development has been observed in 10% of patients after treatment with Firmagon for 1 year. There is no indication that the efficacy or safety of Firmagon treatment is affected by antibody formation after 1 year of treatment. Efficacy and safety data in relation to antibody development beyond 1 year is not available.
Pharmacokinetics: Absorption: Following SC administration of degarelix 240 mg at a concentration of 40 mg/mL to prostate cancer patients in the pivotal study CS21, AUC0-28 days was 635 (602-668) day*ng/mL, Cmax was 66 (61-71) ng/mL and occurred at tmax at 40 (37-42) hrs. Mean trough values were approximately 11-12 ng/mL after the starting dose and 11-16 ng/mL after maintenance dosing of 80 mg at a concentration of 20 mg/mL. Degarelix is eliminated in a biphasic fashion, with a median terminal half-life half-life of approximately 43 days for the starting dose or 28 days for the maintenance dose, as estimated based on population pharmacokinetics modelling. The long t½ after SC administration is a consequence of a very slow release of degarelix from the depot formed at the injection site(s). The pharmacokinetic behavior of Firmagon is influenced by its concentration in the solution for injection. Thus, Cmax and bioavailability tend to decrease with increasing dose concentration while the t½ is increased. Therefore, no other dose concentrations than the recommended should be used.
Distribution: The distribution volume in healthy elderly men is approximately 1 L/kg. Plasma protein-binding is estimated to be approximately 90%.
Metabolism: Degarelix is subject to common peptidic degradation during the passage of the hepatobiliary system and is mainly excreted as peptide fragments in the faeces. No significant metabolites were detected in plasma samples after SC administration. In vitro studies have shown that degarelix is not a substrate for the human CYP450 system.
Excretion: In healthy men, approximately 20-30% of a single IV administered dose is excreted in the urine, suggesting that 70-80% is excreted via the hepatobiliary system. The clearance of degarelix when administered as single IV doses (0.864-49.4 mcg/kg) in healthy elderly men was found to be 35-50 mL/hr/kg.
Renal Impairment: No pharmacokinetic studies in renally impaired patients have been conducted. Only about 20-30% of a given dose of degarelix is excreted unchanged by the kidneys. A population pharmacokinetics analysis of the data from the confirmatory phase III study has demonstrated that the clearance of degarelix in patients with mild to moderate renal impairment is reduced by approximately 23%; therefore, dose adjustment in patients with mild or moderate renal impairment is not recommended. Data on patients with severe renal impairment is scarce and caution is therefore warranted in this patient population.
Hepatic Impairment: Degarelix has been investigated in a pharmacokinetic study in patients with mild to moderate hepatic impairment. No signs of increased exposure in the hepatically impaired subjects were observed compared to healthy subjects. Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group.
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