Summary Basis of Decision for Firmagon ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Firmagon®
Degarelix, 80 mg/vial, 120 mg/vial (as degarelix acetate), Powder for solution, Subcutaneous injection
Ferring Pharmaceuticals, Inc.
Submission control no: 120421
Date issued: 2010-12-16
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02337029 - 80 mg/vial
- 02337037 - 120 mg/vial
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On November 16, 2009, Health Canada issued a Notice of Compliance to Ferring Pharmaceuticals for the drug product, Firmagon.
Firmagon contains the medicinal ingredient degarelix which is a gonadotropin-releasing hormone (GnRH) receptor antagonist.
Firmagon is indicated for testosterone suppression in patients with advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted. Firmagon is a selective GnRH receptor antagonist (blocker) that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone by the testes. Approval of Firmagon for prostate cancer is based on testosterone suppression to castrate levels. Evidence of palliation or prolongation of survival was not established for Firmagon in patients with prostate cancer.
The market authorization was based on quality, non-clinical, and clinical information submitted. The single pivotal study providing evidence of safety and efficacy to support the proposed indication was a Phase III, open-label, multicentre, randomized, active comparator, parallel-group study. A total of 620 patients with prostate cancer requiring androgen deprivation therapy were randomized to one of three treatment groups: a starting dose of 240 mg (40 mg/mL) followed by monthly doses via subcutaneous injections of either 160 mg (40 mg/mL) or 80 mg (20 mg/mL), in comparison to monthly intramuscular injections of leuprolide 7.5 mg. The approval of Firmagon for prostate cancer was based on testosterone suppression to castrate levels. Results showed that Firmagon is effective in achieving and maintaining testosterone at castrate levels ≤1.735 nmol/L (≤0.5 ng/mL). Furthermore, this effect was maintained in both Firmagon treatment groups for the duration of the study (12 months). For patients in the 160 mg and 80 mg Firmagon treatment groups, the cumulative probabilities of maintaining testosterone at castration level were 98% and 97% from day 28 to day 364, respectively. In addition, none of the patients treated with Firmagon experienced a testosterone surge, that is (i.e.) a testosterone level exceeding baseline by ≥15% within the first 2 weeks. Possible clinically significant serious adverse events include QT prolongation and osteoporosis effects associated with androgen deprivation therapy.
Firmagon (80 mg and 120 mg, degarelix as degarelix acetate) is presented as a powder for solution. The recommended starting dose for Firmagon is 240 mg given as two subcutaneous injections of 120 mg each at a concentration of 40 mg/mL. The maintenance dose is 80 mg given as one subcutaneous injection at a concentration of 20 mg/mL administered once a month. The maintenance dose is usually given one month after the starting dose. The therapeutic effect of Firmagon should be monitored by clinical parameters and by measuring prostate specific antigen (PSA) serum levels. Dosing guidelines are available in the Product Monograph.
Firmagon is contraindicated in patients with a known hypersensitivity to the drug or the other components of the product. Firmagon is not indicated for use in women and is contraindicated in women who are or who may become pregnant. Firmagon has not been studied in patients with severe hepatic or renal impairment.
Firmagon should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Firmagon are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Firmagon is favourable for testosterone suppression in patients with advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission for Firmagon was filed with Health Canada on June 2, 2008. Due to a number of safety, efficacy and minor quality deficiencies, a Notice of Non-Compliance (NON) was issued on May 14, 2009. In the sponsor's response to the NON, all of the safety, efficacy and minor quality deficiencies were satisfactorily addressed. This resulted in the issuance of a Notice of Compliance on November 16, 2009. A timeline of these events are captured in section 4 Submission Milestones.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Degarelix acetate, the medicinal ingredient of Firmagon, is a gonadotropin-releasing hormone (GnRH) receptor antagonist. Firmagon is indicated for testosterone suppression in patients with advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted. Firmagon is a selective GnRH receptor antagonist (blocker) that competitively and reversibly binds to the pituitary GnRH receptors, thereby rapidly reducing the release of gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH), and thereby reducing the secretion of testosterone by the testes.
Manufacturing Process and Process Controls
The drug substance, degarelix acetate, is synthetically derived. Materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process consists of a multi-step synthesis. In-process controls performed during manufacture were reviewed and are considered acceptable.
Characterization
The structure of degarelix acetate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference on Harmonisation (ICH)-established limits and/or were qualified from toxicology studies and batch analyses; and therefore considered to be acceptable.
Control of Drug Substance
The analytical methods and validation reports are considered satisfactory for all analytical procedures used for release and stability testing of the drug substance. The specifications are considered adequate to control the quality of the drug substance.
Data from the batch analysis were reviewed and are considered to be acceptable according to the specifications of the drug substance.
The drug substance packaging is considered acceptable.
Stability
Based on long-term and accelerated stability data, the proposed retest period, shelf-life, and storage conditions for the drug substance are supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Firmagon is presented as a white to off-white lyophilized powder which is reconstituted with sterile water for subcutaneous injection. Firmagon is provided in two different strengths 80 mg and 120 mg. Firmagon is supplied in a kit containing either two vials of Firmagon 120 mg with two vials of sterile water for injection, two reconstitution needles, and two injection syringes with injection needles; or one vial of Firmagon 80 mg with one vial of sterile water for injection, one reconstitution needle, and one injection syringe with an injection needle.
The non-medicinal ingredient mannitol, used as an isotonicity and bulking agent in the drug product, is acceptable for use in drugs according to the Food and Drug Regulations. Compatibility of degarelix with this non-medical ingredient has been demonstrated by stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
A detailed description of the manufacturing process was provided. The drug product manufacturing process includes sterilization by filtration of the bulk solution, aseptic filling into sterile pyrogen free vials, and freeze-drying under aseptic conditions. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Firmagon is tested using Professed Standards with specifications that conform to ICH requirements. Validation results of the analytical method used in manufacturing of Firmagon were determined suitable for the intended use. Data from final batch analyses were also reviewed and complied with the proposed drug specifications. Impurities arising from manufacturing and/or storage were reported and characterized and are considered to be acceptable.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed shelf-life of 36 months is considered acceptable for the product when stored at 25°C.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Firmagon are considered suitable for the activities and products manufactured. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations. In addition, all sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. None of the materials used in the synthesis of the drug product are of human or animal origin.
3.1.5 Conclusion
During the Chemistry and Manufacturing review, a few minor discrepancies were noted with regards to the pharmaceutical section of the Product Monograph, carton label, and the Certified Product Information Document (CPID). In response to the NON the sponsor adequately addressed all discrepancies noted.
The Chemistry and Manufacturing information submitted for Firmagon has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Pharmacology studies, both in vitro and in vivo, have provided adequate evidence that Firmagon causes a fast and sustained suppression of testosterone to castrate levels and has an anti-tumour efficacy, equivalent to surgical castration, on androgen dependent tumours. When injected subcutaneously at doses 0.3-10 μg/kg, Firmagon produced a dose-dependent suppression of plasma testosterone in rats. The minimum effective dose was 1 μg/kg, producing 71% suppression of plasma testosterone.
Pharmacology studies were conducted to assess whether Firmagon has the potential to increase the duration of the QT (QTc) interval on an electrocardiogram (ECG). In vitro and in vivo assays conducted revealed that Firmagon had no or little potential to induce QT prolongation. In vitro assays (hERG and Purkije fibres assays) have demonstrated no potential for these effects when evaluated at more than 200 times the human exposure, based on Cmax comparison. Similarly, no significant effects in the in vivo assays in monkeys have been observed at more than 20 times of human plasma level, based on Cmax comparison.
3.2.2 Pharmacokinetics
Absorption
Pharmacokinetic studies have shown that following subcutaneous administration, degarelix forms a unique depot at the injection site which acts like a sustained release drug. The absorption from the depot is dependent on the concentration of degarelix in the dosing solution and the dose volume. Degarelix has a median terminal half-life of approximately 43 days for the starting dose, or 28 days for the maintenance dose, as estimated based on population pharmacokinetics modeling.
Distribution
Degarelix is widely distributed throughout the entire body with no evidence of accumulation. Distribution of radioactivity following administration of radio-labelled degarelix (3H-degarelix) in rats, dogs, and monkeys showed highest concentrations in tissues related to hepatic and renal excretion within a few hours following administration. Lower concentrations, but still higher than those in plasma, were seen in some organs of the endocrine and reproductive systems most of which contain specific receptors for luteinizing hormone-releasing hormone (LHRH).
In vitro, degarelix was highly bound to plasma proteins in rats, mice, dogs and monkeys. No evidence of concentration-dependent binding was reported for any of the species tested.
Metabolism
In vitro studies conducted in liver microsomes of the rat, guinea pig, rabbit, and dog showed negligible to minor degradation of degarelix. The metabolic pathway of degarelix appears to be not by oxidative pathways but rather degradation by peptidases (hydrolytic cleavage) resulting in the formation of truncated peptides, none of which are expected to have biological activities.
Excretion
Studies conducted with 3H-degarelix in rats and dogs revealed that degarelix is mainly excreted unchanged through the urine. In the monkey, degarelix is mainly excreted through the faeces rather than urine.
3.2.3 Toxicology
Single-Dose Toxicity
Subcutaneous Administration
Toxicology studies conducted in rats and mice administered degarelix subcutaneously revealed the drug was well tolerated and no acute signs of systemic toxicity were evident. Given this, establishment of the maximum tolerated doses in both the rat and mice were assessed based on local reactions which occurred at the injection site. The local effect was considered as an inflammatory response which resulted in macrophage infiltration and granuloma formation. The no-observed-adverse-effect-level (NOAEL) for direct systemic effects in mice and rats was established to be approximately 100 mg/kg. In monkeys, the NOAEL was determined to be 50 mg/kg.
Intravenous Administration
The intravenous administration of degarelix to rats and monkeys resulted in direct systemic toxicity, mainly due to the accumulation of the drug in cells of the reticuloendothelial system in the liver, kidney and lung. The main toxicity findings, related to the accumulation of the drug in the kidney and liver were microscopic changes in these organs. The lowest lethal dose observed after a single intravenous injection was 12.5 mg/kg in rats.
It should be noted that the intravenous route of administration is considered as an alternate route for investigation and is not the recommended route to be used in humans. In addition, the histopathological changes observed in the liver and the lung were not seen when the drug was administered subcutaneously in monkeys.
Repeat-Dose Toxicity
Repeat-dose toxicity studies were conducted via subcutaneous administration with durations of 6 and 12 months in rats and monkeys. In addition, a 13-week subcutaneous toxicity study was also conducted in mice. Results of these studies showed that the pharmacological effect of degarelix was evident at the lowest dose level tested: 1.0 mg/kg/2 weeks in mice, 0.5 mg/kg/2 weeks in rats, and 0.5 mg/kg/4 weeks in monkeys.
At higher dose levels tested: 100 mg/kg/2 weeks in mice, 50 and 100 mg/kg/2 weeks in rats, and 50 mg/kg/4 weeks in monkeys, subcutaneous injections administered caused a dosage-related increase in the local site reactions and occasionally lead to premature euthanasia or caused signs of systemic toxicity (decreased body weight development).
In cynomolgus monkeys treated for 12 months by the subcutaneous route, the NOAEL was estimated to be 50 mg/kg/4 weeks, which represents 13 times the human exposure based on the concentration time curve (AUC). Although no functional or histopathological changes was evident in the liver, elevated levels of gamma-glutamyl transpeptidase (GGT) was observed (1.7 times of control). An increase of this liver enzyme in the serum is considered to be indicative of biliary lesion. Thus, some liver damage as indicated by the increased serum levels of GGT has been observed. Furthermore, although there is limited evidence for liver toxicity in animal studies, a thorough examination of liver functions in human should be carried out.
Genotoxicity
There is no evidence that degarelix has the potential to induce gene mutation or clastogenicity, based on the results of genotoxicity assays.
Carcinogenicity
Degarelix was administered subcutaneously to mice every 2 weeks for 2 years at doses of 2, 10 and 50 mg/kg/2 weeks (about 3, 15 and 75 times the recommended human maintenance dose on a mg/kg basis; or about 1, 4.6 and 17 times the expected human exposure at the recommended dose). An increased incidence of sarcomas was observed in the treated groups as compared to the controls, but this was not statistically significant. The occurrence of sarcomas, mainly at the injection sites, can be attributed to a mechanism associated with foreign body carcinogenesis, which is generally recognised to occur in rodents but not in other species, including man.
Degarelix was also administered subcutaneously to rats every 2 weeks for 2 years at doses of 2, 10 and 25 mg/kg/2 weeks (about 3, 15 and 38 times the recommended human maintenance dose on a mg/kg basis; or about 1.8, 6.2 and 12.4 times the expected human exposure at the recommended dose). In female rats, there was a statistically significant increase in the incidence of combined haemangiomas and hemangiosarcomas in the high dose group (25 mg/kg/2 week). At this dose, the ratio of exposure levels in rats versus humans was estimated to be twelve times higher than that of the human recommended dose. Overall, the carcinogenic potential of degarelix is considered negligible, despite the fact that there was an increased incidence of combined hemangioma and hemangiosarcoma in female rats. This conclusion is based on lack of carcinogenic activity in male rats (including no observed increase in the incidence of hemangiosarcoma) and mice of both sexes, and because it is not genotoxic.
Reproductive and Developmental Toxicity
Degarelix produces reversible infertility in both male and female rats. A single subcutaneous dose caused reversible infertility at ≥1 mg/kg and ≥0.1 mg/kg in males and females, respectively.
3.2.4 Summary and Conclusion
Overall, the non-clinical data provided sufficient evidence to support the use of degarelix in humans for treatment of advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted. No major safety issues have been identified and only minor adverse effects resulting from local tolerability to the depot at the injection site is expected in humans. Thus, degarelix is recommended for use in humans.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In the clinical studies, it was demonstrated that a single dose of Firmagon 240 mg followed by a monthly maintenance dose of 80 mg rapidly caused a decrease in the concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and subsequently testosterone. The plasma concentration of dihydrotestosterone (DHT) decreased in a similar manner to testosterone. Monthly maintenance doses of Firmagon 80 mg resulted in sustained testosterone suppression in 97% of patients for at least one year. In addition, prostate specific antigen (PSA) levels were lowered by 64% two weeks after the administration of Firmagon, 85% after one month, 95% after three months, and remained suppressed throughout the one-year of treatment. These PSA results should be interpreted with caution given the heterogeneity of the patient population studied. In addition, no evidence has shown that the rapidity of PSA decline is related to a clinical benefit.
3.3.2 Pharmacokinetics
Absorption
Following subcutaneous administration, Firmagon forms a unique gel-like depot at the injection site. Firmagon is released from the depot into the circulation in two phases: a fast release phase immediately after dosing, accounting for the initial peak plasma concentration levels observed, followed by a very slow release phase which then defines the plasma concentration levels. The pharmacokinetic behaviour of the drug is strongly influenced by its concentration in the injection solution. The maximum observed serum concentration and bioavailability tend to decrease as the concentration of the dose increases, while the terminal half-life is increased. Therefore, no other dose concentrations than the recommended should be used.
In the Phase III pivotal study (see section 3.3.4 Clinical Efficacy for further details of the study) following subcutaneous administration of Firmagon 240 mg at a concentration of 40 mg/mL, the AUC from 0-28 days was 635 day ng/mL (range: 602-668), the maximum drug concentration (Cmax) was 66.0 ng/mL (range: 61.0-71.0) and occurred at 40 hours (range: 37-42). 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. Firmagon decreases in a biphasic fashion, with an estimated median terminal half-life of approximately 43 days for the starting dose or 28 days for the maintenance dose, as estimated based on population pharmacokinetics modeling. The long half-life after subcutaneous administration is a consequence of a very slow release of the drug from the Firmagon depot formed at the injection site(s).
Distribution
The distribution volume of Firmagon after intravenous administration is approximately 1 L/kg in healthy elderly men. This indicates that Firmagon is distributed throughout total body water. In vitro plasma protein binding of Firmagon is estimated to be approximately 90%.
Metabolism
Firmagon undergoes common peptidic degradation during passage through the hepato-biliary system and is mainly excreted as peptide fragments in the faeces. No quantitatively significant metabolites were detected in plasma samples after subcutaneous administration. In vitro metabolism studies demonstrated Firmagon is not a substrate for the human cytochrome P450 or P-glycoprotein transporter systems. Therefore, clinically significant pharmacokinetic drug-drug interactions are unlikely.
Excretion
Firmagon is predominantly eliminated through the faeces with a smaller amount through the urine.
Drug Interaction Studies
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of Firmagon with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes should be carefully evaluated.
Local Tolerance
Injection site reactions involving pain, irritation or oedema were reported in approximately a third of patients administered Firmagon.
Antibody Development
A safety concern regarding the development of antibodies to Firmagon was reported in the NON. Approximately 10% of the patients that received Firmagon developed antibodies to this drug during a 12-month follow-up period. However, there is no indication that the efficacy or safety of Firmagon treatment is affected by antibody formation after one year of treatment. There is no indication that the development of anti-Firmagon antibodies is a predictive factor for experiencing immune-related adverse events. In the regular safety surveillance of Firmagon, there have been no cases of severe immediate onset hypersensitivity and no new safety concerns identified.
Special Populations and Conditions
Renal Impairment
No pharmacokinetic studies in renally impaired patients have been conducted. Only about 20-30% of a given dose of Firmagon is excreted unchanged by the kidneys. A population pharmacokinetics analysis of the data from the confirmatory Phase III trial has demonstrated that the clearance of Firmagon in patients with moderate renal impairment is reduced by 23%; therefore dose adjustment in patients with mild or moderate renal impairment is not recommended. Data on patients with severe renal impairment are scarce and caution is therefore warranted when prescribing to this population. As a result, a note has been inserted in the Serious Warnings and Precautions box within the Product Monograph.
Hepatic Impairment
Firmagon has been studied in a pharmacokinetic study in patients with mild to moderate hepatic impairment. No signs of increased exposure in the hepatically impaired were observed compared to healthy subjects. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. The exposure of Firmagon decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, recommendations for monitoring of testosterone concentrations in patients with mild and moderate hepatic impairment are suggested. Patients with severe hepatic impairment have not been studied. Caution is warranted when prescribing to this population. As a result, a note has been inserted in the Serious Warnings and Precautions box within the Product Monograph. Monitoring of liver function in patients with known or suspected hepatic disorder is advised during treatment.
Age, Weight and Race
Population pharmacokinetic analysis shows only a small change in clearance of Firmagon related to age and weight. Therefore, dose adjustment is not warranted.
Geriatrics
The patient population in the clinical program is typical of the intended target population of patients with prostate cancer. The mean age was 74 years (age range 47 to 98 years).
3.3.3 Clinical Efficacy
The efficacy of Firmagon was evaluated in one Phase III, open-label, multicentre, randomized, active comparator, parallel-group study conducted in 620 patients with prostate cancer requiring androgen deprivation therapy. Of the 620 patients enrolled, 610 patients were randomized in a 1:1:1 ratio to one of three treatment groups; a starting dose of Firmagon 240 mg (40 mg/mL) followed by monthly subcutaneous injections of either Firmagon 80 mg (20 mg/mL) or Firmagon 160 mg (40 mg/mL), in comparison to monthly intramuscular injections of leuprolide 7.5 mg.
The study design consisted of patients in the Firmagon treatment groups receiving a starting dose of Firmagon 240 mg at Day 0, followed by a maintenance dose of Firmagon 160 mg (40 mg/ml) or Firmagon 80 mg (20 mg/ml) every 28 days. Patients in the comparator group received treatment with leuprolide 7.5 mg at Day 0 and continued to receive leuprolide 7.5 mg every 28 days thereafter. The primary objective of the study was to demonstrate that Firmagon was effective with respect to achieving and maintaining testosterone suppression to castrate levels, evaluated by proportion of patients with testosterone suppression ≤1.735 nmol/L (≤0.5 ng/ml) during 12 months of treatment.
All patients in this study had histologically proven adenocarcinoma of the prostate of all stages. Of the 610 randomized patients, 191 (31%) had localized cancer, 178 (29%) had locally advanced cancer, 125 (20%) had metastatic cancer, 13% had previous curative intent surgery or radiation and a rising PSA, and 7% had an unknown metastatic status at the time of enrollment.
Results of the study showed that Firmagon was effective in achieving and maintaining testosterone at castrate levels ≤0.5 ng/ml. Furthermore, this effect was maintained in both Firmagon treatment groups for the duration of the 12-month study. The cumulative probabilities of maintaining testosterone at castration level from day 28 to day 364 were 98.3% and 97.2%, and 96.4% for the Firmagon 240/160 mg, Firmagon 240/80 mg and leuprolide 7.5 mg groups, respectively. Treatment with Firmagon was thereby demonstrated to be non-inferior to leuprolide 7.5 mg therapy with respect to the probability of testosterone ≤0.5 ng/ml. In addition, none of the patients treated with Firmagon experienced a testosterone surge, that is (i.e.) a testosterone level exceeding baseline by ≥15% within the first 2 weeks, compared with 161 patients (80.1%) in the leuprolide group (p<0.0001). The cumulative probabilities of maintaining testosterone at castration level from day 28 to day 364 were similar among subgroups based on stage of prostate cancer.
PSA levels decreased rapidly following Firmagon administration. On Day 14 the median percentage change in PSA decreased 64.3% from baseline for the pooled Firmagon groups, with a further decrease in PSA levels observed on Day 28 with the median % reduction in PSA from baseline being 83.6%. In contrast, the suppression of PSA levels in patients who received leuprolide was much slower with a median percentage decline in PSA from baseline of 17.9% and 66.7% on Day 14 and Day 28 respectively. In the leuprolide group, a greater median percentage change in PSA levels from baseline was observed for patients who received anti-androgen therapy compared with those who did not. For patients who started anti-androgen therapy on or before Day 7, median percentage change in PSA levels from baseline was similar to that for patients treated with Firmagon.
The profiles for serum levels of LH over time were as expected similar to those observed for testosterone. Following administration of Firmagon, median LH levels decreased rapidly and were < 0.7 IU/L on Day 1, a decrease of approximately 88% from baseline, and 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 group with a peak at 31.0 IU/L on Day 1 before decreasing exponentially to 0.035 IU/L by Day 56 and remaining at this level until Day 364. FSH levels were rapidly decreased following administration of Firmagon with median decreases from baseline of 41% at Day 1 and 96% at Day 28. At the end of the study on Day 364, FSH levels were decreased approximately 87% relative to baseline. In contrast, there was an initial surge ion FSH levels after leuprolide with a median increase in FSH of 146% relative to baseline at Day 1. Subsequently FSH was decreased to a lesser extent than Firmagon with median decreases of 75% and 53% relative to baseline at Day 28 and Day 364 (end of study), respectively.
An assessment of quality of life was completed by using two validated questionnaires to measure generic and cancer-specific quality of life respectively. However, there were technical problems in data transfer as well as issues with patient compliance. The limited quality of life data available were unable to demonstrate any significant difference between the study drug regimens.
It should be noted that efficacy endpoints within the above study were limited to serum measurements of levels of testosterone, LH, FSH, and PSA. The changes in PSA are difficult to interpret due to the inclusion of patients with various stages of prostate cancer in the pivotal study and to the unknown clinical relevance of a rapid PSA decline. No direct assessment of the anatomic sites of the disease was made before or after treatment. Because of the short duration of the study, no comparative survival data between treatment groups are available. Testosterone suppression served as the primary efficacy endpoint and as the endpoint relevant to approval.
Concerns regarding the study population were identified in the NON. Although the study population of the Phase III study reflected the broad indication proposed by the sponsor, Health Canada was concerned that this population did not reflect the population for which the active comparator is approved (advanced [stage D2] prostate cancer). While testosterone suppression to below 0.5 ng/mL is considered to be a valid surrogate endpoint for clinical benefit in the treatment of metastatic prostate cancer, there was concern that effective testosterone suppression by Firmagon had not been demonstrated in the stage D2 prostate cancer population as the confirmatory study was conducted in patients with all stages of prostate cancer, with a relatively small proportion actually having metastatic prostate cancer (20%).
Following review of the NON response, it was acknowledged that while the indication for the active comparator (leuprolide) in the pivotal trial is the palliative treatment of sex hormone responsive advanced (stage D2) carcinoma of the prostate, the pivotal trial used to assess Firmagon was designed to recapitulate current practice in that it included patients with advanced prostate cancer, as well as earlier stages of prostate cancer (for which the benefit of androgen deprivation therapy is unproven). Although successful achievement and maintenance of testosterone at castrate levels from Day 28 to Day 364 was demonstrated in all stages of the disease, Health Canada recommends approval of Firmagon with an indication for testosterone suppression in patients with advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted. As testosterone suppression is not a validated surrogate endpoint in the advanced prostate cancer setting, a qualifying statement to clarify that there was no demonstration of palliation or prolongation of survival was included in the Indication section of the Product Monograph.
3.3.4 Clinical Safety
The clinical safety of Firmagon was primarily assessed in one pivotal Phase III study conducted in 610 patients treated for prostate cancer for one year. For a description of the study, see section 3.3.3 Clinical Efficacy. In addition, further data was provided through analyses of pooled data from the Firmagon safety database where the median duration of follow-up has been 1.2 years (mean 1.7 years).
In the pivotal Phase III study, adverse events (AEs) were regarded as "treatment emergent" if they occurred in the time interval from initial dosing to End-of-Study. For patients without an End-of-Study Visit, adverse events were considered treatment-emergent if the event occurred within 45 days after the last visit for the patient. The percentages of patients experiencing AEs were comparable across all three treatment groups. Overall, 167 (83%) patients in the Firmagon 240/160 mg treatment group reported AEs, compared with 163 (79%) patients in the Firmagon 240/80 mg treatment group and 156 (78%) patients in the 7.5 mg leuprolide treatment group. The most frequently reported AE for both Firmagon and leuprolide patients during the study were hot flushes: 52 (26%) patients in the Firmagon 240/160 mg group compared to 53 (26%) patients in the Firmagon 240/80 mg group, and 43 (21%) patients in the leuprolide group.
Injection site reactions occurred most frequently with the administration of Firmagon. Injection site reactions in Firmagon-treated patients included pain at injection site (28%), erythema (17%), swelling (6%), and induration (4%) and injection site nodules (3%). In comparison, injection site reactions occurred in <1% patients in the leuprolide group. Fewer patients in the Firmagon 240/80 mg group reported injection site reactions as compared to the Firmagon 240/160 mg (35% patients versus 44% patients respectively) suggesting that the lower Firmagon maintenance dose may result in fewer injections site reactions. None of the injection site reactions were considered serious adverse events (SAEs) and no immediate onset hypersensitivity reactions occurred after dosing. Injection site reactions which led to withdrawal were reported by five (1.2%) of the Firmagon-treated patients.
A total of 19 patients died during the course of the study, as a result of 21 treatment-emergent SAEs, with relatively equal incidence across treatment groups: 10 (2%) patients receiving Firmagon and 9 (4%) patients receiving leuprolide. None of these deaths were related to the study drug.
There were no patients receiving Firmagon who reported a serious adverse event (SAE) which was deemed drug-related. A single patient in the leuprolide group had an abnormal prostate examination which was considered a drug-related SAE.
Changes in clinical chemistry and haematology parameters were monitored during the study. As expected, a decrease of testosterone induced by the study drug did lead to decreased haemoglobin and haematocrit values (shifts from high/normal to low) in approximately 40% of patients in the pooled Firmagon group and in the leuprolide group. An analysis of renal function also showed that 68% of patients in the pooled Firmagon group and 69% of patients in the leuprolide group had a shift from low/normal to high for urea nitrogen. Marked changes for urea nitrogen were not generally accompanied by concomitant changes in serum creatinine. It has been shown that androgen deprivation can cause increases in urea nitrogen.
In the pivotal Phase III study, changes in hepatic laboratory values were similar for patients treated with Firmagon and for patients treated with leuprolide. Markedly abnormal, as defined by greater than 3 times the upper limit of normal (ULN), liver transaminase values (alanine transaminase, aspartate aminotransferase and gamma-gllutamyltransferase) were seen in 2-6% of patients who had normal values prior to initiation of treatment. These peaks in transminases occurred in the initial period of treatment and generally were reversible in spite of continued exposure. Only in a few cases, reversibility could not be determined since there were no further measurements available after the patient either completed or was withdrawn from the study. Two patients in the Firmagon group had increases in ALT greater than 10 times ULN (range: 10-15 times ULN) and both patients recovered in spite of continued exposure. While elevations of ALT are a sensitive sign of hepatic toxicity, they are not very specific. Therefore, in addition to hepatocellular injury it is important to evaluate cases of potential drug-induced altered liver function. Abnormal total bilirubin levels were reported in 33 (8%) patients in the pooled Firmagon group and 23 (11%) patients in the leuprolide group. For the majority of these patients abnormal total bilirubin values were less than 1.5 times ULN. No patients had concurrent increases in ALT greater than 3 times ULN and bilirubin greater than 1.5 times ULN. In the pooled safety data (1848 patients with evaluable liver function tests), a total of 8 (<1%) patients had increased ALT greater than 10 times ULN; 3 of these patients had increased ALT greater than 25 times ULN, up to ALT greater than 31 times ULN. All 5 patients with concurrent increase in ALT and bilirubin also had increased alkaline phosphatase greater than 2 times ULN, suggesting cholestasis. Although no cases of severe drug induced liver injury were identified for Firmagon, the sponsor plans to continue monitoring hepatic parameters (laboratory values and adverse events) in their clinical program. Warnings and precautions regarding hepatic function are also included in the Product Monograph.
Safety concerns regarding the drug effect on QT interval, bone density, and the effect on safety and efficacy as a result of the known antibody development to Firmagon were identified in the NON.
Due to the pharmacological action of the drug (androgen deprivation), Firmagon has the potential to increase the duration of the QT interval on an electrocardiogram (ECG). As such, ECG measurements were performed to investigate any possible effects of Firmagon on cardiac repolarisation. In clinical trials in general, a prolongation of the QT interval greater than 500 msec during therapy has been a threshold of particular concern. In this study, emphasis was placed on the QTc results based on Fridericia's correction (QTcF). Results showed that there was no significant difference between the treatment groups for the mean change in QTcF from baseline to Day 3 and to End-of-Study. The mean changes in QTcF were 10.3 msec for the 160 mg maintenance Firmagon dose, 11.7 msec for the 80 mg Firmagon maintenance dose, and 13.0 msec for the leuprolide group. In total, 84 (21%) patients who received Firmagon and 41 (20%) patients treated with leuprolide had a post-baseline QTcF equal to or above 450 msec. A further 20 patients had QTcF results equal or above 480 msec: 13 (3%) in the pooled Firmagon group and 7 (3%) patients in the leuprolide group. A total of 7 patients, 3 (<1%) in the pooled Firmagon group and 4 (2%) patients in the leuprolide group had a markedly abnormal QTcF equal or greater than 500 msec. An increase in QTcF may be related to prolonged testosterone suppression. The direct pharmacological effect of Firmagon on the QT interval will be addressed in a planned thorough QT/QTc study (FE200486 CS22) expected to start in 2010. Meanwhile, QT prolongation has been identified as a clinically significant adverse event, and warnings and precautions are included in the Product Monograph.
Decreased bone density with an increased risk of fracture 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. Skeletal fracture in prostate cancer patients may be negatively associated with overall survival. Therefore, there is a need for caution in the use of androgen deprivation therapies in settings without clear evidence of a benefit. During the 12-month treatment period in the pivotal Phase III study, 0.7% of Firmagon and 2.5% of leuprolide patients reported fractures and/or osteoporosis or osteopenia. The leuprolide group had a higher proportion of patients (23%) with metastatic cancer compared with the Firmagon treatment groups (18-20%); 7-16% of the fractures in prostate cancer are secondary to bone metastases. In the pooled Firmagon safety database, where the median duration of follow-up has been 1.2 years (mean 1.7 years), 3.3% of prostate cancer patients have reported bone mineral density/osteoporosis-related adverse events. The pooled Firmagon safety database includes the extension studies during which patients have aged further and bone mass density/osteoporosis incidence rates are well known to increase with age. These frequencies are not considered to be above what could be expected in a study population of this age and disease stage. The sponsor plans to investigate the effect of Firmagon on bone mass density and osteoporosis in a dedicated study scheduled to start in 2010. In addition, a comparative three-year observational Post-Authorisation Safety Study (PASS) is also planned to start in 2010 to investigate the long-term safety (incidence rate of bone fractures, cardiovascular events and new-onset diabetes mellitus) of Firmagon versus any marketed GnRH agonist. Meanwhile, osteoporosis has been listed as a clinically significant adverse event, and warnings and precautions are included in the Product Monograph.
The remainder of the safety concerns identified were addressed satisfactorily in the NON response with revisions to the Product Monograph highlighting the basis of the indication on demonstration of testosterone suppression limited to a one year treatment period and to alert the health professional and patient to clinically significant adverse effects associated with androgen deprivation therapy in general (for example [e.g.], ECG QT interval prolongation, bone mineral density decreases, cardiovascular effects, changes in glucose tolerance, anemia), as well as with Firmagon therapy in particular.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Firmagon is a gonadotropin releasing hormone (GnRH) receptor antagonist (blocker) which results in the suppression of pituitary gonadotropins and leads to decreased testosterone production by the testes. The nonclinical and clinical programs have demonstrated that Firmagon decreased circulating levels of luteinising hormone (LH), follicle-stimulating hormone (FSH) and testosterone. The phase III confirmatory study has shown Firmagon to be effective in achieving suppression of testosterone to a plasma level below 0.5 ng/mL (i.e., castrate level) within 3 days and maintaining suppression for at least one year, as well as to be non-inferior to leuprolide (the active comparator in this study) with respect to the probability of testosterone suppression from Day 28 to Day 364. Adverse events were generally comparable between Firmagon and leuprolide, with the exception of injection site reactions which occurred most frequently with the administration of Firmagon. Clinically significant adverse effects associated with androgen deprivation therapy in general include ECG QT interval prolongation, cardiovascular effects, decreases in bone mineral density, fractures and/or osteoporosis or osteopenia; and treatment-emergent adverse effects observed in clinical studies in association with Firmagon included ECG QT interval prolongation, cardiovascular effects, and fractures and/or osteoporosis or osteopenia. Safety data provided were limited to 1.2 years median duration of follow-up. Development of antidegarelix antibody was observed in 10% of patients treated with Firmagon in the phase III study; however, there was no indication that the efficacy or safety of Firmagon treatment was affected by antibody formation. Despite Firmagon being a new active substance, a thorough QT study to investigate the potential intrinsic effect of Firmagon to prolong the QT-interval has not been conducted.
While testosterone suppression to below 0.5 ng/mL is considered to be a valid surrogate endpoint for clinical benefit in the treatment of metastatic prostate cancer, the confirmatory study was conducted in patients with all stages of prostate cancer with a relatively small proportion (20%) actually having metastatic prostate cancer. Leuprolide (to which Firmagon was shown to be non-inferior) is indicated for the palliative treatment of sex hormone responsive advanced (stage D2) carcinoma of the prostate. However, as the management of prostate cancer has evolved since the GnRH agonists entered the market in the late 80s, patients with hormone naïve stage D2 prostate cancer are now rare. The pivotal study recapitulates current practice in that it included patients with all stages of prostate cancer.
The direct pharmacological effect of Firmagon on the QT interval will be addressed in a planned thorough QT/QTc study expected to start in 2011. Cautionary statements regarding QT prolongation have been included in the Product Monograph.
While adverse events associated with Firmagon were comparable to those associated with leuprolide, and androgen deprivation therapy in general, the long-term safety profile of Firmagon, especially with respect to bone mineral density decreases and cardiovascular effects, has not been established. In addition, while there was no indication that the efficacy or safety of treatment with Firmagon was affected by antibody formation in the phase III study, data beyond one year are not available.
An advantage of Firmagon in comparison with LHRH agonists is the capacity of Firmagon to rapidly suppress (less than 48 hours) the release of pituitary gonadotropins resulting in a decreased secretion of testosterone. LHRH agonists may initially trigger an increased production of gonadotropins and testosterone with aggravation of the symptomatology of prostatic cancer. However, clinical benefit for Firmagon compared to leuprolide plus antiandrogen for surge protection in the initial phase of treatment has not been demonstrated. The clinical advantage of suppression of the initial flare is only relevant in a minority of metastatic patients.
Health Canada considers this benefit risk profile to support approval of Firmagon with an indication for testosterone suppression in patients with advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted. As testosterone suppression is not a validated surrogate endpoint in the advanced prostate cancer setting, a qualifying statement to clarify that there was no demonstration of palliation or prolongation of survival is included in the Indication in the Product Monograph.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Firmagon is favourable for testosterone suppression in patients with advanced hormone-dependent prostate cancer in whom androgen deprivation is warranted. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Firmagon®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-05-15 |
| Submission filed: | 2008-06-02 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-07-18 |
| Review 1 | |
| Quality Evaluation complete: | 2009-05-14 |
| Clinical Evaluation complete: | 2009-05-14 |
| Notice of Non-Compliance issued by Director General (safety, efficacy, and quality issues): | 2009-05-14 |
| Response filed: | 2009-07-13 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2009-08-05 |
| Review 2 | |
| Quality Evaluation complete: | 2009-10-02 |
| Clinical Evaluation complete: | 2009-11-05 |
| Labelling Review complete: | 2009-10-29 |
| Notice of Compliance (NOC) issued by Director General: | 2009-11-16 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| FIRMAGON | 02337029 | FERRING INC | DEGARELIX (DEGARELIX ACETATE) 80 MG / VIAL |
| FIRMAGON | 02337037 | FERRING INC | DEGARELIX (DEGARELIX ACETATE) 120 MG / VIAL |