Summary Basis of Decision for Vantas ®

3.3.1 Clinical Program

A total of four clinical studies were conducted to demonstrate the safety and efficacy of the histrelin acetate subdermal implant for the treatment of patients with advanced prostate cancer. Study #07-03-100 was a Phase I, open study that collected single-dose pharmacokinetic data in 6 healthy male volunteers. Study BAR-002-0591A-USA was a Phase II, open, parallel-group, international study that collected continuous-dosing pharmacokinetic and dose-ranging data, as well as therapeutic efficacy and safety outcomes, in 42 males with prostate cancer. Study #301 was a Phase II/III, open-label, international, pivotal efficacy and safety study that administered a single histrelin acetate subdermal 50 mg implant every 12 months into 138 males with advanced prostate cancer, and Study #302 was a non-pivotal, Phase II/III open-label study that administered a histrelin acetate subdermal 50 mg implant every 12 months into 33 patients with advanced prostate cancer.

A total of 185 patients with metastatic prostate carcinoma or patients having failed or proven refractory to definitive therapy were administered Vantas^® (50 mg histrelin acetate subdermal implant) once every 12 months. These patients were the population base for demonstrating the efficacy and safety of the histrelin acetate subdermal implant.

3.3.2 Pharmacodynamics

An indirect pharmacodynamic relationship between serum testosterone and serum histrelin concentrations was observed in 119 prostate cancer patients. This relationship was consistent with the mechanism of action . Following an initial stimulatory phase, chronic subcutaneous administration of histrelin acetate desensitizes the responsiveness of the pituitary, which in turn causes reductions in ovarian and testicular steroidogenesis, including the production of testosterone.

3.3.3 Pharmacokinetics

The pharmacokinetics of histrelin acetate has been appropriately investigated in healthy volunteers as well as in the target patient population. The pharmacokinetics were characterized in three studies: #07-03-100 (n = 6); #BAR-002-0591A-USA (n = 42), and #301 (n = 138).

From the single-dose healthy volunteer study 07-03-100, following a single 500 µg subcutaneous (SC) bolus of histrelin acetate, peak serum concentrations occurred at 0.75 to 2 hrs post-dosing, with a peak of 13.5±3.00 ng/mL (mean+SD). With prostate cancer patients enrolled in studies BAR-002-0591A and #301, peak serum histrelin concentrations were achieved more slowly with the histrelin subdermal implant (median 12 hrs post-implant insertion) while peak concentrations averaged 1.10±0.375 ng/mL. Continuous SC release was evident throughout in contrast to the rapid decline in blood levels which followed the single bolus SC injection of histrelin. The average rate of SC drug release observed in Study #301, based on residual drug content of the implant device, was >56.7  µg/day over the 52-week dosing period which is consistent to the in vitro release rate of 56-57 µg/day. This results in a bioavailability of 92% for the histrelin SC implant in males with advanced prostate carcinoma with normal renal and hepatic function.

The apparent volume of distribution after the single 500 µg SC bolus injection in healthy males was 58.4±7.86 L. The fraction of unbound drug in plasma measured in vitro was 29.5%±8.9%. The in vitro drug metabolism data for histrelin were obtained using human hepatocytes. A single metabolite was found resulting from C-terminal dealkylation. Peptide fragments resulting from hydrolysis were also likely metabolites.

Excretion data from healthy volunteers given a single SC injection of 500 µg showed an apparent histrelin clearance of 179 +37.8 mL/min with a terminal half-life of 3.92±1.01 hrs. These figures compare to corresponding figures of 174±56.6 mL/min and 20 weeks, respectively for prostate cancer patients implanted with the hydrogel system loaded with 50 mg of histrelin.

The pharmacokinetics of histrelin were evaluated in prostate cancer patients with renal or hepatic failure. Although C_max, T_max, Vd, and half-life were prolonged when impairment was present either at baseline or post-baseline, no dose adjustments were considered necessary as is the case with other currently employed Luteinizing Hormone-Releasing Hormone (LHRH) analogue depot products used in the same clinical setting. The wide margin of safety for histrelin appears to support this recommendation.

Study #301 enrolled patients that were Caucasian, Black, and Hispanic. A subset exploratory analysis of race indicated that race did not have an impact on the kinetics of histrelin in the target population.

No specific pharmacokinetic drug-drug interaction studies were conducted for the histrelin hydrogel implant. However, given the minimal involvement of hepatic microsomal enzymes in the metabolism of GnRH agonists, induction or inhibition of drug metabolism of other drugs is unlikely. Also, as the extent of binding is not extensive (average fraction unbound was 29.5%), protein binding interactions are unexpected. In addition, no pharmacokinetic drug-drug interactions have been reported for any other GnRH agonists.

3.3.4 Clinical Efficacy

Efficacy results were submitted from pivotal Study 301 and two non-pivotal studies, Study 302 and Study BAR-002-0591A-USA. A total of 174 patients were treated with the proposed dose for the proposed indication. In all three studies, the primary and secondary efficacy endpoints were the same, the collection of data was consistent with regard to time and frequency, and the results were summarized with the same statistical methods.

The study results indicate that the 50 mg histrelin acetate hydrogel subdermal implant device produced a rapid (within 4 weeks), consistent and sustained reduction in serum testosterone levels below castration levels (<50 ng/dL) for more than 12 months in >90% of treated males, median age 75 years with advanced prostate carcinoma. The primary endpoint of chemical castration is a well-established and accepted surrogate efficacy endpoint for hormone-dependent prostate carcinoma and its reliability is further confirmed by a mirrored final reduction in patient serum LH, PSA and PAP levels, all indicating an inhibition of the pituitary-gonadal axis characteristic of the LHRH agonist analogues. When hormone-dependent prostate tumour cells are deprived of testosterone, tumour activity is minimized or halted, and disease progression is stabilized or ceased. Disease progression (treatment failure) while receiving hormone-blockade therapy is reflected in rising testosterone and PSA levels and clinical signs and symptoms of the spreading tumour.

The submitted clinical trial efficacy data indicate that the 50 mg histrelin acetate hydrogel 12-month implant device is an effective therapy for depriving prostate cancer cells of testosterone. The observed sustained and month-to-month consistent reduction in serum testosterone to below castration levels over the 12-month lifespan of the implant in the studied target patient population confirms the sponsor-reported in vitro implant drug release data. The lack of acute-on-chronic effects from repeated implant exposure in patients who continued treatment with a second, third or fourth implant further supports the efficacy of both the active drug substance and the implant device.

Indirect subjective evidence for the efficacy of this product was found in the improved perceived clinical benefit patients reported while on therapy (i.e. performance status, pain levels, analgesic use) as well as from the fact that >80% of the enrolled and treated patients completed the 60-week study for all three trials.

The target population represents a complex, varied patient group with characteristic age-related medical co-morbidities, differing levels of age and disease-related performance status, prior prostate cancer treatment histories and varying lifestyles. The demographic and disease-related characteristics of the male prostate cancer patients enrolled in the three histrelin clinical trials are representative of the intended target population cared for in the outpatient clinic setting and therefore the reported clinical trial efficacy results are considered reliable for when the drug is administered to the larger patient population in Canada.

Data submitted in support of the therapeutic efficacy of the histrelin implant device are considered sufficiently robust and reliable based on total patient numbers studied, the characteristics of the patient population enrolled and treated, the results of the primary efficacy endpoint and corroboration by the secondary efficacy endpoint outcomes, as well as the known pharmacologic actions of this drug class. The sponsor has demonstrated, to the same standard as the other approved products for this indication in Canada, the efficacy of the 50 mg histrelin acetate 12-month implant device in the proposed target population.

3.3.5 Clinical Safety

A total of 213 patients with advanced prostate cancer were treated with the histrelin acetate 12-month implant, of which 185 were treated specifically with the 50 mg histrelin implant (Studies 301 and 302, n = 171; Study BAR-002-0591A-USA, n = 14). The two efficacy trials, Studies 301 and 302, shared an identical study design including the same schedule and nature of patient evaluation throughout the 60-week study period and therefore a combined safety analysis is appropriate. The small, Phase II dose-range finding study (Study BAR-002-0591A-USA) included higher doses of histrelin than proposed for marketing and only contributed an additional 14 patients dosed at the 50 mg level. The most important safety conclusion from that study was that although no dose-dependent therapeutic effect was observed between the 50 mg, 100 mg and 200 mg histrelin implants, the incidence of adverse reactions was higher (but not differing in nature) for the 100 mg and 200 mg histrelin implants when compared to the 50 mg dose.

For the combined efficacy trials Study 301 and Study 302 (n = 171), the study populations were reflective of the proposed target population: males, median age 74 years (range 48-92 yrs), 85% >65 yrs; ~73% Caucasian, 20% Black; with advanced or metastatic hormone-dependent prostate carcinoma. The study criteria excluded patients with prior androgen-ablative or systemic corticosteroid therapy within one year of study entry, and patients that were orchidectomized. No on-study androgen, anti-androgen or biologic response modifier concomitant therapies were permitted. The study did permit palliative procedures such as transurethral resection of the prostate and irradiation for painful bone metastases.

Adverse Reaction Profile

In the combined safety population almost 100% of the patients reported an adverse event (AE), and ~77% a treatment-related AE of which ~27% of events were rated as serious. No patient in either study discontinued the histrelin treatment due to an AE, however 2% of patients withdrew due to implant site reactions or expulsions. For the 21 patients in Study 301 who received a second implant, 95% reported an AE, 71% treatment-related and 24% experienced a serious event. The consistency in these data underscores the identical study design and on-study patient monitoring and evaluation. A limited comparison is available for the 16 patients in Study 301 that were treated with Lupron 3-month depot and the 25 patients in Study 302 treated with Zoladex 3-month depot. Approximately 94% of the Lupron and 100% of the Zoladex patients reported an AE and 31% and 28%, respectively, experienced a serious AE. Although limited by small patient numbers, the similarity in event rates is likely a reflection of the drug class rather than individual drug formulation or drug delivery system.

In the histrelin-implant population, ~65% of the patients experienced possible or probably treatment-related hot flushes (2% severe, 25% moderate and 38% mild); 13.5% insertion site or local reactions; 10% fatigue; ~5% each for mild renal impairment, gynecomastia and testicular atrophy; and ~3% each for constipation, weight increase, headache, insomnia, decreased libido, and erectile dysfunction. These are all predictable adverse events observed for this class of drug in this patient population. The nature of these AEs as well as the incidence rates are similar to data published in the approved Product Monographs for the depot formulations Lupron, Zoladex and Eligard. The incidence of hot flushes with Suprefact (buserelin acetate) was reported at ~28%.

Death resulting from an AE occurred in 12/171 (7%) of patients in the combined study set. None were judged as treatment-related by the investigator and upon evaluation of each patient's narrative history, the nature of the event leading to death, the timing in relationship to drug administration and the patient's co-morbid conditions as well as prostate cancer response to treatment, no event can be clearly related directly to the effects of histrelin alone. The causes of death in this patient population with a median age of 75 years were either cardiovascular [myocardial infarction (AMI), cardiac heart failure (CHF), cerebrovascular accident (CVA)], pulmonary, or progression or complications of a second malignancy (i.e. brain, colo-rectal). Although this drug class is associated with a slight increase in hypercholesterolemia, a direct causality to enhanced AMI or coronary artery disease (CAD) cannot be determined without studying a patient group of similar age and stage of prostate cancer without any prior CV history. Serious adverse events reported at an incidence of ≥2% included AMI (8/171 or 4.6%) and CVA (5/171 or 2.9%). The relationship of these events to a direct adverse study drug effect is difficult to determine due to the median age of this population (i.e. CV co-morbidity is common) as well as a lack of any clear pharmacological basis for the event. No investigator judged the event to be drug-related based on the timing of the event to drug administration. Also, no serious allergic or anaphylactic reaction was recorded for any study patient.

Regarding adverse events related to the actual implant insertion or implant site, for the 13.5% of patients experiencing a local or insertion-site reaction, all reactions were mild in intensity. The majority of these AEs were associated with initial insertion, or removal and insertion of a new implant, and were resolved within 2 weeks. Reactions persisted in 4 patients (2.8%) and an additional 2.8% of patients developed an application-site reaction after the first two weeks following insertion. Local reactions were characterized by pain/soreness/tenderness (3.6%), erythema (2.8%) and swelling (0.7%). No increased intensity of reaction occurred in patients with a second implant-associated reaction. In the first 12 months after initial implant insertion, 8 (4.6%) patients experienced extrusion of the implant from the insertion site. These reactions were more likely to occur when a manual technique or loading device #2 was employed and not the currently proposed insertion technique and loading device.

Changes in clinical laboratory parameters were reviewed by an independent medical reviewer and the findings take into consideration the advanced age of the patient population and the multiple medical comorbid conditions. Clinically relevant changes were values that were greater than 30% of the upper limit of normal on two consecutive occasions. Based on these criteria, the following laboratory parameter changes occurred at a frequency of <2%: ALT, BS, LDH, CrCL, testosterone, PAP, Ca, cholesterol. No histrelin-specific effects can be identified from these data and similar changes are observed for the currently marketed LHRH agonist analogues when used in this patient population.

A total of 8 patients (4.6%) were judged as experiencing treatment-related renal impairment (CrCL <60 mL/min), 5 with single isolated occurrences and 1 had 2 occasions of such an abnormality. Only 2 (1%) patients were considered as suffering clinically relevant renal impairment when CrCL values fell below 60 mL/min on 3 and 4 occasions, respectively.

The safety issue regarding immediate post-implant testosterone flare and the accompanying risk of worsening bladder outlet obstruction and bone pain, fracture or spinal cord compression remains a potential risk for this class of drugs in this patient population. Testosterone levels fell to castration levels by week 4 in >90% of all patients. Examination of testosterone levels pre-treatment and in the following 4 weeks up until castration levels were achieved, did not show evidence of a significant rise or "flare" of testosterone levels. In Study 301, for all 138 treated patients, the mean group baseline testosterone level was 376 ng/dL, increased to 531 ng/dL by approximately day 3-4 and then decreased to 86 ng/dL at week 2, and to 9.7 ng/dL at week 4. Random review of individual patient data listings did not reveal any clustering of data to confirm a high incidence of testosterone flare upon insertion of the histrelin implant. Clinically this can also be confirmed by the reported low (<0.6%) incidence of clinically significant bladder outlet obstruction and indication for transurethal resection of prostateprocedures during the study. Other clinical conditions that could indicate a significant flare reaction would be worsening bone pain, spinal cord compression or increased fracture risk. None of these events occurred with an incidence of >1%. Although no time tracking of these events was incorporated into the study plan, the rapid achievement of chemical castration associated with a minimal increase in serum testosterone levels in the 4 weeks post-implantation and the lack of a significant incidence of adverse events associated with flare reactions, it appears that histrelin implant patients are not at any increased risk for this phenomenon over the currently marketed LHRH depot formulation analogues.

Special Populations

For patients with renal impairment (CrCl <60 mL/min) at study entry (n = 55), no dose adjustment was practiced. In these patients, 27 were classified as experiencing clinically relevant renal impairment during the study. In 1.2% of the patients, investigators reported an aggravation of the baseline renal impairment which occurred with full dosing in this subset of patients. Given the advanced age and co-morbid medical conditions in this patient population, administration of histrelin acetate in the presence of renal impairment requires monitoring but a downward dose adjustment does not appear warranted based on the pharmacokinetic studies and the small subset of patients in whom the initial renal impairment deteriorated. It appears that downward dose adjustment is unlikely to be required in patients with baseline renal impairment; however, renal function monitoring would be required.

Although 7 patients with mild baseline liver impairment entered the study and received the proposed dose of histrelin acetate, no patient deteriorated in baseline hepatic functioning; neither those with initial impairment nor those with normal liver function. Multiple patients did experience elevations in various liver function parameters, however, no pattern emerged in any one patient, indicating a concern regarding hepatotoxicity. The exact effect of histrelin acetate on liver functioning and the impact of liver impairment on histrelin pharmacokinetics have not yet been clearly elucidated. The pharmacokinetic studies that did evaluate these potential effects did not involve a sufficiently large enough patient population to make any clear conclusions. Also, metastatic prostate carcinoma can in itself result in elevations in LDH and if liver metastases are present other liver function parameters can be elevated. It is considered at this time that caution should be exercised in administering histrelin acetate to patients with liver impairment and patients should be monitored for possible drug-induced liver toxicity.

The potential risk of enhanced osteoporosis while receiving any LHRH agonist on a chronic basis has been documented in the literature. The Product Monographs of the approved LHRH agonists used in this patient population in Canada carry a standard precaution. In the combined clinical trial data, the risk of osteoporosis was not specifically determined with bone marrow density studies. However, in this patient population the risk of pathological fracture secondary to bone metastases is present. The incidence of fracture in all patients treated with the histrelin implant was 1.4% (3/213): one ankle, one rib and one hip fracture with 78% of all patients achieving drug exposure of ≥12 months. It is recommended that the Product Monograph for histrelin acetate also carry the standard drug class precaution regarding the potential risk of osteoporosis.