Reimbursement Review

Leuprolide Mesylate (Camcevi)

Sponsor: Accord Healthcare Inc.

Therapeutic area: Prostate cancer

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Sources: Drug Reimbursement Review Sponsor Submission,¹ product monograph for leuprolide injectable emulsion (Camcevi).²

Introduction

Prostate cancer is one of the most commonly diagnosed cancers in males in Canada, with an estimated 27,900 patients diagnosed in 2024, accounting for 22% of all new cancer cases in males.³ Prostate cancer is also one of the most common causes of cancer deaths in Canada, with an estimated 5,000 deaths in 2024.³ The median age at diagnosis is 66 years, but 20% of patients diagnosed are older than 75 years.^4,5 Most patients with prostate cancer do not have initial or early symptoms.⁶ As the tumour grows locally, or as it metastasizes, symptoms can intensify and start to interfere with the physiological functions of the body. Diagnostic tests for prostate cancer include blood screening for prostate-specific antigen (PSA), physical digital rectal examination, biopsy of the prostate, and imaging with CT or MRI scans.^6-9 The tumour, node, metastasis (TNM) classification system, commonly used to determine tumour stage in patients with prostate cancer, has 4 stages (stage I to stage IV), and the higher the stage, the more the tumour has spread.^7,8,10 Terms such as localized prostate cancer (limited to the prostate), locally advanced prostate cancer (spread outside of the prostate but not metastatic), and metastatic prostate cancer (spread beyond the tissue surrounding the prostate to lymph nodes or other parts of the body, such as the lungs, liver, or bones) are also used to describe the growth and spread of prostate cancer.^11,12 For patients with localized prostate cancer at the time of diagnosis, the 5-year overall survival (OS) rate is reported to be nearly 100%, whereas for patients with distant metastases, the 5-year OS rate is only 29%.⁶

Both the sponsor and the clinical experts consulted by Canada's Drug Agency (CDA-AMC) review team noted that androgen-deprivation therapy (ADT) is the backbone of treatment when systemic anticancer therapies are considered for the treatment of metastatic prostate cancer. According to the clinical experts consulted by the review team, ADT is continued throughout a patient’s life after diagnosis, and other medicines are used on top of ADT. The clinical experts consulted by the review team noted that ADT is typically continued even when a patient’s disease progresses or when a patient transitions to best supportive care near the end of life. The clinical experts also noted that some treatment protocols use ADT for a finite period (e.g., as neoadjuvant treatment before definitive surgery or radiotherapy, or as adjuvant therapy with radiotherapy). Gonadotropin-releasing hormone (GnRH) analogues, a type of ADT, are available as antagonists, such as degarelix and relugolix,^13,14 or as GnRH agonists, such as leuprolide products, which include leuprolide acetate (Eligard, Lupron Depot, Zeulide Depot) and goserelin acetate (Zoladex).^15-18 The main goals of treatment for advanced prostate cancer are to delay disease progression with the achievement of castrate levels of testosterone, which is defined as less than 50 ng/dL by the American Urological Association (AUA) and European Association of Urology (EAU).^19,20 The EAU also indicates that testosterone levels of less than 20 ng/dL might be associated better outcomes than levels that range from 20 ng/dL to 50 ng/dL.¹⁹

This is a tailored review submission of a new salt formulation of leuprolide, leuprolide mesylate (Camcevi). The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of leuprolide mesylate, extended-release emulsion, 42 mg of leuprolide, administered by subcutaneous (SC) injection for the treatment of adult patients with advanced prostate cancer.

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups that responded to our call for input and from clinical experts consulted by for the purpose of this review.

Patient Input

No patient group input was received by the review team for this review.

Clinician Input

Input From Clinical Experts Consulted for This Review

According to the clinical experts consulted by the CDA-AMC review team, there is no universal definition for advanced prostate cancer, and the phrase “patients with advanced prostate cancer,” which is used in the Health Canada–approved indication, is subject to interpretation. The clinical experts consulted by the CDA-AMC review team noted that ADT can be used in patients with intermediate-risk or high-risk localized prostate cancer, as well as in those with biochemically recurrent or metastatic disease, which is the more common definition of advanced prostate cancer. According to the clinical experts consulted by the CDA­AMC review team, for patients with biochemically recurrent or metastatic disease, the treatment goal is to achieve a castrate testosterone level, which controls the disease by decreasing PSA levels, delaying the development of metastatic disease (in the context of biochemical recurrence), and reducing disease burden (in metastatic prostate cancer), which often results in improved symptoms, OS, and progression-free survival (PFS). According to the clinical experts consulted by the review team, the long-term use of ADT with currently available GnRH analogues typically results in the development of refractory disease or castrate resistance, which was considered one of the main unmet needs. Leuprolide mesylate, a GnRH analogue, does not address this major unmet need in the clinical experts’ opinions. However, according to the clinical experts consulted by the CDA-AMC review team, the availability of leuprolide mesylate, which does not require reconstitution like Eligard does, provides an additional formulation option for patients and clinicians.

According to the clinical experts consulted by the review team, there are currently several approved preparations of leuprolide products in Canada, including Lupron Depot (3-month, 4-month, and 6-month depots administered as intramuscular injections), Eligard (1-month, 3-month, 4-month, and 6-month depots administered as SC injections), and goserelin acetate (3-month depot administered as SC pellet implants). Despite prescribing heterogeneity in Canada, most patients do not receive the 6-month preparations. The clinical experts consulted by the review team noted that leuprolide mesylate is not expected to shift the current treatment paradigm; rather, leuprolide mesylate would share the same place in therapy as other GnRH analogues and provide an additional option to the existing GnRH analogues.

According to the clinical experts consulted by the review team, patients with advanced prostate cancer are most likely to respond to treatment with leuprolide mesylate. The clinical experts consulted by the review team noted that the indications for GnRH analogue injections for patients with advanced prostate cancer have been well established for several decades, and that there are several other drugs with very similar chemical formulations and pharmaceutical actions already on the market. According to the clinical experts consulted by the review team, there are no particular disease characteristics that would warrant or contraindicate the use of leuprolide mesylate relative to other GnRH analogues, and there are no identifiable patient or disease features (clinical, histological, or biochemical) that render patients more suited to leuprolide mesylate than to other GnRH analogues.

According to the clinical experts consulted by the review team, the outcome measures for advanced prostate cancer treatment used in clinical practice are aligned with those used in clinical trials. The clinical experts consulted by the review team noted that for advanced prostate cancer, efficacy is determined by evaluating a number of metrics, including the clinical status of the patient, radiologic response and/or progression, and PSA dynamics. The clinical experts consulted by the review team noted that the definition of a clinically meaningful response is well established in current clinical guidelines and should not vary among physicians, and the parameters applied to leuprolide mesylate should be identical to those already accepted for other GnRH analogue drugs. The clinical experts consulted by the CDA-AMC review team noted that a serum testosterone level of 50 ng/dL or less is an accepted surrogate end point for efficacy, and that recent evidence suggests that the suppression of serum testosterone levels to less than 20 ng/dL might be associated with better biochemical relapse-free survival.

According to the clinical experts consulted by the review team, ADT with GnRH analogues is typically intended to be continued throughout a patient’s lifetime; however, in some instances, GnRH analogues are prescribed for a finite period as an adjunct to other definitive therapies (e.g., as neoadjuvant treatment before surgery or as neoadjuvant and adjuvant therapy to radiotherapy). The clinical experts consulted by the review team noted that GnRH analogue therapy is typically not discontinued, even when there is disease progression or when a patient transitions to best supportive care near the end of life; instead, other medicines are added to ADT. According to the clinical experts consulted by the review team, ADT with GnRH analogues may be occasionally discontinued in cases of significant or intolerable side effects or at patient or clinician discretion.

According to the clinical experts consulted by the review team, appropriate treatment settings for leuprolide mesylate include outpatient or ambulatory care clinics, physicians’ offices, and injection clinics in the community setting. The clinical experts consulted by the review team also noted that treatment may be administered through a home injection program by nursing personnel. According to the clinical experts consulted by the review team, a specialist (most commonly a urologist) usually establishes the diagnosis; treatment may be administered by a urologist, a radiation oncologist, or a medical oncologist, depending on the stage of disease; and monitoring is provided by a specialist or by a primary care physician, depending on treatment response and stability of disease.

Clinician Group Input

The clinician group input on leuprolide mesylate was received from 1 clinician group: the Ontario Health (Cancer Care Ontario) Genitourinary Cancers Drug Advisory Committee (GU DAC). A total of 2 clinicians provided the input.

According to the GU DAC, the treatment goals for patients with hormone-dependent advanced prostate cancer are to improve survival, delay disease progression, reduce cancer-related complications (e.g., skeletal-related events with reduced need for palliative radiotherapy, spinal cord compression, urinary obstruction, and the need for palliative procedures, such as transurethral resection of the prostate), improve patients’ quality of life (QoL), maintain the independence of patients, and reduce the burden on caregivers. The GU DAC noted that there are unmet needs for effective methods of suppressing testosterone with reduced side effects in patients with advanced prostate cancer, as well as an unmet need for reduced drug costs for these patients.

According to the GU DAC, leuprolide mesylate is a 6-month depot injection, and the Eligard 6-month depot injection is currently available and reimbursed in Canada. According to the GU DAC, leuprolide mesylate may improve convenience for patients who prefer a 6-month dosing schedule because of their lifestyle, the location of their residence, as well as their ability to travel to get treatment, to have vacations, or to work. According to the GU DAC, leuprolide mesylate would not change the current treatment paradigm, but it would provide an alternative to the 6-month Eligard product. According to the GU DAC, any patients who require GnRH agonist therapy for prostate cancer would be candidates for leuprolide mesylate. The GU DAC noted that the selection of leuprolide mesylate versus other available drugs would be based mostly on the preferences of the prescriber and patient for a longer, 6-month injection interval.

According to the GU DAC, testosterone levels, PSA response, and radiographic response are used to determine whether a patient is responding to treatment in clinical practice and in clinical trials. The GU DAC noted that a common standard follow-up would be the measurement of a PSA level and testosterone level every 3 months, and interval imaging would depend on the scenario. The GU DAC also noted that for patients with symptoms related to either locally advanced disease or metastatic disease, a clinically meaningful response is a reduction or resolution of urinary tract obstruction or pain from bone metastases. The magnitude of response is standard among prescribers and should not depend on the drug chosen if the testosterone level is suppressed adequately.

Echoing the clinical experts consulted by the review team, the GU DAC noted that for patients with metastatic prostate cancer, current evidence supports the continuation of GnRH agonist therapy indefinitely through the next lines of therapy, even with disease progression. The GU DAC noted that GnRH agonist therapy can be discontinued because of severe intolerance or side effects that significantly interfere with a patient’s QoL. The GU DAC noted that community, academic, outpatient, and hospital settings are all appropriate for treatment with leuprolide mesylate.

Drug Program Input

Input was obtained from the drug programs that participate in the reimbursement review process. The following were identified as key factors that could potentially affect the implementation of a recommendation for leuprolide mesylate:

• relevant comparators

• considerations for continuation or renewal of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• generalizability

• funding algorithm

• system and economic issues.

The responses to the issues raised are presented in Table 3.

Clinical Evidence

The CDA-AMC Clinical Review was based on a summary of clinical evidence provided by the sponsor, in accordance with the CDA-AMC tailored review process.

Description of Studies

A phase III, multicentre, single-arm, open-label pivotal study (FP01C-13-001) and a phase III, single-arm, open-label, safety extension study (FP01C-13-001-EX) were submitted by the sponsor and assessed by the CDA-AMC review team.

The FP01C-13-001 study evaluated the efficacy, safety, and pharmacokinetics of leuprolide mesylate in 137 adult patients with histologically confirmed prostate carcinoma and a baseline morning serum testosterone level of more than 150 ng/dL. Patients were enrolled in the FP01C-13-001 study at 26 sites (no sites in Canada) and scheduled to receive a total of 2 doses of leuprolide mesylate with a 6-month interval. There were 3 primary objectives of the FP01C-13-001 study: to establish the efficacy of leuprolide mesylate for up to 1 year, measured as the percentage of patients with a serum testosterone concentration suppressed to castrate levels (≤ 50 ng/dL) by day 28 with or without 1 day after the first injection of leuprolide mesylate and the percentage of patients with serum testosterone suppression (≤ 50 ng/dL) from day 28 through day 336 (remaining duration of the study); to determine the safety and tolerability of leuprolide mesylate for up to 1 year of exposure; and to evaluate the pharmacokinetic behaviour of serum leuprolide. The median age of the patients in the FP01C-13-001 study was 71.0 years (range, 51 to 88 years). The race composition of the study population was 89.8% white, 5.8% Black or African American, 3.6% Asian, and 0.7% unknown. Approximately 2.9%, 22.6%, 27.0%, and 23.4% had, respectively, stage I, stage II, stage III, or stage IV prostate cancer; the disease stage in the remaining 24.1% of the study population was unknown.

The FP01C-13-001-EX extension study was conducted at 7 sites in the US and enrolled 30 patients who participated in the FP01C-13-001 pivotal study and assessed the safety and tolerability of leuprolide mesylate in these patients for up to 1 year.

Efficacy Results

Serum Testosterone Levels of 50 ng/dL or Less (Primary End Point)

In the FP01C-13-001 study, serum testosterone level suppression to castrate levels (≤ 50 ng/dL) was reached by 98.5% (95% confidence interval [CI], 94.8% to 99.8%) of the intention-to-treat (ITT) population by day 28 with or without 1 day after the first dose of leuprolide mesylate. By day 336, 97.0% (95% CI, 92.2% to 98.9%) of the ITT population achieved castrate testosterone levels (≤ 50 ng/dL).

The sponsor provided post hoc subgroup analyses, including subgroup results by disease stage and by disease characteristics at enrolment in response to the CDA-AMC information request²¹ seeking the sponsor’s input on how to define advanced prostate cancer. The summary of the subgroup analyses on the proportion of patients who achieved a castrate testosterone level (≤ 50 ng/dL) is presented in Appendix 1. In general, the proportion of patients who achieved a castrate testosterone level (≤ 50 ng/dL) was similar across subgroups.

Pharmacokinetic Parameters (Primary End Point)

In the FP01C-13-001 study, after the first and second doses of leuprolide mesylate, mean serum leuprolide concentrations reached the maximum observed serum concentration (C_max) of 94.5 ng/mL (standard deviation [SD] = 53.7) and 99.0 ng/mL (SD = 73.0), respectively, at 3.23 hours and 2.08 hours (median time to the maximum serum concentration [T_max]). After the first dose of leuprolide mesylate, the mean values of observed serum concentration 4 weeks after dosing (C_wk4); observed serum concentration 6 months after dosing (C_mon6); area under the concentration-time curve calculated using the linear up, log down trapezoidal method from 0 weeks to 4 weeks after dosing (AUC_0-4wk); area under the concentration-time curve calculated using the linear up, log down trapezoidal method from 0 months to 6 months after dosing (AUC_0-6mon); and mean serum concentration in the 6 months after dosing (C_avg[0-6mon)] were, respectively, 1.04 ng/mL, 0.497 ng/mL, 91.6 day ng/mL, 224 day ng/mL, and 1.34 ng/mL. After the second dose of leuprolide mesylate, the mean values of C_wk4, C_mon6, AUC_0-4wk, AUC_0-6mon, and C_avg(0-6mon) were, respectively, 1.64 ng/mL, 0.511 ng/mL, 125 day ng/mL, 268 day ng/mL, and 1.59 ng/mL.

Postsuppression Excursion of Serum Testosterone to More Than 50 ng/dL (Secondary End Point)

The FP01C-13-001 study examined the proportion of patients who exhibited postsuppression excursions of serum testosterone (> 50 ng/dL), either through breakthrough (i.e., episodes unrelated to leuprolide mesylate dosing) or through the acute-on-chronic surge (i.e., related to the second dose of leuprolide mesylate). Overall, no postsuppression breakthrough effect was observed, other than the acute-on-chronic surge, during the study period. Two of 137 patients did not reach the castrate testosterone level (≤ 50 ng/dL) by day 28. Two patients exhibited postsuppression excursions of serum testosterone (> 50 ng/dL) after the second dose of leuprolide mesylate, between day 28 and day 336, but their serum testosterone returned to the castration levels on day 336.

Serum Testosterone Suppression of Less Than 20 ng/dL (Secondary End Point)

In the ITT population of the FP01C-13-001 study, 69.3% and 95.9% of patients achieved a testosterone suppression level of less than 20 ng/dL by day 28 and by day 336, respectively.

PSA Levels (Secondary End Point)

In the ITT population (N = 137) of the FP01C-13-001 study, the mean baseline PSA level was ██████ █████ ███ █ █████████, and it decreased to ██████ █████ ███ █ ████████ on day 28. The mean PSA level was █████ █████ ███ █ ███████ on day 168 and ██████ █████ ███ █ ████████ on day 336.

Luteinizing Hormone Levels (Secondary End Point)

In the ITT population of the FP01C-13-001 study, the mean luteinizing hormone (LH) level at baseline was █████ ████ ███ █ ████████ The mean serum LH level was ███████ ████ ███ █ █████████ on day 28, ███████ ████ ███ █ █████████ on day 168, and ███████ ████ ███ █ █████████ on day 336.

QoL (Primary End Point)

In the ITT population of the FP01C-13-001 study, approximately 68.6% (94 of 137) of patients felt satisfied (rated QoL as 0, indicating delighted; as 1, indicating pleased; or as 2, indicating mostly satisfied) with their condition at baseline. Of the patients who reported QoL on day 168, approximately 69.7% (90 of 129 patients) felt satisfied. Of the patients who reported QoL on day 336, approximately 65.9% (87 of 132 patients) felt satisfied.

Harms Results

The FP01C-13-001 Study

In the pivotal FP01C-13-001 study, the median duration of follow-up was ███ ████ ███████ ██ ██ ████ and approximately █████ ████ ██ ████ of the study population received both doses of leuprolide mesylate. The most common treatment-emergent adverse event (TEAE) in the safety analysis set of the FP01C-13-001 study (N = 137) was hot flush (48.9%), followed by hypertension (14.6%), pain in extremity (9.5%), injection-site pain (7.3%), arthralgia (6.6%), fatigue (6.6%), nocturia (5.8%), back pain (5.1%), and nasopharyngitis (5.1%). Serious adverse events (SAEs) occurred in █████ of the safety analysis set, with injury, poisoning, and procedural complications ██████ being the most frequent SAEs. There were ██████ deaths: ███ due to stroke, ███ due to metastatic prostate cancer and acute renal failure, and ███ ██ for unknown reasons. Five patients (3.6%) discontinued the study because of TEAEs, which included acute kidney injury, atrial fibrillation, cerebrovascular accident, death, hormone-refractory prostate cancer, and metastatic prostate cancer.

The FP01C-13-001-EX Extension Study

In the FP01C-13-001-EX extension study (██), the median duration of follow-up was ███ ████ ███████ ██ ██ █████ The most common TEAEs that occurred during the extension study were acute kidney injury ████████ increased blood triglycerides (6.67%), dehydration ███████, dizziness ███████, fall ███████, fatigue ███████, and hypertension ███████. Four patients ████████ reported SAEs, and no discontinuations due to adverse events (AEs) or death were reported during the extension study.

Critical Appraisal

Internal Validity

The evidence for leuprolide mesylate included in the sponsor’s summary was based on 1 phase III, single-arm, open-label pivotal study (FP01C-13-001) and 1 phase III, single-arm, open-label, safety extension study (FP01C-13-001-EX). From a methodological perspective, the absence of an internal comparison group in the FP01C-13-001 pivotal study is a key limitation; because of the intrinsic nature of the single-arm design, this absence leads to low confidence in how well the findings reflect the truth. Consequently, it is a challenge to make inferences about the efficacy and safety of leuprolide mesylate. However, from a regulatory perspective, it was considered acceptable for the pivotal FP01C-13-001 study to adopt the single-arm design, per current FDA guidance for the establishment of the efficacy and safety of GnRH analogues for the treatment of advanced prostate cancer.²² Health Canada was in agreement with the FDA guidance, finding that the single-arm study design was appropriate for the assessment of leuprolide mesylate.²³ The design of the FP01C-13-001 study was, overall, well aligned with the FDA guidance because it met the major criteria outlined in the guidance.²²

The FP01C-13-001-EX safety extension study provided 2 additional doses of leuprolide mesylate, approximately 6 months apart, to patients from the pivotal FP01C-13-001 study and assessed the safety of leuprolide mesylate for up to 2 years (i.e., 1 year in the FP01C-13-001 study plus 1 year in the extension study). Although all ██ ████████ received the first dose of leuprolide mesylate, it was noted that approximately ███ ███ ██ ███ of the patients in the FP01C-13-001-EX extension study did not receive the second dose, including ████████ who discontinued due to early termination unrelated to AEs and ████████ who discontinued due to drug supply expiration. The large proportion of patients missing the second dose of treatment might result in a potential risk of underestimation in the incidence of harms, although the magnitude of the impact remains unknown.

A gap remains in the sponsor-submitted evidence because of the absence of direct or indirect evidence (i.e., the pivotal FP01C-13-001 study used a single-arm design), which limited the ability of the CDA-AMC review team to draw any evidence-based conclusions about the efficacy of leuprolide mesylate relative to other ADTs (including leuprolide products) currently available in Canada.

External Validity

The pivotal FP01C-13-001 study does not completely align with the population in the Health Canada–approved indication in terms of advanced prostate cancer. The Health Canada–approved indication targets patients with advanced prostate cancer, whereas the pivotal FP01C-13-001 study did not limit enrolment to patients with advanced prostate cancer; it included patients with stage I to stage IV disease. Of note, according to the clinical experts consulted by the CDA-AMC review team, there is no universal definition for advanced prostate cancer; the phrase “patients with advanced prostate cancer” used in the Health Canada–approved indication is subject to interpretation. The clinical experts consulted by the CDA-AMC review team noted that advanced prostate cancer commonly refers to biochemically recurrent or metastatic disease, yet patients with intermediate-risk or high-risk localized prostate cancer can also be eligible for ADT. The sponsor, in its response to a CDA-AMC information request,²¹ stated that: “In clinical practice, the standard definition [of advanced prostate cancer] is disease that has progressed beyond localized treatment options, including locally advanced disease (e.g., T3 or T4 classification) that is not amenable to curative treatment, metastatic disease, and castration-resistant prostate cancer.” Treatment recommendations and guidelines for prostate cancer recognize that advanced prostate cancer encompasses both localized disease with high-risk features and metastatic disease, and that all patients with advanced prostate cancer would typically require ADT.^8,24,25 Nonetheless, both clinical experts consulted by the CDA-AMC review team agreed that the results generated from the FP01C-13-001 study population would still be generalizable to the Health Canada–indicated population.

The clinical experts consulted by the CDA-AMC review team noted that the pivotal FP01C-13-001 study excluded patients who had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of greater than 2; who received combination therapy with chemotherapy, immunotherapy, cryotherapy, radiotherapy, concomitant ADT, or LH–releasing hormone (LHRH) therapy during the study; and who had a baseline morning serum testosterone level of 150 ng/dL or less. In contrast, the Health Canada indication did not restrict the use of leuprolide mesylate in these patients. According to the clinical experts consulted by the CDA-AMC review team, the patients who were excluded from the FP01C-13-001 study would benefit from leuprolide mesylate treatment and account for a large proportion of patients with advanced prostate cancer. Nonetheless, the clinical experts felt that the results from the pivotal FP01C-13-001 study would still be generalizable to the patients who were excluded.

Cost Information

The sponsor submitted a cost comparison that evaluated the annual drug and health care resource-use costs associated with leuprolide mesylate and other available ADTs.

At the submitted price of $1,499.00 per 42 mg extended-release emulsion for injection, the annual drug acquisition cost of leuprolide mesylate is estimated to be $2,998 per patient. Based on publicly available list prices, the annual cost of leuprolide mesylate is expected to be lower than the annual cost of all other ADTs (i.e., buserelin acetate, degarelix, goserelin acetate, leuprolide acetate [Eligard], leuprolide acetate [Lupron Depot], relugolix, and triptorelin). Leuprolide mesylate is to be administrated once every 6 months; compared with the 6-month ADT comparator formulations (i.e., 45 mg of leuprolide acetate [Eligard] and 22.5 mg of triptorelin), leuprolide mesylate is estimated to be associated with cost savings of $322 annually. The incremental savings associated with leuprolide mesylate are based on publicly available list prices and may not reflect actual prices paid by drug plans.

The sponsor estimated health care resource-use costs based on treatment-specific administration times and the cost of nonsteroidal antiandrogen therapy for GnRH agonists during the first year. Differences in administration times among ADTs were deemed to be uncertain, as clinical expert feedback received by CDA-AMC indicated that some patients receiving ADT treatments are enrolled in patient support programs, which cover administration costs, and the time differences associated with administration may not result in clinically meaningful differences in administration times; therefore, it is uncertain whether these differences will translate to cost savings to the health care system.

The cost comparison assumes clinical similarity between leuprolide mesylate, and the other ADTs included in the analysis. The CDA-AMC Clinical Review was unable to draw a conclusion on the relative efficacy and safety of leuprolide mesylate and other ADTs currently available in Canada, given the absence of direct and indirect comparative evidence. However, according to the CDA-AMC Clinical Review, Health Canada and the clinical experts consulted by the CDA-AMC review team did not express any major concerns with the lack of such evidence in their assessment of the relative efficacy and safety of leuprolide mesylate. As well, any conclusions regarding incremental savings associated with the reimbursement of leuprolide mesylate are uncertain, given the uncertainty in the comparative clinical effectiveness.

Conclusions

Leuprolide mesylate is a new salt formulation of leuprolide that has been in use broadly for more than 30 years for the treatment of prostate cancer. A phase III, single-arm, open-label pivotal study submitted by the sponsor (FP01C-13-001) assessed the efficacy and safety of leuprolide mesylate in 137 adult patients with histologically confirmed prostate carcinoma and a baseline serum testosterone level greater than 150 ng/dL. The absence of a comparator group in the pivotal FP01C-13-001 study is a key limitation that, from the methodological perspective, leads to low certainty in the evidence of leuprolide’s efficacy in treating prostate cancer. However, the single-arm study design of FP01C-13-001 is acceptable, from the regulatory perspective, as it met the requirements of current guidance for establishing the efficacy and safety of GnRH analogues for advanced prostate cancer.

The results of the pivotal FP01C-13-001 study showed that leuprolide mesylate could effectively suppress serum testosterone to the castrate level (≤ 50 ng/dL) in 98.5% (95% CI, 94.8% to 99.8%) of the ITT population by day 28 after the first dose of leuprolide mesylate and help maintain the castrate testosterone level in 97.0% (95% CI, 92.2% to 98.9%) of the ITT population by day 336. The ability of leuprolide mesylate to suppress testosterone levels was further supported by findings that showed a low incidence of testosterone excursions ██ █████████ of more than 50 ng/dL during the study, as well as the high proportion of the ITT population that achieved (69.3%) and maintained (95.9%) testosterone suppression at 20 ng/dL or less. Based on the harms data from the pivotal FP01C-13-001 study and the phase III, single-arm, FP01C-13-001-EX extension study, which enrolled 30 patients who participated in the FP01C-13-001 pivotal study, the clinical experts consulted by the CDA-AMC review team considered leuprolide mesylate to be, overall, safe and tolerable.

The CDA-AMC review team was unable to draw any conclusions about the relative efficacy and safety of leuprolide mesylate and other ADTs (including leuprolide products) currently available in Canada in the absence of direct and indirect comparative evidence, although Health Canada and the clinical experts consulted by the CDA-AMC review team did not express any major concerns about the lack of such evidence in their assessment of the relative efficacy and safety of leuprolide mesylate.

At the sponsor’s submitted price, drug-acquisition costs for leuprolide mesylate are estimated to be $2,998 annually, which, at public list prices, is less costly than the annual costs associated with other available ADTs. The sponsor’s cost comparison assumes clinical similarity between leuprolide mesylate and other ADTs; however, no direct or indirect evidence was submitted to support this assumption. According to the CDA-AMC Clinical Review, Health Canada and the clinical experts consulted by the CDA-AMC review team did not express any major concerns about the lack of direct or indirect evidence in their assessment of the relative efficacy and safety of leuprolide mesylate. Incremental savings are based on publicly available list prices and may not reflect the actual prices paid by public drug plans in Canada. Overall, given the lack of direct or indirect comparative efficacy data for leuprolide mesylate versus other ADTs, there is insufficient evidence for leuprolide mesylate to have a price premium over currently reimbursed ADTs.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of leuprolide mesylate (extended-release emulsion, 42 mg of leuprolide, and SC injection) in the treatment of advanced prostate cancer in adults.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

Prostate cancer is one of the most commonly diagnosed cancers in males in Canada, with an estimated 27,900 patients diagnosed in 2024, accounting for 22% of all new cancer cases in males.³ Prostate cancer is also one of the most common causes of cancer deaths in Canada, with an estimated 5,000 deaths in 2024.³ The median age at diagnosis is 66 years, but 20% of patients are older than 75 years.^4,5 Most patients with prostate cancer do not have initial or early symptoms.⁶ As the tumour grows locally, or as it metastasizes, symptoms can intensify and start to interfere with the physiological functions of the body.

Diagnostic tests for prostate cancer include blood screening for PSA, physical digital rectal examination, biopsy of the prostate, and imaging with CT or MRI scans.^6-9 According to the clinical experts consulted by the review team, the Gleason grading system is often used to give a histological grade for prostate cancer; however, a newer Grade Group system is increasingly used around the world for this purpose. The TNM classification system, commonly used to determine tumour stage in patients with prostate cancer, has 4 stages (stage I to stage IV), and the higher the stage, the more the tumour has spread.^7,8,10

Terms such as localized prostate cancer (limited to the prostate), locally advanced prostate cancer (spread outside of the prostate but not metastatic), and metastatic prostate cancer (spread beyond the tissue surrounding the prostate to lymph nodes or other parts of the body, such as the lungs, liver, or bones), are also used to describe the growth and spread of prostate cancer.^11,12 For patients with localized prostate cancer at the time of diagnosis, the 5-year OS rate is reported to be nearly 100%, whereas for patients with distant metastases, the 5-year OS rate is only 29%.⁶

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

According to the clinical experts consulted by the CDA-AMC review team, metastatic prostate cancer is incurable in nature, but there are a wide variety of clinical therapeutic options, and survival times range from weeks to many years.

Both the sponsor and the clinical experts consulted by the review team noted that ADT is the backbone of treatment when systemic anticancer therapies are considered for the treatment of metastatic prostate cancer. According to the clinical experts consulted by the review team, ADT is continued throughout a patient’s life after diagnosis, and other medicines are used in addition to ADT. The clinical experts consulted by the review team noted that ADT is typically continued even when a patient’s disease progresses or when a patient transitions to best supportive care near the end of life. The clinical experts also noted that some treatment protocols use ADT for a finite period (e.g., as neoadjuvant treatment before definitive surgery or radiotherapy, or as adjuvant therapy with radiotherapy).

GnRH analogues, a type of ADT, are available as antagonists, such as degarelix and relugolix,^13,14 or as GnRH agonists, such as leuprolide products, which include leuprolide acetate (Eligard, Lupron Depot, and Zeulide Depot) and goserelin acetate.^15-18 The main goals of treatment for advanced prostate cancer are to delay disease progression with the achievement of castrate levels of testosterone, which is defined as less than 50 ng/dL by the AUA and the EAU.^19,20 The EAU also indicates that testosterone levels of less than 20 ng/dL might be associated with better outcomes than levels that range between 20 ng/dL and 50 ng/dL.¹⁹

Drug Under Review

Leuprolide is a GnRH receptor agonist, and the continuous use of leuprolide in therapeutic doses decreases testosterone in males to levels associated with castration (≤ 50 ng/dL in serum).^2,26-28

Leuprolide mesylate is one of the various formulations of leuprolide but is the first available formulation that does not require reconstitution before administration. Leuprolide mesylate received a Notice of Compliance from Health Canada on November 16, 2021, for the treatment of adult patients with advanced prostate cancer.² The sponsor’s reimbursement request is in line with the Health Canada indication. Leuprolide mesylate has not been previously reviewed by CDA-AMC.

The recommended dose of leuprolide mesylate is 42 mg, administered every 6 months as a single SC injection.²

The key characteristics of leuprolide mesylate and other relevant treatments available for adult patients with advanced prostate cancer are summarized in Table 2.

Table 2: Key Characteristics of Leuprolide Mesylate and Its Main Comparators

AUA = American Urological Association; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; LHRH = luteinizing hormone–releasing hormone; SC = subcutaneous; TNM = tumour, node, metastasis.

^aHealth Canada–approved indication.

Sources: Product monographs for leuprolide mesylate (Camcevi),² Eligard,¹⁷ Lupron Depot,¹⁵ Zeulide Depot,¹⁶ relugolix (Orgovyx),¹³ buserelin acetate (Suprefact Depot),²⁹ degarelix (Firmagon),¹⁴ goserelin acetate (Zoladex),¹⁸ triptorelin (Trelstar).³⁰

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

No patient group input was received by the CDA-AMC review team for this review.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of advanced prostate cancer.

Unmet Needs

According to the clinical experts consulted by the CDA-AMC review team, there is no universal definition for advanced prostate cancer, and the phrase “patients with advanced prostate cancer” used in the Health Canada–approved indication is subject to interpretation. The clinical experts consulted by the CDA-AMC review team noted that ADT can be used in intermediate-risk and high-risk localized prostate cancer, as well as in the context of biochemically recurrent and metastatic disease, which would be the more common definition of advanced prostate cancer. According to the clinical experts consulted by the CDA­AMC review team, for patients with biochemically recurrent or metastatic disease, the treatment goal is to achieve a castrate testosterone level, which controls the disease by decreasing PSA levels, delaying the development of metastatic disease (in the context of biochemical recurrence), and reducing disease burden (in metastatic prostate cancer), which often result in improved symptoms, OS, and PFS.

According to the clinical experts consulted by the review team, the long-term use of ADT with currently available GnRH analogues typically results in the development of refractory disease or castrate resistance, which was considered one of the main unmet needs. Leuprolide mesylate, as a GnRH analogue, does not address this major unmet need in the clinical experts’ opinions.

According to the clinical experts consulted by the CDA-AMC review team, the availability of leuprolide mesylate, which does not require reconstitution like Eligard does, provides an additional formulation option for patients and clinicians.

Place in Therapy

According to the clinical experts consulted by the review team, there are currently several approved preparations of leuprolide products in Canada, including Lupron Depot (3-month, 4-month, and 6-month depots given as intramuscular injections), Eligard (1-month, 3-month, 4-month, and 6-month depots given as SC injections), and goserelin acetate (3-month depot given as SC pellet implants). Despite prescribing heterogeneity in Canada, most patients do not receive the 6-month preparations. The clinical experts consulted by the review team noted that leuprolide mesylate is not expected to shift the current treatment paradigm; rather, leuprolide mesylate would share the same place in therapy as other GnRH analogues, providing an additional option to the existing GnRH analogues.

Patient Population

According to the clinical experts consulted by the review team, patients with advanced prostate cancer are most likely to respond to treatment with leuprolide mesylate. The clinical experts consulted by the review team noted that the indications for GnRH analogue injections for patients with advanced prostate cancer have been well established for several decades, and that there are several other drugs with very similar chemical formulations and pharmaceutical actions already on the market. According to the clinical experts consulted by the review team, there are no particular disease characteristics that would warrant or contraindicate the use of leuprolide mesylate relative to other GnRH analogues, and there are no identifiable patient or disease features (clinical, histological, or biochemical), that render patients more suited for leuprolide mesylate than to other GnRH analogues.

The clinical experts consulted by the review team noted that although patients with very high-grade prostate cancer and patients with unusual histology (e.g., sarcomatoid or neuroendocrine) are likely to become refractory to treatment with GnRH analogues sooner than those with lower-grade prostate cancer, it is not possible to identify patients who are more likely to respond to leuprolide mesylate than to other GnRH analogues already on the market.

Assessing the Response Treatment

According to the clinical experts consulted by the review team, the outcome measures for advanced prostate cancer treatment used in clinical practice are aligned with those used in clinical trials. The clinical experts consulted by the review team noted that for advanced prostate cancer, efficacy was determined by evaluating a number of metrics, including the clinical status of the patient, radiologic response and/or progression, and PSA dynamics. The clinical experts consulted by the review team noted that the definition of a clinically meaningful response is well established in current clinical guidelines, and the parameters applied to leuprolide mesylate should be identical to those already accepted for other GnRH analogue drugs. The clinical experts consulted by the CDA-AMC review team noted that a serum testosterone level of 50 ng/dL or less is an accepted surrogate end point for efficacy, and that recent evidence suggests that suppression of serum testosterone levels to less than 20 ng/dL might be associated with better biochemical relapse-free survival.³¹

Discontinuing Treatment

According to the clinical experts consulted by the review team, ADT with GnRH analogues is typically intended to be continued for a patient’s lifetime; however, in some instances, GnRH analogues are prescribed for a finite period as an adjunct to other definitive therapies (e.g., as neoadjuvant treatment before surgery or as neoadjuvant and adjuvant therapy to radiotherapy). The clinical experts consulted by the review team noted that GnRH analogue therapy is typically not discontinued, even when there is disease progression or when a patient transitions to best supportive care near the end of life; instead, other medicines are added to ADT. According to the clinical experts consulted by the review team, ADT with GnRH analogues may be occasionally discontinued in cases of significant or intolerable side effects or at patient or clinician discretion.

Prescribing Considerations

According to the clinical experts consulted by the review team, appropriate treatment settings for leuprolide mesylate include outpatient or ambulatory care clinics, physicians’ offices, and injection clinics in the community setting. The clinical experts consulted by the review team also noted that treatment may be administered through a home injection program by nursing personnel.

According to the clinical experts consulted by the review team, a specialist (most commonly a urologist) usually establishes the diagnosis, and treatment may be administered by a urologist, a radiation oncologist, or a medical oncologist, depending on the stage of disease. The clinical experts consulted by the review team noted that monitoring is provided by either a specialist or by a primary care physician, depending on treatment response and stability of disease.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

The clinician group input on the review of leuprolide mesylate was received from 1 clinician group: the Ontario Health (Cancer Care Ontario) GU DAC. A total of 2 clinicians provided the input.

According to the GU DAC, the treatment goals for patients with hormone-dependent advanced prostate cancer are to improve survival, delay disease progression, reduce cancer-related complications (e.g., skeletal-related events with reduced need for palliative radiotherapy, spinal cord compression, urinary obstruction, and the need for palliative procedures, such as transurethral resection of the prostate), improve patients’ QoL, maintain the independence of patients, and reduce the burden on caregivers.

According to the GU DAC, there are unmet needs for effective methods of suppressing testosterone with reduced side effects in patients with advanced prostate cancer. In addition, there is also a need for reduced drug costs for these patients.

According to the GU DAC, leuprolide is a GnRH agonist and is the active ingredient not only in leuprolide mesylate, but also in Eligard, Lupron Depot, and Zeulide Depot, which have been approved by Health Canada for patients with prostate cancer. The GU DAC noted that what distinguishes these drugs are the mode of injection and the delivery system, which create long-acting release and suppress testosterone for 1 to 6 months. Leuprolide mesylate is a 6-month depot injection; the Eligard 6-month depot injection is currently available and reimbursed in Canada. According to the GU DAC, leuprolide mesylate may improve convenience for patients who prefer a 6-month dosing schedule because of their lifestyle, the location of their residence, as well as their ability to travel to get treatment, to have vacations, or to work.

According to the GU DAC, leuprolide mesylate would not change the current treatment paradigm, but it would provide an alternative to the 6-month Eligard product. The GU DAC noted that leuprolide mesylate would fit into first-line therapy.

According to GU DAC, any patients who require GnRH agonist therapy for prostate cancer would be candidates for leuprolide mesylate. The GU DAC noted that the selection of leuprolide mesylate versus other available drugs would be based mostly on the preferences of the prescriber and patients for a longer, 6-month injection interval. According to the GU DAC, patients who need customization of their GnRH agonist treatment interval may not be candidates (e.g., intermittent therapy, which most commonly involves 9-month courses treatment rather than a 6-month depot), but this is a very small population.

According to the GU DAC, testosterone levels, PSA response, and radiographic response are used to determine whether a patient is responding to treatment in clinical practice and in clinical trials. The GU DAC noted that a common standard follow-up would be the measurement of a PSA level and testosterone level every 3 months, and interval imaging would depend on the scenario. The GU DAC also noted that for patients with symptoms related to either locally advanced disease or metastatic disease, a clinically meaningful response is a reduction or resolution of urinary tract obstruction or pain from bone metastases. The magnitude of response is standard across prescribers and should not depend on the drug chosen if the testosterone level is suppressed adequately.

The GU DAC noted that for patients with metastatic prostate cancer, current evidence supports the continuation of GnRH agonist therapy indefinitely through the next lines of therapy, even with disease progression. The GU DAC noted that GnRH agonist therapy can be discontinued because of severe intolerance or side effects that significantly interfere with a patient’s QoL.

The GU DAC noted that community, academic, outpatient, and hospital settings are all appropriate for treatment with leuprolide mesylate.

Drug Program Input

The drug programs provide input on each drug being reviewed through the CDA-AMC reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 3.

Table 3: Summary of Drug Plan Input and Clinical Expert Response

ADT = androgen-deprivation therapy; CDA-AMC = Canada's Drug Agency; ECOG PS = Eastern Cooperative Oncology Group Performance Status; GnRH = gonadotropin-releasing hormone; LHRH = luteinizing hormone–releasing hormone; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

Note that the clinical evidence summarized in this section was prepared by the sponsor in accordance with the CDA-AMC tailored review process and has not been modified by CDA-AMC except for some editorial changes.

Sponsor Submitted Pivotal Study and Long Extension Study

Effective testosterone suppression through medical castration is the standard of care for patients diagnosed with advanced prostate cancer. There is considerable clinical and real-world evidence demonstrating the effectiveness of leuprolide in achieving castrate levels.^32-41

CAMCEVI® (leuprolide mesylate injectable suspension - LMIS 50 mg) differs from existing leuprolide products as the salt used is mesylate instead of acetate. LMIS 50 mg is a pre-mixed product containing leuprorelin mesylate equivalent to 42 mg of leuprorelin and is equivalent to existing 45 mg leuprorelin therapies. Accordingly, based on the same active moiety and therapeutic use, similar clinical pharmacodynamics (PD) and pharmacokinetic (PK) characteristics, LMIS 50 mg can be compared to therapies such as Eligard® (leuprolide acetate). Similar to the clinical development of Eligard, which was studied in a 12-month, open-label, multicentre trial, a 12-month, phase III, open-label, multicentre clinical trial was conducted to study the efficacy, safety and PK/PD of LMIS 50 mg. A 12-month extension was conducted to assess the safety of LMIS 50 mg over a prolonged period.

Table 4: Details of the Included Study

AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate aminotransferase; BP = blood pressure; BUN = blood urea nitrogen; Ca = calcium; Cr = creatinine; dL = decilitre; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HDL = high density lipoprotein; HR = heart rate; LDL = low density lipoprotein; HbA1c = hemoglobin A1c; K = potassium; LH = luteinizing hormone; LHRH = luteinizing hormone–releasing hormone; LMIS = leuprolide mesylate injectable suspension; mg = milligram; Mg = magnesium; Na = sodium; ng = nanogram; OTC = over the counter; P = phosphorus; PSA = prostate-specific antigen; SC = subcutaneous

Source: FPC01C-13 to 001 Clinical Study Report (Sections 9 and 10);⁴⁵ FP01C-13-001-EX Clinical Study Report (Section 9)⁴⁶

Description of Study

FP01C-13-001 was a phase III, single-arm, open-label, multicentre trial that enrolled a total of 137 patients with histologically confirmed prostate cancer eligible for androgen ablation therapy. Patients were enrolled between August 12, 2014 and September 2, 2016 from 26 sites in 8 countries in Europe, Taiwan, and the United States. There were no sites in Canada.

The trial was conducted in two parts. Part I was designed to assess the safety of LMIS 50 mg after receiving the first dose. Thirty-three patients were enrolled in Part I and assessed at Week 4 (Day 28). Of these 33 patients, the first 10 to enrol served as a ‘sentinel’ group for safety. For these subjects, additional safety reviews were conducted at the end of Week 2, Month 1, Month 3, and Month 6. At the interim review of safety, serum leuprolide concentrations and serum testosterone suppression assessments were completed. Enrollment was temporarily suspended until the interim safety review was completed. Since³ 90% of Part I patients achieved serum testosterone suppression to castrate levels (≤ 50 ng/dL), enrollment was re-opened for Part II and the remaining patients were enrolled.

Figure 1: Study Design of FP01C-13-001

D = day; EOS = end of study; ET = extension trial; sub = subjects

The primary efficacy end points in the FP01C-13-001 trial were the percentage of patients with serum testosterone ≤ 50 ng/dL by Day 28 (i.e., within 28 days following the first dose of LMIS 50 mg) and the percentage of patients with testosterone suppression ≤ 50 ng/dL from Day 28 through Day 336. The secondary end points were the proportion of patients exhibiting post-suppression excursion of serum testosterone > 50 ng/dL, either through ‘breakthrough’ (i.e., episodes unrelated to LMIS 50 mg) or through the ‘acute-on-chronic’ effect (i.e., related to the second dose of LMIS 50 mg), commonly referred to as ‘surge’. Other secondary end points included the effect of LMIS 50 mg on serum PSA and serum LH levels. The primary safety endpoint was measured through laboratory parameters, adverse events, local skin tolerability, bone pain, and urinary symptom exacerbations. The PK behavior of leuprolide was evaluated by full PK profiles from serum leuprolide concentrations in Part I subjects. The safety objective was to assess the tolerability and safety of LMIS 50 mg.

The extension study evaluated the safety of LMIS 50 mg of subjects who participated in FP01C-13-001. Subjects were administered 2 doses of LMIS 50 mg approximately 6 months apart over 48 weeks. As this was a safety study, no efficacy analysis was performed.

Populations

Inclusion and Exclusion Criteria

In FP01C-13-001, males³ 18 years of age with confirmed advanced prostate cancer and ECOG performance status ≤ 2 with a life expectancy of at least 18 months were included in the trial. Baseline morning testosterone serum needed to be < 150 ng/dL at the Screening Visit.

If patients had received chemotherapy, immunotherapy, cryotherapy, radiotherapy, or concomitant ADT within 8 weeks of the Screening Visit, they were excluded from the study. Patients should not have received any luteinizing hormone–releasing hormone (LHRH) therapy within 6 months of the Screening Visit. If patients had a clinically significant abnormal ECG or cardiovascular disease, as judged by the investigator, they were not included in the trial. Another exclusion criterion was the presence of type 1 diabetes, however, patients with type 2 diabetes were allowed if they were well-controlled on oral hypoglycemics.

The extension study enrolled patients who participated in FP01C-13-001. If participants enrolled in the study > 28 days after completion in FP01C-13-001, their baseline serum testosterone was measured to confirm castrate-level testosterone was confirmed. Additionally, examination of ECOG, PE, ECG, lab and PSA tests were repeated. These were not repeated if enrollment was < 28 days after completion in FP01C-13-001.

Baseline Characteristics

The baseline characteristics of patients enrolled in the FP01C-13-001 study are provided in Table 5. A total of 137 patients were enrolled and received LMIS 50 mg. Thirty-three patients were enrolled in Part I and additional 104 patients were enrolled in Part II.

For all subjects in Part I and Part II of the study (N = 137), the median (range) age was 74.0 (54-86) years, and most subjects were White (75.8%). For the total study population (N = 137), median (min, max) LH was 4.320 (1.54, 16.20) IU/L and median (min, max) PSA was 8.310 (0.06, 2,748.44) ng/mL.

Median (min, max) days since diagnosis was 633.0 (0, 13,290) for the full study population and most patients were Stage III (27%). The ECOG status of most patients was 0 (83.2%). These were similar to the baseline characteristics in the extension study with the key difference being that most patients were Stage II (30%).

Table 5: Summary of Baseline Characteristics – ITT Set For FP01C-13-001 and Safety Set for FP01C-13-001-EX

^aAge was calculated as (Date of informed consent – Date of birth)/365.25 and rounded down to integer. ^bdiagnosis of prostate carcinoma history (days) was calculated as

(Date of informed consent - Date of diagnosis). Subject TW12-001's date of diagnosis was the same as date of informed consent. ^cStaging of prostate carcinoma history.^dEfficacy analysis was not conducted for the extension study

CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; IU = international units; L = litre; LH = luteinizing hormone; n/N = number; NA = not available; NR = not reported; PSA = prostate-specific antigen; SD = standard deviation

Source: FP01C-13-001 Clinical Study Report (Section 11.2);⁴⁵ FP01C-13-001-EXClinical Study Report (Table 11 to 6)⁴⁶

Interventions

In the FP01C-13-001 and FP01C-13-001-EX trials, LMIS 50 mg was administered via SC injection by study personnel and no reconstitution was required. Patients received a single SC injection of LMIS 50 mg every 24 weeks (approximately every 6 months) with the first dose administered on Day 1 and the second dose on Day 168.

The dosage form of the intervention was leuprolide mesylate injection suspension, a pre-mixed drug product containing 50 mg leuprolide mesylate equivalent to 42 mg of leuprolide free base, formulated in a solution of N-methyl-2-pyrrolidone (NMP) and poly (D, L-lactide) (PLA) to control and sustain the release over a 6-month period after SC administration.

Concomitant Medications and Co-Interventions

Therapies permitted in the pivotal and extension trials included bisphosphonates and denosumab. Patients were also allowed to take vitamin D and calcium supplementation, if needed, as well as plain, over-the-counter multi-vitamins. Non-prescription and prescription pain medication, if prescribed by a physician, were allowed, in addition to radiation for pain. Patients were also permitted glucocorticosteroids for replacement therapy. For patients with Type 2 diabetes, oral hypoglycemic drugs were allowed.

Outcomes

A listing of trial outcomes, including the end point type, as well as their respective assessment timepoints, is provided in Table 6.

Table 6: Summary of Outcomes

AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase;; AST = aspartate aminotransferase; AUA = American Urological Association; BP = blood pressure; BUN = blood urea nitrogen; Ca = calcium; dL = decilitre; ECG = electrocardiogram; HgbA1c = hemoglobin A1c; HDL = high density lipoprotein; HR = heart rate; LDL = low density lipoprotein; LH = luteinizing hormone; LMIS = leuprolide mesylate injectable suspension; K = potassium; mg = milligram; Mg = magnesium; Na = sodium; NA = not available; ng = nanogram; P = phosphorus; PSA = prostate-specific antigen; QoL = quality of life; RR = length of ventricular cardiac cycle measured between two successive R waves; SCr = serum creatine; VAS = visual analogue scale

Source: FP01C-13-001 Clinical Study Report (Section 9.5)⁴⁵

Testosterone Suppression ≤ 50 ng/dL

Testosterone suppression ≤ 50 ng/dL was a primary outcome in the FP01C-13-001. Proliferation and survival of prostate cancer cells are dependent upon androgen stimulation via testosterone and dihydrotestosterone (DHT).⁴⁷ Thus it is critical to achieve serum testosterone levels to castrate levels to minimize stimulation of cancer cells.⁴⁸ Accordingly, the threshold of ≤ 50 ng/dL has been well established to achieve chemical castration and is a recognized outcome in clinical trials.⁴⁸

Testosterone Suppression ≤ 20 ng/dL

Testosterone suppression to ≤ 20 ng/dL was a secondary outcome in the FP01C-13-001. Orchiectomy or surgical castration achieves castrate levels of serum testosterone ≤ 20 ng/dL and has been suggested to be a clinically meaningful outcome for patients undergoing androgen deprivation therapy.⁴⁹

Prostate-Specific Antigen (PSA) Response Rate

PSA response rate was a secondary outcome measure outcome in the FP01C-13-001 trial. PSA is a well-established biomarker to assess treatment response.⁵⁰ PSA increases with age and age-based reference ranges are suggested: men < 50 years, 0–2.5 ng/mL; 50–59 years, 0–3.5 ng/mL; 60–69 years, 0–4.5 ng/mL; and 70+ years, 0–6.5 ng/mL.⁵⁰ In the FP01C-13-001 study, PSA > 4 ng/mL was considered elevated.⁴²

Luteinizing Hormone (LH)

LH was a secondary outcome measure outcome in the FP01C-13-001. LH acts on the Leydig cells to increase testosterone production.⁵¹ A reduction in LH manifests as a reduction in testosterone.⁵² No minimally important difference (MID) was identified in the literature for LH.

Serum Leuprolide Levels

Evaluating the pharmacokinetic properties of LMIS 50 mg was conducted through measurement of serum leuprolide levels, which was a primary outcome. A concentration > 90 ng/mL was characterized as a high serum leuprolide concentration in FP01C-13-001.⁴² There is no MID level identified in the literature.

Adverse Events (AEs)

In the trial, safety was assessed through the incidence of adverse events (AEs), serious adverse events (SAEs), and treatment emergent adverse events (TEAEs). All AE terms in FP01C-13-001 were coded using the MedDRA dictionary version 19.1 and classified by system organ class (SOC) and preferred terms (PTs) whereas those in FP01C-13-001-EX were coded as 20.1 using the MedDRA dictionary.

Visual Analog Scale (Bone and Urinary Pain)

The visual analog scale (VAS) is a validated pain rating scale that includes a 10-point continuum. One end notes ‘no pain’ (0) and the other end notes ‘worst pain’ (10). The values can be used to track pain progression and to compare between baseline and different points in the study.⁵³ In FPC01-13-001, the VAS was used to track bone and urinary pain progression.

Bone and urinary pain were used to evaluate the safety of LMIS 50 mg as part of the primary safety end point outcome in the FP01C-13-001 trial. Leuprolide acetate causes an increase in serum testosterone in the first week of treatment and this may cause some patients to experience symptoms such as bone pain. No MID was identified in literature for bone or urinary pain.

AUA Symptom Score Sheet (Urinary Symptoms)

The American Urological Association (AUA) Symptom Score sheet includes six questions on urinary signs and one question on urinary symptoms. The first six questions are scaled from 0 to 5 with 0 indicating no symptom at all, 1 suggesting 1 out of 5 times, 2 indicating 2 out of 5 times, 3 indicating 3 out of 5 times, 4 indicating 4 out of 5 times, and 5 indicating constant presence of symptoms. The last question is also scaled from 0 to 5, however 1 indicates one time, 2 indicates two times, 3 indicates three times, 4 indicates 4 times, and 5 indicates 5 or more times. The questions were:

• Over the past month, how often have you had the sensation of not emptying your bladder completely after you finished urinating?

• During the past month, how often have you had to urinate again less than 2 hours after you finished urinating?

• During the past month, how often have you found you stopped and started again several times when you urinate?

• During the past month, how often have you found it difficult to postpone urination?

• During the past month, how often have you had a weak urinary stream?

• During the past month, how often have you had to push or strain to begin urination?

• Over the past month, how many times did you most typically get up to urinate during the night?

Vital Signs, Weight, and Physical Examination

Vital signs, weight, and physical examination were included as part of the primary safety end point.

Hematological, Biochemical Assessments, and Urinalysis

As part of the primary safety end point in both the FP01C-13-001 and FP01C-13-001-EX trials, blood samples were collected, and laboratory tests run to obtain complete blood counts, as well as alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN) total bilirubin, serum creatinine (Cr), electrolyte (potassium (K), magnesium (Mg), calcium (Ca), and phosphorus (P)), blood glucose, and lipid profile levels. Reference ranges are dependent on the assays, equipment, and technique used.

Skin Tolerability

Skin tolerability assessment was completed to assess tolerability to the SC injection in the F901C-13 to 001 trial. The skin tolerability assessment included itchiness, erythema, burning, and stinging sensation. Grading of local tolerability symptoms were from 0 (none) to 3 (severe).

Electrocardiogram

ECG in test subjects was performed by standard 12-lead at baseline and by end of study to assess the cardiac effects of leuprolide and examine the QT interval (QTc) durations as a primary safety outcome in both the FP01C-13-001 and FP01C-13-001-EX trials. Normal values for QTc range from 350 to 450 ms for adult men.⁵⁴

Quality of Life Assessment

Quality of life as a result of urinary symptoms was also assessed through the use of a validated questionnaire in FP01C-13-001. Subjects were asked ‘How would you feel if you had to live with your current condition for the rest of your life?’ Respondents could answer on a scale from 0 to 6, with 0 being delighted, 1 being pleased, 2 being most pleased, 3 being mixed, 4 being mostly dissatisfied, 5 being unhappy, and 6 being terrible.

Statistical Analysis

Statistical analysis was conducted using SAS^® (version not specified). Continuous variables were described using descriptive statistics such as number of observations, mean, median, standard deviation, minimum, maximum, Hodges−Lehmann estimator, and 95% confidence intervals. The paired t test or Wilcoxon signed-rank test were used to test the change from baseline for continuous variables.

Frequencies and percentages were used for summarizing discrete variables. The denominator (unless specified otherwise) was the number of subjects in the specified population.

Additional details on the statistical model used in the pivotal and extension study are provided in Table 7.

Table 7: Statistical Analysis of Efficacy and Safety End Points

^aThese were analyses conducted for both the FP01C-13-001 and FP01C-13-001-EX studies

AE = adverse event; ALT = alanine transaminase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; AUA = American Urological Association; BP = blood pressure; BUN = blood urea nitrogen; Ca = calcium; dL = decilitre; ECG = electrocardiogram; HbA1c = hemoglobin A1c; HDL = high density lipoprotein; HR = heart rate; LDL = low density lipoprotein; LH = luteinizing hormone; LMIS = leuprolide mesylate injectable suspension; K = potassium; mg = milligram; Mg = magnesium; Na = sodium; ng = nanogram; NR = not reported; P = phosphorus; PSA = prostate-specific antigen; QoL = quality of life; RR = length of ventricular cardiac cycle measured between two successive R waves; SCr = serum creatinine; VAS = visual analogue scale

Primary Outcomes

Power Calculation

██████ ████ ██ ███ ███ █████████ ██ ███████ ███ ███ █████ ██ ██████ █ ██████████ ███ █ ███ ██ ██████ █████ █ █████████ ████████ █████ ███ ██████ ████████████ █████ ███ ███████ ████ ███████ ████ ███ ██████████ ██████████ █████ ███ ████ ██████████ ███ ██████ ███ █████ ███ ███████████ ███ █████ ███ ████████ ████ ███ ████████ ██ ██ ███ ██████████████ ██ █████████ ██████ ███ ████ █ █████ ██ ███ ████████ ████ ████████ ██ ███ ██████. A total of 137 subjects were enrolled in the study.

No sample size calculations were performed for FP01C-13-001-EX as it was a safety study and no efficacy analysis was conducted.

Statistical Test or Model

The baseline values that were included in the statistical model for each outcome are provided in Table 7. FP01C-13-001 had three primary end points and FP01C-13-001-EX only had the safety end point. The results presented in this report are the final analyses.

Data Imputation Methods

Missing data related to an efficacy and safety end point did not have a method of imputation applied. Details on how missing data was handled is reported in Table 7. No data imputation was applied for missing data in FP01C-13-001-EX.

Subgroup Analyses

No subgroup analyses were conducted in FP01C-13-001 or FP01C-13-001-EX.

Sensitivity Analyses

The sensitivity analysis was performed for the primary efficacy end point in FP01C-13-001 to determine whether censoring for any missing data would affect the analysis of duration time of subject with a serum testosterone of ≤ 50 ng/dL from Day 28 through Day 336. In this analysis, the subject was censored at the last testosterone measurement before the first missing visit if no prior escape occurred. The subject was considered having event at the escape visit otherwise. If a subject maintained suppression from Day 28 through Day 336 and completed the study without missing any testosterone tests, the subject was censored at the end of study (EOS) visit. Also, given that the missing testosterone value may not have been missing at random, a sensitivity analysis of the duration time of a subject with serum £ 50 ng/dL from Day 28 through Day 336 was performed for the subset of subjects who did complete the study and did not have any testosterone data missing. This analysis was done for the ITT and PP set.

Sensitivity analyses for the duration of serum testosterone levels ≤ 50 ng/dL was conducted, in which patients missing testosterone level at any visit were censored for the analysis of duration time of subject with a serum testosterone of ≤ 50 ng/dL from Day 28 through Day 336. Subjects were censored at the last testosterone measurement before the first missing visit if no prior escape occurred; otherwise, subjects were considered to have an event at the escape visit. If a subject maintained suppression from Day 28 through Day 336 and completed the study without missing any testosterone tests, the subject was censored at the EOS visit. The analysis with censoring for any missing data was performed for patients in the ITT as well as the PP population.

No sensitivity analyses were conducted in FP01C-13-001-EX.

Secondary Outcomes

Statistical analyses for secondary outcomes for FP01C-13-001 are described in Table 7. There were no secondary outcomes in the extension study.

Analysis Populations

All efficacy analyses were conducted for the ITT set and the PP set in FP01C-13-001. Safety analyses were conducted for the Safety set. The ITT set included patients who received at least one dose of LMIS 50 mg, and the PP set included those who received both doses of LMIS 50 mg with no major protocol deviations. The Safety set included patients who received a dose of LMIS 50 mg in both FP01C-13-001 and FP01C-13-001-EX. Details are provided in Table 8.

Table 8: Analysis Populations of FP01C-13-001 and FP01C-13-001-EX

ITT = intention-to-treat; LMIS = leuprolide mesylate injectable suspension; mg = milligram; PP = per protocol

Source: FP01C-13-001 Clinical Study Report (Section 11);⁴⁵ FP01C-13-001-EX Clinical Study Report (Section 11.1)⁴⁶

Sponsor’s Summary of the Results

Patient Disposition

In Part I of FP01C-13-001, 4 patients (12.1%) discontinued, out of whom 1 discontinued as a result of AEs (25% of total discontinuations). In Part II, 11 patients (10.6%) discontinued, out of whom 4 discontinued because of AEs. Overall, a total of 15 patients (10.9%) discontinued, 5 (33.3%) as a result of AEs. These events were investigated to be unrelated to LMIS 50 mg. One patient in Part I discontinued as a result of a protocol violation. There were no protocol violations in Part II.

In the extension study, 5 subjects discontinued, but none were due to AEs.

Table 9: Patient Disposition

AE = adverse event; ITT = intention-to-treat; N = number; NA = not applicable; NR = not reported; PP = per protocol; PSA = prostate-specific antigen; TID = three times a day

Source: FP01C-13-001 Clinical Study Report (Tables 11 to 6, 14.1.2);⁴⁵ FP01C-13-001-EX Clinical Study Report (Table 10 to 2)⁴⁶

Exposure to Study Treatments

Study Treatments

The summary of study drug exposure is provided in Table 10. All patients who received one dose were included in the safety analysis in both the pivotal and extension trials. In Part I (n = 33) of FP01C-13-001, all patients (100%) received the first dose and most (87.9%) went on to receive the second dose. The mean (SD) duration was 308.6 (80.89) days. In Part II (n = 104), all patients (100%) received the first administration and 95.2% received the second dose. The mean (SD) duration was 325.7 (42.44) days. In the total population (N = 137), 93.4% of patients received both doses, with a mean (SD) study duration of 321.6 (54.39) days. Compliance to treatment was 93.4% in FP01C-13-001. In the extension study, compliance was 56.7%.

In the extension trial however, only 56.7% of subjects received both doses. 9 subjects did not receive their second dose as a result of expiration of drug supply in November 2016 and 4 subjects terminated the study early.

Table 10: Patient Exposure (Safety Population)

CI = confidence interval; N = number; NR = not reported; SD = standard deviation

Source: FP01C-13-001 Clinical Study Report (Table 12-30);⁴⁵ FP01C-13-001-EX Clinical Study Report (Table 12-7)⁴⁶

Concomitant Medications

In Part I (n = 33), ███ ████████ ██████ took concomitant medication, with the most common therapies being anti-thrombotic agents ████████ lipid-modifying agents ████████ ACE inhibitors ████████ and systemic antibacterials ████████ In Part II (n = 104), most subjects ███████ took concomitant medications, the most common being ACE inhibitors ███████ and systemic antibacterials ████████ Overall, in the total population (N = 137), most patients ███████ took concomitant medications. Table 11 provides the most common (³ 10% of subjects) concomitant medications used in FP01C-13-001.

Concomitant medications such as oral antihyperglycemics, statins, pain, antiplatelets were taken by subjects in FP01C-13-001-EX. Table 11 provides details on concomitant medications used in FP01C-13-001. While individual therapies taken by subjects was available, a summary of concomitant drug classes was not available for FP01C-13-EX.

Table 11: Concomitant Medications in FP01C-13-001

ACE = angiotensin converting enzyme; N = number

Source: FP01C-13-001 Clinical Study Report (Table 14.3.10)⁴⁵

Efficacy (FP01C-13-001 Only)

Summary of Efficacy Outcomes

Serum Testosterone Levels ≤ 50 ng/dL (Primary End Point)

The primary efficacy end point of serum testosterone level suppressed to castrate levels ≤ 50 ng/dL was reached by 98.5% of patients in the ITT population and 99.2% of subjects in the PP population by Day 28 ± 1 day following the first dose of LMIS 50 mg. The administration of LMIS 50 mg successfully suppressed serum testosterone levels at castrate levels (≤ 50 ng/dL) from Day 28 until Day 336 in 97% and 97.6% of subjects in the ITT and PP populations, respectively (Table 12).

Figure 2: Serum Testosterone Over Time (ITT Population)

dL = decilitre; ITT = intent-to-treat; ng = nanogram

Source: FP01C-13-001 Clinical Study Report (Figure 11-3)⁴⁵

Figure 3: Serum Testosterone Over Time (PP Population) [Redacted]

dL = decilitre; ITT = intent-to-treat; ng = nanogram

Source: FP01C-13-001 Clinical Study Report (Figure 11-4)⁴⁵

Table 12: Serum Testosterone Levels (≤ 50 ng/dL) – Primary End Point

^aThe Kaplan–Meier method was used to analyze the duration of subjects with testosterone suppression from Day 28 through Day 336. Event was defined as subjects had testosterone to > 50 ng/dL. ^bThe suppression rate of subjects with testosterone suppression (≤ 50 ng/dL) by Day 336 was provided. ^cThe 95% RCI by Day 336 was provided by ADDPLAN software and manually scribed to the SAS generated table.

CI = confidence interval; dL = decilitre; ITT = intention-to-treat; n/N = number; ng = nanogram; NR = not reported; PP = per protocol; RCI = repeated-confidence interval

Source: FP01C-13-001 Clinical Study Report (Tables 11-0, Table 11-9, 14.2.5, 14.2.6)⁴⁵

Pharmacokinetic Parameters of LMIS 50 mg (Primary End Point)

Part I

After the first and second doses of LMIS 50 mg, mean serum leuprolide concentrations rose to reach the C_max of 94.5 ± 53.7 and 99.0 ± 73.0 ng/mL at 3.23 and 2.08 hours (median T_max), respectively. The mean values of C_wk4, C_mon6, AUC_0-4wk, AUC_0-6mon, and C_avg(0-6mon) were 1.04 ng/mL, 0.497 ng/mL, 91.6 day ng/mL, 224 day ng/mL, and 1.34 ng/mL, respectively, post the first dose of LMIS 50 mg SC injection. The mean values of C_wk4, C_mon6, AUC_0-4wk, AUC_0-6mon, and C_avg(0-6mon) were 1.64 ng/mL, 0.511 ng/mL, 125 day ng/mL, 268 day ng/mL, and 1.59 ng/mL, respectively, post the second dose of LMIS 50 mg SC injection (Table 13).

Figure 4: Arithmetic Mean Leuprolide and Testosterone Serum Concentration−Time After LMIS 50 mg SC in Part I [Redacted]

dL = decilitre; LMIS = leuprolide mesylate injectable suspension; ng = nanogram; SC = subcutaneous

Source: FP01C-13-001 Clinical Study Report (Figure 11-11)⁴⁵

Table 13: Summary of Serum Pharmacokinetic Parameters of Leuprolide After LMIS 50 mg SC in Part I

^aNot reportable for two subjects; ^bT_max is reported as median (min, max)

AUC_0-4wk = area under the concentration curve from time 0 to 4 weeks; AUC_0-6mon = area under the concentration time curve from time 0 to 24 weeks; C_avg(0-6mon) = mean serum concentration within 24 weeks post dosing; C_max = maximum concentration; h = hour; mL = millilitre; n = number; ng = nanogram; NR = not reported; SD = standard deviation; T_max = time to maximum serum concentration

Source: FP01C-13-001 Clinical Study Report (Table 11-20)⁴⁵

Part II

After the first and second doses of LMIS 50 mg SC injection, mean serum leuprolide concentrations rose rapidly to reach C_max of 99.7 ± 65.6 and 93.7 ± 60.8 ng/mL at 3.67 and 3.78 hours (median T_max), respectively. The mean values of C_wk4, C_mon6, AUC_0-4wk, AUC_0-6mon, and C_avg(0-6mon) were 1.47 ng/mL, 0.370 ng/mL, 103 day ng/mL, 219 day ng/mL, and 1.31 ng/mL, respectively, post the first dose of LMIS 50 mg SC injection. The mean values of C_wk4, C_mon6, AUC_0-4wks, AUC_0-6mon, and C_avg(0-6mon) were 2.40 ng/mL, 0.410 ng/mL, 131 day ng/mL, 250 day ng/mL, and 1.49 ng/mL, respectively, post the second dose of LMIS 50 mg SC injection (Table 14).

Figure 5: Arithmetic Mean Leuprolide and Testosterone Serum Concentration−Time After LMIS 50 mg SC in Part II [Redacted]

dL = decilitre; LMIS = leuprolide mesylate injectable suspension; ng = nanogram; SC = subcutaneous

Source: FP01C-13-001 Clinical Study Report (Figure 11-12)⁴⁵

In general, the LMIS 50-mg formulation resulted in multi-phasic leuprolide concentration versus time profiles characterized by a distinctive burst phase and a plateau phase. The initial acute increase of leuprolide mesylate concentration, followed by the rapid decline to a steady-state level, was similar to the release pattern seen with the other leuprolide depot formulations. After an initial burst phase characterized by mean high serum leuprolide concentrations (> 90 ng/mL), mean serum leuprolide levels maintained relatively constant over the majority of each 6-month dosing interval.

Table 14: Summary of Serum Pharmacokinetic Parameters of Leuprolide After LMIS 50 mg SC in Part II

^aNot reportable for two subjects; ^bNot reportable for one subject; ^cNot reportable for three subjects; ^{d b}T_max is reported as median (min, max)

AUC_0−4wk = area under the concentration curve from time 0₋4 weeks; AUC_0−6mon = area under the concentration time curve from time 0 to 24 weeks; C_{avg(0−6mon)} = mean serum concentration within 24 weeks post dosing; C_max = maximum concentration; h = hour; mL = millilitre; N = number; ng = nanogram; NR = not reported; SD = standard deviation; T_max = time to maximum serum concentration

Source: FP01C-13-001 Clinical Study Report (Table 11-25)⁴⁵

Post-Suppression Excursion of Serum Testosterone to > 50 ng/dL (Secondary End Point)

Most subjects did not exhibit post-suppression testosterone > 50 ng/dL after achieving castration levels of testosterone on Day 28. Two patients did exhibit post-suppression excursions of serum testosterone > 50 ng/dL during the study period. However, the percentage of subjects exhibiting post-suppression excursion of serum testosterone > 50 ng/dL was 0% in both the ITT and PP sets at the end of study (Day 336). Results are summarized in Table 15.

Table 15: Post-Suppression Excursions of Testosterone to > 50 ng/dL

CI = confidence interval; dL = decilitre; ITT = intention-to-treat; n/N = number; ng = nanogram; PP = per protocol

Source: FP01C-13-001 Clinical Study Report (Tables 11-11)⁴⁵

Serum Testosterone Suppression < 20 ng/dL (Secondary End Point)

Results are only reported for the total ITT (N = 137) population. By Day 28, 69.3% of patients achieved testosterone suppression < 20 ng/dL and by Day 336, most patients (95.9%) were able to achieve testosterone suppression < 20 ng/dL (Table 16).

Table 16: Summary of Patients With Testosterone Suppression

dL = decilitre; ITT = intention-to-treat; n/N = number; ng = nanogram

Source: FP01C-13-001 Clinical Study Report (Tables 11-11)⁴⁵

PSA Levels (Secondary End Point)

The administration of LMIS 50 mg significantly reduced serum PSA levels after its first injection and this effect remained until end of study. In the total ITT population (N = 137), mean baseline of PSA level was ██████ █ ████████ █████ and it decreased to ██████ █ ███████ █████ on Day 28. PSA levels appeared to approach normal on Day 168 with mean PSA level of ████████████ █████ (Table 17) The decline from baseline to Day 28 was significant (p < 0.001) and from baseline to Day 336 (p < 0.001) (Table 18). These findings were similar for Part I and Part II. In Part I, patients achieved a significant change from baseline to end of study (p < 0.001). Similarly, in Part II, patients experienced a significant reduction in PSA levels from baseline to Day 336 (p < 0.001). Table 19 additionally reports that most patients in ITT group were able to achieve PSA decreases between 50% and < 90% by Day 28. By Day 336, █████ of subjects achieved a reduction of ³ 95%. For subjects with elevated PSA at baseline, █████ were able to achieve PSA ≤ 4 ng/mL by Day 336 (Table 20).

Figure 6: PSA Levels Over Time (ITT Population) [Redacted]

ITT = intent-to-treat; mL = millilitre; ng = nanogram; PSA = prostate-specific antigen

Source: FP01C-13-001 Clinical Study Report (Figure 11-5)⁴⁵

Figure 7: PSA Levels Over time (PP Population) [Redacted]

mL = millilitre; ng = nanogram; PP = per protocol; PSA = prostate-specific antigen

Source: FP01C-13-001 Clinical Study Report (Figure 11-6)⁴⁵

Table 17: PSA Levels in the ITT and PP Populations (Part I, Part II, and Total)

CI = confidence interval; dL = decilitre; ITT = intention-to-treat; n/N = number; ng = nanogram; PP = per protocol; SD = standard deviation

Source: FP01C-13-001 Clinical Study Report (Table 14.2.13)⁴⁵

Table 18: PSA Level (ng/mL) Change From Baseline

^aPaired t test or Wilcoxon signed-rank test used to test the change from baseline for continuous variables

CI = confidence interval; dL = decilitre; ITT = intention-to-treat; n/N = number; ng = nanogram; PP = per protocol; SD = standard deviation

Source: FP01C-13-001 Clinical Study Report (Table 14.2.13)⁴⁵

Table 19: Summary of PSA Level Percent Change From Baseline (ITT Population), n (%)

ITT = intention-to-treat; n = number; PP = per protocol

Source: FP01C-13-001 Clinical Study Report (Table 14.2.24)⁴⁵

Table 20: Summary of PSA Level Percent Change From Baseline for Subjects With Elevated PSA at Baseline (ITT Population), n (%)

ITT = intention-to-treat; mL = millilitre; n = number; ng = nanogram

Source: FP01C-13-001 Clinical Study Report (Table 14.2.30 and 14.2.31)⁴⁵

LH Levels (Secondary End Point) (Results Measured by BA Lab)

The data demonstrated that the administration of LMIS 50 mg significantly reduced serum LH levels after the first dose. In the ITT (N = 137) population, the mean LH level at baseline was 5.125 ± 3.0421 IU/L. On Day 168 the mean serum LH level was 0.10699 ± 0.251897 IU/L, and that this effect remained until the end of study (Day 336).

A significant decrease in mean serum LH level was observed by end of study on Day 336 (0.10650 ± 0.256015 IU/L) in the PP population. This was also observed in the PP population with mean level at baseline being 5.016 ± 2.9666 IU/L and 0.08545 ± 0.186483 IU/L by Day 336. Summary of results are presented in Table 21 and Table 22.

Figure 8: LH Levels Over Time (ITT Population)

Note: Analysis was run at two labs, and were similar. The results presented are those from the BA lab.

ITT = intent-to-treat; IU = international units; L = litre; LH = luteinizing hormone

Source: FP01C-13-001 Clinical Study Report (Figure 11-7)⁴⁵

Figure 9: LH Levels Over Time (PP Population) [Redacted]

Note: Analysis was run at two labs, and were similar. The results presented are those from the BA lab.

IU = international units; L = litre; LH = luteinizing hormone; PP = per protocol

Source: FP01C-13-001 Clinical Study Report (Figure 11-8)⁴⁵

Table 21: Luteinizing Hormone Levels

CI = confidence interval; dL = decilitre; ITT = intention-to-treat; n/N = number; PP = per protocol; SD = standard deviation

Source: FP01C-13-001 Clinical Study Report (Table 14.2.19)⁴⁵

Table 22: Luteinizing Hormone Level Change From Baseline (IU/L)

^aPaired t test or Wilcoxon signed-rank test used to test the change from baseline for continuous variables

CI = confidence interval; dL = decilitre; ITT = intention-to-treat; n/N = number; ng = nanogram; PP = per protocol; SD = standard deviation

Source: FP01C-13-001 Clinical Study Report (Tables 14.2.16 and 14.2.17)⁴⁵

Harms

The evaluation of safety was based on the following parameters: adverse events, change in bone and urinary pain, change in urinary symptoms, change in vital signs, physical examination, local skin tolerability, lab data including liver function, complete blood counts, clinical chemistries, lipid levels, HbA1c, and significant changes in 12-lead resting ECG. Safety assessment was done on the Safety set for both FP01C-13-001 and FP01C-13-001-EX.

Safety Evaluation Plan

AEs were recorded throughout the study, with five interim analyses. The first four interim analyses were conducted in the first 10 patients at the end of Week 2, Month 1, Month 3 and Month 6. Safety interim analysis was conducted for the first 30 patients after Day 28. Similarly, in FP01C-13-001-EX, safety parameters were collected throughout the study.

An AE was defined as any untoward medical occurrence in a patient administered a pharmaceutical product and does not necessarily have a causal relationship to the study treatment. It can therefore be any unfavourable and unintended sign, symptom, or disease, temporally associated with the use of study medication, irrespective of its relationship. However, abnormal laboratory values or changes were not automatically reported as AEs if they were not clinically significant. They were only recorded as AEs if the investigator judged them to be clinically significant or if therapeutic action was required.

Overview of Safety

Key harms data including treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) are presented in Table 23 below.

Table 23: Key Harms Data in FP01C-13-001 and FP01C-13-001-EX