Summary Basis of Decision for Illuccix
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Illuccix is located below.
Recent Activity for Illuccix
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
The following table describes post-authorization activity for Illuccix, a product which contains the medicinal ingredient gallium (68Ga) gozetotide. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Updated: 2025-02-05
Drug Identification Number (DIN):
DIN 02531836 – 25mcg gozetotide per vial, powder for solution, intravenous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
SNDS # 279567 |
2023-10-06 |
Issued NOC 2024-09-20 |
Submission filed as a Level I – Supplement to seek an indication expansion for Illuccix (kit for the preparation of gallium [68Ga] gozetotide injection) to include the identification of patients with progressive metastatic castration-resistant prostate cancer (mCRPC), for whom prostate-specific membrane antigen (PSMA)-targeted therapy is indicated. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published. |
|
Drug product (DIN 02531836) market notification |
Not applicable |
Date of first sale 2023-04-03 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 242332 |
2020-12-06 |
Issued NOC 2022-10-13 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Illuccix
Date SBD issued: 2023-02-03
The following information relates to the New Drug Submission for Illuccix.
Kit for the preparation of gallium (68Ga) gozetotide for intravenous injection
Drug Identification Number (DIN):
- DIN 02531836 - 25 mcg gozetotide (also known as prostate-specific membrane antigen-11 [PSMA-11]) per vial, powder for solution, intravenous administration (only after radiolabelling with gallium [68Ga])
Telix Pharmaceuticals (US), Inc.
New Drug Submission Control Number: 242332
On October 13, 2022, Health Canada issued a Notice of Compliance to Telix Pharmaceuticals (US), Inc. for Illuccix, a kit for the preparation of gallium (68Ga) gozetotide (also known as 68Ga-PSMA-11) injection. Gallium (68Ga), a positron (β+)-emitting radionuclide, is not supplied with Illuccix.
The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-risk profile of Illuccix, after radiolabelling with gallium (68Ga), is favourable for diagnostic use with the positron emission tomography of PSMA-positive lesions in men with prostate cancer:
- with suspected metastasis who are suitable for initial definitive therapy.
- with suspected recurrence with elevated serum prostate-specific antigen (PSA) level.
1 What was approved?
Illuccix is a kit for the preparation of gallium (68Ga) gozetotide (also known as 68Ga-PSMA-11) for intravenous injection. It is indicated, after radiolabelling with gallium (68Ga), for use with the positron emission tomography of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer:
- with suspected metastasis who are suitable for initial definitive therapy.
- with suspected recurrence with elevated serum prostate-specific antigen (PSA) level.
No data are available to Health Canada regarding the use of Illuccix in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.
Based on the data submitted to and reviewed by Health Canada, Illuccix has been extensively studied in men 65 years of age or older. No clinically relevant differences in efficacy were observed between patients 65 years of age or older and those younger than 65 years of age.
Illuccix is supplied as a three-vial kit that contains the non-radioactive ingredients required for the preparation of gallium (68Ga) gozetotide injection. Gallium (68Ga), a positron (β+)-emitting radionuclide used for radiolabelling of gozetotide, is not supplied with Illuccix.
There are two different Illuccix configurations (A and B) that use gallium (68Ga) chloride (68GaCl3) from different sources: cyclotron-produced 68GaCl3 (Configuration A), 68GaCl3 from the commercially available germanium (68Ge)/68Ga generator GalliaPharm (Configuration A), and 68GaCl3 from the commercially available 68Ge/68Ga generator Galli Eo (Configuration B).
The kit consists of:
- Vial 1 (gozetotide blue-capped vial), which contains a lyophilized powder of 25 mcg of gozetotide and 10 mcg of D-mannose (a stabilizer).
- Vial 2 (sterile diluent vial, in two configurations: red-capped “2A” vial or green-capped “2B” vial), which contains the diluent of 150 mg of sodium acetate in hydrochloric acid.
- Vial 3 (sterile evacuated white-capped reaction vial), which is intended for the collection of 68GaCl3 and for the radiolabelling reaction.
Following the reconstitution and radiolabelling procedures (described in the Illuccix Product Monograph), Vial 3 is a multiple-dose vial containing up to 1,850 MBq (50 mCi) of gallium (68Ga) gozetotide in 7.5 mL of a sterile solution at a strength of up to 247 MBq (6.7 mCi) per mL.
The use of Illuccix, after radiolabelling with gallium (68Ga), is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Illuccix Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was Illuccix approved?
Health Canada considers that the benefit-risk profile of Illuccix, after radiolabelling with gallium (68Ga), is favourable for use with the positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer:
- with suspected metastasis who are suitable for initial definitive therapy.
- with suspected recurrence with elevated serum prostate-specific antigen (PSA) level.
Prostate cancer is the most frequently diagnosed cancer (excluding non-melanoma skin cancers) among Canadian men. In Canadian men, prostate cancer accounts for approximately 20% of all new cancer cases and represents the third leading cause of death from cancer. While several imaging modalities play an important role in the detection and management of prostate cancer, their diagnostic performance is suboptimal. The need for improved prostate cancer imaging is shown by the relatively high recurrence rate of up to 50% within 10 years after definitive therapy (surgery or radiation) of what was considered to be a localized disease, and by the failure to localize lesions by imaging in many patients with biochemical recurrence.
The prostate-specific membrane antigen is a cell-surface protein that shows a significant overexpression in prostate cancer and has been recognized as a highly promising target for diagnostic and therapeutic applications. One of the various PSMA ligands developed for radiolabelling with radioisotopes such as gallium (68Ga) is gozetotide (also known as PSMA-11), which is a component of the authorized Illuccix kit. The radioisotope gallium (68Ga) is not supplied with Illuccix.
The market authorization of Illuccix was primarily based on literature sources. In accordance with the conditions and requirements set out in Health Canada’s Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), the sponsor provided evidence from published clinical studies and market experience demonstrating the efficacy and safety of gallium (68Ga) gozetotide injection for PET imaging of prostate cancer in two distinct patient populations: patients with intermediate- to high-risk prostate cancer before initial definitive therapy, and patients with biochemically recurrent prostate cancer based on elevated serum PSA levels. The sponsor also provided the required evidence that the gallium (68Ga) gozetotide preparation used in the studies reported in the literature (i.e., the reference product, prepared in an automated synthesis unit and approved by the United States Food and Drug Administration [FDA] in 2020) is representative of gallium (68Ga) gozetotide prepared from the Illuccix kit, by submitting a comparative physicochemical analysis of the gallium (68Ga) gozetotide solution obtained from an automated synthesis unit and the gallium (68Ga) gozetotide solution prepared from the Illuccix kit.
Pivotal clinical data were derived from two prospective clinical studies, herein referred to as PSMA-PreP and PSMA-BCR, published in peer-reviewed journals. Both published articles (Hope et al., 2021; and Fendler et al., 2019) included the study protocols as supplementary content. A redacted FDA multidisciplinary review of the two studies was provided as supportive evidence. Both studies were conducted at the University of California, Los Angeles and the University of California, San Francisco.
PSMA-PreP was a prospective, open-label, single-arm, Phase III study of gallium (68Ga) gozetotide PET for imaging of prostate cancer. It enrolled 764 patients with intermediate- to high-risk prostate cancer who were considered candidates for prostatectomy and pelvic lymph node dissection. The enrolled patients met at least one of the following criteria: serum PSA of at least 10 ng/mL, tumour stage cT2b or greater, or Gleason score greater than 6. All patients underwent a single gallium (68Ga) gozetotide PET imaging study. The mean (standard deviation) intravenously injected radioactivity of gallium (68Ga) gozetotide was 196 (35) MBq (5.3 [0.9] mCi). Patients were imaged using either a PET with computed tomography (CT) or PET with magnetic resonance imaging (MRI) from mid-thigh to skull base.
The primary efficacy endpoints of the PSMA-PreP study were the sensitivity, specificity, positive predictive value, and negative predictive value of gallium (68Ga) gozetotide PET for the detection of regional nodal metastases compared with pathology at radical prostatectomy on a per-patient basis using nodal regional correlation (left, right, and other for perivesical, perirectal, and presacral areas).
Each imaging study of the efficacy analysis population (comprising 277 patients who underwent radical prostatectomy and pelvic lymph node dissection and had sufficient histopathology data for evaluation) was interpreted by three blinded independent central readers. The remaining 487 patients either underwent other treatments (379 patients) or were lost to follow-up (108 patients). Based on the majority reads, the sensitivity, specificity, positive predictive value, and negative predictive value of gallium (68Ga) gozetotide PET for pelvic nodal metastases detection compared with histopathology on a per-patient level were 40% (95% confidence interval [CI]: 34%-46%), 95% (95% CI: 92%-97%), 75% (95% CI: 70%-80%), and 81% (95% CI: 76%-85%).
While the PSMA-PreP study did not meet the predefined sensitivity threshold for pelvic nodal metastases detection of 65%, it did meet the specificity target of 90%. Notably, in accordance with current treatment guidelines, patients with more extensive disease on PSMA PET underwent treatments other than prostatectomy (radiation therapy, systemic therapy, surveillance, or other treatments). Consequently, patients with pelvic nodal metastases that were more easily detected by PSMA PET were not included in the primary efficacy population, thereby introducing a bias that likely lowered the sensitivity estimate.
PSMA-BCR was a prospective, open-label, single-arm study of gallium (68Ga) gozetotide PET for localization of biochemically recurrent prostate cancer. It enrolled 635 patients with biochemically recurrent prostate cancer after definitive therapy. The PSA levels in the studied population varied between 0.1 and 1,154 ng/mL. Patients received a single dose of gallium (68Ga) gozetotide followed by a PET/CT or PET/MRI scan from mid-thigh to skull base. The mean (standard deviation) intravenously injected radioactivity of gallium (68Ga) gozetotide was 188.7 (40.7) MBq (5.1 [1.1] mCi).
The primary endpoint of the PSMA-BCR study was positive predictive value on a per-patient and per-region basis of gallium (68Ga) gozetotide PET for detection of tumour location confirmed by histopathologic analysis. In the cohort of 93 patients with histopathologic validation, the estimated positive predictive value was 84% on a per-patient and per-region basis (95% CI: 75%-90% and 76%-91%, respectively). The study met the predefined threshold of achieving a positive predictive value of at least 70%.
No serious adverse events occurred in the studies. In the PSMA-PreP study, Grade 1 events were reported in 44 of 764 patients (6%), and none required intervention. The most commonly reported adverse events were diarrhea (in 16 of 764 patients [2%]) and fatigue (in 6 of 764 patients [1%]). Rash and nausea were reported by 4 patients apiece. In the PSMA-BCR study, Grade 1 events were reported in 15 of 635 patients (2%). The most commonly reported adverse events were diarrhea (in 3 of 635 patients [0.5%]), nausea (in 2 of 635 patients [0.3%]), and headache (in 2 of 635 patients [0.3%]). Other adverse events were dysphagia, dizziness, paresthesia, insomnia, rash, fatigue, injection site pruritus, and renal calculi occurring at a rate lower than 0.2%.
A Risk Management Plan (RMP) was not submitted for Illuccix. The PSMA ligand, gozetotide, has no inherent pharmacological activity, no known adverse effects, and no identified or potential risks that require further characterization. Therefore, an RMP was not needed for this product.
The submitted inner and outer labels, package insert, and Patient Medication Information section of the Illuccix Product Monograph meet the necessary regulatory labelling, plain language, and design element requirements.
The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Illuccix was accepted.
Overall, the evidence submitted supports the diagnostic efficacy and safety of Illuccix, after radiolabelling with 68Ga, for PET imaging of prostate cancer in the target patient populations. Appropriate warnings and precautions are in place in the Illuccix Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box highlights that radiopharmaceuticals should be used only by those health professionals who are appropriately qualified in the use of radioactive prescribed substances.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Illuccix?
The New Drug Submission (NDS) for Illuccix was filed as a submission that substantially relies on literature and market experience, in accordance with the conditions and requirements set out in Health Canada’s Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). While a submission relying on third-party data differs in the source of information used to support safety and effectiveness, it has to meet the same standards for approval as a conventional submission (that contains complete study reports of clinical safety and efficacy), i.e., to provide substantial evidence of safety and efficacy, as stipulated in the Food and Drug Regulations.
In the process of reviewing the NDS for Illuccix, Health Canada issued a Notice of Deficiency (NOD) based on deficiencies identified with respect to the submitted systematic review and meta-analysis of the published literature. Subsequently, these issues were satisfactorily addressed in the sponsor’s response to the NOD, which provided pivotal evidence from two published prospective and controlled clinical studies. The sponsor also provided the United States Food and Drug Administration review report based on these published studies, which was used as an added reference, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. A Notice of Compliance was issued on October 13, 2022.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Illuccix
| Submission Milestone | Date |
|---|---|
| New Drug Submission filed | 2020-12-06 |
| Screening | |
| Screening Acceptance Letter issued | 2021-02-05 |
| Review | |
| Quality evaluation completed | 2021-09-28 |
| Clinical/medical evaluation completed | 2021-09-28 |
| Notice of Deficiency issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2021-09-29 |
| Response to Notice of Deficiency filed | 2021-12-06 |
| Screening of Response to Notice of Deficiency | |
| Screening Acceptance Letter issued | 2021-12-21 |
| Review of Response to Notice of Deficiency | |
| Biostatistics evaluation completed | 2022-07-12 |
| Non-clinical evaluation completed | 2022-08-24 |
| Clinical/medical evaluation completed | 2022-08-24 |
| Quality evaluation completed | 2022-10-11 |
| Labelling review completed | 2022-10-13 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2022-10-13 |
4 What follow-up measures will the company take?
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Gallium (68Ga) gozetotide prepared from the Illuccix kit is administered at microdose levels and is not intended to elicit any pharmacological effects. It has no inherent pharmacodynamic activity. After binding to and internalization by prostate-specific membrane antigen (PSMA)-expressing cells, gallium (68Ga) gozetotide undergoes endosomal recycling.
In line with Health Canada’s Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), third-party published clinical pharmacology studies were submitted to support the intended use of gallium (68Ga) gozetotide prepared from the Illuccix kit. Data from a small clinical pharmacology study conducted by the sponsor in three healthy volunteers showed comparable pharmacokinetics, biodistribution, and dosimetry for gallium (68Ga) gozetotide prepared using the Illuccix kit and gallium (68Ga) gozetotide prepared using an automated synthesis module.
The recommended radioactivity dose of gallium (68Ga) gozetotide for positron emission tomography (PET) imaging in adult patients is 111 to 259 MBq (3 to 7 mCi) administered via a bolus intravenous injection. The maximum mass dose in an individual dose does not exceed 25 mcg.
Based on the submitted publications, intravenously injected gallium (68Ga) gozetotide was accumulated preferentially in the liver (15%), kidneys (7%), spleen (2%), and salivary glands (0.5%). The blood activity showed a bi-exponential behaviour, containing a fast component with a half-life of 6.5 minutes, and an additional slow component with a half-life of 4.4 hours reflecting biological clearance from blood.
The urinary excretion of gallium (68Ga) gozetotide can produce PET image artifacts that can obscure lesions in the pelvic area. Given the frequent occurrence of pelvic lesions in patients with prostate cancer, it is critical to consider these artifacts. The administration of a diuretic at the time of radiotracer injection may improve image quality by reducing background activity in the urinary system. In the published pivotal clinical studies (described in the Clinical Efficacy section), most patients (93%) received 20 mg of furosemide at the time of gallium (68Ga) gozetotide injection to minimize pelvic scatter artifacts.
The management of certain patients with prostate cancer may entail receiving androgen deprivation therapy or other treatments targeting the androgen pathway. Evidence from the published literature suggests that concomitant androgen deprivation therapy or other treatments targeting the androgen pathway might affect the uptake of gallium (68Ga) gozetotide in the setting of either hormone-sensitive or castration-resistant tumours. The impact of these therapies on the performance of gallium (68Ga) gozetotide has not been established. This information has been included in the Drug-Drug Interactions section of the Illuccix Product Monograph.
For further details, refer to the Illuccix Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
In accordance with the conditions and requirements set out in Health Canada's Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), evidence supporting the diagnostic efficacy of gallium (68Ga) gozetotide PET for imaging of prostate cancer was obtained from published clinical studies. Pivotal clinical data were derived from two prospective clinical studies, herein referred to as PSMA-PreP and PSMA-BCR, published in peer-reviewed journals. Both published articles (Hope et al., 2021; and Fendler et al., 2019) included the study protocols as supplementary content. A redacted United States Food and Drug Administration (FDA) multidisciplinary review of the two studies was provided as supportive evidence. Both studies were conducted at the University of California, Los Angeles and the University of California, San Francisco. The sponsor also provided evidence that gallium (68Ga) gozetotide used in the pivotal studies (i.e., the reference product, prepared in an automated synthesis unit) is representative of gallium (68Ga) gozetotide prepared from the Illuccix kit, by submitting the results of a comparative physicochemical analysis of the gallium (68Ga) gozetotide solution obtained from an automated synthesis unit and the gallium (68Ga) gozetotide solution obtained from the Illuccix kit.
PSMA-PreP was a prospective, open-label, single-arm, Phase III study of gallium (68Ga) gozetotide PET for imaging of prostate cancer patients. It enrolled 764 patients with intermediate- to high-risk prostate cancer who were considered candidates for prostatectomy and pelvic lymph node dissection. All patients underwent a single gallium (68Ga) gozetotide PET imaging study. The mean (standard deviation) intravenously injected radioactivity of gallium (68Ga) gozetotide was 196 (35) MBq (5.3 [0.9] mCi). Patients were imaged using either a PET with computed tomography (CT) or PET with magnetic resonance imaging (MRI) from mid-thigh to skull base. Given that this was an open-label study, the PSMA PET results were allowed to be used for treatment decisions.
The primary efficacy endpoints of the PSMA-PreP study were the sensitivity, specificity, positive predictive value, and negative predictive value of gallium (68Ga) gozetotide PET for the detection of regional nodal metastases compared with pathology at radical prostatectomy on a per-patient basis using nodal regional correlation (left, right, and other for perivesical, perirectal, and presacral areas).
Of the 764 patients, 277 underwent prostatectomy and pelvic lymph node dissection after imaging and were included in the primary analysis. The remaining 487 patients either underwent other treatments (379 patients) or were lost to follow-up (108 patients).
Each imaging study of the efficacy analysis population (the 277 patients who underwent radical prostatectomy) was interpreted by three blinded independent central readers. Based on the majority reads, the sensitivity, specificity, positive predictive value, and negative predictive value of gallium (68Ga) gozetotide PET for pelvic nodal metastases detection compared with histopathology on a per-patient level were 40% (95% confidence interval [CI]: 34%-46%), 95% (95% CI: 92%-97%), 75% (95% CI: 70%-80%), and 81% (95% CI: 76%-85%).
The PSMA-PreP study did not meet the predefined sensitivity threshold for pelvic nodal metastases detection of 65%; however, it did meet the specificity target of 90%. Of note, in accordance with current treatment guidelines, patients with more extensive disease on PSMA PET underwent treatments other than prostatectomy (radiation therapy, systemic therapy, surveillance, or other treatments). Consequently, patients with pelvic nodal metastases that were more easily detected by PSMA PET were not included in the primary efficacy population, thereby introducing a bias that likely lowered the sensitivity estimate.
PSMA-BCR was a prospective, open-label, single-arm study of gallium (68Ga) gozetotide PET for localization of biochemically recurrent prostate cancer. It enrolled 635 patients with biochemically recurrent prostate cancer. Biochemical recurrence was defined as a serum prostate-specific antigen (PSA) of 0.2 or more ng/mL measured more than 6 weeks after prostatectomy or as an increase in serum PSA of at least 2 ng/mL above nadir after definitive radiation therapy. The mean (standard deviation) intravenously injected radioactivity of gallium (68Ga) gozetotide was 188.7 (40.7) MBq (5.1 [1.1] mCi). Patients received a single dose of gallium (68Ga) gozetotide followed by a PET/CT or PET/MRI scan from mid-thigh to skull base. Three members of a pool of nine independent central readers evaluated each scan for the presence and regional location of gallium (68Ga) gozetotide uptake suggestive of recurrent prostate cancer. The readers were blinded to all clinical information other than the type of primary therapy (prostatectomy versus radiation therapy) and the most recent serum PSA level.
The primary endpoint of the PSMA-BCR study was positive predictive value on a per-patient and per-region basis of gallium (68Ga) gozetotide PET for detection of tumour location confirmed by histopathologic analysis. Secondary endpoints included positive predictive value using a composite reference standard of follow-up imaging and PSA response to treatment.
The efficacy analysis cohorts included 223 patients with composite validation and 93 patients with histopathologic validation.
The PSMA-BCR study met the predefined threshold of achieving a positive predictive value of at least 70%. In cases with histopathologic validation, the estimated positive predictive value was 84% on a per-patient and per-region basis (95% CI: 75%-90% and 76%-91%, respectively).
Indication
The New Drug Submission for Illuccix was filed by the sponsor with the following indication:
Illuccix (kit for the preparation of 68Ga-PSMA-11 injection), after radiolabelling with 68Ga, is indicated for:
- staging and re-staging in intermediate and high-risk prostate cancer;
- localizing tumour tissue in recurrent prostate cancer.
Health Canada revised the proposed indication to adequately reflect the two patient populations in the pivotal studies. Accordingly, Health Canada approved the following indication:
Illuccix (kit for the preparation of gallium [68Ga] gozetotide injection), after radiolabelling with gallium (68Ga), is indicated for use with positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer:
- with suspected metastasis who are suitable for initial definitive therapy.
- with suspected recurrence with elevated serum prostate-specific antigen (PSA) level.
For more information, refer to the Illuccix Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Illuccix, after radiolabelling with gallium (68Ga), has been established based on the provided published studies (described in the Clinical Efficacy section). All enrolled patients who received a gallium (68Ga) gozetotide injection represented the safety population.
There were no serious adverse events reported in the studies. In the PSMA-PreP study, Grade 1 events occurred in 44 of 764 patients (6%), and none required intervention. The most commonly reported adverse events were diarrhea (in 16 of 764 patients [2%]) and fatigue (in 6 of 764 patients [1%]). Rash and nausea were reported by 4 patients apiece. In the PSMA-BCR study, Grade 1 events occurred in 15 of 635 patients (2%). The most commonly reported adverse events were diarrhea (in 3 of 635 patients [0.5%]), nausea (in 2 of 635 patients [0.3%]), and headache (in 2 of 635 patients [0.3%]). Other adverse events were dysphagia, dizziness, paresthesia, insomnia, rash, fatigue, injection site pruritus, and renal calculi occurring at a rate lower than 0.2%.
The risk from radiation exposure is typical of PET oncology imaging and estimated to be minimal.
For more information, refer to the Illuccix Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In line with Health Canada’s Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience), third-party non-clinical information on gallium (68Ga) gozetotide was provided from literature sources. Additionally, the sponsor conducted one in vitro pharmacology study and one single-dose toxicity study.
Gallium (68Ga) gozetotide binds to the prostate specific membrane antigen (PSMA), a protein that is overexpressed in most prostate cancers. The in vitro pharmacology study, conducted by the sponsor, compared the cellular binding and internalization of gallium (68Ga) gozetotide prepared at room temperature using the Illuccix kit to those of gallium (68Ga) gozetotide prepared at high temperature (95 °C) through an automated synthesis module. While the radiolabelling methods carried out at two different temperatures produced gallium (68Ga) gozetotide preparations with different stereoisomer compositions, there was no significant difference in the binding affinities and internalization rates.
The sponsor also conducted one single-dose toxicity study to evaluate the acute toxicity of gozetotide. Male and female Wistar rats received a single intravenous injection of 86 mcg/kg gozetotide. At 24 hours and at 14 days after the injection, there were no adverse findings with respect to clinical signs, body weights, hematology parameters, clinical chemistry parameters, organ weights, gross pathology, and histopathology. Based on the results, the dose given is below the no-observed-adverse-effect level.
No long-term animal studies were performed to evaluate the carcinogenicity potential of gallium (68Ga) gozetotide. Mutagenesis studies have not been conducted.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Illuccix Product Monograph. In view of the intended use of Illuccix, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Illuccix Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Description of Illuccix
Illuccix is a three-vial kit that contains the non-radioactive ingredients required for the preparation of gallium (68Ga) gozetotide.
The radioisotope gallium (68Ga) is not supplied with Illuccix. Gallium (68Ga) can be produced by a cyclotron or by commercially available generators. Each source provides gallium (68Ga) chloride (68GaCl3) solution for radiolabelling.
There are two different Illuccix configurations (A and B) that use 68GaCl3 from different sources: cyclotron-produced 68GaCl3 (Configuration A), 68GaCl3 from the commercially available germanium (68Ge)/68Ga generator GalliaPharm (Configuration A), and 68GaCl3 from the commercially available 68Ge/68Ga generator Galli Eo (Configuration B).
The kit consists of:
- Vial 1 (gozetotide blue-capped vial), which contains a lyophilized powder of 25 mcg of gozetotide and 10 mcg of D-mannose (a stabilizer).
- Vial 2 (sterile diluent vial, in two configurations: red-capped “2A” vial or green-capped “2B” vial), which contains the diluent of 150 mg of sodium acetate in hydrochloric acid.
- Vial 3 (sterile evacuated reaction vial), which is a white-capped vial intended for the collection of 68GaCl3 solution. It is also the reaction vial for the radiolabelling of the reconstituted gozetotide.
The lyophilized gozetotide (Vial 1) is reconstituted by transferring the diluent from Vial 2 into Vial 1. The reconstituted gozetotide is then transferred into Vial 3 where it is radiolabelled. After completing these steps (described in detail in the Illuccix Product Monograph), Vial 3 is a multiple-dose vial containing up to 1,850 MBq (50 mCi) of gallium (68Ga) gozetotide in 7.5 mL of a sterile solution at a strength of up to 247 MBq (6.7 mCi) per mL. Reconstituted and radiolabelled Illuccix should be injected within 4 hours of preparation.
The quality data package submitted for each of the components of the Illuccix kit included satisfactory information with respect to the manufacturing process and process controls, control of materials and excipients, manufacturing process development, manufacturing process validation, drug product specifications and batch analysis, analytical procedures and method validations, reference standards, container-closure system, and stability. The following sections focus primarily on the information regarding gozetotide.
Characterization of gozetotide
Gozetotide is a small-molecule prostate-specific membrane antigen (PSMA) ligand. It is supplied as a lyophilized powder in Vial 1 of the Illuccix kit. Following reconstitution, gozetotide can be radiolabelled in situ prior to use by either cyclotron-derived or generator-derived 68GaCl3.
The structural identity of gozetotide has been established by a number of different analytical methods and compared with literature data.
Actual and potential impurities and degradation products most likely to arise during the manufacturing and storage of gozetotide were reported and characterized. These products were found to be within established limits and are considered acceptable. The radiolabelling procedure of gozetotide with gallium (68Ga) is not expected to generate any new chemical impurities.
Manufacturing Process of gozetotide
The manufacturing process of gozetotide includes steps of chemical synthesis of intermediates, conjugation, and purification, followed by a filling process.
The manufacturing process of the lyophilized gozetotide (supplied in Vial 1 of the Illuccix kit) involves formulation of gozetotide with D-mannose, filtration, filling into vials, lyophilization, and capping of the vials.
In-process controls have been identified for each step of the manufacture of gozetotide and are deemed satisfactory. The extensive batch analysis presented provides documented evidence, with a high degree of assurance, that the manufacturing process consistently produces a drug substance and a drug product that meet the required specifications.
Control of gozetotide
The identity and purity of gozetotide are tested against a suitable reference standard to verify that they meet the required specifications. The compendial and non-compendial analytical procedures are appropriately validated.
All materials and excipients meet the required specifications.
Stability of Illuccix
Based on the stability data submitted, the proposed shelf life of 24 months at 2 °C to 8 °C for Illuccix is considered acceptable.
Reconstituted and radiolabelled Illuccix (stored at ambient room temperature in a suitable lead shield) should be injected within 4 hours of preparation.
The compatibility of the non-radioactive ingredients of Illuccix with the container-closure system (identical for the three vials) was demonstrated through compendial testing and stability studies.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
Adventitious Agents Safety Evaluation
The manufacturing process of Illuccix incorporates adequate control measures to prevent contamination and maintain microbial control.
No materials of animal or human origin are used during the manufacture of Illuccix.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ILLUCCIX | 02531836 | TELIX PHARMACEUTICALS (US), INC. | GALLIUM (68Ga) GOZETOTIDE 25 MCG / VIAL |