Summary Basis of Decision for Pluvicto
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 Pluvicto is located below.
Recent Activity for Pluvicto
SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Pluvicto
Updated:
The following table describes post‑authorization activity for Pluvicto, a product which contains the medicinal ingredient lutetium (177Lu) vipivotide tetraxetan. 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 that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Drug Identification Number (DIN):
DIN 02530198 – 1,000 MBq/mL lutetium (177Lu) vipivotide tetraxetan, solution, intravenous administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02530198) market notification | Not applicable | Date of first sale:2022-11-07 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 260951 | 2022-01-28 | Issued NOC2022-08-25 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Pluvicto
Date SBD issued: 2023-01-20
The following information relates to the new drug submission for Pluvicto.
Lutetium (177Lu) vipivotide tetraxetan
Drug Identification Number (DIN):
- DIN 02530198 – 1,000 MBq/mL lutetium (177Lu) vipivotide tetraxetan, solution, intravenous administration
Advanced Accelerator Applications USA, Inc.
New Drug Submission Control Number: 260951
On August 25, 2022, Health Canada issued a Notice of Compliance to Advanced Accelerator Applications USA, Inc. for the therapeutic radiopharmaceutical Pluvicto.
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 Pluvicto is favourable for the treatment of adult patients with prostate‑specific membrane antigen (PSMA)‑positive metastatic castration‑resistant prostate cancer (mCRPC) who have received at least one androgen receptor pathway inhibitor (ARPI) and taxane‑based chemotherapy.
1 What was approved?
Pluvicto, a therapeutic radiopharmaceutical, was authorized for the treatment of adult patients with prostate‑specific membrane antigen (PSMA)‑positive metastatic castration-resistant prostate cancer (mCRPC) who have received at least one androgen receptor pathway inhibitor (ARPI) and taxane‑based chemotherapy.
Pluvicto is not authorized for use in pediatric patients (<18 years of age), as no clinical safety or efficacy data are available for this population.
No clinically relevant differences in efficacy were observed between patients ≥65 years of age and younger patients.
Pluvicto (1,000 MBq/mL lutetium [177Lu] vipivotide tetraxetan) is presented as a solution. In addition to the medicinal ingredient, the solution contains acetic acid, gentisic acid, pentetic acid, sodium acetate, sodium ascorbate, and water for injections. Pluvicto contains up to 88.75 mg sodium (main component of cooking/table salt) in each vial. This is equivalent to 4.4% of the recommended maximum daily dietary intake of sodium for an adult.
The use of Pluvicto 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 Pluvicto 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 Pluvicto approved?
Health Canada considers that the benefit‑risk profile of Pluvicto is favourable for the treatment of adult patients with prostate‑specific membrane antigen (PSMA)‑positive metastatic castration-resistant prostate cancer (mCRPC) who have received at least one androgen receptor pathway inhibitor (ARPI) and taxane‑based chemotherapy.
Prostate cancer is the most commonly diagnosed cancer in Canadian men, accounting for approximately 20% of all new cancer cases in men, and is the third leading cause of cancer death in men after lung cancer and colorectal cancer. Prostate cancer is divided into two major categories: castration-sensitive (or hormone-sensitive) and castration-resistant. Castration-resistant prostate cancer can progress to mCRPC, which is a serious and incurable condition. Patients with mCRPC whose disease progresses after androgen deprivation therapies (ADTs) and taxanes have a poor prognosis and limited treatment options.
Several approved drugs have a proven overall survival benefit in patients with mCRPC, including abiraterone and enzalutamide (ARPIs), docetaxel, cabazitaxel, radium‑223, and olaparib. Denosumab, zoledronic acid, systemic corticosteroid therapy, and palliative radiation are used as supportive agents in these patients. Prolonged survival has been demonstrated with the use of each of these therapies.
There is still a need for new therapies that improve survival in patients who have already progressed after treatment with two or three prior lines of therapy with ARPIs and taxanes. Additionally, some patients may be frail and not medically fit to receive some of the available therapies due to the risk of toxicities. Therefore, there remains an unmet medical need for effective and tolerable treatments for patients with mCRPC who have received prior lines of therapy.
Prostate-specific membrane antigen is a type II transmembrane glycoprotein and is highly expressed in all forms of prostate tissue, including adenocarcinoma. This protein is overexpressed in prostate cancer, particularly in advanced‑stage, high‑grade, metastatic, and androgen‑independent prostate carcinomas.
Pluvicto (lutetium [177Lu] vipivotide tetraxetan) is a radioligand therapy that targets PSMA‑expressing prostate cancer lesions by exploiting cell surface proteins mainly expressed by malignant cells. The high expression of PSMA in prostate cancer and low expression in normal tissues provide a mechanism by which targeted therapeutic radiation can be delivered to cancer cells while minimizing radiation‑related side effects.
Lutetium (177Lu) vipivotide tetraxetan has two components:
- vipivotide tetraxetan, the non‑radioactive component which binds to PSMA, and
- lutetium‑177 (177Lu), the anti‑tumour radionuclide.
Lutetium (177Lu) vipivotide tetraxetan binds to PSMA on prostate cancer cells, and the beta‑minus emission from lutetium‑177 delivers therapeutic radiation to PSMA‑expressing cells and surrounding cells. The radiation induces deoxyribonucleic acid (DNA) damage which can lead to cell death.
Clinical evidence of the efficacy of Pluvicto was provided primarily through results from the pivotal Phase III study, VISION (PSMA‑617‑01). The VISION study was designed to evaluate the efficacy of Pluvicto plus the best standard of care (BSoC; 551 patients) compared to the BSoC alone (280 patients) in men with PSMA‑positive mCRPC. As part of the eligibility criteria, patients were required to have received at least one prior ARPI therapy and taxane‑based chemotherapy. Patients randomized to receive Pluvicto were administered a 7.4 GBq dose once every 6 weeks for up to 6 doses, or until disease progression or unacceptable toxicity.
The major efficacy outcome measures were overall survival and radiographic progression‑free survival (rPFS) assessed by blinded independent central review. A statistically significant improvement was observed for overall survival and rPFS. The median estimates for overall survival were 15.3 months in patients treated with Pluvicto plus BSoC and 11.3 months in patients treated with BSoC alone. There was an estimated 38% reduction in the risk of death in favour of treatment with Pluvicto plus BSoC (hazard ratio [HR] = 0.62, 95% confidence interval [CI]: 0.52, 0.74, p<0.001). Unbalanced early dropout in the BSoC arm resulted in the exclusion of large proportion of subjects from the analysis of rPFS, creating uncertainty and limiting the interpretation of the results.
The clinical safety of Pluvicto was evaluated in a subset of 734 patients from the pivotal VISION study who received at least one dose of randomized treatment. Within this subset, 529 patients received at least one dose of Pluvicto 7.4 GBq administered every 6 to 10 weeks plus BSoC, and 205 patients received BSoC alone.
In the group treated with Pluvicto plus BSoC, treatment‑emergent adverse events (TEAEs) led to dose interruption in 16.1% of patients, dose reduction in 5.7% of patients, and permanent discontinuation of Pluvicto in 11.9% of patients. Adverse events leading to dose interruption or reduction included anemia, thrombocytopenia, leukopenia, and neutropenia, along with increased aspartate aminotransferase, hematuria, and dry mouth. Permanent discontinuation of Pluvicto was due to adverse events of anemia, thrombocytopenia, leukopenia, neutropenia, and pancytopenia. The frequencies at which these TEAEs were reported and led to each outcome are listed in the Clinical Safety section.
Treatment-emergent serious adverse events (SAEs) were reported in 36.3% of patients who received Pluvicto plus BSoC and 27.8% in patients who received BSoC only. The treatment-emergent SAEs reported in >1% of patients who received Pluvicto plus BSoC were anemia (2.8%), urinary tract infection (2.5%), hematuria (2.1%), sepsis (1.9%), acute kidney injury (1.7%), back pain (1.7%), pneumonia (1.3%), pyrexia (1.3%), bone pain (1.1%), pancytopenia (1.1%), pulmonary embolism (1.1%), and spinal cord compression (1.1%). The safety profile of Pluvicto is considered acceptable in the context of the serious and life‑threatening condition for which it is indicated.
Fatal SAEs occurred in 3.6% of patients who received Pluvicto plus BSoC, and in 2.9% of patients who received BSoC alone. The death rate due to SAEs in patients treated with Pluvicto plus BSoC was not unexpectedly higher than in patients treated with BSoC alone (control arm).
A Serious Warnings and Precautions box is included in the Pluvicto Product Monograph to emphasize that radiopharmaceuticals should only be used by health professionals who are appropriately qualified in the use of radioactive prescribed substances in or on humans. Additionally, it highlights the risks of severe and life‑threatening myelosuppression and severe renal toxicity in patients treated with Pluvicto.
A Risk Management Plan (RMP) for Pluvicto was submitted by Advanced Accelerator Applications USA, Inc. to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Pluvicto 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 Pluvicto was accepted.
Pluvicto has an acceptable safety profile based on the non‑clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Pluvicto Product Monograph to address the identified safety concerns.
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 Pluvicto?
The New Drug Submission (NDS) for Pluvicto was subject to an expedited review process under the Priority Review of Drug Submissions Policy. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Pluvicto provides effective treatment of metastatic castration-resistant prostate cancer (mCRPC), a serious, life-threatening or severely debilitating disease or condition that is not adequately managed by a drug marketed in Canada.
The NDS for Pluvicto was reviewed under Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership designed to give cancer patients faster access to promising cancer treatments. The NDS for Pluvicto was classified as a Project Orbis Type C submission, where the FDA had already issued a positive decision and subsequently shared its completed review documents with the Project Orbis partners. Along with the FDA and Health Canada, the Swiss Agency for Therapeutic Products (Swissmedic) was also involved in this review as a Project Orbis partner. Review reports prepared by the FDA and the European Medicines Agency (EMA) were used as added references as part of Project Orbis. Foreign review reports were also used as references for the clinical, nonclinical, and quality components of the NDS, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Pluvicto NDS was made independently based on a critical assessment of the data package submitted to Health Canada.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Pluvicto
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2021-10-15 |
| Request for priority status filed | 2021-11-22 |
| Request for priority status approved by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics | 2021-12-17 |
| New Drug Submission filed | 2022-01-28 |
| Screening | |
| Screening Acceptance Letter issued | 2022-02-28 |
| Review | |
| Non-clinical evaluation completed | 2022-07-27 |
| Review of Risk Management Plan completed | 2022-08-08 |
| Quality evaluation completed | 2022-08-10 |
| Clinical/medical evaluation completed | 2022-08-19 |
| Biostatistics evaluation completed | 2022-08-19 |
| Labelling review completed | 2022-08-19 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2022-08-25 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
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
As described above, the review of the clinical component of the New Drug Submission for Pluvicto was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission.
Clinical Pharmacology
Pluvicto (lutetium [177Lu] vipivotide tetraxetan injection) is a prostate‑specific membrane antigen (PSMA)‑targeted radioligand therapy with two components:
- vipivotide tetraxetan, the non‑radioactive component which binds to PSMA, and
- lutetium‑177 (177Lu), the anti‑tumour radionuclide.
The active moiety of Pluvicto is the radionuclide lutetium‑177. It is linked to a targeting moiety that binds with high affinity to PSMA, a transmembrane protein that is highly expressed in prostate cancer, including metastatic castration‑resistant prostate cancer (mCRPC). Upon the binding of Pluvicto to PSMA‑expressing cancer cells and its internalization, the beta-minus emission from lutetium‑177 delivers therapeutic radiation to the targeted cell, as well as to surrounding cells, and induces deoxyribonucleic acid (DNA) damage which can lead to cell death.
The primary data reviewed to assess the clinical pharmacology of Pluvicto are from dosimetry/biodistribution, pharmacokinetics, and urine metabolic stability evaluations in 30 patients from a sub‑study (hereafter called the VISION sub‑study). The dosing regimen for Pluvicto (7.4 GBq once every 6 weeks [Q6W]) was chosen based on data published in scientific literature evaluating various dosing regimens (1.1 to 12.0 GBq every 4 to 12 weeks, for 1 to 9 cycles) during the planning of the VISION study and a Phase II study, RESIST‑PC.
The major pharmacokinetic aspects of absorption, distribution, metabolism, and elimination of Pluvicto have been characterized in the VISION sub‑study. Pluvicto is administered intravenously, and is therefore immediately and completely bioavailable. Following injection, primary uptake was detected in the lacrimal glands, salivary glands, kidneys, urinary bladder wall, liver, small intestine, and large intestine. Pluvicto does not undergo hepatic or renal metabolism, and is primarily eliminated renally.
Data from a population pharmacokinetic analysis indicate that exposure of Pluvicto is expected to increase with the degree of renal impairment. No dose adjustment is recommended for patients with mild renal impairment (baseline creatinine clearance [CrCl] 60 to 89 mL/min by Cockcroft‑Gault). The data available in patients with moderate renal impairment (CrCl 30 to 59 mL/min) are not sufficient to draw a conclusion regarding dose adjustment. However, patients with mild or moderate renal impairment may be at greater risk of toxicity, and renal function and adverse reactions should be monitored frequently in these patients. The pharmacokinetic profile and safety of Pluvicto have not been studied in patients with severe renal impairment (CrCl 15 to 29 mL/min) or end‑stage renal disease.
The data available in patients with mild hepatic impairment are not sufficient to draw a conclusion regarding dose adjustment. Pluvicto has not been studied in patients with moderate or severe hepatic impairment.
Cardiac electrophysiology was assessed in the VISION sub‑study. No large mean increase from baseline was detected with respect to the observed corrected QT (QTc) interval (i.e., 10 ms) following single dose administration of Pluvicto at the recommended therapeutic dose (7.4 GBq) when assessed 24 hours post dose. The relationship between Pluvicto concentration and baseline‑adjusted QTc interval was studied through pharmacokinetic/pharmacodynamic modelling. Following the recommended therapeutic dose of Pluvicto, the magnitude of prolongation of the QT interval corrected using Fridericia's formula (QTcF) at maximal plasma concentration (Cmax; 6.58 ng/mL) was predicted to be 8.7 ms (90% confidence interval [CI]: 3.8, 13.6) based on non‑compartmental analysis.
No exposure‑response analysis for efficacy was performed. Based on exposure response analysis for safety at cycle 1, no consistent trend was detected due to the small sample size of the VISION sub‑study.
For further details, please refer to the Pluvicto Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Clinical evidence of the efficacy of Pluvicto was provided primarily through results from the pivotal Phase III study, VISION (PSMA‑617‑01).
The VISION study was designed to evaluate the efficacy of Pluvicto plus the best standard of care (BSoC; 551 patients) compared to the BSoC alone (280 patients) in men with PSMA‑positive mCRPC. Patients were randomized 2:1, with randomization stratified by baseline lactase dehydrogenase (LDH), the presence of liver metastases, Eastern Cooperative Oncology Group (ECOG) performance status score, and inclusion of an androgen receptor pathway inhibitor (ARPI) as part of the BSoC at the time of randomization. Eligible patients were required to have PSMA‑positive mCRPC, defined as having at least one tumour lesion with gallium‑68 (68Ga)‑PSMA‑11 positron emission tomography (PET)/computed tomography (CT) uptake greater than normal liver uptake. Additionally, eligible patients were required to have received at least one prior ARPI therapy and taxane‑based chemotherapy. Patients randomized to receive Pluvicto were administered a 7.4 GBq dose once every 6 weeks for up to 6 doses, or until disease progression or unacceptable toxicity.
The major efficacy outcome measures were overall survival and radiographic progression‑free survival (rPFS) assessed by blinded independent central review. A statistically significant improvement was observed for overall survival and rPFS. The median estimates for overall survival were 15.3 months in patients treated with Pluvicto plus BSoC and 11.3 months in patients treated with BSoC alone. There was an estimated 38% reduction in the risk of death in favour of treatment with Pluvicto plus BSoC (hazard ratio [HR] = 0.62, 95% CI: 0.52, 0.74, p<0.001). Unbalanced early dropout in the BSoC arm resulted in the exclusion of large proportion of subjects from the analysis of rPFS, creating uncertainty and limiting the interpretation of the results.
Indication
|
Sponsor's proposed indication |
Health Canada-approved indication |
|
Pluvicto (lutetium [177Lu] vipivotide tetraxetan) is indicated for: · The treatment of adult patients with prostate‑specific membrane antigen (PSMA)‑positive metastatic castration‑resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane‑based chemotherapy or who are not medically suitable for taxanes. |
Pluvicto (lutetium [177Lu] vipivotide tetraxetan injection) is indicated for: · The treatment of adult patients with prostate-specific membrane antigen (PSMA)‑positive metastatic castration‑resistant prostate cancer (mCRPC) who have received at least one androgen receptor pathway inhibitor (ARPI) and taxane‑based chemotherapy. The indication is authorized based on overall survival. |
The proposed indication was revised to more accurately reflect the population of patients evaluated in the pivotal VISION study, and to clarify the therapeutic place of Pluvicto (i.e., after treatment with ARPI and taxane‑based chemotherapy). This clarification is vital, as the sequence of available therapies can affect the clinical outcome for incurable and life‑threatening diseases such as progressive mCRPC, for which effective therapies are limited.
For more information, refer to the Pluvicto Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Pluvicto was evaluated in a subset of 734 patients from the pivotal VISION study (described in the Clinical Efficacy section) who received at least one dose of randomized treatment. Within this subset, 529 patients received at least one dose of Pluvicto 7.4 GBq administered every 6 to 10 weeks plus BSoC, and 205 patients received BSoC alone.
In the group treated with Pluvicto plus BSoC, treatment‑emergent adverse events (TEAEs) led to dose interruption in 16.1% of patients and dose reduction in 5.7% of patients. Adverse events leading to dose interruption/dose reduction of Pluvicto in ≥0.5% of patients who received Pluvicto plus BSoC included anemia (5.1%/1.3%), thrombocytopenia (3.6%/1.9%), leukopenia (1.5%/0.6%), neutropenia (0.8%/0.6%), increased aspartate aminotransferase (0.6%/0%), hematuria (0.6%/0%), and dry mouth (0%/0.6%). Additionally, TEAEs led to permanent discontinuation in 11.9% of patients. Adverse events leading to permanent discontinuation of Pluvicto in ≥0.5% of patients who received Pluvicto plus BSoC included anemia (2.8%), thrombocytopenia (2.8%), leukopenia (1.3%), neutropenia (0.8%), and pancytopenia (0.6%). A case of acute myeloid leukemia was reported outside of the treatment‑emergent period, which was defined as the 30‑day post‑treatment follow‑up, but before the capture of long‑term follow‑up events.
The most common laboratory abnormalities to have worsened from baseline (reported in ≥30% of patients who received Pluvicto plus BSoC) were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.
Treatment-emergent serious adverse events (SAEs) were reported in 36.3% of patients who received Pluvicto plus BSoC and 27.8% in patients who received BSoC only. The treatment-emergent SAEs reported in >1% of patients who received Pluvicto plus BSoC were anemia (2.8%), urinary tract infection (2.5%), hematuria (2.1%), sepsis (1.9%), acute kidney injury (1.7%), back pain (1.7%), pneumonia (1.3%), pyrexia (1.3%), bone pain (1.1%), pancytopenia (1.1%), pulmonary embolism (1.1%), and spinal cord compression (1.1%). The safety profile of Pluvicto is considered acceptable in the context of the serious and life-threatening condition for which it is indicated.
Fatal SAEs occurred in 3.6% of patients who received Pluvicto plus BSoC, including sepsis (0.8%), pancytopenia (0.4%), acute hepatic failure, bone marrow failure, coronavirus disease 2019 (COVID‑19), disease progression, Escherichia coli sepsis, euthanasia, intracranial hemorrhage, hepatic failure, ischemic stroke, metastases to the central nervous system, multiple organ dysfunction syndrome, aspiration pneumonia, and subdural hematoma (0.2% each). Fatalities due to adverse events occurred in 2.9% of patients who received BSoC alone. The death rate due to SAEs in patients treated with Pluvicto plus BSoC was not unexpectedly higher than in patients treated with BSoC alone (control arm).
A Serious Warnings and Precautions box is included in the Pluvicto Product Monograph to emphasize that radiopharmaceuticals should only be used by health professionals who are appropriately qualified in the use of radioactive prescribed substances in or on humans. Additionally, it highlights the risks of severe and life‑threatening myelosuppression and severe renal toxicity in patients treated with Pluvicto.
Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Pluvicto, and to support its safe and effective use. For more information, refer to the Pluvicto Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As described above, the review of the non-clinical component of the New Drug Submission for Pluvicto was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission.
Non-clinical pharmacology, pharmacokinetic, and toxicology studies have been conducted with lutetium (177Lu) vipivotide tetraxetan (the medicinal ingredient in Pluvicto), non‑radioactive lutetium (175Lu) vipivotide tetraxetan, and the unlabelled precursor vipivotide tetraxetan.
Lutetium (177Lu) vipivotide tetraxetan bound to prostate‑specific membrane antigen (PSMA)‑positive cells in an in vitro pharmacology study, consistent with reports published in scientific literature.
In safety pharmacology studies, a formulation containing a 1:1 ratio of vipivotide tetraxetan and non‑radioactive lutetium (175Lu) vipivotide tetraxetan was administered to rats and minipigs. No adverse effects were observed on central nervous system (CNS) or respiratory function in rats, or on cardiovascular function in minipigs. Additionally, no inhibition of the human ether‑a‑go‑go‑related gene (hERG) potassium channel current was observed.
A dosimetry study in rats revealed radioactivity in the kidneys after intravenous administration of lutetium (177Lu) vipivotide tetraxetan, and the radiolabelled drug exhibited major clearance through a renal pathway. Accumulation of radioactivity was also detected in the blood after a single intravenous injection, although lutetium (177Lu) vipivotide tetraxetan was completely cleared from the blood one day after administration. No distribution of lutetium (177Lu) vipivotide tetraxetan into erythrocytes was observed in vitro. Based on observations in rats, renal and hematological toxicities are expected following treatment with lutetium (177Lu) vipivotide tetraxetan. Transient accumulation of lutetium (177Lu) vipivotide tetraxetan in the muscle, skeleton, intestine, and liver in rats has been reported in the published literature (a study cited by the sponsor). Except for the skeleton, the uptake of radioactivity in these organs decreased gradually over the course of the 7‑day study. Distribution of lutetium (177Lu) vipivotide tetraxetan was not detected in CNS tissues in rats. Myelosuppression, gastrointestinal toxicity, renal toxicity, liver toxicity, and nervous system disorders were observed in patients treated with lutetium (177Lu) vipivotide tetraxetan.
The ligand‑mediated toxicities of lutetium (177Lu) vipivotide tetraxetan were evaluated in a single‑dose toxicity study in rats and minipigs and a repeat‑dose toxicity study in male rats. The single‑dose toxicity study was conducted using the formulation of 1:1 vipivotide tetraxetan and non‑radioactive lutetium (175Lu) vipivotide tetraxetan administered intravenously. No toxicologic effects were observed in rats at doses up to 4 mg/kg. In minipigs, acute inflammation at the injection site was observed at all doses on Day 2, with associated vascular and perivascular necrosis and hemorrhage. After 14 days, minimal or mild vascular and perivascular necrosis was still present with recovery trends that were more evident in females than in males. Safety margins for total vipivotide tetraxetan, relative to a 275 mcg theoretical maximum human dose, were approximately 150‑fold and 400‑fold in rats and minipigs, respectively (based on body surface area [BSA] scaling). In the repeat‑dose toxicity study, unlabelled vipivotide tetraxetan was administered weekly to male rats for 4 weeks. No adverse treatment‑related effects were observed at doses up to 0.4 mg/kg (15‑fold higher than the recommended dose based on BSA scaling).
The unlabelled precursor molecule, vipivotide tetraxetan, is non‑mutagenic. However, radiation is a carcinogen. The DNA‑reactive mechanism of action for therapeutic radiation associated with the active agent, lutetium (177Lu) vipivotide tetraxetan, would indicate that it is genotoxic/mutagenic and potentially carcinogenic.
Although reproductive and developmental toxicity testing was not performed, lutetium (177Lu) vipivotide tetraxetan is expected to have toxic reproductive and developmental effects due to the induction of DNA damage. Based on its mechanism of action, lutetium (177Lu) vipivotide tetraxetan can cause fetal harm. Patients are advised to use effective contraception during treatment and for 14 weeks after the last dose. No studies were conducted to determine the effects of lutetium (177Lu) vipivotide tetraxetan on fertility. However, the recommended cumulative dose of 44.4 GBq (44,400 MBq) of Pluvicto results in a radiation absorbed dose to the testes within the range where Pluvicto may cause temporary or permanent infertility.
The results of the non‑clinical studies as well as the potential risks to humans have been included in the Pluvicto Product Monograph. Considering the intended use of Pluvicto, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Pluvicto Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As described above, the review of the quality component of the New Drug Submission for Pluvicto was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration as a Project Orbis Type C submission, and as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Characterization of the Drug Substance
The molecular structure of vipivotide tetraxetan, a precursor to the drug substance lutetium (177Lu) vipivotide tetraxetan, was confirmed by high–resolution mass spectrometry, infrared spectroscopy, proton nuclear magnetic resonance and carbon nuclear magnetic resonance.
Evaluation of the stereoisomers of vipivotide tetraxetan showed that there was minimal isomerization of the stereogenic centers during the synthesis of vipivotide tetraxetan.
Impurities and degradation products arising from starting materials, manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
The drug substance, lutetium (177Lu) vipivotide tetraxetan, is synthesized from the precursor vipivotide tetraxetan and lutetium–177 chloride.
The intermediates from which vipivotide tetraxetan is synthesized are produced from well–defined, commercially available starting materials with acceptable specifications. The bulk vipivotide tetraxetan is prepared by purification and lyophilisation. It is then dissolved, filtered, and filled into vials. The filled vials are lyophilized and sealed.
The in–process controls confirm the purity and identity of the intermediates and final product, and to monitor the completion of the reactions. The manufacturing process has been validated and the results confirm that it is robust and consistently produces vipivotide tetraxetan that meets the predetermined quality characteristics.
Lutetium–177 chloride may be prepared using one of two different sources of stable isotopes (either lutetium–176 or ytterbium–176) that is required for manufacturing of the lutetium (177Lu) vipivotide tetraxetan drug substance.
The drug substance, lutetium (177Lu) vipivotide tetraxetan, is synthesized in a self–contained closed–system synthesis module through an automated process remotely controlled by Good Manufacturing Practices (GMP)–compliant software.
The synthesis of the drug substance and its formulation into the drug product are part of an automated continuous process. This process does not allow for isolation and testing of the drug substance due to its radioactive decay and rapid synthesis time. All quality control and stability tests are performed on the drug product.
Dilution solution is added to reach the required volumetric activity at calibration time, thereby producing the lutetium (177Lu) vipivotide tetraxetan bulk solution, which is sterile filtered into drug product vials. The vials are weighed to confirm that they contain the required volume of the drug product solution, and then stoppered and capped by the automated system. The activity is measured, and each filled vial is visually inspected and then loaded into a prelabelled shielded secondary container located outside the dispensing area.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of lutetium (177Lu) vipivotide tetraxetan with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance and drug product specifications are justified with available data from the clinical trial and process validation batches, and meet the United States Pharmacopeia (USP) and European Pharmacopeia (Ph. Eur.) standards for radiopharmaceuticals. A specification for elemental impurities is not considered necessary based on a risk assessment and on batch analysis data demonstrating that each relevant elemental impurity was not detected above the limit of the respective permitted daily exposure (PDE). The estimated quantities of potential residual solvents are significantly lower that the specified limits in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. The testing of residual solvents is therefore not necessary for product release.
The nitrosamine risk assessment was performed according to the guidelines for potential sources of nitrosamine impurities outlined by the European Medicines Agency (EMA), FDA, Health Canada and the Swiss Agency for Therapeutic Products (Swissmedic). No risk was identified of the presence or introduction of nitrosamines during the drug product manufacturing process, or of the formation of nitrosamines in the Pluvicto drug product solution.
The high performance liquid chromatography and instant thin layer chromatography test methods have been validated according to ICH guidelines. All validation parameters met the predefined acceptance criteria in the validation protocols, demonstrating the suitability of the test methods for assessing the drug product. The methods used to conduct bacterial endotoxin and sterility tests have been verified according to USP and Ph. Eur. requirements.
Batch analysis data for the process validation batches showed that all batches complied with the acceptance criteria of the drug product specifications. These data demonstrated that the batches can be produced with reproducible and comparable quality for the proposed batch sizes and independently of the source of lutetium–177 chloride selected.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug product were adequately supported and are considered to be satisfactory. Pluvicto has a shelf life of 120 hours (5 days) from the date and time of calibration. Pluvicto must be stored below 30 °C in the original package to protect from ionizing radiation (lead shielding). It must not be frozen.
The compatibility of the drug product with the container closure system was demonstrated through release testing and stability studies.
Storage and Disposal of the Drug Product
Radiopharmaceuticals must be stored according to national regulations on radioactive materials. Disposal of any unused medicinal product or waste material should be carried out according to national regulations.
Lutetium–177 used in Pluvicto may be prepared using one of two different sources of stable isotopes (either lutetium–176 or ytterbium–176) that require different waste management. Unless otherwise stated on the product batch release certificate, lutetium–177 for Pluvicto is prepared using ytterbium–176 (“non–carrier added”). Additional storage and special handling instructions are included in the Pluvicto Product Monograph.
Facilities and Equipment
The design, operations, and controls of one of the two facilities and equipment that are involved in the production is considered suitable for the activities and products manufactured and is compliant with Good Manufacturing Practices.
At the time of authorization, an inspection report prepared by the United States Food and Drug Administration (FDA) in 2021 for one of the drug substance and drug product manufacturing sites was under review by Health Canada. The Health Canada rating was pending. Although the quality data submitted from the site was found to be acceptable, the sponsor will not be authorized to manufacture Pluvicto at this site until it receives a compliant rating from Health Canada.
Adventitious Agents Safety Evaluation
The manufacturing process is designed to avoid microbiological contamination by using disposable sterile equipment and filling in an appropriately classified area. The control of the microbiological attributes of the drug product is achieved through tests. Sterility and bacterial endotoxins are controlled through in–process controls. Sterility testing is performed according to Ph. Eur. requirements.
The excipients used in the drug product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| PLUVICTO | 02530198 | NOVARTIS PHARMACEUTICALS CANADA INC | LUTETIUM (177LU) VIPIVOTIDE TETRAXETAN 1000 MBq / ML |