Summary Basis of Decision for Koselugo
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 Koselugo is located below.
Recent Activity for Koselugo
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.
The following table describes post-authorization activity for Koselugo, a product which contains the medicinal ingredient selumetinib (supplied as selumetinib sulfate). 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.
Updated: 2023-09-13
Drug Identification Number (DIN):
- DIN 02530139 – 10 mg selumetinib, capsule, oral administration
- DIN 02530147 – 25 mg selumetinib, capsule, oral administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NDS # 278054 | 2023-08-03 | Issued NOC 2023-09-06 | Submission filed to transfer ownership of the drug product from AstraZeneca Canada Inc. to Alexion Pharma GmbH. An NOC was issued. |
| Drug product (DINs 02530139, 02530147) market notification | Not applicable | Date of first sale: 2023-01-03 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 243733 | 2020-09-09 | Issued NOC 2022-08-31 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Koselugo
Date SBD issued: 2022-12-20
The following information relates to the New Drug Submission for Koselugo.
Selumetinib (supplied as selumetinib sulfate)
Drug Identification Number (DIN):
- DIN 02530139 - 10 mg selumetinib, capsule, oral administration
- DIN 02530147 - 25 mg selumetinib, capsule, oral administration
AstraZeneca Canada Inc.
New Drug Submission Control Number: 243733
On August 31, 2022, Health Canada issued a Notice of Compliance to AstraZeneca Canada Inc. for the drug product Koselugo.
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-harm-uncertainty profile of Koselugo is favourable for the treatment of pediatric patients aged 2 years and above with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas.
1 What was approved?
Koselugo, an antineoplastic agent, was authorized for the treatment of pediatric patients aged 2 years and above with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas.
The safety and effectiveness of Koselugo have not been established in pediatric patients younger than 2 years of age.
No data are available regarding the use of this drug product in patients 65 years of age and older. Consequently, Health Canada has not authorized an indication for use of Koselugo in the geriatric population.
Koselugo (10 mg and 25 mg of selumetinib, supplied as selumetinib sulfate) is presented as a capsule. In the 10 mg capsule, non-medicinal ingredients include ammonium hydroxide, carnauba wax, carrageenan, hypromellose, iron oxide black, potassium chloride, propylene glycol, purified water, shellac glaze, titanium dioxide, and vitamin E polyethylene glycol succinate (D-α-tocopheryl polyethylene glycol 1000 succinate). In the 25 mg capsule, non-medicinal ingredients are carnauba wax and/or corn starch, carrageenan, FD&C Blue 2, FD&C Blue 2 aluminum lake, ferric oxide red, ferric oxide yellow, glyceryl monooleate, hypromellose, potassium chloride, purified water, titanium dioxide, vitamin E polyethylene glycol succinate (D-α-tocopheryl polyethylene glycol 1000 succinate), and white shellac.
The use of Koselugo 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 Koselugo 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 Koselugo approved?
Health Canada considers that the benefit-harm-uncertainty profile of Koselugo is favourable for the treatment of pediatric patients aged 2 years and above with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas.
Neurofibromatosis type 1 is an autosomal dominant disorder caused by mutations in the neurofibromatosis type 1 gene that encodes the tumour suppressor protein neurofibromin 1. Neurofibromin 1 functions as a negative regulator of RAS proteins, which are key signalling molecules in the control of cell growth. Therefore, the loss of function of neurofibromin 1 may remove this regulation and lead to uncontrolled cell proliferation.
The incidence of neurofibromatosis type 1 is approximately 1 in every 3,000 live births. The disorder is characterized by cutaneous findings, skeletal dysplasias, and by the growth of both benign and malignant nervous system tumours, most notably benign neurofibromas. Neurofibromas fall into two main subtypes: cutaneous and plexiform. About half of patients with neurofibromatosis type 1 have plexiform neurofibromas, which are nerve sheath tumours that typically grow along large nerves and plexuses and are present at birth. Plexiform neurofibromas may be located around the orbit, face, upper and lower limbs, back, thorax, abdomen, neck brachial plexus and/or lumbosacral plexus, causing disfigurement, motor dysfunction (weakness and restricted range of motion), pain, respiratory impairment, visual dysfunction, and neurological dysfunction. In addition, malignant peripheral nerve sheath tumours may arise in pre-existing plexiform neurofibromas. Other malignancies associated with neurofibromatosis type 1include gliomas, breast cancer, leukemia, pheochromocytomas, and gastrointestinal stromal tumours.
Treatment options for patients with neurofibromatosis type 1 and symptomatic plexiform neurofibromas are limited. In some patients, surgical excision of the plexiform neurofibroma may be performed. However, most plexiform neurofibromas are not amenable to complete resection due to encasement of, or close proximity to, vital structures. There are no authorized therapies in Canada that have been shown to prevent, cure, slow, or reverse the growth of neurofibromatosis type 1-related plexiform neurofibromas.
Selumetinib, the medicinal ingredient in Koselugo, is a potent, selective, orally available, small-molecule inhibitor of mitogen-activated protein kinase kinases, MEK1 and MEK2. The MEK1 and MEK2 proteins are critical components of the RAS-regulated, RAF-MEK-extracellular signal-regulated kinase (ERK) signalling pathway, which is often activated in neurofibromatosis type 1 syndrome and different types of cancers.
The market authorization of Koselugo was based on pivotal efficacy and safety data derived from an open-label, single-arm, multicentre study (Phase II SPRINT, Stratum 1). Stratum 1 of the Phase II SPRINT study enrolled 50 pediatric patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas that caused significant morbidity. The median age of patients was 10.2 years (range of 3.5 to 17.4 years). All patients received Koselugo 25 mg/m2 twice daily for 28 days (one treatment cycle), on a continuous dosing schedule.
The primary efficacy endpoint of the study was objective response rate, defined as the percentage of patients with complete response (disappearance of the target plexiform neurofibroma) or confirmed partial response (a reduction of at least 20% in the target plexiform neurofibroma volume compared to baseline, confirmed at a subsequent tumour assessment within 3 to 6 months), based on the United States National Cancer Institute (NCI) central review. The target plexiform neurofibroma was defined as the plexiform neurofibroma that caused relevant clinical symptoms or complications (i.e., plexiform neurofibroma-related morbidities).
Results from Stratum 1 of the Phase II SPRINT study demonstrated an objective response rate of 66% (33/50; 95% confidence interval [CI]: 51.2, 78.8) based on the NCI central review and 44% (22/50; 95% CI: 30, 59) based on an independent central review. All responses were confirmed partial responses. Responses were durable, and the probabilities of remaining in response after 12 and 16 cycles, estimated using the Kaplan-Meier method, were 100% (95% CI not estimated) and 96.2% (95% CI: 75.7, 99.4), respectively. At the median follow-up of 2.2 years, the median duration of response and the median time from treatment initiation to disease progression while on treatment were not reached.
Supportive data from the Phase I SPRINT study showed similar efficacy. Among 24 patients who received Koselugo (20, 25, or 30 mg/m2), the objective response rate based on the NCI central analysis was 66.7% (16/24; 95% CI: 44.7, 84.4), and the median duration of response was not reached at the median exposure duration of 4.4 years (maximum of 5.5 years).
Additionally, supportive data from the NCI natural history study of neurofibromatosis type 1 showed that while spontaneous regression of plexiform neurofibromas was observed in a small number of patients, there was never a spontaneous decrease of 20% or greater in the tumour volume within one year. Considering these observations, the tumour volume reduction reported in the SPRINT study can be attributed to the treatment with Koselugo and not to the natural course of the disease.
In addition to the volumetric evaluation of tumour response, clinical outcome assessments were conducted in Stratum 1 of the Phase II SPRINT study to evaluate a range of patient-reported outcomes (pain and health-related quality of life) and functional outcomes. The results indicated a trend toward an association between reduction in tumour volume and durable improvement in clinical outcomes.
Pivotal safety data from Stratum 1 of the Phase II SPRINT study showed that the most commonly reported adverse reactions of any grade (at an incidence of at least 20%) were vomiting, rash, increased blood creatine phosphokinase, diarrhea, nausea, dry skin, asthenic events, pyrexia, acneiform rash, hypoalbuminemia, stomatitis, increased aspartate aminotransferase, paronychia, decreased hemoglobin, increased alanine aminotransferase, hair changes, increased blood creatinine, and decreased ejection fraction. Serious adverse events occurred in 24% of patients, and those occurring in at least two patients were anemia, hypoxia, and diarrhea. Permanent discontinuation of Koselugo due to adverse events occurred in 12% of patients. The adverse events that led to discontinuation included increased creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumour, acute kidney injury, and skin ulcer. Dose interruptions and reductions due to adverse events were reported in 80% and 24% of patients, respectively. The adverse events that led to dose modification of Koselugo in at least 5% of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia, and weight gain. No deaths were reported on study treatment or during the 30-day follow-up period.
Adverse events of special interest identified based on the MEK inhibitor class effects, non-clinical findings, and safety data from clinical trials in adults with cancer included gastrointestinal, ocular, cardiac, and muscular events, skin and nail disorders, and elevations of creatine phosphokinase and liver enzymes.
There were no new important safety signals identified in the pediatric population with neurofibromatosis 1 and symptomatic, inoperable plexiform neurofibromas in the long-term setting. Most of the adverse drug reactions occurred in the first year of exposure to Koselugo. There were no adverse events reported pertaining to physeal dysplasia or impairment in sexual maturation in patients treated for a maximum of 71 months. While limited conclusions can be drawn based on the fewer than 20 patients exposed to Koselugo beyond 3 years, the safety profile of Koselugo does not appear to notably worsen over time. The safety profile of Koselugo observed in the pediatric population was similar to the safety profile observed in adult cancer patients and consistent with the reported effects of other MEK inhibitors.
A Risk Management Plan (RMP) for Koselugo was submitted by AstraZeneca Canada 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 Koselugo 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 Koselugo was accepted.
Overall, the therapeutic benefits of Koselugo for the target population are considered to outweigh the potential risks. The well-characterized safety profile of Koselugo is consistent with the safety profile of other MEK inhibitors. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Koselugo 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 Koselugo?
The New Drug Submission (NDS) for Koselugo 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 treatments. It provides a framework for concurrent submission and review of oncology products among international partners. The NDS for Koselugo was classified as a Project Orbis Type C submission, which refers to submissions where the FDA had already issued a positive decision and subsequently shared its completed review documents with the Project Orbis partners.
Health Canada used the foreign review completed by the FDA in accordance with Method 2 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, i.e., the FDA review was critically assessed, while the data package submitted to Health Canada was referred to as necessary. The Canadian regulatory decision is based on the Canadian review.
In the process of reviewing the NDS for Koselugo, Health Canada issued a Notice of Deficiency (NOD) based on quality issues identified. Subsequently, these issues were satisfactorily addressed in the sponsor’s response to the NOD, and a Notice of Compliance was issued on August 31, 2022.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Koselugo
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2019-09-10 |
| New Drug Submission filed | 2020-09-09 |
| Screening | |
| Screening Deficiency Notice issued | 2020-10-15 |
| Response to Screening Deficiency Notice filed | 2020-11-06 |
| Screening Acceptance Letter issued | 2020-11-23 |
| Review | |
| Review of Risk Management Plan completed | 2021-06-20 |
| Biopharmaceutics evaluation completed | 2021-07-02 |
| Biostatistics evaluation completed | 2021-08-11 |
| Quality evaluation inactive | 2021-08-30 |
| Non-clinical evaluation inactive | 2021-08-30 |
| Clinical/medical evaluation inactive | 2021-08-30 |
| Labelling review completed | 2021-08-31 |
| Notice of Deficiency issued by Director General, Therapeutic Products Directorate (quality issues) | 2021-09-02 |
| Response to Notice of Notice of Deficiency filed | 2021-12-01 |
| Screening of Response to Notice of Deficiency | |
| Screening Acceptance Letter issued | 2021-12-14 |
| Review of Response to Notice of Deficiency | |
| Quality evaluation completed | 2022-08-03 |
| Non-clinical evaluation completed | 2022-08-03 |
| Clinical/medical evaluation completed | 2022-08-23 |
| Labelling review completed | 2022-08-23 |
| Notice of Compliance issued by Director General, Pharmaceutical Products Directorate | 2022-08-31 |
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
The clinical pharmacology programme of selumetinib (the medicinal ingredient in Koselugo) had robustly characterized the pharmacokinetics of selumetinib in adult healthy subjects (doses of 75 mg) and in patients with advanced solid malignancies (doses of 25, 50, 75, and 100 mg twice daily) before selumetinib was administered to pediatric patients (doses of 20 to 30 mg/m2 based on body surface area). A pediatric selumetinib dose of 25 mg/m2 is considered approximately equivalent to an adult selumetinib dose capped at 50 mg twice daily when the body surface area was 1.9 m2 or greater.
The sponsor provided sufficient information to support the statement that the pharmacokinetics of selumetinib was very similar in pediatric patients older than 3 years of age and adults. In adult healthy volunteers and adult patients with cancer, following single oral doses across the dose range of 25 to 100 mg, selumetinib was absorbed rapidly and reached maximum observed plasma concentrations (Cmax) with a median time to Cmax (tmax) of 1 to 1.5 hours. In pediatric patients, the median tmax was 1 hour after a single oral dose across the dose range of 20 to 30 mg/m2.
Following a single oral administration of radiolabelled selumetinib to healthy male subjects, unchanged selumetinib was identified as the major circulating drug-related component (approximately 40% of the radioactivity). The main circulating metabolites identified in human plasma were glucuronide of imidazoindazole metabolite (22%), selumetinib glucuronide (7%), N-desmethyl selumetinib (3%), and N-desmethyl carboxylic acid (4%). N-desmethyl selumetinib represents less than 10% of selumetinib levels in human plasma but is approximately three to five times more potent than the parent compound, contributing to about 21% to 35% of the overall pharmacologic activity of selumetinib.
The pharmacokinetics of selumetinib in subjects with renal impairment was evaluated in a dedicated clinical study. Based on this study, no dose adjustment of selumetinib is recommended in patients with mild, moderate, and severe renal impairment, or those with end-stage renal disease.
A dedicated clinical study and a population pharmacokinetic analysis evaluated the pharmacokinetics of selumetinib in subjects with mild, moderate, and severe hepatic impairment. Results from the study demonstrated that moderate or severe hepatic impairment caused an increase in selumetinib exposure. While no dose adjustment is required in patients with mild hepatic impairment, for those with moderate hepatic impairment, the starting dose should be reduced to 20 mg/m2 twice daily. Furthermore, selumetinib is not recommended for use in patients with severe hepatic impairment.
In vitro studies indicate that cytochrome P450 (CYP) 3A4 is the predominant CYP isoform responsible for selumetinib oxidative metabolism, whereas CYP2C19, CYP1A2, CYP2C9, CYP2E1, and CYP3A5 are involved to a lesser extent. Accordingly, drug-drug interactions were evaluated in clinical studies with itraconazole (a strong CYP3A4 inhibitor), fluconazole (a strong CYP2C19 and moderate CYP3A4 inhibitor) and rifampicine (a strong CYP3A4 inducer), and in a physiologically based pharmacokinetic model. Selumetinib exposure increased by approximately 50% when co-administered with the strong CYP3A4 inhibitor itraconazole or the strong CYP2C19 and moderate CYP3A4 inhibitor fluconazole. Increased selumetinib plasma concentrations may increase the risk of adverse reactions. Therefore, co-administration of selumetinib and strong CYP3A4 or CYP2C19 inhibitors should be avoided. If co-administration is necessary and unavoidable, patients should be carefully monitored for adverse events and the selumetinib dose should be reduced. In addition, the concomitant use of strong and moderate CYP3A4 inducers with selumetinib is not recommended in order to avoid decreased selumetinib plasma concentrations, which may reduce selumetinib efficacy.
Food-effect studies demonstrated that co-administration of selumetinib with a high-fat or low-fat meal had a significant effect on the absorption of selumetinib. Based on these findings, Koselugo should be administered orally on an empty stomach (i.e., without any food intake for 2 hours before and 1 hour after taking Koselugo).
For further details, refer to the Koselugo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Pivotal evidence of the efficacy of Koselugo in pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas was derived from an open-label, single-arm, multicentre study (Phase II SPRINT, Stratum 1). Supportive efficacy data were provided from the Phase I of SPRINT. Data from a natural history study of neurofibromatosis type 1, conducted by the United States National Cancer Institute (NCI), and data from the placebo arm from Phase A of the NCI Study 01-C-0222 (a placebo-controlled study of tipifarnib in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas) were used as external controls.
Stratum 1 of the Phase II SPRINT study enrolled 50 patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas that caused significant morbidity. The median age of patients was 10.2 years (range of 3.5 to 17.4 years). Patients had a median of three neurofibroma-related morbidities (range of one to five). All patients received Koselugo 25 mg/m2 twice daily, for 28 days (one treatment cycle), on a continuous dosing schedule, i.e., with no rest period between cycles.
The primary efficacy endpoint of the study was objective response rate, defined as the percentage of patients with complete response (disappearance of the target plexiform neurofibroma) or confirmed partial response (a reduction of at least 20% in the target plexiform neurofibroma volume compared to baseline, confirmed at a subsequent tumour assessment within 3 to 6 months), based on the NCI central review. The target plexiform neurofibroma was defined as the plexiform neurofibroma that caused relevant clinical symptoms or complications (i.e., plexiform neurofibroma-related morbidities). Changes in the tumour volume were assessed by volumetric magnetic resonance imaging (MRI) analysis per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria. The volumetric MRI analysis of the target plexiform neurofibroma was conducted at baseline and after every 4 cycles for 2 years, and then every 6 cycles.
Results from Stratum 1 of the Phase II SPRINT study demonstrated an objective response rate of 66% (33/50; 95% CI: 51.2, 78.8) based on the NCI central review and 44% (22/50; 95% CI: 30, 59) based on an independent central review. All responses were confirmed partial responses. Responses were durable, and the probabilities of remaining in response after 12 and 16 cycles, estimated using the Kaplan-Meier method, were 100% (95% CI not estimated) and 96.2% (95% CI: 75.7, 99.4), respectively. At the median follow-up of 2.2 years, the median duration of response and the median time from treatment initiation to disease progression while on treatment were not reached.
In addition to the volumetric evaluation of tumour response, clinical outcome assessments were conducted to evaluate a range of patient-reported outcomes (pain and health-related quality of life) and functional outcomes.
The target plexiform neurofibroma pain intensity was self-reported by patients 8 years of age and older using an 11-point Numeric Rating Scale (NRS-11). There were 24 patients who completed the NRS-11 both at baseline and pre-Cycle 13. After one year of treatment, the mean decrease in the target tumour pain intensity scores was 2 points compared to baseline, which was considered a clinically meaningful improvement. Twelve patients (50%) reported no change in pain scores (10 of whom had a baseline score of 0 or 1) and no patients showed deterioration.
Parent-reported (for all patients) and patient-reported (by patients 8 years of age and older) health-related quality of life was assessed using the Pediatric Quality of Life Inventory (PedsQL) questionnaire. Based on Mixed Model Repeated Measures analysis, a clinically meaningful improvement in health-related quality of life (based on a clinically meaningful threshold of 11.9) was reported by parents at pre-Cycle 13 with a mean change from baseline in PedsQL total score of 12.7 (95% CI: 8.91, 16.55). Improvement in health-related quality of life was also reported by patients with a mean change from baseline in PedsQL total score of 6.68 (95% CI: 1.34, 12.02).
The supportive Phase I SPRINT study showed that among 24 patients who received Koselugo (20, 25, or 30 mg/m2), the objective response rate based on the NCI central analysis was 66.7% (16/24; 95% CI: 44.7, 84.4). The median duration of response was not reached at the median exposure duration of 4.4 years (maximum of 5.5 years).
Furthermore, supportive data from the NCI natural history study of neurofibromatosis type 1 showed that while spontaneous regression of plexiform neurofibromas was observed in some patients, there was never a spontaneous decrease of 20% or greater in the tumour volume within one year. Based on these observations, the tumour volume reduction reported in the SPRINT study can be attributed to the treatment with Koselugo and not to the natural course of the disease.
Overall, the submitted data demonstrated that within the target population of pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas, treatment with Koselugo led to clinically meaningful sustained reductions in tumour volume associated with improved clinical outcomes.
Indication
The New Drug Submission for Koselugo was filed by the sponsor with the following indication, which Health Canada subsequently approved:
- Koselugo (selumetinib) is indicated for the treatment of pediatric patients aged 2 years and above with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas.
For more information, refer to the Koselugo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Koselugo was evaluated in 50 pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas enrolled in Stratum 1 of the pivotal Phase II SPRINT study (see Clinical Efficacy section). These patients were exposed to the recommended dose of Koselugo 25 mg/m2 twice daily for a median period of 2.2 years. Supportive safety data were provided from a pooled population of 74 pediatric patients treated with 20, 25 or 30 mg/m2 twice daily in the SPRINT study (24 patients from Phase I in addition to the 50 patients from the pivotal Phase II Stratum 1). The median total duration of exposure among the pooled pediatric patients was 28 months (range of 1 to 71 months).
Among the 50 patients in Stratum 1 of the Phase II SPRINT study, the most commonly reported adverse reactions of any grade (at an incidence of at least 20%) were vomiting, rash, increased blood creatine phosphokinase, diarrhea, nausea, dry skin, asthenic events, pyrexia, acneiform rash, hypoalbuminemia, stomatitis, increased aspartate aminotransferase, paronychia, decreased hemoglobin, increased alanine aminotransferase, hair changes, increased blood creatinine, and decreased ejection fraction. Serious adverse events occurred in 24% of patients, and those occurring in at least two patients were anemia, hypoxia, and diarrhea. Permanent discontinuation of Koselugo due to adverse events occurred in 12% of patients. The adverse events that led to discontinuation included increased creatinine, increased weight, diarrhea, paronychia, malignant peripheral nerve sheath tumour, acute kidney injury, and skin ulcer. Dose interruptions and reductions due to adverse events were reported in 80% and 24% of patients, respectively. The adverse events that led to dose modification of Koselugo in at least 5% of patients were vomiting, paronychia, diarrhea, nausea, abdominal pain, rash, skin infection, influenza-like illness, pyrexia, and weight gain. No deaths were reported on study treatment or during the 30-day follow-up period.
In the pooled pediatric population, 73 of the 74 patients (98.6%) had at least one adverse event. Adverse events were assessed by the investigator as causally related to Koselugo in 73 (98.6%) patients. Approximately 68% of patients had an adverse event of Grade 3 or 4, and 23% of patients experienced a serious adverse event. The most commonly reported serious adverse events were anemia, increased blood creatine phosphokinase, diarrhea, hypoxia, and pyrexia (reported in two [2.7%] patients, each). The incidence of adverse events resulting in discontinuation was 12%. Dose interruptions as a result of adverse events occurred in 78% of patients, whereas dose reductions due to an adverse events occurred in 32% of patients.
Adverse events of special interest identified based on the mitogen-activated protein kinase kinase (MEK) inhibitor class effects, non-clinical findings, and safety data from clinical trials in adults with cancer included gastrointestinal, ocular, cardiac, and muscular events, skin and nail disorders, and elevations of creatine phosphokinase and liver enzymes.
There were no new important safety signals identified in the pediatric population with neurofibromatosis 1 and symptomatic, inoperable plexiform neurofibromas in the long-term setting. Most of the adverse drug reactions occurred in the first year of exposure to Koselugo. There were no adverse events reported pertaining to physeal dysplasia or impairment in sexual maturation in patients treated for a maximum of 71 months. While limited conclusions can be drawn based on the fewer than 20 patients exposed to Koselugo beyond 3 years, the safety profile of Koselugo does not appear to notably worsen over time.
Overall, Koselugo monotherapy at a dose of 25 mg/m2 twice daily has a well-characterized and manageable safety profile in pediatric patients with neurofibromatosis 1 and inoperable symptomatic plexiform neurofibromas. Most of the adverse events reported in Stratum 1 of the Phase II SPRINT study did not affect the ability of patients to remain on Koselugo treatment. The safety profile of Koselugo observed in the pediatric population was similar to the safety profile observed in adult cancer patients and consistent with the reported effects of other MEK inhibitors. Appropriate warnings and precautions are in place in the approved Koselugo Product Monograph to address the identified safety concerns.
For more information, refer to the Koselugo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Selumetinib, the medicinal ingredient in Koselugo, is a potent, selective, orally available, small-molecule inhibitor of mitogen-activated protein kinase kinases, MEK1 and MEK2. The MEK1 and MEK2 proteins are critical components of the RAS-regulated, RAF-MEK-extracellular signal-regulated kinase (ERK) signalling pathway, which is often activated in neurofibromatosis type 1 syndrome and different types of cancers.
In non-clinical studies, selumetinib inhibited the activity of purified MEK1 enzyme with the half-maximal (50%) inhibitory concentration (IC50) values of 14.1 nM to15.3 nM, and showed similar potency against both MEK isoforms (MEK 1 and 2). The metabolite N-desmethyl selumetinib was 3- to 5-fold more potent than selumetinib in inhibiting MEK-mediated ERK1 phosphorylation, whereas the amide metabolite was 40- to 50-fold less potent than selumetinib. Selumetinib exhibited antitumour activity in diverse human tumour cell lines. In mice bearing human tumour xenografts and in genetically engineered mouse models of neurofibromatosis type 1 that generate neurofibromas recapitulating the genotype and phenotype of the human disease, oral administration of selumetinib inhibited ERK phosphorylation and reduced tumour growth.
Selumetinib and its N-desmethyl metabolite had low potential for off-target activity at the expected human therapeutic plasma levels of selumetinib. The compound did not inhibit significantly human ether-a-go-go-related gene (hERG) potassium channel currents in vitro or alter the circulatory function of minipigs. At doses of up to 100 mg/kg (around 5- to 6-fold higher than the clinical unbound maximum plasma concentration [Cmax] at the recommended dose of 25 mg/m2 twice daily), oral dosing of selumetinib to rats had no significant effects on open-field behaviour, respiratory parameters, and gastric secretion parameters. However, it induced a slight (non-significant) increase in gastrointestinal motility and gastric mucosal lesions.
Selumetinib hydrogen sulfate (the clinically relevant capsule formulation) and its metabolite selumetinib amide showed evidence of accumulation in monkeys. Plasma exposure levels of the metabolite N-desmethyl selumetinib were low. Sex differences in exposure to selumetinib were noted in mice and rats, with higher exposure values in females, especially at high doses.
Repeat-dose toxicity studies showed that the gastrointestinal tract was the main target of selumetinib toxicity, which was manifested clinically by diarrhea and dehydration. Administration of selumetinib in rats was linked to skin lesions (scabs, ulcerations) and microscopic changes in bone (physeal dysplasia). Soft tissue mineralization and changes in hematology and clinical chemistry parameters were noted mainly in rodents across different studies. Tissue mineralization did not show evidence of reversibility.
Selumetinib did not demonstrate mutagenicity, carcinogenicity, or phototoxicity. However, selumetinib induced micronuclei in mouse erythrocytes in vivo at exposures at least 10 times higher than the clinical exposure. The metabolite N-desmethyl selumetinib did not show evidence of mutagenicity.
No adverse effects on fertility were noted upon administration of selumetinib at doses up to 30 times (males) or 5 times (females) the human exposure (based on the area under the plasma concentration-time curve) at the clinical recommended dose. However, in pregnant mice, administration of selumetinib at doses resulting in clinically relevant plasma exposure levels was associated with embryo-fetal toxicity. There was an increased incidence in fetal abnormalities (open eyes and cleft palate), even in the absence of apparent maternal toxicity. Furthermore, selumetinib and N-methyl selumetinib were present in the milk of lactating mice.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Koselugo Product Monograph. In view of the intended use of Koselugo, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Koselugo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The chemistry and manufacturing information submitted for Koselugo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 °C to 30 °C).
Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).
All sites involved in production are compliant with good manufacturing practices.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| KOSELUGO | 02530139 | ALEXION PHARMA GMBH | SELUMETINIB (SELUMETINIB SULFATE) 10 MG |
| KOSELUGO | 02530147 | ALEXION PHARMA GMBH | SELUMETINIB (SELUMETINIB SULFATE) 25 MG |