Summary Basis of Decision for Winlevi
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)
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Winlevi is located below.
Recent Activity for Winlevi
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 Winlevi, a product which contains the medicinal ingredient clascoterone. 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: 2025-01-28
Drug Identification Number (DIN):
DIN 02538881 - 1% (w/w) clascoterone, cream, topical administration
Post-Authorization Activity Table (PAAT)
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
Drug product (DIN 02538881) market notification |
Not applicable |
Date of first sale 2023-09-08 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
NDS # 265619 |
2022-06-29 |
Issued NOC 2023-06-15 |
NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Winlevi
Date SBD issued: 2023-08-30
The following information relates to the New Drug Submission for Winlevi.
Clascoterone
Drug Identification Number (DIN): DIN 02538881 – 1% (w/w) clascoterone, cream, topical administration
Sun Pharmaceutical Industries Limited
New Drug Submission Control Number: 265619
Submission Type: New Drug Submission (New Active Substance)
Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): D10 Anti-acne preparations
Date Filed: 2022-06-29
Authorization Date: 2023-06-15
On June 15, 2023, Health Canada issued a Notice of Compliance to Sun Pharmaceutical Industries Limited for the drug product Winlevi.
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 Winlevi is favourable for the topical treatment of acne vulgaris in patients 12 years of age and older.
1 What was approved?
Winlevi (clascoterone), an anti-acne preparation, was authorized for the topical treatment of acne vulgaris in patients 12 years of age and older.
Winlevi is authorized for use in pediatric patients aged 12 to less than 18 years, as the data reviewed by Health Canada demonstrated the safety and efficacy of Winlevi for patients in this age group.
Winlevi is not authorized for use in pediatric patients less than 12 years of age, as the safety and efficacy of Winlevi have not been established for patients in this age group.
The clinical studies did not include participants 65 years of age and older, and therefore did not demonstrate whether patients in this age group respond differently from younger patients.
Winlevi (1% [w/w] clascoterone) is presented as a cream. In addition to the medicinal ingredient, the cream contains cetyl alcohol, citric acid monohydrate, edetate disodium, DL-alpha tocopherol (vitamin E), mono- and di-glycerides, mineral oil, polysorbate 80, propylene glycol, and water.
The use of Winlevi 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 Winlevi 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 Winlevi approved?
Health Canada considers that the benefit-harm-uncertainty profile of Winlevi is favourable for the topical treatment of acne vulgaris in patients 12 years of age and older.
Acne vulgaris (commonly known as acne) affects 5.6 million Canadians, which is nearly 20% of the population. More than 80% of patients with acne are between the ages of 12 and 24 years. Acne primarily affects the face (in 99% of cases) but can also affect the body (in 50% of cases). Acne develops with sebum over-production in sebocytes due to androgen activity, altered follicular growth, follicular bacterial colonization, and inflammation. These pathogenic factors result in the formation of microcomedones: dilated hair follicles filled with keratin, bacteria, and sebum. The microcomedone is the precursor to visible acne lesions such as comedones and inflammatory papules. Bacteria form biofilms within the pilosebaceous unit that can promote inflammation, comedo formation, and antibiotic resistance.
Winlevi is an androgen receptor inhibitor that acts locally and competes with dihydrotestosterone (DHT) for binding to the androgen receptors when applied topically to the skin. While its precise mechanism of action has not been confirmed, it is believed to act as a competitive inhibitor of androgen receptor signalling which diminishes androgenic gene activation, thereby reducing the production of sebum and inflammatory cytokines.
The clinical efficacy of Winlevi was primarily evaluated in two pivotal Phase III randomized controlled trials (Trial 1 and Trial 2) in patients 9 years of age or older with acne vulgaris. Collectively, 1,440 patients were enrolled in the two trials, of whom 1,421 were 12 years of age or older. Of the 1,421 patients, 45.1% (641 patients) were 12 to less than 18 years of age and 54.9% (780 patients) were 18 years of age or older. The treatment groups in each trial had similar demographic and baseline characteristics. At baseline, patients had a mean inflammatory lesion count (ILC) of 42.4 and a mean non-inflammatory lesion count (NILC) of 61.4.
Winlevi 1% (w/w) or the vehicle control was administered to the face twice daily. At Week 12, three co-primary endpoints were assessed followed by four secondary endpoints. The co-primary efficacy endpoints were the proportion of patients in each treatment group who achieved "Investigator’s Global Assessment (IGA) success" (defined as at least a 2-point reduction in IGA score relative to baseline and a final IGA score of 0 [clear] or 1 [almost clear]), the absolute change from baseline in non-inflammatory lesion count (NILC), and the absolute change from baseline in inflammatory lesion count (ILC). The secondary efficacy endpoints were the absolute change from baseline in total lesion count (TLC), the percent change from baseline in TLC, the percent change from baseline in NILC, and the percent change from baseline in ILC.
Statistical significance was achieved for all primary and secondary efficacy endpoints in both the individual pivotal trials and in the pooled analysis. Results were comparable between Trial 1 and Trial 2. For the co-primary endpoints, in patients 12 years of age and older, the odds ratios for IGA success with Winlevi were 2.42 (95% confidence interval [CI]: 1.46, 4.01) in Trial 1 and 3.77 (95% CI: 2.20, 6.45) in Trial 2. Secondly, with respect to the absolute change from baseline in NILC, a reduction of 7.3 lesions (95% CI: 3.5, 11.1) in Trial 1 and 8.7 lesions (95% CI: 4.7, 12.6) in Trial 2 was observed for patients treated with Winlevi versus (vs.) vehicle. Similarly, with respect to the absolute change from baseline in ILC, a reduction of 3.9 lesions (95% CI: 1.3, 6.5) in Trial 1 and 7.5 (95% CI 5.2, 9.9) in Trial 2 was observed for patients treated with Winlevi vs. vehicle.
For the primary efficacy outcomes, effect-size estimates were less favourable in the subgroups of racialized patients (e.g., Fitzpatrick skin types IV, V, and VI). Poorer effect estimates in racialized patients have also been observed with other acne treatments. The less favourable results in racialized groups could be due to differences in outcome assessment, differences in treatment effect, and/or chance.
The total safety analysis was based on data from 2,318 participants, including 1,421 participants 12 years of age and older who were treated either with Winlevi or the vehicle control (placebo cream) twice daily for 12 weeks in one of the two pivotal Phase III trials. Of the 2,318 participants in the total safety analysis, 1,757 were exposed to Winlevi (352 healthy participants and 1,405 participants with acne).
In the pooled pivotal Phase III studies, 709 participants 12 years of age and older received Winlevi. The proportions of participants who reported treatment-emergent adverse events (TEAEs) were slightly lower in the group treated with Winlevi than in the group that received the vehicle with respect to the total number of TEAEs (11.7% vs. 12.7%), serious TEAEs (0% vs. 0.3%), TEAEs related to study cream application (1.7% vs. 3.1%), TEAEs leading to dose modification (0.8% vs. 1.0%), and TEAEs leading to discontinuation (0.7% vs. 1.7%).
In the pivotal studies, the approximate annual incidence of polycystic ovaries was 0.6% of participants per year (based on three emergent cases, one of which had been diagnosed previously). None of the TEAEs of polycystic ovaries were found to be related to treatment, however the observed rate appeared slightly higher than the population rates reported in medical literature. Polycystic ovaries are therefore listed in the labelling as a less common adverse drug reaction.
Local skin findings were common in patients treated with Winlevi in the pivotal Phase III trials. These included erythema (12.2%), scaling/dryness (10.5%), pruritus (7.7%), stinging/burning (4.2%), edema (3.6%), and striae rubrae (2.5%). Most of these were trace findings or mild in nature.
Although the pivotal trials included participants 9 to less than 12 years of age, this age group was excluded from the approved indication primarily due to safety findings, but also due to greater uncertainty around efficacy. The safety concerns are explained in greater detail in the Clinical Safety section.
A Risk Management Plan (RMP) for Winlevi was submitted by Sun Pharmaceutical Industries Limited 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 Winlevi Product Monograph met 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 Winlevi was accepted.
Winlevi has an acceptable safety profile based on data from the non-clinical studies and the pivotal clinical trials. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Winlevi 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 Winlevi?
The review of the quality, non-clinical, and clinical components of the New Drug Submission (NDS) for Winlevi was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Winlevi NDS was made independently based on the Canadian review.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: Winlevi
Submission Milestone |
Date |
---|---|
Pre-submission meeting |
2022-05-17 |
New Drug Submission filed |
2022-06-29 |
Screening |
|
Screening Acceptance Letter issued |
2022-08-22 |
Review |
|
Review of Risk Management Plan completed |
2023-05-26 |
Quality evaluation completed |
2023-06-05 |
Non-clinical evaluation completed |
2023-06-07 |
Clinical/medical evaluation completed |
2023-06-14 |
Labelling review completed |
2023-06-14 |
Notice of Compliance issued by Director General, Pharmaceutical Products Directorate |
2023-06-15 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
5 What post-authorization activity has taken place for Winlevi?
Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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 PAAT will continue to be updated during the product life cycle.
The PAAT for Winlevi is found above.
For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
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See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
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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.
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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.
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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.
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See the Patent Register for patents associated with medicinal ingredients, if applicable.
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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 outlined in the What steps led to the approval of Winlevi? section, the clinical review of the New Drug Submission for Winlevi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Clinical Pharmacology
Clascoterone (the medicinal ingredient in Winlevi) is an androgen receptor inhibitor. Androgen receptor inhibitors may reduce sebaceous gland activity. While the precise mechanism of action of Winlevi cream for the topical treatment of acne vulgaris is unknown, it is believed to act as a competitive inhibitor of androgen receptor signalling. This diminishes androgenic gene activation, thereby reducing the production of sebum and inflammatory cytokines.
The absorption, distribution, and metabolism of Winlevi have been characterized in patients with moderate to severe acne vulgaris. Winlevi was applied topically twice daily for 2 weeks, at a mean dose of 6 g. On Day 14, the mean maximum plasma concentration (Cmax) was 4.5 ng/mL, the mean area under the plasma concentration-time curve over the dosing interval (AUCꞇ) was 37.1 h*ng/mL and the mean average plasma concentration (Cavg) was 3.1 ng/mL. Following treatment, the plasma concentrations of cortexolone (a possible primary metabolite of clascoterone) were detectable and were generally below or near the lower limit of quantitation (0.5 ng/mL) in patients 9 years of age and older with acne vulgaris. The elimination of clascoterone has not been fully characterized in humans.
Hypothalamic-pituitary-adrenal (HPA) axis suppression was evaluated in 20 adult, 22 adolescent, and 27 pediatric patients with acne vulgaris in two maximum use pharmacokinetic studies, each two weeks long. At Day 14, HPA axis suppression was observed in 5% of adult patients, 9% of adolescent patients, and 8.7% of pediatric patients. All patients had returned to normal HPA axis function four weeks after the end of treatment. No patients experienced clinical signs and symptoms of adrenal suppression or associated complications.
In a two-week Phase II maximum use clinical study, hyperkalemia (an increase in plasma potassium levels) was observed in 9 out of 27 (33%) patients who were 9 to less than 12 years of age. No clinical symptoms of hyperkalemia were reported. In patients 12 to 64 years of age, shifts from normal to elevated potassium levels were comparable between clascoterone-treated of vehicle-treated participants.
In a dedicated study, Winlevi did not prolong the QT interval to any clinically relevant extent in healthy volunteers at an exposure level approximately two times the systemic exposure observed at the maximum dose.
For further details, please refer to the Winlevi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Winlevi was primarily evaluated in two pivotal Phase III randomized controlled trials (Trial 1 [CB-03-01/25] and Trial 2 [CB-03-01/26]). Patients eligible for the trials were 9 years of age or older with an Investigator's Global Assessment (IGA) of moderate or severe facial acne vulgaris (score of 3 or 4), with 30 to 75 inflammatory lesions and 30 to 100 non-inflammatory lesions. Patients with two facial nodules or nodulocystic acne were not eligible. Concurrent use of other treatments for acne were not permitted and patients were expected to employ a stable skincare regimen.
Collectively, 1,440 patients were enrolled in the two trials, of whom 1,421 patients were 12 years of age or older. The treatment groups in each study were well-balanced with similar demographic and baseline characteristics in the intent-to-treat (ITT) population. Of the 1,421 patients, 45.1% (641 patients) were 12 to less than 18 years of age and 54.9% (780 patients) were 18 years of age or older. Additionally, 62.1% of these patients were female, and 90.6% were Caucasian. At baseline, patients had a mean inflammatory lesion count of 42.4 and a mean non-inflammatory lesion count of 61.4. Approximately 83.3% of patients had an IGA score of 3 (moderate), and 16.7% had an IGA score of 4 (severe).
Winlevi 1% (w/w) or the vehicle control was applied to the face twice daily. At Week 12, three co-primary endpoints were assessed followed by four secondary endpoints. The acceptable and validated co-primary efficacy endpoints were the proportion of patients in each treatment group who achieved "IGA success" (defined as at least a 2-point reduction in IGA score relative to baseline and a final IGA score of 0 [clear] or 1 [almost clear]), the absolute change from baseline in non-inflammatory lesion count (NILC), and the absolute change from baseline in inflammatory lesion count (ILC). The secondary efficacy endpoints were the absolute change from baseline in total lesion count (TLC), the percent change from baseline in TLC, the percent change from baseline in NILC, and the percent change from baseline in ILC.
Statistical significance was achieved for all primary and secondary efficacy endpoints in both the individual pivotal trials and in the pooled analysis. Results were comparable between Trial 1 and Trial 2. For the co-primary endpoints, in patients 12 years of age and older, the odds ratios for IGA success with Winlevi were 2.42 (95% confidence interval [CI]: 1.46, 4.01) in Trial 1 and 3.77 (95% CI: 2.20, 6.45) in Trial 2. Secondly, with respect to the absolute change from baseline in NILC, a reduction of 7.3 lesions (95% CI: 3.5, 11.1) in Trial 1 and 8.7 lesions (95% CI: 4.7, 12.6) in Trial 2 was observed for patients treated with Winlevi versus (vs.) vehicle. Similarly, with respect to the absolute change from baseline in ILC, a reduction of 3.9 lesions (95% CI: 1.3, 6.5) in Trial 1 and 7.5 (95% CI 5.2, 9.9) in Trial 2 was observed for patients treated with Winlevi vs. vehicle. These differences were considered clinically meaningful.
In patients 12 years of age and older, the pooled adjusted proportions of patients with end-of-study IGA success were 19.8% for Winlevi treatment and 7.8% for vehicle (odds ratio 2.9, p<0.0001). From a mean baseline of 62 non-inflammatory lesions, the pooled least-square mean difference in change from baseline in the NILC was -7.9 (-19.8 for Winlevi versus [vs.] -11.9 for vehicle). From a mean baseline of 42 inflammatory lesions, the pooled least-square mean difference in change from baseline in the ILC was ‑5.7 (‑19.7 for Winlevi vs. ‑13.9 for vehicle).
For the primary efficacy outcomes, effect-size estimates were less favourable in the subgroups of racialized patients (e.g., Fitzpatrick skin types IV, V, and VI). Poorer effect estimates in racialized patients have also been observed with other acne treatments. The less favourable results in racialized groups could be due to differences in outcome assessment, differences in treatment effect, and/or chance.
Indication
The New Drug Submission for Winlevi was filed by the sponsor with the following indication:
Winlevi (clascoterone) cream 1% is indicated for the topical treatment of acne vulgaris in patients 9 years of age or older.
To support safe and effective use of the product, Health Canada approved the following indication:
Winlevi (clascoterone) is indicated for the topical treatment of acne vulgaris in patients 12 years of age or older.
Although the pivotal trials included participants who were 9 to less than 12 years of age, this age group was excluded from the approved indication primarily due to safety findings but also due to greater uncertainty around efficacy. The safety concerns are explained in greater detail in the Clinical Safety section.
For more information, refer to the Winlevi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The total safety analysis was based on data from all Phase I and II trials and the two pivotal Phase III trials (described in the Clinical Efficacy section). Of the 2,318 participants in these studies, 1,421 were 12 years of age and older and treated with either Winlevi or the vehicle control (placebo cream) twice daily for 12 weeks in one of the two pivotal Phase III trials. In total, 1,757 of the 2,318 participants in the total safety analysis were exposed to Winlevi (352 healthy participants and 1,405 participants with acne vulgaris).
In the pivotal pooled Phase III studies, 709 participants 12 years of age and older received Winlevi. The proportions of participants that reported treatment-emergent adverse events (TEAEs) were slightly lower in the group that received Winlevi than in the group that received the vehicle with respect to the total number of TEAEs (11.7% vs. 12.7%), serious TEAEs (0% vs. 0.3%), TEAEs related to study cream application (1.7% vs. 3.1%), TEAEs leading to dose modification (0.8% vs. 1.0%), and TEAEs leading to discontinuation (0.7% vs. 1.7%).
In a long-term follow-up study (CB-03-01/27) which included a subset of participants from the pivotal Phase III trials, 607 participants received Winlevi. Seven serious TEAEs were reported in six participants, none of which were determined by the investigator to be related to Winlevi.
In the pivotal trials, the approximate annual incidence of polycystic ovaries was 0.6% of participants per year (based on three emergent cases, one of which had been diagnosed previously). None of the TEAEs of polycystic ovaries were found to be related to treatment, however, the observed rate appeared slightly higher than the population rates reported in medical literature. Polycystic ovaries are therefore listed in the labelling as a less common adverse drug reaction.
Local skin findings were common in the pivotal Phase III trials, including erythema (12.2%), scaling/dryness (10.5%), pruritus (7.7%), stinging/burning (4.2%), edema (3.6%), and striae rubrae (2.5%). Most of these were trace findings or mild in nature.
Pediatric Participants (9 to less than 12 years of age)
Although the pivotal trials included 19 participants who were 9 to less than 12 years of age, this age group was excluded from the approved indication primarily due to safety findings, but also due to greater uncertainty around efficacy. In this age group, the odds ratio of global IGA success with Winlevi vs. the vehicle control was 0.8 (15.4% vs. 18.0%). Lesion counts increased from baseline levels with the use of Winlevi compared to the vehicle, with differences of +31 in the NILC and +6 in the ILC between Winlevi and the vehicle. With the limited number of participants in this age group, effect estimates had wide confidence intervals and an elevated risk of an unequal balance of clinically important covariates.
In two Phase II trials, instances of hypothalamic-pituitary-adrenal (HPA) axis suppression were observed in 5% (1 out of 20) of adults (18 years of age and older), 9% (2 out of 22) of adolescents (12 to less than 18 years of age), and 8.7% (2 out of 23) of pediatric subjects (9 to less than 12 years of age) following 2 weeks of treatment under maximum dose conditions. The pivotal trials did not test for biochemical HPA axis suppression. The Product Monograph for Winlevi contains warnings and precautions related to HPA axis suppression. If HPA axis suppression is suspected, consideration should be given to withdrawing use of Winlevi.
In addition to the findings above, 33% (9 out of 27) of pediatric participants (9 to less than 12 years of age) experienced shifts from normal to elevated plasma potassium levels (i.e., hyperkalemia) following treatment.
Overall, the Phase II trial data suggest that pediatric patients may be more susceptible to systemic toxicity than adults when treated with Winlevi. Based on these safety findings and the uncertainty of the efficacy data in participants 9 to less than 12 years of age, the indication was limited to patients 12 years of age and older.
For more information, refer to the Winlevi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
As outlined in the What steps led to the approval of Winlevi? section, the review of the non-clinical component of the New Drug Submission for Winlevi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
Consistent with its function as an androgen receptor inhibitor, clascoterone (the medicinal ingredient in Winlevi), was found to bind to the human androgen receptor with high affinity in in vitro studies.
Acute toxicity studies were conducted in rats and mice. A single dose of clascoterone was generally well-tolerated, with some clinical signs of toxicity observed at doses up to 1,000 mg/kg administered subcutaneously to rats and mice, and 100 mg/kg administered intravenously to mice. Immediately following intravenous administration of a 30 mg/kg dose, slight or moderate sedation and deep respiration were observed in female Wistar rats, which was no longer present after 30 minutes. Following a 100 mg/kg dose administered intravenously to rats, 3 of the 7 rats died. Clinical signs of toxicity (including ruffled fur, poor coordination, ventral recumbency, tachypnea, and convulsions) were also observed within the first 30 minutes post dose. These resolved by Day 2. In female Wistar rats administered a 1,000 mg/kg dose subcutaneously, one animal exhibited scabs and/or wounds and one animal developed erythema at the injection site. Transient weight loss was observed in all these studies, and the animals recovered by Day 15.
In a 26-week repeat-dose toxicity study in Wistar rats, no test article-related changes occurred which could be considered as adverse following repeated subcutaneous injection of clascoterone at any of the dose levels investigated (0.1, 0.5 and 2.5 mg/kg/day). The high dose of 2.5 mg/kg/day was considered the no-observed-adverse-effect level (NOAEL) in this study. On Day 182, the 2.5 mg/kg/day dose was associated with exposure values (as measured by the area under the concentration-time curve [AUC]) of 298.61 ng·hr/mL in males and 173.19 ng·hr/mL in females.
A 28-day dermal toxicity study was conducted in rabbits. Hematological and clinical chemistry changes consistent with glucocorticoid effects were observed in animals treated with a dose of 50 mg/kg/day. The changes observed included decreased lymphocytes, and increases in plasma phospholipids, albumin, and liver function enzyme levels. Increased liver weight and decreased adrenal weight was also observed. Additionally, leucopenia was observed in rats in a 13-week subcutaneous toxicity study at a dose of 25 mg/kg/day.
A 9-month dermal toxicity study was conducted in Göttingen minipigs. Mild transient erythema was observed in male and female animals at all dose levels of clascoterone (1%, 2.5%, and 5%), with a few isolated incidences of moderate to severe erythema. The mean adrenal gland weight was lower in animals treated with 2.5% and 5% clascoterone cream, which correlated with adrenal cortical atrophy. This was not fully reversible in males after the recovery period. Mild to minimal atrophy of the skin was observed at all dose levels tested. The testes of one male in the 5% treatment group had minimal interstitial cell hypertrophy. Hair follicles were found to be in the resting stage in skin treated with clascoterone cream more often than skin treated with the vehicle control. As these findings were not considered to be adverse, the NOAEL was determined to be 5% clascoterone cream. At Day 272, this concentration was associated with mean exposure values (as measured by the AUC from time 0 to 24 hours [AUC0-24]) of 401 ng·hr/mL in males and 269 ng·hr/mL in females.
The results of a two-year carcinogenicity study in rats indicated that clascoterone was not carcinogenic after daily topical administration at concentrations of 0.1%, 1%, or 5%. A slight increase in benign sebaceous cell adenoma was observed at the topical application site in males treated with 5% clascoterone cream. An increased incidence of atrophy of the skin and subcutis at the application site (a non-neoplastic finding) was reported in male and female rats treated with 1% and 5% clascoterone cream.
The results of genotoxicity studies indicate that clascoterone does not pose a genotoxic risk. Clascoterone was not clastogenic in the in vitro human lymphocyte chromosomal aberration assay. The results of the bacterial reverse mutation test (Ames test) were considered equivocal. An isolated slight increase of revertants was noted in the TA98 strain at 333 mcg/plate, while negative responses were observed in all other strains. The results of a rat bone marrow erythrocyte micronucleus test were also considered equivocal. A significant increase in micronucleated polychromatic erythrocytes was observed at the 2,000 mg/kg dose (administered subcutaneously) at the 24-hour timepoint, with increases above the historical control range in 2 of 5 rats. Clascoterone administered subcutaneously at 500 mg/kg or 1,000 mg/kg did not induce micronuclei in the bone marrow. The main degradation product of clascoterone, cortexolone-21-propionate, did not demonstrate genotoxic potential.
A fertility and early embryonic development study was conducted in rats administered clascoterone subcutaneously at doses of 0.5, 2.5, or 12.5 mg/kg/day from 2 to 4 weeks before mating and through the mating period. At the 12.5 mg/kg/day dose level (163 times the maximum recommended human dose [MRHD] based on AUC comparison), increased pre-implantation loss was observed, along with decreased testicular sperm counts and increased caudal epididymis sperm counts in males. No effects were observed on mating or fertility in rats at doses up to 12.5 mg/kg/day. No effects were observed on development at doses up to 2.5 mg/kg/day (33 times the MRHD based on AUC comparison).
In an embryofetal development study, clascoterone was administered subcutaneously to pregnant rats at 1, 5, or 25 mg/kg/day during the period of organogenesis. No clascoterone-related maternal toxicity or effects on uterine parameters were noted at doses up to 25 mg/kg/day (336 times the MRHD based on AUC comparison). Malformations attributed to clascoterone were observed at all dose levels, without a dose relationship. Omphalocele was noted in a single fetus (0.5% of fetuses examined) at each dose level. External and visceral malformations were also detected in two additional fetuses (0.9% of fetuses examined) at 1 mg/kg/day (8 times the MRHD based on AUC comparison).
An embryofetal development study was also conducted in pregnant rabbits administered clascoterone subcutaneously at doses of 0.1, 0.4, or 1.5 mg/kg/day during the period of organogenesis. Post-implantation loss and resorptions increased at 1.5 mg/kg/day (39 times the MRHD based on AUC comparison). No signs of developmental toxicity were detected at doses up to 0.4 mg/kg/day (12 times the MRHD based on AUC comparison). No fetal malformations were observed at doses up to 1.5 mg/kg/day.
A pre- and postnatal development study was conducted in pregnant rats. Clascoterone was administered subcutaneously at 0.5, 2.5, and 12.5 mg/kg/day from Gestation Day 6 through Lactation Day 20. No significant maternal or developmental toxicity was observed at doses up to 12.5 mg/kg/day (163 times the MRHD based on AUC comparison).
In estrogen-pretreated immature female rabbits, clascoterone administered subcutaneously at 1 mg/kg showed progestational activity characterized by endometrial stimulation and increased uterine weight.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Winlevi Product Monograph. Given the intended use of Winlevi, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Winlevi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
As outlined in the What steps led to the approval of Winlevi? section, the review of the quality component of the New Drug Submission for Winlevi was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
The chemistry and manufacturing information submitted for Winlevi 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 for the 30 g and 60 g aluminum tubes and the 10 g health professional samples, and 24 months for the 2 g health professional samples, is acceptable when the drug product is stored at a refrigerated temperature of 2 ºC to 8 ºC.
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 [ICH] 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.
None of the excipients used in the formulation of Winlevi is of human or animal origin.