Regulatory Decision Summary for Zoryve
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of Submission:
New Drug Submission
Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations
What was the purpose of this submission?
The purpose of this New Drug Submission (NDS) is to request marketing approval for roflumilast cream (0.3%), marketed as Zoryve, for topical treatment of plaque psoriasis, including treatment of psoriasis in the intertriginous areas, in patients 12 years of age and older.
It is a phosphodiesterase 4 (PDE 4) inhibitor topical cream containing 3 mg of the active substance per gram of cream and intended for once daily topical administration to affected areas of skin.
Why was the decision issued?
Zoryve (roflumilast cream 0.3%), administered topically to affected areas, once-daily, was shown to be efficacious and safe in two identical phase 3 randomised, double-blinded, vehicle-comparator controlled pivotal trials (Studies 301 and 302). Both trials enrolled people with mild to severe plaque psoriasis with a body surface area (BSA) of 2 to 20% with or without intertriginous area involvement. The vast majority (98%) of participants were adults over 18 years of age. Both studies met their primary objective of Investigator Global Assessment (IGA) success at Week 8 compared to placebo. Study 301 had an IGA success rate of 41.5% for participants treated with roflumilast cream compared to 5.8% for those treated with vehicle cream, while Study 302 reported 36.7% and 7.1% for participants treated with roflumilast and vehicle cream, respectively. Likewise, statistically significant and clinically meaningful improvements in intertriginous areas (I-IGA) and pruritis at 8 weeks of treatment were observed for participants receiving roflumilast cream compared to vehicle cream in both studies. The primary and key secondary endpoints are considered standard, validated measurements of plaque psoriasis disease burden and symptom severity.
A small number of adolescents aged 12 to 17 years were treated with roflumilast (8 across both pivotal trials and 20 in the clinical program). The approval of an adolescent indication was based primarily on extrapolation of data generated in adult participants, comparable pharmacokinetic parameters and the absence of pediatric-specific safety signals or concerns. The basis for this approval was captured in the Product Monograph (PM).
Across the clinical program, a total of 1,452 participants, including 1,057 with psoriasis, received the to-be-marketed formulation of roflumilast cream 0.3%. Zoryve was well-tolerated. The most common adverse drug reactions (ADRs) are diarrhea, headache, insomnia, and nausea. Upper respiratory tract and urinary tract infections and application site pain were also included as common adverse events (AEs) in the PM. Few participants discontinued due to treatment-related AEs. An increased incidence of weight loss of greater than 5% of body weight was also seen in participants treated with roflumilast compared to vehicle. Human dermal safety studies found no evidence of repeat-insult or cumulative irritation, phototoxicity or photo-allergy.
Similar efficacy and safety profiles were observed across various sub-populations based on age, sex, race, or disease severity/BSA.
There are several areas of clinical uncertainty surrounding Zoryve. These include the small number of pediatric participants treated, minimal long term topical exposure data, the unknown relevance of cardiovascular, neurological and psychiatric events observed in oral roflumilast clinical trials, and risks during pregnancy and breast feeding. These uncertainties have all been addressed with adequate labeling and post-market pharmacovigilance commitments.
The non-clinical and clinical pharmacology package provided in this NDS was based largely on previously submitted data for the active ingredient as an oral tablet. The formulation-specific non-clinical pharmacology, pharmacokinetic and toxicology studies submitted were appropriate in establishing a suitable clinical safety margin and did not raise any major safety concern.
A risk management plan was submitted and reviewed by the Marketed Health Products Directorate and found to be acceptable.
Zoryve provides a convenient topical therapeutic option for adolescents and adults suffering from plaque psoriasis with or without intertriginous involvement. The uncertainties and risks associated with its use have been appropriately mitigated with labeling and planned post-market surveillance activities. The benefit-harm-uncertainty profile of Zoryve for the treatment of plaque psoriasis is positive.
For further details about Zoryve, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.
Date of Decision:
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Drug Identification Number(s) Issued:
Available by prescription only