Regulatory Decision Summary for Zoryve

This Supplemental New Drug Submission (SNDS) – Clinical/Chemistry and Manufacturing (CLIN/C&M) was filed for (roflumilast foam 0.3% w/w) to obtain post-Notice of Compliance (post-NOC) market authorization for a new indication and dosage form.

The recommended new indication for Zoryve (roflumilast foam 0.3% w/w) was for the topical treatment of seborrheic dermatitis in patients 9 years of age and older. The safety and efficacy data submitted in patients 9 to 17 were limited. Health Canada has authorized an indication for Zoryve foam 0.3% for pediatric use primarily from extrapolation of data generated from adult patients. The proposed formulation and dose for this indication was 0.3% w/w foam administered once daily to affected areas via topical application.

The Sponsor previously received a Notice of Compliance (NOC) for the cream formulation of Zoryve (roflumilast cream 0.3% w/w) on April 28, 2023, for the topical treatment of plaque psoriasis, including treatment of psoriasis in the intertriginous areas, in patients 12 years of age and older.

Zoryve (roflumilast foam 0.3%) administered once daily (QD) demonstrated acceptable safety and efficacy profiles in the pivotal phase 3 ARQ-154-304 study. The phase 3 ARQ-154-304 study was an 8-Week, parallel group, double blind, vehicle-controlled study of the safety and efficacy of roflumilast foam 0.3% administered QD in adult subjects (aged 18 to 87 years) and adolescent participants (aged 9 to 17 years) with moderate to severe seborrheic dermatitis involving up to 20% body surface area (BSA). The phase 3 study met the primary objective of Investigator Global Assessment (IGA) success at Week 8 compared to vehicle control. The phase 3 study demonstrated that a significantly higher number of roflumilast foam-treated participants (n = 304) achieved IGA success at Week 8 compared to participants treated vehicle control (n = 153) (roflumilast 79.5% vs. vehicle 58.0%, OR [99% confidence interval (CI)] 2.79 [1.51, 5.51]; proportion difference [99% CI] 20.6% [8.19, 33.01]; p <0.0001). The phase 3 study also reported significant improvements in key symptoms of seborrheic dermatitis, as demonstrated in the achievements of secondary endpoints of changes in erythema and scaling severity grade, and worst-itch numeric scale (WI-NRS) success.

The majority of treatment-emergent adverse events (TEAEs) in the roflumilast foam group were mild (43 participants [14.1%]) or moderate (23 participants [7.6%]). Four participants (1.3%) experienced severe TEAE (2 events of type 2 diabetes mellitus, blood potassium, and keratoacanthoma; allsevere TEAEs were considered unrelated to the treatment). The most common TEAEs (more than 1%) in the roflumilast group were COVID-19 (11 [3.6%] participants out of 304), nausea (5 [1.6%] participants), urinary tract infection (4 [1.3%] participants) and nasopharyngitis (4 [1.3%] participants). All events of nausea were mild, and one was considered possibly related to the treatment. Out of 2 participants in the roflumilast group who discontinued treatment due to a TEAE, only 1 participant discontinued the treatment due to TEAEs considered probably related to roflumilast (abdominal pain and diarrhoea of moderate severity, and mild haematochezia). These TEAEs resolved after treatment discontinuation. The adverse events of nausea and diarrhoea are captured in the proposed Product Monograph (PM) given that PDE-4 inhibitors have been shown to be associated with gastrointestinal adverse events. Overall, data from the phase 3 study showed that 8-week, QD topical application of roflumilast foam 0.3% showed an acceptable safety profile with low occurrence of treatment-related TEAEs of mild and moderate severity, as well as clinically meaningful improvements in key symptoms of seborrheic dermatitis.

The reliance on a single phase 3 trial was acceptable in part due to similarities in composition of roflumilast foam 0.3% and the approved roflumilast cream 0.3%. Robust safety and efficacy results from the supportive phase 2a study ARQ-154-203 (n=226), which was similar to the phase 3 study in study design, randomization ratio, and treatment duration, further justified the reliance on a single phase 3 study. Moreover, data from the long-term, open-label phase 2 study ARQ-154-214 (n=408) demonstrated a safety profile comparable to the phase 3 study and showed no evidence of decreased efficacy up to 52 weeks. Additionally, pooled safety data from phase 3 and phase 2a studies showed that most of the TEAEs were either mild or moderate and less than 1% of TEAEs led to discontinuation of roflumilast foam 0.3% treatment. The TEAEs that led to the discontinuation of IP and that were also considered related to the roflumilast treatment were abdominal pain, diarrhoea, and haematochezia in 1 participant and application site pain in another participant. These roflumilast-related TEAEs resolved on their own following discontinuation of the treatment. Subgroup analysis of the pooled vehicle-controlled safety data did not raise safety concerns in participants administered roflumilast foam 0.3%.

The pediatric safety and efficacy data in participants aged between 9 and 17 years old in the phase 3 study was limited to 32 participants. There were no safety concerns among the pediatric participants. The proportion of participants with TEAEs was similar across the age groups of 9-17 years old, 18-64 years old, and 65 years and older. The majority of adverse events (AEs) in all three age groups were of mild or moderate severity. None of the participants in the adolescent age group of 9-17 years experienced AEs related to roflumilast foam 0.3%. Subgroup analysis of IGA success at week 8 of participants aged 9 - 17 years showed a trend toward efficacy of roflumilast foam 0.3% in pediatric participants (76.5% of roflumilast-treated participants achieved IGA success at Week 8 compared to 46.7% of vehicle-treated participants) but efficacy could not be could not be ascertained due to the limited number of participants.

The safety and efficacy uncertainties associated with pediatric participants were mitigated by extrapolating the safety and efficacy data from the adult participants as per recommendations outlined in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E11 Clinical Investigation of Medicinal Products in the Pediatric Population. The approval of a pediatric indication was based on the similarities between pediatrics and adults in i) the pathophysiology of seborrheic dermatitis, ii) the response to roflumilast foam 0.3% treatment, and iii) the pharmacokinetic (PK), efficacy, and safety profiles of roflumilast foam 0.3%. The proposed pediatric indication addresses the prevalence of seborrheic dermatitis in pediatrics as the pathogenesis of seborrheic dermatitis is closely linked to increased sebaceous gland activity at the onset of puberty between the ages of 9 and 13. The limitations of safety and efficacy data in pediatrics is captured in the proposed PM.

Given that roflumilast is extensively metabolized by cytochrome P450 (CYP) 3A4, concomitant use of roflumilast with systemic CYP3A4 inhibitors, including oral contraceptives containing gestodene and ethinyl estradiol, may increase roflumilast systemic exposure. However, assessments of submitted data on women of childbearing potential (WOCBP) using oral contraceptives containing gestodene and ethinyl estradiol (combination oral contraceptives) compared to WOCBP using non-hormonal and other hormonal forms of contraception showed no evidence of drug-drug interaction between topical roflumilast with concomitant use of combination oral contraceptives. These findings concur with published literature demonstrating that combination oral contraceptives have no clinical effect on CYP3A4 activity in vivo. Therefore, information pertaining to this potential risk was removed from the PM.

The final labelling and Product Monograph were considered acceptable.

An updated Risk Management Plan (RMP) for Zoryve foam was reviewed by Health Canada and considered acceptable with revisions.

The chemistry and manufacturing information submitted for Zoryve foam has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Overall, the benefit-harm-uncertainty profile was favourable for Zoryve (roflumilast foam 0.3% w/w) for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Zoryve, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.