Regulatory Decision Summary for Nduvra

This New Drug Submission (NDS) was filed by Dermavant Sciences GmbH, to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, of Nduvra (tapinarof cream) for the following indication:

Ndvura (tapinarof cream) is indicated for the topical treatment of plaque psoriasis in adults.

The dosing regimen consists of applying a thin layer of Ndvura 1% cream to affected areas once daily. Nduvra may be used on all skin surfaces, including the head, neck, and intertriginous areas.

Nduvra is a new active substance (NAS) and a first-in-class (FIC) product.

The Canadian regulatory decision of the review of Nduvra was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as added reference.

Psoriasis is a common, chronic, relapsing, multi-system inflammatory disease with predominant skin and joint involvement. Plaque psoriasis is the most common form of psoriasis and affects approximately 80-90% of patients. It is characterized by well-demarcated symmetric and erythematous plaques with silvery scales on the skin.

Nduvra (tapinarof cream) is an aryl hydrocarbon receptor (AhR) agonist. The specific mechanisms by which Nduvra exerts its therapeutic action in psoriasis are unknown. The primary data in support of Nduvra cream for the proposed indication of the treatment of plaque psoriasis in adults was derived from two identical Phase 3 clinical studies. Study DMVT-505-3001 (PSOARING 1) and Study DMVT-505-3002 (PSOARING 2) were 12-week, pivotal, double-blind, randomized, vehicle-controlled, multicenter studies that evaluated the efficacy and safety of Nduvra compared to vehicle cream in adults with plaque psoriasis. In addition to the pivotal clinical efficacy and safety, the long-term safety of Nduvra in the treatment of plaque psoriasis was assessed via Study DMVT-505-3003 (PSOARING 3), a 40-week, Phase 3, open-label, single-arm, multicenter long-term extension (LTE) study, in patients who completed treatment with Nduvra or vehicle cream in one of two pivotal studies.

The primary endpoint in the pivotal studies was defined as the proportion of patients who achieved a Physician Global Assessment (PGA) score of clear (0) or almost clear (1) with a minimum 2-grade improvement from baseline at Week 12 (PGA treatment success). Both studies met their respective primary endpoints, Nduvra was superior to vehicle cream in achieving PGA treatment success at Week 12. The mean PGA treatment success at Week 12 was 35.4% and 40.2% in the Nduvra arm compared to 6.0% and 6.3% in the vehicle cream arm in PSOARING 1 and PSOARING 2, respectively. The treatment effect of Nduvra compared to vehicle cream in PSOARING 1 and PSOARING 2 was statistically significant (both p<0.0001) with relative risks (RR) of 5.8 (95% confidence interval [CI]: 2.9, 11.6) and 6.1 (95% CI: 3.3, 11.4), respectively. The sensitivity and supportive analyses were all consistent and corroborated the findings of the primary endpoint (all analyses had p <0.0001).

The clinically relevant secondary endpoints included: the proportion of patients with ≥75% improvement in Psoriasis Area Severity Index (PASI) from baseline at Week 12 (PASI75); mean change in percent body surface area (% BSA) affected from baseline at Week 12 and the proportion of patients with ≥90% improvement in PASI score from baseline at Week 12 (PASI90). Nduvra demonstrated statistically significant superiority to vehicle cream in all the secondary endpoints measured. All the secondary endpoints, along with the corresponding sensitivity and supportive analyses, were consistent and corroborated the findings of the primary endpoint.

In the pivotal studies pool, folliculitis was the most commonly reported treatment-emergent adverse event (TEAE) occurring in 20% of patients in the Nduvra arm compared to 1% of patients in the vehicle arm. Other TEAEs with ≥2% incidence in the Nduvra arm, with corresponding incidence in the vehicle arm, in the pivotal studies pool, included nasopharyngitis (11% versus [vs] 9%), contact dermatitis (7% vs 1%), headache (4% vs 1%), pruritus (3% vs 1%) and influenza (2% vs 1%). No new safety signals emerged from the LTE study. The majority of TEAEs in the pivotal studies and the LTE study were mild or moderate in severity. The incidence of serious adverse events (SAE) in the 3 Phase 3 studies were low and none of the SAE were considered related to study drug. The most commonly reported TEAEs leading to study treatment and study discontinuation were folliculitis and contact dermatitis. There were no deaths in the pivotal studies. There was one death unrelated to Nduvra treatment in the LTE study.

The findings derived from the pivotal studies represented substantial evidence of clinical efficacy of Nduvra compared to vehicle cream for the treatment of plaque psoriasis in adults. On the basis of the information reviewed from the Phase 3 studies, Nduvra presented an acceptable and manageable safety profile in consideration of the intended population.

A Risk Management Plan (RMP) for Nduvra was submitted by Dermavant Sciences, GmbH to Health Canada. Upon review, the RMP was considered to be acceptable. 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 minimise risks associated with the product.

A Notice of Non-Compliance (NON) was previously issued for this submission on March 12, 2024, from a Quality perspective based on observed major deficiencies with respect to the classification and evaluation of identified extractable/potential leachable impurities. Additional supportive toxicological data, provided by the Sponsor in response to the NON, was considered acceptable and resolved this issue.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Nduvra 1% cream 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 Nduvra, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.