Regulatory Decision Summary for Opzelura

The purpose of this New Drug Submission (NDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drug Regulations for Opzelura, filed by Incyte Corporation. This submission was filed for Opzelura (ruxolitinib cream, 1.5%) for the topical treatment of nonsegmental vitiligo in patients 12 years of age and older and for the topical treatment of atopic dermatitis in patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Upon review of the submitted data package, Health Canada authorized Opzelura for the following indications: for the topical treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older, and for the topical treatment of mild to moderate atopic dermatitis in adult and pediatric patients 12 years of age and older whose disease is not adequately controlled with conventional topical prescription therapies (topical corticosteroids, topical calcineurin inhibitors) or when those therapies are not advisable.

The Sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

The proposed vitiligo indication is supported by data from two duplicate vehicle-controlled, double-blind, randomized, multicenter Phase 3 studies conducted in patients ≥12 years with a clinical diagnosis of nonsegmental vitiligo. Both Phase 3 studies consisted of a double-blind, vehicle-controlled and open-label treatment-extension periods lasting 24 and 28 weeks, respectively.

Efficacy was assessed using the VASI. Specifically, F-VASI was used for facial vitiligo and T-VASI for total body vitiligo. The VASI is a composite measurement of percent of vitiligo involvement (%body surface area) and the “degree of depigmentation” for each region affected by vitiligo site, estimated to the nearest of the following percentages: 0%, 10%, 25%, 50%, 75%, 90%, or 100%. The primary efficacy endpoint was the proportion of subjects achieving a 75% improvement in F-VASI at Week 24 (F-VASI75). The primary efficacy endpoint was achieved at Week 24; F-VASI75 was statistically significantly higher in the Opzelura group compared to vehicle (p<0.001) (Opzelura: 29.8% and 30.9% in Study 306 and 307, respectively; vehicle: 7.4% and 11.4%, respectively). The results of F-VASI75 at Week 24 were consistent across different subgroups, including, age, sex, race and geographical regions, and analyses based on different missing data handling assumptions.

The efficacy of Opzelura in treating vitiligo was further supported by the study’s key multiplicity controlled secondary endpoints, including proportion of subjects achieving a 50% improvement in F-VASI, 90% improvement in F-VASI, 50% improvement in T-VASI, and a vitiligo noticeability scale ( VNS) score of 4 or 5 (vitiligo "a lot less noticeable" or "no longer noticeable"). The proportion of subjects who achieved the key secondary endpoints at Week 24 was significantly higher in subjects who applied Opzelura compared with subjects who applied vehicle.

The vitiligo safety review was based on the integrated safety database in vitiligo patients across one Phase 2 and three phase 3 trials. In total, there were 789 patients with vitiligo who applied ruxolitinib cream, 546 of whom applied Opzelura (ruxolitinib cream, 1.5%) twice daily for ≥52 weeks. In the vehicle-controlled period of clinical trials, 683 were exposed to Opzelura for up to 24 weeks. In this population, the most frequent treatment emergent adverse events (TEAEs) (≥1% in any treatment group) that occurred more commonly in the Opzelura group than vehicle were: application site acne (Opzelura: 5.8% vs. vehicle: 1.3%), application site pruritus (5.1% vs. 2.7%), nasopharyngitis (4.2% vs. 2.2%), upper respiratory tract infection (2.9% vs. 2.2%), headache (3.8% vs. 2.7%), application site erythema (1.6% vs. <0.4%), application site rash (1.6% vs. 0.9%), influenza (1.3% vs. 0.4%), pyrexia (1.3% vs. 0%), urinary tract infection (1.3% vs. 0.4%), alanine aminotransferase increased (1.1% vs. 0.4%), and application site exfoliation (1.1% vs. 0.4%). Through Week 24, the types and frequencies of TEAEs were generally similar between adolescent and adult participants, with the exception of nasopharyngitis, COVID-19, and headache, which occurred more frequently in adolescents. Overall, Opzelura was safe and well-tolerated in participants ≥12 years of age with a clinical diagnosis of nonsegmental vitiligo. No fatal TEAEs occurred during the study, and few participants had Grade 3 or higher TEAEs, TEAEs leading to study drug discontinuation, and TEAEs leading to study drug interruption.

Overall, the benefit-harm-uncertainty profile is acceptable for ruxolitinib 1.5% cream twice daily for the treatment of nonsegmental vitiligo up to a maximum of 10% BSA.

The proposed atopic dermatitis indication is supported by data from duplicate, randomized, vehicle controlled, double-blind multicenter Phase 3 studies in adults and adolescent patients aged 12 years and older with mild to moderate atopic dermatitis (Study INCB-1824-303 and INCB-1824-304). Based on the results of a dose ranging study, doses of 0.75% ruxolitinib cream and Opzelura cream (ruxolitinib 1.5%) administered twice daily were evaluated in the pivotal studies.

Both studies had an 8 week vehicle-controlled, double-blind period, followed by a 44 week double-blind, long-term safety period in male and female patients 12 years and older. A total of 631 patients (Study 303) and 618 patients (Study 304) were randomized 1:2:2 to vehicle cream, 0.75% ruxolitinib cream or Opzelura cream during the 8 week vehicle-controlled period. Approximately 20% of patients were aged 12 to <18 years of age and 9% were aged 65 years and older. Patients were to have an Investigators Global Assessment (IGA) score (a 5 point scale measuring severity of atopic dermatitis) of 2 (mild) or 3 (moderate) and a maximum of 20% body surface area affected. After 8 weeks, those in the ruxolitinib treatment groups continued with the same dose, and patients in the vehicle controlled group were randomized to either of the active treatment groups. Patients were to administer cream to a maximum of 20% BSA twice daily.

The primary and secondary efficacy endpoints were evaluated at Week 8, at the end of the vehicle-controlled period. The primary efficacy endpoint was the proportion of patients with an Investigator’s Global Assessment (IGA) score of 0 or 1 with at least a 2 point reduction from baseline (treatment success; IGA-TS).

The results for efficacy were generally consistent between the two Phase 3 confirmatory studies. For the primary efficacy endpoint, the proportion of participants achieving IGA-TS at Week 8 was statistically significantly superior for Opzelura cream compared to vehicle cream (p<0.0001). The response rate difference from vehicle in study 303 was 38.7% (95% CI: 29.9, 47.4), and in study 304 was 43.7% (95% CI: 35.6, 51.8).

The results for the multiplicity controlled key secondary endpoints of proportion of patients who achieved a ≥75% improvement in Eczema Area and Severity Index Score (EASI75), and the proportion of subjects with a ≥4 point improvement in Itch Numerical Rating Scale (NRS; 11-point scale) showed statistically significant greater improvement for Opzelura cream compared to vehicle cream in both studies.

The atopic dermatitis Phase 3 safety database consisted of 1249 patients aged 12 years and older with atopic dermatitis who were enrolled in the duplicate Phase 3 52-week studies, 303 and 304 and who received at least 1 dose of Opzelura. Overall, 90% of patients completed the 8-week vehicle-controlled period, and few patients treated with Opzelura cream (<1%) discontinued study treatment due to a TEAE. The incidence of TEAEs was similar between the Opzelura group (27%) and the vehicle cream group (33%). The incidence of serious or severe TEAEs was low in all treatment groups, and there were no deaths. The most common TEAEs reported in the Opzelura group and at a higher rate than in the vehicle group were nasopharyngitis, upper respiratory tract infection and headache. All TEAEs were reported in fewer than 3% of patients in the Opzelura group. There was no relevant difference in the safety profile for patients aged 12 to 18 years or for patients aged 65 years and older. There were no clinically meaningful trends in hematology, clinical chemistry or vital sign evaluations.

Overall, the benefit-harm-uncertainty profile is acceptable for ruxolitinib 1.5% cream twice daily for the treatment of mild to moderate atopic dermatitis for administration to active lesions up to a maximum of 20% body surface area.

Ruxolitinib is an inhibitor of the Janus Kinases 1 and 2 (JAK). Adverse events of special interest associated with JAK inhibitors were identified in the clinical program across vitiligo and/or atopic dermatitis, including cytopenias, herpes zoster, viral skin infections, malignancies, and thromboembolic events. In pharmacokinetic analysis with Opzelura in vitiligo and/or AD patients, plasma concentrations of ruxolitinib were quantifiable in all subjects. While systemic exposures after topical Opzelura were generally lower than following orally administered ruxolitinib, some phase 3 trial patients exhibited plasma exposure exceeding JAK1/2 inhibition at the half-maximal inhibitory concentration (IC50). The pharmacokinetic analysis showed an overlap in exposure ranges between topical ruxolitinib 1.5% BID and oral ruxolitinib 5 mg. Therefore, the possibility of systemic effects following topical administration of Opzelura cream twice daily cannot be excluded. The Product Monograph is adequately labelled with systemic class effects of JAK inhibitors including ruxolitinib.

Risks have been communicated in the approved Product Monograph and will continue to be monitored post-market as outlined in the Risk Management Plan, with routine pharmacovigilance activities.

A Notice of Non-Compliance (NON) was issued by Health Canada due to deficiencies in the toxicological qualification of impurities and leachable impurities in Opzelura that negatively affected the benefit-harm-uncertainty profile for Opzelura, in addition to labelling changes to the Product Monograph related to the efficacy and safety of Opzelura identified during review. In response to the NON, the Sponsor submitted toxicological data and approaches for the toxicological qualification of the impurities and leachable impurities in Opzelura, which addressed the relevant objections. The Sponsor additionally addressed and complied with the labelling changes to the Product Monograph related to the efficacy and safety of Opzelura, which addressed theappropriate labeling objections.

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

Following review and requested revisions, the final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Opzelura (ruxolitinib cream, 1.5%) for the approved indications when used under the conditions of use recommended in the approved Product Monograph. Therefore a Notice of Compliance was recommended.

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