Leaflet OPZELURA 15mg / g cream

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excludingcorticosteroids, ATC code: D11AH09

Ruxolitinib is a Janus Kinase (JAK) inhibitor with selectivity for the JAK1 and JAK2 isoforms.

Intracellular JAK signalling involves recruitment of STATs (signal transducers and activators oftranscription) to cytokine receptors, and subsequent modulation of gene expression.

Autoimmune IFNγ producing cytotoxic T lymphocytes are thought to be directly responsible formelanocyte destruction in human vitiligo. Recruitment of cytotoxic lymphocytes to lesional skin ismediated via IFNγ dependent chemokines, such as CXCL10. Downstream signalling of IFNγ is

JAK1/2 dependent and treatment with ruxolitinib reduces CXCL10 levels in vitiligo patients.

Multiple inflammatory and pruritic cytokines involved in the pathogenesis of atopic dermatitis, such as

IL-4, IL-5, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin (TSLP), require JAK/STATpathway activation for downstream biological activity.

Clinical efficacy and safety in vitiligo

Two double-blind, randomised, vehicle-controlled studies of identical design (TRuE-V1 and

TRuE-V2) enrolled a total of 674 patients who have vitiligo on the face and total body vitiligo area(facial and nonfacial) not exceeding 10% BSA, with disease extent at initiation ranging from 3.2% to10.1% of BSA, aged 12 years and older (10.7% of patients were 12 to 17 years of age and 6.7% were65 years or older). Females constituted 53.1% of patients, 81.9% of patients were White, 4.7% were

Black, and 4.2% were Asian. The majority of patients had Fitzpatrick skin types III, IV, V, or VI(67.5%).

In both studies, patients were randomised 2:1 to treatment with ruxolitinib cream or vehicle twicedaily for 24 weeks with affected BSA not exceeding 10%, followed by an additional 28 weeks oftreatment with ruxolitinib cream BID for all patients. The primary efficacy endpoint was theproportion of patients achieving a 75% repigmentation in the facial Vitiligo Area Scoring Index(F-VASI75) at week 24. Key secondary endpoints included the proportions of patients achieving a90% repigmentation in F-VASI (F-VASI90), 50% improvement in total body Vitiligo Area Scoring

Index (T-VASI50), and a Vitiligo Noticeability Scale (VNS) score of 4 or 5 (vitiligo 'a lot lessnoticeable' or 'no longer noticeable').

Repigmentation of treated vitiligo lesions and superiority of ruxolitinib cream over vehicle cream wereobserved for both studies, as demonstrated by statistically significant differences in response rates for

F-VASI75/90, T-VASI50, and VNS score of 4 or 5 at week 24 (Table 2).

The treatment effect difference from vehicle emerges numerically as early as week 12. Continuedrepigmentation as assessed by VASI and VNS scores was observed through week 52 for patients whohad continuously applied ruxolitinib cream twice daily from baseline. The proportion of patients whoachieved F-VASI75 over the 52-week treatment period in pooled data from study TRuE-V1 and

TRuE-V2 are shown in Figure 1.

Similar treatment responses at week 52 are seen for those who crossed over from vehicle to ruxolitinib(Figure 1).

Table 2: Percent of patients with vitiligo achieving the primary and key secondaryendpoints at week 24 (intent-to-treat)a

TRuE-V1 TRuE-V2

Opzelura Vehicle Opzelura Vehicle(N = 221) (N = 109) (N = 222) (N = 109)

F-VASI75 (%) 29. 8 7. 4 30.9 11.4

Response rate 22.3b - 19.5c -difference (95% CI) (14.214, 30.471) (10.537, 28.420)

F-VASI90 (%) 15. 3 2.2 16.3 1.3

Response rate 13.2d - 15.0e -difference (95% CI) (7.497, 18.839) (9.250, 20.702)

T-VASI50 (%) 20.6 5.1 23.9 6.8

Response rate 15.5d - 17.1c -difference (95% CI) (8.339, 22.592) (9.538, 24.721)

VNS 4 or 5 (%) 24.5 3.3 20.5 4.9

Response rate 21.2c - 15.5d -difference (95% CI) (14.271, 28.143) (8.515, 22.561)a Primary and key secondary outcomes were corrected using multiple imputation method.b p-value < 0.0001c p-value < 0.001d p-value < 0.005e p-value < 0.01

Figure 1: Proportion of patients achieving F-VASI75 during the 52 week treatment period(intent-to-treat) - pooled data from study TRuE-V1 and TRuE-V2

At week 52, the observed response rate for F-VASI90, T-VASI50 and VNS was 30.3%, 51.1%, and36.3% respectively for the ITT pooled population.

Durability of response

A Phase 3, double-blind, vehicle-controlled, randomised, withdrawal and treatment-extension study ofruxolitinib cream twice daily enrolled 458 eligible patients with vitiligo who had completed either ofthe parent studies using ruxolitinib (TRuE-V1 and TRuE-V2; week 52); patients were assigned toeither cohort A or B with a follow-up up to 104 weeks.

Cohort A comprised 116 patients who reached ≥ F-VASI90 at week 52 of the parent study. Thesepatients were re-randomised to either ruxolitinib or vehicle (i.e. withdrawal) to study relapse(< F-VASI75). A relapse occurred in 15% of patients in the ruxolitinib group, and in 29% of patientsin the vehicle group. In the latter group, the majority of relapses (9/16) occurred during the first 4months after stopping ruxolitinib cream. Among the 16 patients in the vehicle group who relapsed andwere retreated, re-treatment resulted in a regained F-VASI75 in 12 (75%) patients in a median of 12weeks and F-VASI90 was regained by 11 (69%) patients in a median of 15 weeks.

Cohort B comprised 342 patients who reached < F-VASI90 at week 52 of the parent study. Thesepatients continued with open-label ruxolitinib treatment; at week 104, among patients originallyrandomised to ruxolitinib cream twice daily, 66% reached F-VASI75, and 34% reached F-VASI90.

Safety

Safety in the long-term extension study up to 104 weeks cumulatively was consistent with the profilereported in the parent studies up to 52 weeks.

Clinical efficacy in atopic dermatitis

The efficacy and safety of ruxolitinib cream was evaluated in a pivotal double-blind, randomised,vehicle-controlled study (TRuE-AD4) in adult patients with moderate atopic dermatitis who hadinadequate response to, were intolerant to, or were contraindicated to topical corticosteroids andtopical calcineurin inhibitors.

The pivotal, double-blind, randomised, vehicle-controlled study (TRuE-AD4), enrolled a total of 241patients, 18 years of age and older with moderate atopic dermatitis, defined by an Eczema Area and

Severity Index (EASI) score > 7, an Investigator’s Global Assessment (IGA) score of 3, 10-20% Body

Surface Area (BSA) involvement (excluding scalp), an Itch Numeric Rating Scale (Itch NRS) score of≥ 4, and a Dermatology Life Quality Index (DLQI) score > 10. Enrolled patients had a documentedinadequate response to, were intolerant to, or were contraindicated to topical corticosteroids andtopical calcineurin inhibitors. Patients were randomised 2:1 to treatment with ruxolitinib 1.5% creamtwice daily (BID) or vehicle cream BID for 8 weeks, followed by a 16-week, vehicle-controlledextension, double-blind period for patients with an adequate response (at least EASI50 frombaseline) and an open-label escape arm. During the double-blind, vehicle-controlled extension period,patients applied study drug to active lesions only.

Endpoints

In study TRuE-AD4, the co-primary efficacy endpoints were the proportion of patients reaching

EASI75 (defined as ≥ 75% improvement in EASI score from baseline) and the proportion of patientsachieving IGA Treatment Success (IGA-TS; defined as an IGA score of 0 [clear] or 1 [almost clear]and a ≥ 2-grade improvement from baseline) at week 8. Key secondary endpoints included theproportion of patients reaching ITCH4 (defined as ≥ 4-point improvement in Itch NRS score frombaseline) at week 8, day 7, day 3, and day 2. Additional clinically relevant secondary endpointsincluded the proportion of patients achieving IGA-TS, EASI75, ITCH4, as well as change frombaseline in DLQI, Patient-Oriented Eczema Measure (POEM), Patient-Reported Outcomes

Measurement Information System (PROMIS) Short Form Sleep-Related Impairment (8a) and

PROMIS Short Form Sleep Disturbance (8b), at each postbaseline visit.

Baseline characteristics

In study TRuE-AD4, the mean age was 39 years and 7.9% of patients were 65 years of age or older.

Females constituted 54% of patients, 81% of patients were White, 5.8% were Black, and 10% were

Asian. Patients had long-standing atopic dermatitis of 20 years (mean) before study entry. Recent(within the last 12 months) prior treatments for atopic dermatitis included topical corticosteroids(96%) and topical calcineurin inhibitors (81%), as well as systemic therapies (30%) and phototherapy(8.7%). The mean EASI score was 13, the mean Itch NRS score was 7.4, and the mean total % BSAaffected was 15%. The mean DLQI score was 19, the mean POEM score was 20 (with no patientshaving a POEM score of 0-2), and the mean PROMIS 8a and PROMIS 8b scores were 22 and 24,respectively. Baseline characteristics were generally similar across the treatment groups.

In study TRuE-AD4, ruxolitinib cream was statistically significantly superior to vehicle cream at week8 with respect to the co-primary endpoints, EASI75 (Table 3 and Figure 2) and IGA-TS (Table 3), andall of the key secondary endpoints, ITCH4 at week 8 (Table 3 and Figure 3), and ITCH4 at day 7, 3and 2, with separation between the ruxolitinib cream and vehicle cream treatment groups at Day 1(Figure 3).

The proportion of patients reaching IGA-TS increased from baseline during the double-blind, vehicle-controlled period (Table 3), with separation between the ruxolitinib cream and vehicle cream treatmentgroups at week 2 (29% and 2.5%, respectively) and week 4 (49% and 9.9%, respectively).

Table 3: Efficacy results of ruxolitinib cream, co-primary and selected key secondaryendpoints at week 8

TRuE-AD4(intent-to-treat)

Ruxolitinib cream Vehicle(N = 160) (N = 81)

EASI75 (%) 70.0 18.5

Response rate difference (95% CI) 51.4 (40.48, 62.24)a -

IGA-TS (%) 61.3 13.6

Response rate difference (95% CI) 47.6 (36.98, 58.20)a -

ITCH4 (%) 62.5 19.8

Response rate difference (95% CI) 42.8 (31.44, 54.21)a -a p-value < 0.0001

Figure 2: Proportion of patients achieving EASI75 at each visit during the vehicle-controlled period in study TRuE-AD4 (intent-to-treat)

Figure 3: Line Plot of ITCH4 Response Rate from day 1 to day 7 - TRuE-AD4 (intent-to-treat Population)p-value< 0.0001 on D7 and D3; p-value = 0.0072 on D2.

Nominal p-value = 0.0374 on D1, Nominal p-value < 0.0001 on D4, D5 and D6.

Durability of response

During the double-blind, vehicle-controlled extension period of week 8 to week 24, when patientsapplied study drug to active lesions only, the proportion of patients in the ruxolitinib cream group whoreached EASI75, IGA-TS, and ITCH4 remained higher than the level at week 8.

Quality of life/patient-reported outcomes

In study TRuE-AD4, patients treated with ruxolitinib cream had clinically meaningful improvementsin patient-reported symptoms and the impact of atopic dermatitis on health-related quality of life asmeasured by DLQI, and POEM and on sleep as measured by PROMIS Sleep-Related Impairment (8a)and Sleep Disturbance (8b), at week 8.

At week 8, DLQI scores had decreased (mean [STD]) from baseline by 15 (6.4) and 8.4 (7.7) for theruxolitinib 1.5% cream and vehicle cream BID treatment groups, respectively. The proportion ofpatients achieving a 4-point reduction in DLQI was 97% and 78% for the ruxolitinib 1.5% cream andvehicle cream treatment groups, respectively.

At week 8, POEM scores had decreased (mean [STD]) from baseline by 15 (8.1) and 6.4 (7.5) for theruxolitinib 1.5% cream and vehicle cream treatment groups, respectively. The proportion of patientsachieving POEM 0 to 2 increased to 40% and 8.6% for the ruxolitinib 1.5% cream and vehicle creamtreatment groups, respectively.

At week 8, the PROMIS (8a) Sleep-Related Impairment scores and the PROMIS (8b) Sleep

Disturbance scores showed numerically larger improvements in the ruxolitinib 1.5% cream group, ascompared to the vehicle cream treatment group.

Vitiligo

A total of 72 adolescents (12 to < 18 years; n = 55 ruxolitinib cream, n = 17 vehicle) were included inthe pivotal studies. Adolescents showed equal response rates in primary and key secondary endpointsat 24 weeks when treated with ruxolitinib, as compared to adults from 18-65 years of age.

A total of 130 adolescents (12 to < 18 years; n = 87 ruxolitinib 1.5% cream; n = 43 vehicle) with mild-to-moderate atopic dermatitis were included in a pooled analysis of two Phase 3 studies (TRuE-AD1and TRuE-AD2). Ruxolitinib 1.5% cream had a higher response rate than vehicle at week 8 for theprimary endpoint, EASI75 (61% versus 35%), and the key secondary endpoints, IGA-TS (51% versus14%) and ITCH4 (52% versus 17%) (see section 4.2).

The safety of ruxolitinib 1.5% cream in 2 Phase 1 paediatric studies (INCB 18424-102 [39 patientsaged 2 to < 18 years with mild to severe atopic dermatitis] and INCB 18424-103 [21 patients aged12 to < 18 years with mild to severe atopic dermatitis]) was consistent with the profile reported in the

Phase 3 study TRuE-AD4 in adults with moderate atopic dermatitis.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Opzelura in one or more subsets of the paediatric population for the treatment of vitiligo and atopicdermatitis (see section 4.2 for information on paediatric use).