Anzupgo

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids, ATC code: D11AH11 Mechanism of action Delgocitinib is a pan Janus kinase (JAK) inhibitor that targets the activity of all four members of the JAK family of enzymes consisting of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) in a concentration dependent manner. In human cells, inhibition of the JAK-STAT pathway by delgocitinib attenuates the signalling of several pro-inflammatory cytokines (including interleukin (IL)-2, IL-4, IL-6, IL-13, IL-21, IL-23, Granulocyte-Macrophage-Colony-Stimulating Factor (GM-CSF), and Interferon (IFN)-α) downregulating the immune and inflammatory responses in cells of relevance to CHE pathology. Pharmacodynamic effects In a thorough QT study in healthy subjects, there was no indication of a QTc prolonging effect of orally administered delgocitinib at single doses up to 12 mg (approximately 200 times the human exposure following topical application, based on C max ).‍‍‍‍‍‍​​​‍​​​​​​ Therefore, Anzupgo is not expected to affect cardiac repolarisation under conditions of clinical use. Dermal safety studies Clinical studies in healthy subjects demonstrated that delgocitinib cream did not cause phototoxic skin reactions or photoallergic skin reactions. Clinical efficacy and safety The safety and efficacy of delgocitinib cream were evaluated in two pivotal randomised, double-blind, vehicle-controlled studies of similar design (DELTA 1 and DELTA 2). CHE was defined as hand eczema that has persisted for more than 3 months or returned twice or more within the last 12 months. The studies included 960 patients 18 years of age and older with moderate to severe CHE as defined by an Investigator's Global Assessment for chronic hand eczema (IGA-CHE) score of 3 or 4 (moderate or severe) (see Table 2) and required a Hand Eczema Symptom Diary (HESD) itch score of ≥ 4 points at baseline. Eligible patients had a previous inadequate response to topical corticosteroids or were those in which topical corticosteroids are not advisable (e.g. due to important side effects or safety risks). Table 2 Investigator's Global Assessment for chronic hand eczema (IGA-CHE) IGA-CHE severity IGA-CHE score Sign and intensity Clear 0 No signs of erythema, scaling, hyperkeratosis/lichenification, vesiculation, oedema or fissures Almost clear 1 Barely perceptible erythema No signs of scaling, hyperkeratosis/lichenification, vesiculation, oedema or fissures Mild 2 At least one: • Slight but definite erythema (pink) • Slight but definite scaling (mostly fine scales) • Slight but definite hyperkeratosis/lichenification and at least one: • Scattered vesicles, without erosion • Barely palpable oedema • Superficial fissures Moderate 3 At least one: • Clearly perceptible erythema (dull red) • Clearly perceptible scaling (coarse scales) • Clearly perceptible hyperkeratosis/lichenification and at least one: • Clustered vesicles, without visible erosions • Definite oedema • Definite fissures Severe 4 At least one: • Marked erythema (deep or bright red) • Marked and thick scaling • Marked hyperkeratosis/lichenification and at least one: • High density of vesicles with erosions • Marked oedema • One or more deep fissures In DELTA 1 and DELTA 2, patients applied either delgocitinib 20 mg/g cream or vehicle cream twice daily to affected areas on the hands and wrists for 16 weeks. All patients who completed the two pivotal studies were eligible to enrol into the long-term extension study DELTA 3. Endpoints In DELTA 1 and DELTA 2, the primary endpoint was the proportion of patients achieving IGA-CHE treatment success (IGA-CHE TS), defined as an IGA-CHE score of 0 (clear) or 1 (almost clear: barely perceptible erythema only) with at least a 2-step improvement from baseline to Week 16. The IGA-CHE instrument rates the severity of the subject's global disease and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). Additional efficacy outcomes included the Hand Eczema Severity Index (HECSI) and the HESD at various timepoints. The HECSI rates the severity of six clinical signs (erythema, infiltration/papulation, vesicles, fissures, scaling, and oedema) and the extent of the lesions on each of the five hand regions (fingertips, fingers, palm of hands, back of hands, and wrists). The HESD is a daily 6-item patient-reported outcome (PRO) instrument designed to assess the worst severity of signs and symptoms of CHE (itch, pain, cracking, redness, dryness, and flaking) using an 11-point numeric rating scale. Baseline characteristics Across all treatment groups in DELTA 1 and DELTA 2, the mean age was 44.1 years, 7.6% of patients were 65 years of age or older, 64.4% were female, 90.4% were White, 3.5% were Asian, and 0.7% were Black. The frequency of CHE by main subtype was 35.9% atopic hand eczema, 21.5% hyperkeratotic eczema, 19.6% irritant contact dermatitis, 13.9% allergic contact dermatitis, 9.1% vesicular hand eczema (pompholyx), and 0.1% contact urticaria/protein contact dermatitis. In DELTA 1 and DELTA 2, 71.6% of patients had a baseline IGA-CHE score of 3 (moderate CHE), and 28.4% of patients had a baseline IGA-CHE score of 4 (severe CHE). The mean baseline Dermatology Life Quality Index (DLQI) score was 12.5, HECSI score was 71.6, and HESD score was 7.1. The mean HESD itch and pain scores were 7.1 and 6.7, respectively. Clinical response DELTA 1 and DELTA 2 In DELTA 1 and DELTA 2, a statistically significantly greater proportion of patients randomised to delgocitinib cream achieved the primary endpoint of IGA-CHE TS compared to vehicle at Week 16. The results for the primary and most relevant multiplicity-controlled secondary endpoints are presented in Table 3. Figure 1 shows the proportion of patients who achieved HESD itch ≥ 4-point improvement, and HESD pain ≥ 4-point improvement over time in DELTA 1 and DELTA 2. Table 3 Efficacy results of delgocitinib cream at Week 16 in DELTA 1 and DELTA 2 DELTA 1 DELTA 2 Delgocitinib (N=325) Vehicle (N=162) Delgocitinib (N=313) Vehicle (N=159) IGA-CHE TS, % responders a 19.7 # 9.9 29.1 § 6.9 HECSI-90, % responders a, b 29.5 § 12.3 31.0 § 8.8 HECSI-75, % responders a, c 49.2 § 23.5 49.5 § 18.2 HECSI, LS mean % change from baseline (± SE) d -56.5 § (± 3.4) -21.2 (± 4.8) -58.9 § (± 3.2) -13.4 (± 4.5) HESD itch ≥ 4-point improvement, % responders a, e 47.1 § (152/323) 23.0 (37/161) 47.2 § (146/309) 19.9 (31/156) HESD pain ≥ 4-point improvement, % responders a, e 49.1 § (143/291) 27.5 (41/149) 48.6 § (143/294) 22.7 (32/141) HESD ≥ 4-point improvement, % responders a, e 47.2 § (146/309) 24.4 (38/156) 44.5 § (137/308) 20.9 (32/153) #p < 0.01, §p < 0.001 All p-values were statistically significant versus vehicle with adjustment for multiplicity. Abbreviations: LS=least squares; N=number of patients in the full analysis set (all patients randomised and dosed); SE=standard error a. Data after initiation of rescue treatment, permanent discontinuation of treatment, or missing data were considered non-response. b. HECSI-90 responders were patients with ≥ 90% improvement in HECSI from baseline. c. HECSI-75 responders were patients with ≥ 75% improvement in HECSI from baseline. d. Data after initiation of rescue treatment, permanent discontinuation of treatment, or missing data were considered non-response by using worst observation carried forward. e. Based on the number of patients whose baseline value was ≥ 4 (scale from 0-10). In both DELTA 1 and DELTA 2, a statistically significantly greater proportion of patients treated with delgocitinib cream achieved IGA-CHE TS and a ≥ 4-point improvement in HESD as early as Week 4 compared to vehicle. A statistically significantly greater proportion of patients treated with delgocitinib cream achieved HECSI-75 at Week 8 compared to vehicle. Figure 1 Proportion of patients who achieved HESD itch ≥ 4-point improvement and HESD pain ≥ 4-point improvement over time – pooled data from DELTA 1 and DELTA 2 CI = Confidence Interval a. Based on the number of patients whose baseline value was ≥ 4 (scale from 0-10). Additional quality of life/patient-reported outcomes In both DELTA 1 and DELTA 2, patients treated with delgocitinib cream showed a statistically significantly greater improvement from baseline to Week 16 compared to vehicle in the Hand Eczema Impact Scale (HEIS) (see Table 4). HEIS is an instrument used for assessing the patient's perceived impact on their daily activities (use of soaps/cleaning products, housework involving hands getting wet, washing themselves, embarrassment, frustration, sleep, work, and the ability to hold or grip objects). 9 items are scored on a 5-point scale where 0='not at all' and 4='extremely', and the HEIS score is then calculated as the average of the 9 items. Across DELTA 1 and DELTA 2, statistically significantly greater improvements in health-related quality of life, as measured by the DLQI were observed in delgocitinib patients compared to vehicle at Week 16 (see Table 4). Table 4 Quality of life/patient-reported outcomes results of delgocitinib cream at Week 16 in DELTA 1 and DELTA 2 DELTA 1 DELTA 2 Delgocitinib (N=325) Vehicle (N=162) Delgocitinib (N=313) Vehicle (N=159) HEIS, LS mean change from baseline (± SE) a -1.46 § (± 0.05) -0.82 (± 0.08) -1.45 § (± 0.06) -0.64 (± 0.08) HEIS PDAL, LS mean change from baseline (± SE) a, b -1.46 § (± 0.06) -0.86 (± 0.08) -1.48 § (± 0.06) -0.66 (± 0.08) DLQI ≥ 4-point improvement, % responders c, d 74.4 § (227/305) 50.0 (74/148) 72.2 § (216/299) 45.8 (70/153) § p < 0.001 All p-values were statistically significant versus vehicle with adjustment for multiplicity. Abbreviations: LS=least squares; N=number of patients in the full analysis set (all patients randomised and dosed); PDAL=proximal daily activity limitations; SE=standard error a. Data after initiation of rescue treatment, permanent discontinuation of treatment, or missing data were considered non-response by using worst observation carried forward. b. HEIS PDAL assesses the patient's ability to use soaps/cleaning products, to do housework, and to wash themselves. The HEIS PDAL score is calculated as the average of the 3 items. c. Data after initiation of rescue treatment, permanent discontinuation of treatment, or missing data were considered non-response. d. Based on the number of patients whose baseline value was ≥ 4. Extension study (DELTA 3) Patients who completed either DELTA 1 or DELTA 2 were eligible to enrol in a 36-week open-label extension study (DELTA 3). In DELTA 3, the long-term safety and efficacy of as-needed delgocitinib treatment was evaluated in 801 patients. Patients started application of delgocitinib cream twice daily to affected areas whenever the IGA-CHE score was ≥ 2 (mild or worse) and stopped treatment when an IGA-CHE score of 0 or 1 (clear or almost clear) was achieved. Patients entering DELTA 3 with an IGA-CHE score of 0 or 1 remained off treatment until loss of response (IGA-CHE score ≥ 2). The proportions of patients achieving IGA-CHE 0 or 1, HECSI-75, HECSI-90, HESD itch ≥ 4-point improvement, and HESD pain ≥ 4-point improvement after the initial 16-week treatment period of delgocitinib cream were maintained through Week 52 with as-needed treatment. Among the 560 patients randomised to delgocitinib cream treatment in the pivotal studies (DELTA 1 and DELTA 2) enrolled in DELTA 3, the mean number of treatment periods was 1.5 (range 0 to 6), the mean treatment period duration was 123 days, and the mean cumulative number of days in response (days with an IGA-CHE score of 0 or 1 within the 36-week treatment period) was 46. The mean cumulative number of days in response was 111 among those patients who achieved IGA-CHE TS at Week 16 in the pivotal studies. Of the patients randomised to delgocitinib cream in the pivotal studies who achieved IGA-CHE TS at Week 16, the median duration of response while off treatment was 4 weeks with 28.3% maintaining response for at least 8 weeks. The median time to regain an IGA-CHE score of 0 or 1 following re-initiation of treatment was 8 weeks. Among patients who did not achieve an IGA-CHE TS at Week 16 of delgocitinib treatment in the pivotal studies, 48.1% achieved IGA-CHE 0 or 1 with continued delgocitinib treatment in DELTA 3. Phase 3 active comparator study versus alitretinoin (DELTA FORCE) The efficacy and safety of delgocitinib cream compared to alitretinoin was evaluated in a randomised, assessor-blinded, 24-week study with 513 patients 18 years of age and older with severe CHE as defined by an IGA-CHE score of 4. Eligible patients had a previous inadequate response to topical corticosteroids or were those in which topical corticosteroids are not advisable. The patients were randomised to either delgocitinib 20 mg/g cream twice-daily treatment for 16 weeks or alitretinoin 30 mg capsules once-daily treatment (with an option to reduce to 10 mg once daily) for 12 weeks. Treatment could continue up to 24 weeks. Permanent discontinuation of treatment (35.9% for alitretinoin vs. 13.4% for delgocitinib) and use of rescue medications (8.1% for alitretinoin vs. 4.7% for delgocitinib) were more frequent for patients treated with alitretinoin compared to delgocitinib. Statistically significantly greater improvements for the primary endpoint, change in HECSI score from baseline to Week 12, was achieved for delgocitinib cream compared to alitretinoin. Statistically significantly greater improvements were also achieved for delgocitinib cream for HECSI-90 and IGA-CHE TS. The results for the primary and the most relevant secondary endpoints are presented in Table 5. Table 5 Efficacy results at Week 12 from DELTA FORCE – delgocitinib cream versus alitretinoin DELTA FORCE Delgocitinib (N=250) Alitretinoin (N=253) HECSI, LS mean change from baseline (± SE) a -67.6 § (± 3.37) -51.5 (± 3.36) HECSI-90, % responders b, c 38.6 # (96/249) 26.0 (65/250) HECSI-75, % responders b, d, e 55.4 * (138/249) 46.0 (115/250) IGA-CHE TS, % responders b 27.2 # 16.6 *p < 0.05, #p < 0.01, §p < 0.001 All p-values were statistically significant versus alitretinoin with adjustment for multiplicity, except HECSI-75 % responders, which was not a multiplicity adjusted endpoint. Abbreviations: LS=least squares; N=number of patients in the full analysis set; SE=standard error a. Data after initiation of rescue treatment, permanent discontinuation of treatment, or missing data were considered non-response by using worst observation carried forward. b. Data after initiation of rescue treatment, permanent discontinuation of treatment, or missing data were considered non-response. c. HECSI-90 responders were patients with ≥ 90% improvement in HECSI from baseline. d. HECSI-75 responders were patients with ≥ 75% improvement in HECSI from baseline. e. HECSI-75 % responders were not a multiplicity adjusted endpoint. Greater improvements for delgocitinib cream measured by the mean change in HECSI score compared to alitretinoin, were observed at Week 1 and maintained through to Week 24. Paediatric population The licensing authority has deferred the obligation to submit the results of studies with delgocitinib in one or more subset of the paediatric population for the treatment of chronic hand eczema (see section 4.2 for information on paediatric use).