Selective JAK1 Inhibitors for the Treatment of Atopic Dermatitis: Focus on Upadacitinib and Abrocitinib

Sandra Ferreira; Emma Guttman-Yassky; Tiago Torres

Disclosures

Am J Clin Dermatol. 2020;21(6):783-798. 

In This Article

Abrocitinib

Overview on Abrocitinib: Mechanism of Action, Pharmacology, and Indications

Abrocitinib is a small molecule that exhibits a selective JAK1 inhibition. It inhibits several key cytokine signaling pathways known to have a key role in the pathogenesis of AD, including IL-4, IL-13, IL-31, and IFN-γ. Abrocitinib is a potent JAK1 inhibitor with IC50s of 29 nM, 803 nM, > 10,000 nM, and 1259 nM for JAK1, JAK2, JAK3, and TYK2, respectively.[76]

Absorption of abrocitinib was fast following single doses up to 200 mg, with peak plasma concentrations occurring within 1 h, but it was delayed at the higher doses of 400 and 800 mg (1.5–4 h).[77] Maximum plasma concentrations of abrocitinib were proportional across the entire evaluated dose range. The lower doses (3–30 mg) presented a monophasic decline in the plasma concentrations (mean elimination half-life of 2.0–2.5 h), while a biphasic decline was detected at the higher doses of 100–800 mg (mean elimination half-life of 3.6–5.3 h). Maximum plasma concentration exposures demonstrated a tendency for greater than proportional increases with increasing daily doses. Urinary recuperation was low (1.0–4.4%) and renal clearance averaged about 0.6 L h−1. Similar to upadacitinib, abrocitinib also received breakthrough therapy designation from the Food and Drug Administration for the treatment of patients with moderate-to-severe AD in February of 2018.

Clinical Efficacy of Abrocitinib

Phase II. The phase IIb trial (NCT02780167) was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study in which 267 adult patients with moderate-to-severe AD were randomly assigned (1:1.1:1) to receive oral abrocitinib (200, 100, 30 mg, or 10 mg) or placebo once daily (Table 4).[78]

At week 12, the primary endpoint, IGA 0/1, was achieved by 43.8% of patients receiving 200 mg of abrocitinib, 29.6% of patients receiving 100 mg, 8.9% receiving 30 mg, 10.9% of patients receiving 10 mg, and 5.8% of patients receiving placebo.[77] Significantly higher proportions of patients achieved this endpoint in both the 200-mg and the 100-mg dose groups compared with placebo. A dose-dependent response relationship was noted for IGA.[78] A plateau for the percentage of participants achieving IGA 0/1 was reached between weeks 4 and 6 in the 200-mg group and was sustained through week 12, whereas for the 100-mg group it continued to increase through week 12. Among the secondary endpoints, reductions in the EASI were significant, 82.6% (90% CI 72.4–92.8), 59.0% (90% CI 48.8–69.3), and 40.7% (90% CI 29.5–52.0) for those receiving 200 mg, 100 mg, and 30 mg of abrocitinib, respectively, compared with 35.2% (90% CI 24.4–46.1) for placebo. There were significantly higher percentage decreases of EASI in both the 200-mg (least-squares mean [LSM] difference from placebo, − 47.4%; p < 0.001) and 100-mg (LSM difference from placebo, − 23.8%; p = 0.009) groups compared with placebo. However, the reductions observed in the 30- and 10-mg groups were not significant (Table 4). Decreases from baseline in EASI for the 200- and 100-mg groups plateaued by weeks 4–6 and were maintained through week 12. The percentage change in EASI showed meaningful differences from placebo as early as week 1 in the 200-mg group (LSM difference from placebo, − 28.3%; p < 0.001), and at week 2 in the 100-mg group (− 14.9%; p = 0.03). At week 12, 64.6% (p < 0.001) and 40.7% (p = 0.004) of patients treated with 200 and 100 mg of abrocitinib, respectively, achieved a 75% reduction in EASI from baseline (EASI75) compared with 15.4% in the placebo group. Similarly, EASI50 and EASI90 responses were significantly higher in the 200- and 100-mg groups than placebo.

At week 12, there were significant reductions in pruritus NRS scores in the 200-mg (LSM difference from placebo, − 25.4%; p = 0.003) and 100-mg (− 20.7%; p = 0.02) groups compared with placebo (Table 4). Significant differences were noticed as early as day 2 in the 200-mg group (odds ratio, 6.09; 90% CI 1.35–27.59; p = 0.049) and day 5 in the 100-mg group (odds ratio, 8.15; 90% CI 1.84–36.06; p = 0.02) vs placebo. Pruritus NRS decreases plateaued by week 2 in the 200-mg group and week 4 in the 100-mg group and were sustained through week 12 in both groups.

Reductions from baseline were also observed in BSA in all treatment groups, with the highest changes noted in the abrocitinib 200-mg dose. Significant decreases in BSA were observed as early as week 1 in the 200-mg group (LSM difference from placebo, − 10.8%; p < 0.001), and were maintained through week 12 (− 14.9%; p < 0.001). In the 100-mg group, a meaningful decrease in BSA was observed at week 4 (− 11.2%; p < 0.001) and week 8 (− 8.63%; p = 0.04) compared with placebo. Finally, SCORAD scores were reduced in all groups, with the highest percentage decrease occurring in the 200-mg group.

Phase III. In a phase III (JADE-MONO1; NCT03349060), randomized, double-blind, placebo-controlled, 12-week, parallel group study, a total of 387 subjects aged 12 years and older with moderate-to-severe AD were randomized (2:2:1) to receive oral abrocitinib 200 mg, abrocitinib 100 mg, or placebo.[79] Randomization was stratified by baseline disease severity (moderate [IGA = 3] and severe [IGA = 4] AD) and age (< 18 and ≥ 18 years). Eligible subjects completing the 12-week treatment period of the trial had the option to enter a long-term extension study, B7451015.

By week 12, IGA 0/1 was observed in 43.8% (p < 0.0001) and 23.7% (p < 0.05) of patients receiving 200 mg and 100 mg of abrocitinib, compared with 7.9% for those receiving placebo (Table 5). EASI75 was achieved by 62.7% (p < 0.0001), 39.7% (p < 0.0001), and 11.8% of patients in the abrocitinib 200-mg, abrocitinib 100-mg, and placebo groups, respectively. Additionally, a significant EASI90 response was detected for all doses of abrocitinib vs placebo (200 mg: 38.6%; 100 mg: 18.6%, vs 5.3% for placebo; p < 0.0001 and p ≤ 0.05, respectively). An improvement of at least 4 points in the pruritus NRS score was observed in 57.2% (p < 0.0001) and 37.7% (p = 0.0003) of patients receiving 200 and 100 mg of abrocitinib, respectively, vs 15.3% with placebo. In fact, significant reductions in pruritus NRS scores were noted as early as day 2 (1-day post-dose) through week 12 for both abrocitinib doses (p < 0.05 for all), and these effects were in general detected notwithstanding the baseline pruritus NRS score. Similarly, SCORAD response rates were significantly greater in the abrocitinib groups compared with placebo, with 36.6 and 56.8% of patients achieving a SCORAD response of ≥ 50% in the 200-mg (p < 0.0001) and 100-mg (p = 0.0026) arms, respectively, vs 16.4% with placebo. Body surface area percentage changes from baseline at week 12 were − 25.1 and − 33.4% (both p < 0.0001) compared with − 11.4% for placebo.

At week 12, median Dermatology Life Quality Index (DLQI) improvements from baseline were higher for both doses of abrocitinib (200 mg: 14.0 [9.0–20.0] to 2.5 [1.0–6.0]; 100 mg: 14.0 [10.0–18.0] to 6.0 [2.0–10.0]), vs placebo (13.0 [10.0–16.0] to 9.0 [5.0–13.0]). POEM was also improved by abrocitinib, with higher median POEM improvements from baseline to week 12 for 200 mg (21.0 [16.0–24.0] to 7.0 [3.0–14.0]) and 100 mg (20.0 [15.0–26.0] to 12.0 [5.0–19.0]) compared with placebo (21.0 [17.0–24.0] to 15.0 [12.0–23.0]). Identical outcomes were noted for children's DLQI.

JADE MONO-2 (NCT03575871) was a randomized, placebo-controlled, double-blind phase III trial in which patients aged ≥ 12 years with moderate-to-severe AD were randomly assigned (2:2:1) to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks.[80] A total of 391 subjects were randomized and 330 subjects completed the trial.

Higher proportions of abrocitinib-treated (200 mg or 100 mg) vs placebo-treated patients achieved IGA 0/1 (38.1%, 28.4% vs 9.1%, respectively; p < 0.001), EASI-75 (61.0, 44.5% vs 10.4%; p < 0.0001), pruritus NRS ≥ 4-point improvement (55.3, 45.2% vs 11.5%; p < 0.0001), and EASI90 (37.7, 23.9% vs 3.9%) responses at week 12 (Table 5). There were meaningful differences in pruritus NRS scores between both doses of abrocitinib and placebo within 24 h of the first dose of treatment (namely, by day 2; − 0.7 [95% confidence interval (CI) − 0.9 to − 0.5] in the 200-mg group, − 0.6 [95% CI − 0.8 to − 0.4] in the 100-mg group, and − 0.1 [95% CI − 0.4 to 0.2] in the placebo group; p < 0.05 for 200 and 100 mg compared with placebo group).[80] The median time to achieve a 4-point improvement in pruritus from baseline was 29.0 (95% CI 16.0–31.0) days in the 200-mg arm, 58.0 (95% CI 56.0–83.0) days in the 100-mg arm, and 112.0 days (95% CI 112.0 to not evaluable) for placebo.[80] In addition, at week 12, median DLQI changes from baseline were higher for both doses of abrocitinib (200 mg: − 9.8 [− 10.7 to − 8.8], 100 mg: − 8.3 [− 9.3 to − 7.3], vs placebo: − 3.9 [− 5.3 to − 2.4]); POEM was also improved by abrocitinib, with higher median POEM changes from baseline to week 12 for 200 mg (− 11.0 [− 12.1 to − 9.8]) and 100 mg (− 8.7 [− 9.9 to − 7.5]) compared with placebo (− 3.6 [− 5.3 to − 1.9]).[80] In relation to children's DLQI, median changes from baseline for abrocitinib 200 mg, abrocitinib 100 mg, and placebo were − 9.7 (− 12.1 to − 7.4), − 4.8 (− 7.2 to − 2.5), and − 2.7 (− 6.1 to 0.8), respectively.

Recently, data were released from a third clinical trial of the global development program for abrocitinib, the JADE COMPARE study (NCT03720470), a comparative study of 837 participants randomized into five different treatment arms that tested different doses of abrocitinib (100 mg or 200 mg) or dupilumab (300 mg) given with matching placebos from day 1 to week 16 followed by 100 mg or 200 mg of abrocitinib or placebo until week 20.[81] The percentage of patients achieving each co-primary efficacy endpoint at week 12 (IGA 0/1 and a two-point or greater reduction from baseline; and EASI75 response) was statistically superior with both doses of abrocitinib than with placebo. Superiority to placebo with both doses was maintained at week 16. Dupilumab, the active control on these primary endpoints, also demonstrated superiority to placebo at week 12 and week 16. As a key secondary endpoint, the percentage of patients who had a clinically significant reduction in itch by week 2 of treatment (proportion of patients achieving a four-point or larger reduction in itch severity from baseline measured with the Peak Pruritus NRS) was statistically superior for the abrocitinib 200-mg dose compared with dupilumab, and numerically higher, but not statistically significantly higher, for the abrocitinib 100-mg dose compared with dupilumab.[81]

Safety

Overall, abrocitinib was well tolerated, although several AEs were described. The most common AEs reported in phase IIb and III trials were nausea, headache, viral upper respiratory tract infection, nasopharyngitis, and AD, while for placebo, it was AD (Table 6 and Table 7).[79–81] Among the abrocitinib-related AEs, only gastrointestinal disorders were substantially greater for patients treated with abrocitinib than for those receiving placebo.

Globally, SAEs occurred in 3.4% of patients in the phase IIb and JADE MONO-1 trials and 2.0% in the JADE MONO-2 study, and there were no deaths, cases of venous thromboembolism, or major cardiovascular AEs reported. There was one AE of sudden death reported with abrocitinib 100 mg in the JADE MONO-2 trial; however, it was not considered related to treatment. Two patients experienced SAEs that were considered treatment related in the phase IIb study: one patient receiving 200 mg of abrocitinib developed pneumonia during the follow-up after initiating treatment with cyclosporine, which was continued, and the patient completely recovered with antibiotic therapy; and one patient receiving 100 mg of abrocitinib presented with eczema herpeticum during the treatment period, abrocitinib was permanently discontinued, and administration of antiviral therapy led to complete recovery of this patient.[79]

In JADE MONO-1, the SAEs observed for abrocitinib 200 mg were inflammatory bowel disease, peritonsillitis, dehydration, and asthma. Serious AEs seen in the 100-mg group included retinal detachment, acute pancreatitis, appendicitis, dizziness, and seizures. In relation to placebo, reported SAEs were condition aggravated, appendicitis, and meniscal degeneration. Two patients in the 200-mg group (1.3%), five in the 100-mg group (3.2%), and one in the placebo group (1.3%) reported SAEs in the JADE MONO-2 trial.[80] However, the majority of SAEs were considered not related to treatment. No treatment-related SAEs was reported in the 200-mg group, while two patients presented with SAEs in the 100-mg group. In terms of laboratory abnormalities, in phase IIb, the platelet count showed mild dose-related decreases for doses above 10 mg, with maximum reductions detected at week 4 in the 200-mg and 100-mg arms (maximum mean change, − 29.8 and − 11.4%, respectively). However, after week 4, an upward trend toward baseline levels was observed by week 12 with ongoing abrocitinib therapy.[78] No hemorrhage or other clinically important events occurred in association with the decrease in platelet counts. Furthermore, there were no other clinically significant treatment-related tendencies in clinical laboratory test result anomalies, including serum lipid and transaminase levels. Thrombocytopenia was reported by one patient in the abrocitinib 200-mg group in JADE MONO-1.

In JADE MONO-2, dose-related decreases were noted in median platelet counts in the abrocitinib groups. At week 4, diminutions of 26% in the 200-mg group, 19% in the 100-mg group, and less than 1% in the placebo group were observed; however, platelet counts returned toward baseline values by week 12 regardless of continuation of treatment and without clinical sequalae.[80] In regard to hemoglobin levels and neutrophil or lymphocyte counts, no clinically significant changes were noted. There were also increases in creatinine kinase levels in both abrocitinib groups. Additionally, dose-related augmentation of nearly 10% in high- and low-density lipoprotein levels were observed with both abrocitinib doses compared with placebo. Fewer abrocitinib-treated (5.8% for each group) than placebo-treated (7.8%) patients discontinued treatment because of AEs in the JADE MONO-1 study. Concordantly, in the JADE MONO-2 trial, discontinuation because of AEs occurred in 3.2, 3.8, and 12.8% of patients in the 200-, 100-mg, and placebo groups, respectively. Serious infections were uncommon (< 2%) in all treatment arms.[80]

The JADE COMPARE study showed a safety profile of abrocitinib consistent with prior trials. A broader proportion of patients in the abrocitinib 200-mg group experienced AEs (61.9%) compared with the other treatment arms. Comparing abrocitinib 100 mg, dupilumab, and placebo arms, the occurrence of AEs was identical among all treatment groups (50.8, 50, and 53.4%, respectively).[81] Additionally, serious AEs and AEs leading to study discontinuation were similar across all treatment arms (placebo [3.8% each], abrocitinib 100 mg [2.5% each], abrocitinib 200 mg [0.9 and 4.4%, respectively], and dupilumab [0.8 and 3.3%, respectively]).

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