Overview on Upadacitinib: Mechanism of Action, Pharmacology, and Indications
Upadacitinib is an oral, selective, potent JAK1 inhibitor approved for the treatment of rheumatoid arthritis and currently under evaluation for several immune-mediated inflammatory diseases, Crohn's disease, ulcerative colitis, and AD.[62–66] By selectively blocking JAK1, upadacitinib is less potent against the other JAK isoforms. This high selectivity against JAK1 may be associated with a better benefit-risk profile compared with less selective JAK inhibitors.[67,68]
Evidence from healthy volunteers demonstrated that the administration of upadacitinib results in a dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2)-induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. By inhibiting JAK1, it decreases the production of pro-inflammatory mediators induced by IL-6, IL-15, IFN-α, and IFN-γ. In a cell-free enzyme assay, upadacitinib inhibited JAK1 (with a half maximal inhibitory concentration [IC50] of 43 nM) and, to a minor extent, JAK2 (IC50 = 120 nM), but with higher potency than JAK3 (IC50 = 2.3 μM) or TYK2 (IC50 = 4.7 μM), corresponding to > 40-fold selectivity over JAK3 and 100-fold selectivity over TYK2 as compared to JAK1.
Regarding pharmacology, upadacitinib showed rapid absorption with an oral bioavailability of 76%.[70–72] Plasma concentrations peak at around 1–2 h after administration, with an approximately 4-hour half-life and a mean terminal elimination half-life ranged from 6 to 16 h.[70–72] Upadacitinib exposures were dose proportional over the evaluated dose range and displayed no accumulation in plasma with multiple twice-daily dosing.[70–72] Clearance mechanisms of upadacitinib include approximately 20% of the dose eliminated unchanged in urine and nearly 34% of the dose excreted as metabolites.[70–72] Upadacitinib has also moderate plasma protein binding (50%).[70–72] Metabolism is mainly mediated by cytochrome P450 (CYP) 3A4 with a potential minor contribution from CYP2D6. Indeed, upadacitinib interacts with several drug classes: its blood concentrations are increased when co-administered with inhibitors of CYP3A4 (e.g., ketoconazole) and they are diminished when co-administered with potent CYP3A4 inducers (e.g., rifampin).[70–72]
Currently, upadacitinib is approved for the treatment of adult patients with moderate-to-severe active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate at a once-daily 15-mg dose. In addition, the US Food and Drug Administration has granted upadacitinib a breakthrough therapy designation for the treatment of adults with moderate-to-severe AD who are candidates for systemic therapy.
Clinical Efficacy of Upadacitinib
Phase II. The phase IIb trial (NCT02925117) was a 16-week, randomized, double-blind, placebo-controlled study in which 167 adult patients with moderate-to-severe AD inadequately controlled with topical treatment were randomized (1:1.1:1) to receive once-daily upadacitinib oral monotherapy at doses of 7.5, 15, and 30 mg or placebo (Table 2).
At week 16, the primary endpoint, the mean reduction from baseline in the Eczema Area and Severity Index (EASI) score was 39, 62, and 74%, respectively, compared with 23% for placebo (p = 0.03, p < 0.001, and p < 0.001, respectively), with a clear dose–response relationship. All upadacitinib doses achieved 50% or more improvement in EASI (EASI50), 75% or more improvement in EASI (EASI75), and 90% or more improvement in EASI (EASI90) statistically significant responses at week 16, with 50% of participants treated in the 30-mg group achieving EASI90. EASI75 was achieved by 29% (p < 0.05), 52% (p < 0.001), and 69% (p < 0.001) of patients treated with 7.5 mg, 15 mg, and 30 mg of upadacitinib, respectively, compared with 10% in the placebo group, while EASI90 was achieved by 14% (p < 0.05), 26% (p < 0.01), and 50% (p < 0.001) of patients receiving 7.5 mg, 15 mg, and 30 mg of upadacitinib, respectively, vs 2% of patients receiving placebo. In addition, a 100% improvement in EASI (EASI100) was reached by 2.4% (p = 0.43), 9.5% (p = 0.05), and 24% (p = 0.001) of patients in the upadacitinib 7.5-mg, 15-mg, and 30-mg groups, respectively, compared with none in the placebo group. Maximal effectiveness for a percentage improvement in EASI, EASI50, and EASI75 was noted at week 4 and maintained through week 16. EASI90 plateaued between weeks 8 and 16; however, the EASI100 response was still increasing at week 16.
All upadacitinib doses were significantly superior to placebo for the investigator's global assessment (IGA) response (IGA of clear  or almost clear [IGA 0/1]) skin with improvement of 2 grades or more from baseline) and patient assessment of pruritus (improvement in Numerical Rating Scale [NRS] and achievement of NRS reduction ≥ 4) at week 16. Investigator's global assessment 0/1 was achieved by 14% (p < 0.05), 31% (p < 0.001), and 50% (p < 0.001) of patients in the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, compared with 2% of patients in the placebo arm. For every dose, peak values were achieved and maintained after week 4 or 8. Additionally, upadacitinib demonstrated fast achievement of clinically significant improvements in pruritus and cutaneous lesions, exhibiting a dose-dependent pattern.
Scoring Atopic Dermatitis (SCORAD) scores at weeks 8 and 16 were lower with upadacitinib compared with placebo, with statistically significant results achieved for the majority of comparisons. Reduction in body surface area (BSA) percentage was significantly higher with all upadacitinib doses vs placebo at weeks 2, 4, 8, 12, and 16, except for the last evaluation in the upadacitinib 7.5-mg group. Additionally, all upadacitinib dosing groups presented with greater ameliorations in Patient Oriented Eczema Measure (POEM) scores at weeks 4 and 16 compared with the placebo group.
Meaningful reductions over time were observed in serum levels of Th2 (absolute eosinophil count, CCL17/18/26) and Th22 (IL-22)-related biomarkers with upadacitinib doses of 15 and 30 mg. These diminutions occurred as early as week 2 in both dosing groups. In addition, baseline disease severity and clinical improvement were significantly correlated with changes in absolute eosinophil count, CCL18, CCL26, and IL-22. No clear trends were detected for Th17 cytokines IL-17A and IL-17F, or CCL20 levels. There were no remarkable alterations in total or specific IgE levels; however, a significant correlation between changes in IgE and clinical disease improvement measures, namely EASI and pruritus NRS, was observed.
At week 16, patients who completed the first period of this study were blindly re-randomized within their original treatment group to receive either upadacitinib or placebo (126 patients: 63 to 30 mg of upadacitinib and 63 to placebo). Four weeks after re-randomization (week 20), patients who achieved an improvement from baseline in EASI < 50% were rescued with blinded 30 mg of upadacitinib, continuing this dose until the conclusion of the trial. All treatment groups rescued with upadacitinib 30 mg (at weeks 16 and 20) experienced an amelioration in efficacy outcomes by 8 weeks post-rescue, including EASI75, EASI 90, and IGA 0/1. Of note, patients randomized to upadacitinib 30 mg in the first period of this trial were good responders after withdrawal and retreatment.
Phase III. Recently, data were released from the Measure Up 1 study, a phase III, multicenter, randomized, double-blind, parallel-group, placebo-controlled study (NCT03569293). It evaluated the safety and efficacy of upadacitinib in adult and adolescent (aged 12 years or older) patients with moderate-to-severe AD who were candidates for systemic treatment. Patients were randomized to upadacitinib 15 mg, upadacitinib 30 mg, or placebo, followed by either upadacitinib 15 mg or upadacitinib 30 mg at week 16. Of patients receiving upadacitinib 15 and 30 mg, 70 and 80% achieved EASI75 at week 16, respectively, vs 16% in the placebo group (p < 0.001), and 48 and 62% of patients achieved IGA 0/1, respectively, vs 8% of patients receiving placebo (p < 0.001). For both doses, patients experienced an early reduction in itch, which was maintained through week 16. An improvement of NRS ≥ 4 was achieved by 52 and 60% of patients receiving 15 and 30 mg of upadacitinib, respectively, vs 12% in the placebo group (p < 0.001), and these clinically meaningful reductions in itch were observed (vs placebo) as early as 1 day after the first dose for patients receiving upadacitinib 30 mg (12% vs 4%, p < 0.001) and 2 days after the first dose for patients receiving upadacitinib 15 mg (16% vs 3%, p < 0.001).
Upadacitinib showed an acceptable safety profile, with no new adverse events (AEs) compared to previously reported studies. Adverse events were reported in 74, 76, and 79% of patients in the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, vs 63% of patients receiving placebo (Table 3). Upper respiratory tract infection, AD worsening, and acne were the most common AEs (≥ 10% in any group), with all being described as mild or moderate in severity. No relationship between the dosage of upadacitinib and the development of any particular AE was disclosed. Discontinuation because of AEs was low across all treatment groups. Adverse events of interest for JAK inhibitors occurred infrequently.
Serious AEs (SAEs) were uncommon and were observed in no more than two patients in any treatment arm. There were no reports of deaths, herpes zoster, malignancies, or thromboembolic events. Infections occurred more frequently with upadacitinib than with placebo; however, few serious infections were reported (Table 3). Despite 38% of participants having a history of asthma, no AEs of asthma exacerbation were observed during the trial.
In terms of laboratory abnormalities, mild hepatic AEs were identified, namely changes in alanine aminotransferase, aspartate aminotransferase, and blood bilirubin, although none of them was serious and resolved without dosing changes or drug discontinuation. These mild abnormalities were similar among all treatment groups. Increments in mean levels of low-density and high-density lipoprotein cholesterol were also detected in the upadacitinib groups, although lipid ratios demonstrated no obvious pattern of variation. Creatine phosphokinase elevation was detected in some patients, but it was asymptomatic and mild to moderate in severity. Hemoglobin levels diminished more among upadacitinib arms compared with placebo; however, they persisted within the normal ranges for both women and men. There was no decrease in absolute lymphocyte counts in any treatment group. Mean neutrophil counts showed small decreases with upadacitinib that were similar to placebo. In the re-randomization period of the trial, no new safety concerns were identified.
As a result of the positive benefit/risk profile of upadacitinib, its development program proceeded to phase III trials in AD, which are currently ongoing. In the phase III trial, no new safety risks were observed. Serious AEs at week 16 occurred in 2.1, 2.8, and 2.8% of patients receiving upadacitinib 15, 30 mg, and placebo, respectively. The most common treatment-emergent adverse events were acne, observed with both doses of upadacitinib (6.8, 17.2, and 2.1% of patients receiving 15, 30 mg, and placebo, respectively), upper respiratory tract infection, and nasopharyngitis. Eczema herpeticum was observed in 1.1 and 1.4% of patients receiving upadacitinib 30 mg and placebo, respectively, and no cases in patients receiving upadacitinib 15 mg. No deaths, venous thromboembolic events, or major cardiovascular AEs were reported.
Am J Clin Dermatol. 2020;21(6):783-798. © 2020 Adis Springer International Publishing AG