Background:

Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by barrier defect and immune dysfunction.¹ Patients often suffer from severe itch that has a major impact on quality of life. Over 90% of patients report daily itch and over 50% report an impact on sleep patterns.² There are numerous related co-morbidities associated with AD including attention-deficit/hyperactivity disorder, depression, anxiety, insomnia, and poor school performance.³

Part of a successful treatment approach for AD includes patient education and the liberal use of moisturizers (those with ceramides). Additionally, topical corticosteroids and/or non-steroidal agents (such as topical calcineurin inhibitors and phosphodiesterase-4 inhibitors) are mainstays of treatment.¹ For many years, severe atopic dermatitis was treated with the off-label use of phototherapy, methotrexate, cyclosporine, mycophenolate, or azathioprine. The first Health Canada-approved systemic treatment for atopic dermatitis, dupilumab, was approved in 2017. Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes.⁴ Although efficacious and generally well-tolerated, dupilumab can have a slow onset of action and a variable clinical response in some patients. Another monoclonal antibody, tralokinumab, which is a fully human IgG4 monoclonal antibody that specifically binds to the type 2 cytokine IL-13 and inhibits its interaction with the IL-13 receptors, IL-13Rα1 and IL-13Rα2, was approved by Health Canada in October 2021.⁵

JAK-STAT Pathway in AD Pathogenesis:

There have been several oral novel small molecules in development for atopic dermatitis that target the Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway.⁶ The JAK-STAT pathway intersects with key cytokines involved in both Th2 skin disease including IL-4, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP). It can also target Th1, Th22 pathways allowing activity across diverse immune pathways and heterogenous disease presentations, including psoriasiform dermatitis, thereby potentially helping with overlap disease phenotypes. Different JAK inhibitors have variable selectivity (JAK1-3, and tyrosine kinase 2 [TYK2]), and several agents have now been thoroughly studied across clinical trials.

JAK Inhibitors for Atopic Dermatitis:

Upadacitinib:
Upadacitinib (Rinvoq^®) is the first Health Canada approved oral JAK1 selective inhibitor indicated for the treatment of refractory moderate-to-severe atopic dermatitis in individuals aged 12 years or older who are not adequately controlled with systemic therapies.⁷ It is available in 15 mg or 30 mg doses with a recommended starting dose of 15 mg once daily. Dose titration may be considered if an adequate response (e.g., Eczema Area and Severity Index [EASI 75]) is not achieved. The recommended dose of RINVOQ is 15 mg once daily for adolescents weighing at least 40 kg. RINVOQ has not been studied in adolescents weighing less than 40 kg.⁷ In the dual pivotal phase 3 clinical trials (Measure Up 1 & 2), a total of 1,683 subjects were assigned to oral upadacitinib 15 mg daily, upadacitinib 30 mg daily, or placebo. Taking the Measure Up 1 study as an example, patients in both intervention groups met the coprimary endpoint of  EASI-75 at week 16 (70% & 80%, respectively) compared to 16% for placebo (P<0.0001) (Figure 1A).⁸ The studies also achieved their co-primary endpoint of validated Investigator Global Assessment for AD (vIGA-AD) response i.e., score of 0 [clear] or 1 [almost clear] with ≥2 grades of reduction from baseline. (Figure 1B) Importantly, significant changes in EASI-75 and vIGA-AD 0/1 responders were seen as early as after 1 week of treatment. Efficacy at week 16 was maintained through week 52, with EASI-75 and 90 response achieved by 80.6% and 62.0% of patients continuing the 15-mg dose and 84.6% and 71.8% of patients continuing the 30-mg dose, respectively (pooled results from Measure Up 1 [depicted in Figure 1C and D] and Measure Up 2).⁹ The clinical efficacy of upadacitinib remained very consistent in the AD Up trial, compared both doses were compared to placebo on a background of topical corticosteroids (TCS).¹⁰

Figure 1A. EASI-75 response rates at Week 16; adapted from Guttman-Yassky E, et al. Lancet 2021;397:2151–68;Guttman-Yassky E, et al. EADV 2020 abstract [D3T03.4B]
***p≤0.001 vs placebo; p values are multiplicity controlled only at Weeks 2 and 16; p values are nominal at all other time points
aBased on ITT population, NRI-C
CI, confidence interval; EASI 75, ≥75% improvement in Eczema Area and Severity Index; ITT, intent-to-treat for the main study; NRI-C, non-responder imputation incorporating Multiple Imputation to handle missing data due to coronavirus disease 2019

Figure 1B. vIGA-AD 0/1a response rates at Week 16; adapted from Guttman-Yassky E, et al. Lancet 2021;397:2151–68;Guttman-Yassky E, et al. EADV 2020 abstract [D3T03.4B]
*p≤0.05; **p≤0.01; ***p≤0.001 vs placebo; p values are multiplicity controlled only at Week 16; p values are nominal at all other time points
aBased on ITT population, NRI-C CI, confidence interval; ITT, intent-to-treat for the main study; NRI-C, non-responder imputation incorporating multiple imputation to handle missing data due to coronavirus disease 2019; vIGA-AD 0/1, validated Investigator’s Global Assessment for atopic dermatitis of clear (0) or almost clear (1) with ≥2 grades of reduction from baseline

Figure 1C and 1D. Integrated analysis of skin clearance at Week 52 by patients achieving EASI-75 and EASI-90; adapted from Simpson EL, et al. JAMA Dermatol 2022. Online ahead of print; Simpson EL, et al. DERM 2021 poster

The Heads Up study was a 24-week Phase 3b trial comparing oral upadacitinib 30 mg daily vs sub-cutaneous dupilumab, 300 mg every other week (n=692), as monotherapies. It demonstrated superiority of upadacitinib 30 mg daily over dupilumab injections at week 16 with EASI-75 response rates of 71% vs. 61.1% (p= 0.006).¹⁰ Significantly greater proportions of patients achieved high levels of efficacy on skin clearance (90% and 100% improvements in EASI score at baseline, EASI 90 and EASI 100, respectively) at week 16 with upadacitinib compared with dupilumab (EASI 90, 60.6% vs 38.7%; p<0.001; EASI 100, 27.9% vs 7.6%; p<0.001). All published upadacitinib clinical trials to date have met their primary and secondary endpoints (p<0.001 for all).¹¹ Importantly also, beyond improving skin lesions, upadacitinib demonstrated significant, rapid and sustained improvements in itch symptom measures as early one day after treatment initiation, which were maintained throughout 52-weeks of treatment.^{8, 9}

Abrocitinib:
Abrocitinib (CIBINQO^®) is also a systemic JAK1 selective inhibitor.¹² It was studied in the JADE trials for AD comparing abrocitinib 100 mg daily vs. abrocitinib 200 mg daily vs placebo, with or without TCS.^* As an example, in JADE MONO 1, a total of 387 patients with moderate-to-severe AD were enrolled at 69 sites. Results demonstrated that when abrocitinib was used as monotherapy, the EASI-75 response was significantly higher in the abrocitinib 200 mg and 100 mg group compared with placebo (63% vs. 40% vs 12% respectively, p<0·0001).¹³ In the JADE-COMPARE study, a total of 838 subjects underwent randomization to receive 200 mg or 100 mg of abrocitinib orally once daily, or 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo. An IGA  response at week 12 was observed in 48.4% of patients in the 200 mg abrocitinib group, 36.6% in the 100 mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo). In addition, an EASI-75 response at week 12 was observed in 70.3% of patients on abrocitinib 200 mg, 58.7% of patients on abrocitinib 100 mg, 58.1% of patients on dupilumab, and 27.1% of patients on placebo (P<0.001 for both abrocitinib doses vs. placebo).¹⁴ 

Baricitinib:
Baricitinib (Olumiant^®), is an oral JAK 1 and 2 inhibitor that is approved for the treatment moderate-to-severe rheumatoid arthritis in Canada. There have been several clinical trials using baricitinib in patients with AD. The BREEZE-AD5 study was a North American-based phase 3 monotherapy trial that enrolled 440 patients with moderate-to-severe AD. In this study, oral baricitinib at a dose of 2 mg daily appeared efficacious for moderate-to-severe AD vs placebo (EASI-75 at 16 weeks: 30% vs 8%, p < 0.001).¹⁵ Baricitinib is not currently approved in Canada for the treatment of atopic dermatitis and will therefore not be discussed further in this supplement.

Comparative Efficacy of JAK Inhibitors:

Although there are no direct, head-to-head comparisons of the above JAK inhibitors, a recent review offers some insight. Silverberg et al. completed a network meta-analysis (NMA) to assesses the comparative efficacy of targeted systemic therapies in patients with moderate-to-severe AD based on randomized phase 2 and 3 studies. A NMA is a rather complex statistical methodology to compare multiple treatments and is ideal to gain perspective from pooling clinical trial data. A total of 11 trials encompassing 3339 patients treated with 5 different agents (abrocitinib, baricitinib, dupilumab, nemolizumab, and upadacitinib) were included in this analysis. The EASI-50 (or a 50% improvement from baseline in EASI score) response rate was highest for upadacitinib 30 mg QD, followed by abrocitinib 200 mg QD, upadacitinib 15 mg, and dupilumab 300 mg every 2 weeks. For itch improvements (ΔNRS ≥ 4), upadacitinib 30 mg also had the highest response rate, followed by abrocitinib 200 mg, upadacitinib 15 mg, and dupilumab. This rank order was also observed for EASI-75 and EASI-90 response rates. Limitations of this study include the absence of phase 3 data for all agents (upadacitinib only had phase 2b data), and variability in the primary endpoint timepoint across trials (12 weeks for abrocitinib and 16 weeks for other therapies). 

Another group of authors also lead by Silverberg et al. completed a further NMA to assess the comparative efficacy of targeted systemic therapies in adults with moderate-to-severe AD based on the phase III monotherapy pivotal studies.¹⁶ For this NMA, 11 unique phase 3 monotherapy trials encompassing 6254 patients treated with 5 different agents (abrocitinib, baricitinib, dupilumab, tralokinumab, or upadacitinib [or placebo]) were included. The EASI 75 response rate was highest for upadacitinib 30 mg, followed by abrocitinib 200 mg, upadacitinib 15 mg and dupilumab (Figure 2).

Figure 2. Systematic review and network meta-analysis of comparative efficacy of targeted therapies without topical corticosteroids; adapted from Silverberg JI, et al. Dermatol Ther (Heidelb) 2022. Online ahead of print.
EASI 75/90, ≥75%/90% improvement in Eczema Area and Severity Index

This rank order was also observed for the more stringent EASI-90 response rates, as well as for the itch improvements. Again, limitations included variable efficacy timepoints across the various trials (12 weeks for abrocitinib vs 16 weeks for other agents). 

Of note, the above-mentioned NMA data related to clinical efficacy across phase 3 monotherapy trials may most accurately represent the real effect of the treatments as monotherapies (vs placebo), but is likely less representative of the current real-world utilization of targeted systemic therapies in moderate-to-severe AD, which are often utilized in combination with topical medications.¹⁶ Clinicians should keep in mind the limited generalizability of NMA-based comparisons, which remain indirect and do not replace the value of head-to-head trials.