A Review of the Long-Term Safety and Efficacy of Upadacitinib in the Treatment of Atopic Dermatitis

Mohamad R. Taha, BSA¹ and Stephen K. Tyring, MD, PhD, MBA^2,3
1College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA;
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health and Sciences Center at Houston, Bellaire, TX, USA

Conflicts of interest: The authors declare that there is no conflict of interest. Funding sources: None.

Abstract: Atopic dermatitis (AD) is a common inflammatory skin condition characterized by erythema and intense pruritus. A key pathway implicated in its pathogenesis is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Upadacitinib, a JAK inhibitor, has been approved for the treatment of moderate-to-severe AD. This review evaluates the long-term safety and efficacy of upadacitinib in AD, incorporating findings from the Measure Up 1 and Measure Up 2 phase 3 studies.

Keywords: atopic dermatitis, upadacitinib, JAK/STAT pathway, efficacy, immunomodulation

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by recurrent eczematous lesions, xerosis, and pruritus.^1,2 It is a common condition that affects around 20% of children and 10% of adults in high-income countries.³ Risk factors include family history of the disease, living in an urban environment, consumption of a diet high in sugars or polyunsaturated fatty acids, and recurrent exposure to antibiotics before the age of five.¹ Clinical diagnosis of AD is usually simple, although its presentation may vary widely, particularly in infants and the elderly.¹ Key features of the disease, based on the Hanifin and Rajka criteria and the American Academy of Dermatology Consensus Criteria, include intense pruritus, eczematous lesions, and a chronic or relapsing disease course.^1,4

The pathogenesis of AD is complex but involves dysfunction of the innate and adaptive immune system with a subsequent impairment of the epidermal barrier.^1,2,5 In AD, there is an overexpression of T helper type 2 (Th2) cytokines, including interleukin (IL)-4, IL-5, IL-13, IL-31, and thymic stromal lymphopoietin.^5-7 These mediators of chronic inflammation, pruritus, and pain are regulated by the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway.^6,7

Topical treatments such as corticosteroids, moisturizers, occlusive agents, and humectants are typically sufficient for the management of mild to moderate AD.^1,8 Calcineurin inhibitors, cyclic adenosine monophosphate (cAMP)-specific 3′,5′-cyclic phosphodiesterase 4 inhibitors, and phototherapy may also be used.¹ More severe cases typically require treatment with systemic immunosuppressants such as cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil.^1,8 Newer, more specific therapies, including dupilumab, tralokinumab, and nemolizumab (injections) as well as the oral JAK inhibitors, upadacitinib and abrocitinib, can also be used for the treatment of more severe AD.^1,8,9

Indications and Mechanism of Action

Upadacitinib has been approved by the US Food and Drug Administration (FDA) for use in adults and adolescents 12 years and older, weighing at least 40 kg, for the treatment of moderate to severe AD.¹⁰ Treatment is initiated at 15 mg orally once daily, with the option to increase to 30 mg if the response is inadequate.¹⁰ However, patients who are aged 65 years and older, receiving strong CYP3A4 inhibitors, and/or those with severe renal impairment (CrCL <30 mL/min), should only receive a 15 mg daily dose.¹⁰ No dosage adjustment is required for mild or moderate renal impairment (CrCL >30 mL/min).¹⁰ Prior to treatment, baseline hepatic function, complete blood count, and lipid panel should be measured, repeated at 12 weeks, and periodically thereafter.^10,11 Pregnancy status, along with screening for tuberculosis and other infections, should also be monitored.¹⁰

Use of JAK inhibitors, biologic immunomodulators, or immunosuppressants in combination with upadacitinib is not recommended.¹⁰ Additionally, use of live vaccines during treatment should be avoided.¹⁰ Contraindications for upadacitinib use include end-stage renal disease (eGFR <15 mL/min/1.73 m²), severe hepatic impairment, and patients on strong CYP3A4 inducers.¹⁰ It is also not recommended in patients with an absolute lymphocyte count below 500 cells/mm³, an absolute neutrophil count below 1,000 cells/mm³, or a hemoglobin level below 8 g/dL.¹⁰

Activation of the JAK/STAT pathway begins by binding of cytokines to their receptors, which triggers rearrangement of receptor subunits.^12,13 This enables the activation of JAKs, which subsequently phosphorylate the receptor.^12,13 This is followed by binding of STATs to the receptor and becoming phosphorylated by the activated JAKs.^12,13 Finally, STAT dimers translocate into the nucleus and bind their respective promoter elements, allowing them to regulate transcription of their target genes.^12,13 Upadacitinib functions as a JAK inhibitor by competing with adenosine triphosphate (ATP) for binding.¹³ This prevents JAK from phosphorylating its downstream effectors, inhibiting STAT dimer formation and blocking their translocation to the nucleus.¹³

Phase 3 Clinical Trials

Measure Up 1 and Measure Up 2 are two replicate phase 3 randomized clinical trials involving patients between the ages of 12 and 75 years with moderate to severe AD.^14,15 For the first 16 weeks, patients were randomly assigned in a 1:1:1 ratio to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily.¹⁴ At week 16, those originally assigned to upadacitinib 15 mg or 30 mg continued their respective treatments, while placebo recipients were re-randomized in a 1:1 ratio to receive either upadacitinib 15 mg or 30 mg once daily.¹⁴ The severity of AD was reported using three main scales: Eczema Area and Severity Index (EASI), Worst Pruritus Numerical Rating Scale (WP-NRS), and Validated Investigator Global Assessment for AD (vIGA-AD).^14,15

Patients that received 30 mg upadacitinib from day 1 demonstrated no significant difference in efficacy between week 16 and week 52.¹⁴ Similarly, patients receiving 15 mg at the beginning of the study reported a slight improvement in efficacy at week 52 compared to week 16.¹⁴ At week 52, 82.0% of patients on upadacitinib 15 mg and 84.9% on upadacitinib 30 mg achieved EASI-75 (defined as 75% or greater improvement in EASI) in Measure Up 1.¹⁴ In Measure Up 2, 79.1% of those receiving 15 mg and 84.3% of patients taking 30 mg reached the same outcome.¹⁴ Moreover, 59.2% of patients receiving upadacitinib 15 mg and 62.5% receiving 30 mg achieved vIGA-AD 0/1 in Measure Up 1, while 52.6% on 15 mg and 65.1% on 30 mg achieved this in Measure Up 2 at week 52.¹⁴ Finally, WP-NRS improvement of 4 or greater was reached in 67.3% of patients on 15 mg and 67.7% on 30 mg in Measure Up 1, and 62.4% on 15 mg and 72.9% on 30 mg in Measure Up 2.¹⁴

Of the patients in the upadacitinib 15 mg group, 3.0% of patients in Measure Up 1 and 5.6% of patients in Measure Up 2 lost their response.¹⁴ For the upadacitinib 30 mg group, 3.4% of patients in Measure Up 1 and 4.9% of patients in Measure Up 2 lost their response.¹⁴ Loss of response was defined as a loss of 50% or more in EASI response and a vIGA-AD score of 2 or greater.¹⁴ Meaningful improvements in the Dermatology Life Quality Index, Hospital Anxiety and Depression Scale, and the sleep, emotional state, and daily activities domains of the Atopic Dermatitis Impact Scale also remained unchanged between week 16 and week 52.¹⁴

The safety profile of upadacitinib after 52 weeks of treatment was consistent with results at 16 weeks, with a similar exposure-adjusted event rate (EAER) of treatment emergent adverse events (AE) (Table 1).¹⁴ The EAER was calculated as the number of AEs divided by the total exposure in 100 patient years (PY).¹⁴ The EAER was higher in the upadacitinib 30 mg group compared to patients receiving 15 mg (3.6/100 PYs vs. 2.2/100 PYs).¹⁴ However, the rate of opportunistic infections (excluding tuberculosis and herpes) was comparable between the two groups (1.9/100 PYs for 15 mg and 2.0/100 PYs for 30).¹⁴ Additionally, one major adverse cardiovascular event (nonfatal stroke) and two venous thromboembolic events (deep vein thrombosis and pulmonary embolism) were reported, but none were determined to be related to treatment.¹⁴

Table 1.

The most commonly reported AEs were acne, cough, headache, herpes zoster, oral herpes, urinary tract infection, upper respiratory tract infection, nasopharyngitis, atopic dermatitis, and elevation in blood creatine phosphokinase level.¹⁴ Elevated liver enzymes, anemia, lymphopenia, and creatine phosphokinase levels were reported more frequently in the 30 mg group but were infrequent, transient, and rarely led to treatment discontinuation.¹⁴

Phase 3, 76-week Follow-up Study

In the Measure Up 1, Measure Up 2, and AD Up trials (upadacitinib+corticosteroids) 89.1%, 84.4%, and 87.8% of patients, respectively, achieved EASI-75 with 15 mg of upadacitinib at week 76. Comparably, 96.1%, 93.6%, and 82.7% of patients receiving 30 mg of upadacitinib achieved EASI-75, indicating either maintenance or improvement in treatment response over 76 weeks.¹⁶ Patients who received placebo at the start of the study were able to achieve a similar response to those in the treatment group after being switched to upadacitinib in the follow-up study.¹⁶

The proportion of patients achieving a vIGA-AD of 0 or 1 was unchanged or improved through week 76 in those who received or switched to upadacitinib 15 mg or 30 mg across all three studies.¹⁶ Similarly, the proportion of patients achieving a WPNRS improvement of 4 points or more was higher in the treatment groups compared to those receiving placebo through week 16.¹⁶ After week 16, response rates remained stable through week 76 for patients who continued on upadacitinib.¹⁶

Interestingly, in the Measure Up 1 and Measure Up 2 trials, a higher proportion of patients achieved EASI-75 at week 76 with upadacitinib 30 mg compared to 15 mg.¹⁶ However, in the AD Up study, a lower proportion of patients in the upadacitinib 30 mg group achieved EASI-75 at week 76 than in the 15 mg group.¹⁶ The discontinuation of topical corticosteroids at week 52 in the AD Up study may have influenced this outcome.¹⁶

AEs from upadacitinib treatment at week 76 were consistent with its known safety profile (Table 1).¹⁶ Serious infections were rare, and most opportunistic infections were mild eczema herpeticum, with one case reported in the upadacitinib 30 mg group and eight cases in the 15 mg group.¹⁶ Herpes zoster was more frequently reported in patients on upadacitinib 30 mg, except in Measure Up 2.¹⁶ Acne was the most common AE in the AD Up and Measure Up 2 trials and the second most common in Measure Up 1, with most cases being mild and rarely leading to discontinuation.¹⁶ In Measure Up 1, Measure Up 2, and AD Up, nausea occurred in three patients, two patients, and four patients in the upadacitinib 15 mg group, respectively.¹⁶ As for the 30 mg group, nausea occurred in two patients, five patients, and four patients in Measure Up 1, Measure Up 2, and AD Up, respectively.¹⁶

Furthermore, two cases of neutropenia were reported in the 30 mg upadacitinib group, and none in the 15 mg group, without resulting in discontinuation of treatment.¹⁶ Two cases of rhabdomyolysis were also reported, with one resulting in discontinuation of the trial. Height measurements at week 76 revealed no significant effect of upadacitinib on growth.¹⁶

Comparison to Dupilumab

Effective treatment of AD lesions is linked to substantial improvements in overall health-related quality of life.¹⁷ Moderate to severe cases of AD that are more resistant to conventional therapies necessitate the development of newer treatment options to achieve consistently significant reductions in erythema and pruritus.¹⁷ Dupilumab is a monoclonal antibody that inhibits IL-4 and IL-13 signaling, and was the first biologic approved for the treatment of AD.¹⁸ Although it exhibits good efficacy in the management of AD, only one-third of patients achieve complete clearance on dupilumab.¹⁸ In multiple clinical trials, upadacitinib was shown to possess superior efficacy in treating AD compared to dupilumab, while maintaining a favorable safety profile.^17,19,20 However, one potential limitation is the higher incidence of opportunistic infections, herpes zoster, creatine phosphokinase elevations, anemia and hepatic disorders in patients receiving upadactinib compared to dupilumab.¹⁹

In one randomized clinical trial of adults aged 18 to 75 years with moderate to severe AD, 673 patients were randomized 1:1 to receive either 30 mg of upadacitinib orally once daily or 300 mg of dupilumab via subcutaneous injection every 2 weeks.¹⁷ Eligible patients must have had an inadequate response to topical treatments, a history of systemic treatment use, or contraindications to topical therapy.¹⁷ By week 16, significantly more patients treated with upadacitinib achieved EASI90 (61.6% vs. 40.3%) and EASI100 (28.4% vs. 7.9%), as well as clinically meaningful itch improvement (56.1% vs. 36.4%), compared to dupilumab.¹⁷ Moreover, onset of action was faster with upadacitinib, as higher proportions achieved EASI75 at week 2 (44.3% vs. 18.2%) and EASI90 at week 8 (60.2% vs. 26.1%).¹⁷ Drug discontinuation, serious infections, eczema herpeticum, herpes zoster, and laboratory-test–related adverse events occurred more frequently with upadacitinib, whereas conjunctivitis and injection-site reactions were more common with dupilumab.¹⁷ These results demonstrate the higher efficacy and quicker response of upadacitinib in contrast with dupilumab.¹⁷

In a follow-up to the above study, patients receiving once daily oral upadacitinib 30 mg continued with the same dose, while those receiving subcutaneous dupilumab 300 mg were switched to once daily oral upadacitinib 30 mg.²⁰ Patients who were switched from dupilumab to upadacitinib demonstrated significant improvements in symptoms and severity of AD.²⁰ Mean EASI improved from 3.2 at week 24 on dupilumab to 1.0 after 16 weeks on upadacitinib.²⁰ The proportion of patients achieving EASI75 increased from 87.9% to 98.7% within 4 weeks, and 49.4% achieved EASI100 within 4 weeks, compared to 16.4% after 24 weeks of dupilumab.²⁰ Furthermore, over half of the patients achieved both EASI90 and WP-NRS ≤1 by week 16, a significant increase from less than one-third on dupilumab.²⁰

Conclusion

Results of follow-up studies on the use of upadacitinib in treating AD are promising and align with phase 3 findings. Treatment effectiveness 76 weeks after the start of therapy remained comparable to the rates observed at week 16 in patients receiving upadacitinib.¹⁶ It also demonstrates greater efficacy and a more rapid treatment response compared to dupilumab.^17,19,20 In terms of safety, few significant AEs were reported and were generally unrelated to treatment.^14,16 Acne was the most commonly reported AE at 76 weeks, which is similar to the results observed at weeks 16 and 52.^14,16 Overall, upadacitinib is an efficacious JAK/STAT inhibitor that continues to demonstrate a consistent safety profile in long-term studies of patients with moderate to severe AD.